Appendix E — Wikipedia index

Wikipedia is often the most up-to-date overview of a topic, and much of the text of this book is adapted from it. For each main section, this index lists the most relevant articles with the opening sentences of each article (CC BY-SA 4.0). Wikipedia articles change; check the date and the references of an article before relying on it.

E.1 Sequence searching

Wikipedia articles for Chapter 1.

E.1.1 Homology and sequence similarity

• Homology (biology) — In biology, homology is similarity in anatomical structures or genes between organisms of different taxa due to shared ancestry, regardless of current functional differences.
• Sequence homology — Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life.
• Gene — In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce RNA.
• Protein — Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues.
• Convergent evolution — Convergent evolution is the independent evolution of similar features in species of different lineages. Convergent evolution creates analogous structures that have similar form or function but were not present in the last common ancestor of those groups.
• Gene duplication — Gene duplication is a mechanism through which new genetic material is generated during molecular evolution. It can be defined as any duplication of a region of DNA that contains a gene.
• Horizontal gene transfer — Horizontal gene transfer (HGT) or lateral gene transfer (LGT) is the movement of genetic material between organisms other than by the (“vertical”) transmission of DNA from parent to offspring (reproduction).

E.1.2 Dynamic programming and sequence alignment

• Dynamic programming — Dynamic programming (DP) is both a mathematical optimization method and an algorithmic paradigm. The method was developed by Richard Bellman in the 1950s and has found applications in numerous fields, such as aerospace engineering and economics.
• Sequence alignment — In bioinformatics, a sequence alignment is a way of arranging the sequences of DNA, RNA, or protein to identify regions of similarity that may be a consequence of functional, structural, or evolutionary relationships between the sequences.
• Needleman–Wunsch algorithm — The Needleman–Wunsch algorithm is an algorithm used in bioinformatics to align protein or nucleotide sequences. It was one of the first applications of dynamic programming to compare biological sequences. The algorithm was developed by Saul B.
• Smith–Waterman algorithm — The Smith–Waterman algorithm performs local sequence alignment; that is, for determining similar regions between two strings of nucleic acid sequences or protein sequences.
• Gap penalty — In DNA analysis, gap penalty is a method of scoring alignments of two or more DNA sequences. When aligning sequences, introducing gaps in the sequences can allow an alignment algorithm to match more terms than a gap-less alignment can.
• Substitution matrix — In bioinformatics and evolutionary biology, a substitution matrix describes the frequency at which a character in a nucleotide sequence or a protein sequence changes to other character states over evolutionary time.
• BLOSUM — In bioinformatics, the BLOSUM matrix is a substitution matrix used for sequence alignment of proteins. BLOSUM matrices are used to score alignments between evolutionarily divergent protein sequences. They are based on local alignments.
• Point accepted mutation — A point accepted mutation — also known as a PAM — is the replacement of a single amino acid in the primary structure of a protein with another single amino acid, which is accepted by the processes of natural selection.

E.1.3 Heuristic search methods

• BLAST (biotechnology) — In bioinformatics, BLAST is an algorithm and program for comparing primary biological sequence information, such as the amino-acid sequences of proteins, nucleotides of DNA and/or RNA sequences.
• FASTA — FASTA is a DNA and protein sequence alignment software package first described by David J. Lipman and William R. Pearson in 1985. Its legacy is the FASTA format which is now ubiquitous in bioinformatics.
• Gumbel distribution — In probability theory and statistics, the Gumbel distribution is used to model the distribution of the maximum of a number of samples of various distributions.
• Suffix array — In computer science, a suffix array is a sorted array of all suffixes of a string. It is a data structure used in, among others, full-text indices, data-compression algorithms, and the field of bibliometrics.
• Burrows–Wheeler transform — The Burrows–Wheeler transform (BWT) rearranges a character string into runs of similar characters, in a manner that can be reversed to recover the original string.
• FM-index — In computer science, an FM-index is a compressed full-text substring index based on the Burrows–Wheeler transform, with some similarities to the suffix array.

E.1.4 Alignment-free sequence comparison

• Alignment-free sequence analysis — In bioinformatics, alignment-free sequence analysis approaches to molecular sequence and structure data provide alternatives over alignment-based approaches.
• K-mer — In bioinformatics, k-mers are substrings of length contained within a biological sequence.
• MinHash — In computer science and data mining, MinHash is a technique for quickly estimating how similar two sets are.
• Jaccard index — The Jaccard index is a statistic used for gauging the similarity and diversity of sample sets. It is defined in general taking the ratio of two sizes, the intersection size divided by the union size, also called intersection over union (IoU).

E.1.5 Profiles and multiple sequence alignments

• Multiple sequence alignment — Multiple sequence alignment (MSA) is the process or the result of sequence alignment of three or more biological sequences, generally protein, DNA, or RNA.
• Clustal — Clustal is a computer program used for multiple sequence alignment in bioinformatics. It is one of the most widely cited bioinformatics software with two of its academic publications amongst the top 100 papers cited of all time, according to Nature in 2014.
• Sequence motif — In biology, a sequence motif is a nucleotide or amino-acid sequence pattern that is widespread and usually assumed to be related to biological function of the macromolecule.
• Position weight matrix — A position weight matrix (PWM), also known as a position-specific weight matrix (PSWM) or position-specific scoring matrix (PSSM), is a commonly used representation of motifs (patterns) in biological sequences.
• Sequence logo — In bioinformatics, a sequence logo is a graphical representation of the sequence conservation of nucleotides or amino acids . A sequence logo is created from a collection of aligned sequences and depicts the consensus sequence and diversity of the sequences.
• Hidden Markov model — In probability theory, a hidden Markov model (HMM) is a Markov model in which the observations are dependent on a latent Markov process. An HMM requires that there be an observable process whose outcomes depend on the outcomes of in a known way.
• Viterbi algorithm — The Viterbi algorithm is a dynamic programming algorithm that finds the most likely sequence of hidden events that would explain a sequence of observed events. The result of the algorithm is often called the Viterbi path.
• HMMER — HMMER is a free and commonly used software package for sequence analysis written by Sean Eddy. Its general usage is to identify homologous protein or nucleotide sequences, and to perform sequence alignments.

E.1.6 RNA homology search

• Non-coding RNA — A non-coding RNA (ncRNA) is a functional RNA molecule that is not translated into a protein. The DNA sequence from which a functional non-coding RNA is transcribed is often called a non-coding gene or an RNA gene.
• Nucleic acid secondary structure — Nucleic acid secondary structure is the basepairing interactions within a single nucleic acid polymer or between two polymers. It can be represented as a list of bases which are paired in a nucleic acid molecule.
• Nucleic acid structure prediction — Nucleic acid structure prediction is a computational method to determine secondary and tertiary nucleic acid structure from its sequence. Secondary structure can be predicted from one or several nucleic acid sequences.
• Probabilistic context-free grammar — In theoretical linguistics and computational linguistics, probabilistic context free grammars (PCFGs) extend context-free grammars, similar to how hidden Markov models extend regular grammars. Each production is assigned a probability.
• Rfam — Rfam is a database containing information about non-coding RNA (ncRNA) families and other structured RNA elements.

E.1.7 Databases and domains

• Protein domain — In molecular biology, a protein domain is a region of a protein’s polypeptide chain that is self-stabilizing and folds independently from the rest. Each domain forms a compact, folded three-dimensional structure.
• Protein family — A protein family is a group of evolutionarily related proteins. In many cases, a protein family has a corresponding gene family, in which each gene encodes a corresponding protein with a 1:1 relationship.
• Protein superfamily — A protein superfamily is the largest grouping (clade) of proteins for which common ancestry can be inferred. Usually this common ancestry is inferred from structural alignment and mechanistic similarity, even if no sequence similarity is evident.
• Pfam — Pfam is a database of protein families that includes their annotations and multiple sequence alignments generated using hidden Markov models. The latest version of Pfam, 37.0, was released in June 2024 and contains 21,979 families.
• InterPro — InterPro is a database of protein families, protein domains and functional sites in which identifiable features found in known proteins can be applied to new protein sequences in order to functionally characterise them.
• Structural Classification of Proteins database — The Structural Classification of Proteins (SCOP) database is a largely manual classification of protein structural domains based on similarities of their structures and amino acid sequences.
• CATH database — The CATH Protein Structure Classification database is a free, publicly available online resource that provides information on the evolutionary relationships of protein domains.

E.1.8 Protein language models

• Word embedding — In natural language processing, a word embedding is a representation of a word. The embedding is used in text analysis.
• Transformer (deep learning) — In deep learning, the transformer is a family of artificial neural network architectures based on the multi-head attention mechanism, in which input data such as text, images, or audio is converted to a sequence of numerical representations called tokens, and each token is converted into a vector through an embedding layer.
• BERT (language model) — Bidirectional encoder representations from transformers (BERT) is a language model introduced in October 2018 by researchers at Google. It learns to represent text as a sequence of vectors using self-supervised learning.
• Large language model — A large language model (LLM) is an AI model trained on a vast amount of text for natural language processing tasks, especially language generation. LLMs can typically generate, summarize, translate, and analyze text in many contexts.

E.1.9 Benchmarking search methods

• Receiver operating characteristic — A receiver operating characteristic curve, or ROC curve, is a graphical plot that illustrates the performance of a binary classifier model at varying threshold values.
• Precision and recall — In classification, precision and recall are performance metrics that apply to data retrieved from a collection, corpus or sample space.
• Sensitivity and specificity — In medicine and statistics, sensitivity and specificity mathematically describe the accuracy of a test that reports the presence or absence of a medical condition.
• False discovery rate — In statistics, the false discovery rate (FDR) is a method of conceptualizing the rate of type I errors in null hypothesis testing when conducting multiple comparisons.
• Structural Classification of Proteins database — The Structural Classification of Proteins (SCOP) database is a largely manual classification of protein structural domains based on similarities of their structures and amino acid sequences.

E.1.10 Whole-genome alignment and conservation

• Comparative genomics — Comparative genomics is a branch of biological research that examines genome sequences across a spectrum of species, spanning from humans and mice to a diverse array of organisms from bacteria to chimpanzees.
• Conserved sequence — In evolutionary biology, conserved sequences are identical or similar sequences in nucleic acids or proteins across species, or within a genome, or between donor and receptor taxa.
• Phylogenetic footprinting — Phylogenetic footprinting is a technique used to identify transcription factor binding sites (TFBS) within a non-coding region of DNA of interest by comparing it to the orthologous sequence in different species.
• Human accelerated regions — Human accelerated regions (HARs), first described in August 2006, are a set of 49 segments of the human genome that are conserved throughout vertebrate evolution but are strikingly different in humans.

E.2 Databases

Wikipedia articles for Chapter 2.

E.2.1 How biological databases work

• Biological database — Biological databases are libraries of biological sciences, collected from scientific experiments, published literature, high-throughput experiment technology, and computational analysis.
• Accession number (bioinformatics) — An accession number, in bioinformatics, is a unique identifier given to a DNA or protein sequence record to allow for tracking of different versions of that sequence record and the associated sequence over time in a single data repository.
• Entrez — The Entrez Global Query Cross-Database Search System is a federated search engine, or web portal that allows users to search many discrete health sciences databases at the National Center for Biotechnology Information (NCBI) website.
• PubMed — PubMed is an openly accessible, free database which primarily includes the MEDLINE database of references and abstracts on life sciences and biomedical topics.
• Biocuration — Biocuration is the field of life sciences dedicated to organizing biomedical data, information and knowledge into structured formats, such as spreadsheets, tables and knowledge graphs.
• FAIR data — FAIR data is data which meets the 2016 FAIR principles of findability, accessibility, interoperability, and reusability, first formally published in 2016.
• PubMed Central — PubMed Central (PMC) is a free digital repository that archives open access full-text scholarly articles that have been published in biomedical and life sciences journals.
• Europe PubMed Central — Europe PubMed Central is an open-access repository that contains millions of biomedical research works. It was known as UK PubMed Central until 1 November 2012.

E.2.2 Sequence databases

• International Nucleotide Sequence Database Collaboration — The International Nucleotide Sequence Database Collaboration (INSDC) consists of a joint effort to collect and disseminate databases containing DNA and RNA sequences.
• GenBank — The GenBank sequence database is an open access, annotated collection of publicly available nucleotide sequences and their protein translations.
• European Nucleotide Archive — The European Nucleotide Archive (ENA) is a repository providing free and unrestricted access to annotated DNA and RNA sequences.
• Sequence Read Archive — The Sequence Read Archive is a bioinformatics database that provides a public repository for DNA sequencing data, especially the “short reads” generated by high-throughput sequencing, which are typically less than 1,000 base pairs in length.
• RefSeq — The Reference Sequence (RefSeq) database is an open access, annotated and curated collection of publicly available nucleotide sequences and their protein products. RefSeq was introduced in 2000.
• UniProt — UniProt is a freely accessible database of protein sequence and functional information, many entries being derived from genome sequencing projects.
• Pfam — Pfam is a database of protein families that includes their annotations and multiple sequence alignments generated using hidden Markov models. The latest version of Pfam, 37.0, was released in June 2024 and contains 21,979 families.
• InterPro — InterPro is a database of protein families, protein domains and functional sites in which identifiable features found in known proteins can be applied to new protein sequences in order to functionally characterise them.

E.2.3 Genome databases and browsers

• Ensembl genome database project — Ensembl genome database project is a scientific project at the European Bioinformatics Institute, which provides a centralized resource for geneticists, molecular biologists and other researchers studying the genomes of our own species and other vertebrates and model organisms.
• UCSC Genome Browser — The UCSC Genome Browser is an online and downloadable genome browser hosted by the University of California, Santa Cruz (UCSC).
• Model organism database — Model organism databases (MODs) are biological databases, or knowledgebases, dedicated to the provision of in-depth biological data for intensively studied model organisms.
• Genome browser — The completion of the human genome sequencing in the early 2000s was a turning point in genomics research. Scientists have conducted series of research into the activities of genes and the genome as a whole.
• Reference genome — A reference genome is a genome assembly that represents the complete genetic sequence of an organism as a continuous string of nucleotides.
• GENCODE — GENCODE is a scientific project in genome research and part of the ENCODE scale-up project.
• FlyBase — FlyBase is an online bioinformatics database and the primary repository of genetic and molecular data for the insect family Drosophilidae.
• Genome Taxonomy Database — The Genome Taxonomy Database (GTDB) is an online database that maintains information on a proposed nomenclature of prokaryotes, following a phylogenomic approach based on a set of conserved single-copy proteins.

E.2.4 Structure databases

• Protein Data Bank — The Protein Data Bank (PDB) is a database for the three-dimensional structural data of large biological molecules such as proteins and nucleic acids, which is overseen by the Worldwide Protein Data Bank (wwPDB).
• Worldwide Protein Data Bank — The Worldwide Protein Data Bank (wwPDB) is an organization that maintains the archive of macromolecular structure.
• EM Data Bank — The EM Data Bank or Electron Microscopy Data Bank (EMDB) collects 3DEM maps and associated experimental data determined using electron microscopy of biological specimens.
• AlphaFold — AlphaFold is an artificial intelligence (AI) program developed by DeepMind, a subsidiary of Alphabet, which performs predictions of protein structure. It is designed using deep learning techniques.
• CATH database — The CATH Protein Structure Classification database is a free, publicly available online resource that provides information on the evolutionary relationships of protein domains.
• Structural Classification of Proteins database — The Structural Classification of Proteins (SCOP) database is a largely manual classification of protein structural domains based on similarities of their structures and amino acid sequences.

E.2.5 Function and pathways

• Gene Ontology — The Gene Ontology (GO) is a major bioinformatics initiative to unify the representation of gene and gene product attributes across all species.
• KEGG — KEGG is a collection of databases dealing with genomes, biological pathways, diseases, drugs, and chemical substances.
• Reactome — Reactome is a free online database of biological pathways. It is manually curated and authored by PhD-level biologists, in collaboration with Reactome editorial staff. The content is cross-referenced to many bioinformatics databases.
• Ontology (information science) — In information science, an ontology encompasses a representation, formal naming, and definitions of the categories, properties, and relations between the concepts, data, or entities that pertain to one, many, or all domains of discourse.
• Biological pathway — In cell biology, a biological pathway is a series of molecular interactions among molecules within a cell that leads to a specific product or a change in the cell.
• Gene set enrichment analysis — Gene set enrichment analysis (GSEA) (also called functional enrichment analysis or pathway enrichment analysis) is a method to identify classes of genes or proteins that are over-represented in a large set of genes or proteins, and may have an association with different phenotypes (e.g. different organism growth patterns or diseases).
• Critical Assessment of Function Annotation — The Critical Assessment of Function Annotation (CAFA) is an ongoing community-driven experiment designed to evaluate computational methods for protein function prediction.
• Knowledge graph — In knowledge representation and reasoning, a knowledge graph is a knowledge base that uses a graph-structured data model or topology to represent and operate on data.

E.2.6 Interaction databases

• STRING — In molecular biology, STRING is a biological database and web resource of known and predicted protein–protein interactions.
• BioGRID — The Biological General Repository for Interaction Datasets (BioGRID) is a curated biological database of protein-protein interactions, genetic interactions, chemical interactions, and post-translational modifications created in 2003 (originally referred to as simply the General Repository for Interaction Datasets by Mike Tyers, Bobby-Joe Breitkreutz, and Chris Stark at the Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital.
• Interactome — In molecular biology, an interactome is the whole set of molecular interactions in a particular cell. The term specifically refers to physical interactions among molecules but can also describe sets of indirect interactions among genes.
• Protein–protein interaction — Protein–protein interactions (PPIs) are physical contacts of high specificity established between two or more protein molecules as a result of biochemical events steered by interactions that include electrostatic forces, hydrogen bonding and the hydrophobic effect.

E.2.7 Expression and proteomics repositories

• Gene Expression Omnibus — Gene Expression Omnibus (GEO) is a database for gene expression profiling and DNA methylation profiling managed by the National Center for Biotechnology Information (NCBI).
• Human Protein Atlas — The Human Protein Atlas (HPA) is a Swedish-based program started in 2003 with the aim to map all the human proteins in cells, tissues and organs using integration of various omics technologies, including antibody-based imaging, mass spectrometry-based proteomics, transcriptomics and systems biology.
• Gene expression profiling — In the field of molecular biology, gene expression profiling is the measurement of the activity of thousands of genes at once, to create a global picture of cellular function.
• RNA-Seq — RNA-Seq is a next-generation sequencing (NGS) technique used to quantify and identify RNA molecules in a biological sample, providing a snapshot of the transcriptome at a specific time.
• Proteomics — Proteomics is the large-scale study of proteins. The proteome is the entire set of proteins produced or modified by an organism or system.

E.2.8 Medical and variant data

• DbSNP — The Single Nucleotide Polymorphism Database (dbSNP) is a free public archive for genetic variation within and across different species developed and hosted by the National Center for Biotechnology Information (NCBI) in collaboration with the National Human Genome Research Institute (NHGRI).
• ClinVar — ClinVar is a public archive with free access to reports on the relationships between human genetic variations and phenotypes, with supporting evidence. The database includes germline and somatic variants of any size, type or genomic location.
• Online Mendelian Inheritance in Man — Online Mendelian Inheritance in Man (OMIM) is a continuously updated catalog of human genes and genetic disorders and traits, with a particular focus on the gene-phenotype relationship.
• GWAS catalog — The GWAS Catalog is a free online database that compiles data of genome-wide association studies (GWAS), summarizing unstructured data from different literature sources into accessible high quality data.
• The Cancer Genome Atlas — The Cancer Genome Atlas (TCGA) is a project to catalogue the genomic alterations responsible for cancer using genome sequencing and bioinformatics.
• COSMIC cancer database — COSMIC is an online database of somatically acquired mutations found in human cancer. Somatic mutations are those that occur in non-germline cells that are not inherited by children.
• European Genome-phenome Archive — European Genome-phenome Archive (EGA) is a repository for human biomolecular and phenotypic data in the United Kingdom and Spain.
• Variant of uncertain significance — A variant of uncertain significance (VUS) is a genetic variant that has been identified through genetic testing but whose significance to the function or health of an organism is not known.

E.3 Evolution

Wikipedia articles for Chapter 3.

E.3.1 The origin of life

• Abiogenesis — Abiogenesis or the origin of life is the natural process by which life arises from non-living matter, such as simple organic compounds.
• Miller–Urey experiment — The Miller–Urey experiment, or Miller experiment, was an experiment in chemical synthesis carried out in 1952 that simulated the conditions thought at the time to be present in the atmosphere of the early, prebiotic Earth.
• RNA world — The RNA world is a hypothetical stage in the evolutionary history of life on Earth in which self-replicating RNA molecules proliferated before the evolution of DNA and proteins. The term also refers to the hypothesis that posits the existence of this stage.
• Ribozyme — Ribozymes are RNA molecules that have the ability to catalyze specific biochemical reactions, including RNA splicing in gene expression, similar to the action of protein enzymes.
• Iron–sulfur world hypothesis — The iron–sulfur world hypothesis is a set of proposals for the origin of life and the early evolution of life advanced in a series of articles between 1988 and 1992 by Günter Wächtershäuser, a Munich patent lawyer with a degree in chemistry, who had been encouraged and supported by philosopher Karl R.
• Protocell — A protocell is a self-organized, membrane-bound or membraneless compartment that concentrates biomolecules, proposed as a rudimentary precursor to cells during the origin of life. It is a minimal unit that can undergo Darwinian evolution.
• Earliest known life forms — The earliest known life forms on Earth may be as old as 4.1 billion years according to biologically fractionated graphite inside a single zircon grain in the Jack Hills range of Australia.
• Astrobiology — Astrobiology is a scientific field within the life and environmental sciences that studies the origins, early evolution, distribution, and future of life in the universe by investigating its deterministic conditions and contingent events.

E.3.2 Basic evolutionary concepts

• Mutation — In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA.
• Natural selection — Natural selection is the differential survival and reproduction of individuals due to differences in the relative fitness endowed on them by their own particular complement of observable characteristics.
• Genetic drift — Genetic drift is the change in the frequency of an existing allele in a population due to chance.
• Effective population size — The effective population size (Ne) is the size of an idealised population that would experience the same rate of genetic drift as the real population.
• Genetic hitchhiking — Genetic hitchhiking, also called genetic draft or the hitchhiking effect, is when an allele changes frequency not because it itself is under natural selection, but because it is near another gene that is undergoing a selective sweep and that is on the same DNA chain.
• Neutral theory of molecular evolution — The neutral theory of evolution holds that most of the genetic variation within and between species is due to random genetic drift of mutant alleles that are selectively neutral.
• Nearly neutral theory of molecular evolution — The nearly neutral theory of molecular evolution is a modification of the neutral theory of molecular evolution that accounts for the fact that not all mutations are either so deleterious such that they can be ignored, or else neutral.
• Molecular clock — The molecular clock is a figurative term for a technique that uses the mutation rate of biomolecules to deduce the time in prehistory when two or more life forms diverged.

E.3.3 Homologues, orthologues and gene duplication

• Homology (biology) — In biology, homology is similarity in anatomical structures or genes between organisms of different taxa due to shared ancestry, regardless of current functional differences.
• Sequence homology — Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life.
• Gene duplication — Gene duplication is a mechanism through which new genetic material is generated during molecular evolution. It can be defined as any duplication of a region of DNA that contains a gene.
• Subfunctionalization — Subfunctionalization was proposed by Stoltzfus (1999) and Force et al.
• Neofunctionalization — Neofunctionalization, one of the possible outcomes of functional divergence, occurs when one gene copy, or paralog, takes on a totally new function after a gene duplication event.
• Gene conversion — Gene conversion is the process by which one DNA sequence replaces a homologous sequence such that the sequences become identical after the conversion.
• Concerted evolution — Concerted evolution is the phenomenon where paralogous genes within one species are more closely related to one another than to members of the same gene family in closely related species.
• Paleopolyploidy — Paleopolyploidy is the result of genome duplications which occurred at least several million years ago (MYA). Such an event could either double the genome of a single species (autopolyploidy) or combine those of two species (allopolyploidy).

E.3.4 Protein evolution

• Protein domain — In molecular biology, a protein domain is a region of a protein’s polypeptide chain that is self-stabilizing and folds independently from the rest. Each domain forms a compact, folded three-dimensional structure.
• Tandem repeat — In genetics, tandem repeats occur in DNA when a pattern of one or more nucleotides is repeated and the repetitions are directly adjacent to each other, e.g. ATTCG ATTCG ATTCG, in which the sequence ATTCG is repeated three times.
• Intrinsically disordered proteins — In molecular biology, an intrinsically disordered protein (IDP) is a protein that lacks a fixed or ordered three-dimensional structure, typically in the absence of its macromolecular interaction partners, such as other proteins or RNA.
• Short linear motif — In molecular biology short linear motifs (SLiMs), linear motifs or minimotifs are short stretches of protein sequence that mediate protein–protein interaction.
• Direct coupling analysis — Direct coupling analysis or DCA is an umbrella term comprising several methods for analyzing sequence data in computational biology.
• Alternative splicing — Alternative splicing, alternative RNA splicing, or differential splicing is an alternative splicing process during gene expression that allows a single gene to produce different splice variants.
• Ancestral reconstruction — Ancestral reconstruction is the extrapolation back in time from measured characteristics of individuals, populations, or species to their common ancestors.

E.3.5 Detecting selection

• Ka/Ks ratio — In genetics, the Ka/Ks ratio, also known as ω or dN/dS ratio, is used to estimate the balance between neutral mutations, purifying selection and beneficial mutations acting on a set of homologous protein-coding genes.
• Models of DNA evolution — A number of different Markov models of DNA sequence evolution have been proposed. These substitution models differ in terms of the parameters used to describe the rates at which one nucleotide replaces another during evolution.
• Negative selection (natural selection) — In natural selection, negative selection or purifying selection is the selective removal of alleles that are deleterious. This can result in stabilising selection through the purging of deleterious genetic polymorphisms that arise through random mutations.
• Directional selection — In population genetics, directional selection is a mode of natural selection in which individuals with a trait at one extreme of a phenotypic distribution have better fitness than individuals with intermediate or opposite extreme phenotypes.
• McDonald–Kreitman test — The McDonald–Kreitman test is a statistical test often used by evolutionary and population biologists to detect and measure the amount of adaptive evolution within a species by determining whether adaptive evolution has occurred, and the proportion of substitutions that resulted from positive selection.
• Tajima’s D — Tajima’s D is a population genetic test statistic created by and named after the Japanese researcher Fumio Tajima.
• Selective sweep — In genetics, a selective sweep is the process through which a new beneficial mutation that increases its frequency and becomes fixed in a population leads to the reduction or elimination of genetic variation among nucleotide sequences that are near the mutation site.

E.3.6 Genome evolution

• Horizontal gene transfer — Horizontal gene transfer (HGT) or lateral gene transfer (LGT) is the movement of genetic material between organisms other than by the (“vertical”) transmission of DNA from parent to offspring (reproduction).
• Bacterial conjugation — Bacterial conjugation is the transfer of genetic material between bacterial cells by direct cell-to-cell contact or by a bridge-like connection between two cells. This typically takes place through a type IV secretion system, a type of pilus.
• Transduction (genetics) — Transduction is the process by which foreign DNA is introduced into a cell by a virus or viral vector. An example is the viral transfer of DNA from one bacterium to another and hence an example of horizontal gene transfer.
• Genetic transformation — In molecular biology and genetics, transformation is the genetic alteration of a bacterial cell resulting from the direct uptake and incorporation of exogenous genetic material from its surroundings through the cell membrane(s).
• Pan-genome — In the fields of molecular biology and genetics, a pan-genome is the entire set of genes from all strains within a clade. More generally, it is the union of all the genomes of a clade.
• Gene family — A gene family is a set of several similar genes, formed by duplication of a single original gene, and generally with similar biochemical functions.
• Power law — In mathematics and science, a power law is a functional relationship between two quantities, where a relative change in one quantity results in a relative change in the other quantity proportional to the change raised to a constant exponent: one quantity varies as a power of another.
• Preferential attachment — A preferential attachment process is any of a class of processes in which some quantity, typically some form of wealth or credit, is distributed among a number of individuals or objects according to how much they already have, so that those who are already wealthy receive more than those who are not.

E.4 Phylogeny

Wikipedia articles for Chapter 4.

E.4.1 Basic definitions

• Phylogenetics — In biology, phylogenetics is the study of the evolutionary history of life using observable characteristics of organisms, which is known as phylogenetic inference.
• Phylogenetic tree — A phylogenetic tree or phylogeny is a graphical representation which shows the evolutionary history between a set of species or taxa during a specific time.
• Cladistics — Cladistics is an approach to biological classification in which organisms are categorized in groups (“clades”) based on hypotheses of most recent common ancestry.
• Monophyly — In biological cladistics for the classification of organisms, monophyly is the condition of a taxonomic grouping being a clade – that is, a grouping of organisms which meets these criteria:the grouping contains its own most recent common ancestor, i.e. excludes non-descendants of that common ancestor the grouping contains all the descendants of that common ancestor, without exception
• Paraphyly — In taxonomy, a paraphyly is a grouping that consists of the grouping’s last common ancestor and some but not all of its descendant lineages. The grouping is said to be paraphyletic with respect to the excluded subgroups.
• Homology (biology) — In biology, homology is similarity in anatomical structures or genes between organisms of different taxa due to shared ancestry, regardless of current functional differences.
• Molecular clock — The molecular clock is a figurative term for a technique that uses the mutation rate of biomolecules to deduce the time in prehistory when two or more life forms diverged.
• Newick format — In mathematics and phylogenetics, Newick tree format is a way of representing graph-theoretical trees with edge lengths using parentheses and commas. It was adopted by James Archie, William H. E. Day, Joseph Felsenstein, Wayne Maddison, Christopher Meacham, F.

E.4.2 Phylogenetic methods

• Computational phylogenetics — Computational phylogenetics, phylogeny inference, or phylogenetic inference focuses on computational and optimization algorithms, heuristics, and approaches involved in phylogenetic analyses.
• UPGMA — UPGMA is a simple agglomerative (bottom-up) hierarchical clustering method. It also has a weighted variant, WPGMA, and they are generally attributed to Sokal and Michener.
• Neighbor joining — In bioinformatics, neighbor joining is a bottom-up (agglomerative) clustering method for the creation of phylogenetic trees, created by Naruya Saitou and Masatoshi Nei in 1987.
• Maximum parsimony — In evolutionary biology, maximum parsimony is a method used to build phylogenetic trees based on the principle of simplicity. Under the maximum-parsimony criterion, the best tree will minimize the amount of homoplasy.
• Long branch attraction — In phylogenetics, long branch attraction (LBA) is a form of systematic error whereby distantly related lineages are incorrectly inferred to be closely related.
• Felsenstein’s tree-pruning algorithm — In statistical genetics, Felsenstein’s tree-pruning algorithm, attributed to Joseph Felsenstein, is an algorithm for efficiently computing the likelihood of an evolutionary tree from nucleic acid sequence data.
• Bayesian inference in phylogeny — Bayesian inference of phylogeny combines the information in the prior and in the data likelihood to create the so-called posterior probability of trees, which is the probability that the tree is correct given the data, the prior and the likelihood model.
• Models of DNA evolution — A number of different Markov models of DNA sequence evolution have been proposed. These substitution models differ in terms of the parameters used to describe the rates at which one nucleotide replaces another during evolution.

E.4.3 Alignments, genomes and conflicting trees

• Phylogenomics — Phylogenomics is the intersection of the fields of evolution and genomics. The term has been used in multiple ways to refer to analysis that involves genome data and evolutionary reconstructions.
• Multiple sequence alignment — Multiple sequence alignment (MSA) is the process or the result of sequence alignment of three or more biological sequences, generally protein, DNA, or RNA.
• Incomplete lineage sorting — Incomplete lineage sorting (ILS) (also referred to as hemiplasy, deep coalescence, retention of ancestral polymorphism, or trans-species polymorphism) is a phenomenon in evolutionary biology and population genetics that results in discordance between species and gene trees.
• Multispecies coalescent process — Multispecies Coalescent Process is a stochastic process model that describes the genealogical relationships for a sample of DNA sequences taken from several species. It represents the application of coalescent theory to the case of multiple species.
• Coalescent theory — Coalescent theory is a model of how alleles sampled from a population may have originated from a common ancestor.
• Phylogenetic reconciliation — In phylogenetics, reconciliation is an approach to connect the history of two or more coevolving biological entities.
• Phylogenetic network — A phylogenetic network is any graph used to visualize evolutionary relationships between nucleotide sequences, genes, chromosomes, genomes, or species.
• Horizontal gene transfer — Horizontal gene transfer (HGT) or lateral gene transfer (LGT) is the movement of genetic material between organisms other than by the (“vertical”) transmission of DNA from parent to offspring (reproduction).

E.4.4 The tree of life

• Tree of life (biology) — The tree of life or universal tree of life is a metaphor, conceptual model, and research tool used to explore the evolution of life and describe the relationships between organisms, both living and extinct, as described in a famous passage in Charles Darwin’s On the Origin of Species (1859).The affinities of all the beings of the same class have sometimes been represented by a great tree.
• Three-domain system — The three-domain system is a taxonomic classification system that groups all cellular life into three domains, namely Archaea, Bacteria and Eukarya, introduced by Carl Woese, Otto Kandler and Mark Wheelis in 1990.
• Two-domain system — The two-domain system is a biological classification system that groups all cellular organisms in the tree of life into two domains: Archaea and Bacteria, while eukaryotes are considered a specialized clade under Archaea.
• Last universal common ancestor — The last universal common ancestor (LUCA) is the hypothesized latest common ancestral population of single-celled organisms from which all subsequent life forms descend under the three-domain system of Bacteria, Archaea, and Eukarya.
• Asgard (archaea) — Asgard archaea, or Promethearchaeati, are a kingdom belonging to the domain Archaea that contain eukaryotic signature proteins.
• Eukaryogenesis — Eukaryogenesis, the process which created the eukaryotic cell and lineage, is a milestone in the evolution of life, since eukaryotes include all complex cells and almost all multicellular organisms.
• Hominidae — The Hominidae, whose members are known as the great apes, are a taxonomic family of primates that includes eight extant species in four genera: Pongo ; Gorilla ; Pan ; and Homo, of which only modern humans remain.
• Human evolution — Homo sapiens is a distinct species of the hominid family of primates, which includes all the great apes. Over their evolutionary history, humans gradually developed traits such as bipedalism, dexterity, and complex language.

E.5 Genomics

Wikipedia articles for Chapter 5.

E.5.1 Sequencing methods

• DNA sequencing — DNA sequencing is the process of determining the nucleic acid sequence – the order of nucleotides in DNA. It includes any method or technology that is used to determine the order of the four bases: adenine, thymine, cytosine, and guanine.
• Sanger sequencing — Sanger sequencing is a method of DNA sequencing that involves electrophoresis and is based on the random incorporation of chain-terminating dideoxynucleotides by DNA polymerase during in vitro DNA replication.
• Massive parallel sequencing — Massively parallel sequencing (MPS) is any of several high-throughput approaches to DNA sequencing using the concept of massively parallel processing; it is also called next-generation sequencing (NGS) or second-generation sequencing.
• Illumina dye sequencing — Illumina dye sequencing is a technique used to determine the series of base pairs in DNA, also known as DNA sequencing. The reversible terminated chemistry concept was invented by Bruno Canard and Simon Sarfati at the Pasteur Institute in Paris.
• Single-molecule real-time sequencing — Single-molecule real-time (SMRT) sequencing is a parallelized single molecule DNA sequencing method. Single-molecule real-time sequencing utilizes a zero-mode waveguide (ZMW).
• Nanopore sequencing — Nanopore sequencing is a third generation approach used in the sequencing of biopolymers — specifically, polynucleotides in the form of DNA or RNA.
• Phred quality score — A Phred quality score is a measure of the quality of the identification of the nucleobases generated by automated DNA sequencing.
• Coverage (genetics) — In genetics, coverage is one of several measures of the depth or completeness of DNA sequencing, and is more specifically expressed in any of the following terms:Sequence coverage is the number of unique reads that include a given nucleotide in the reconstructed sequence.

E.5.2 Genome assembly

• Sequence assembly — In bioinformatics, sequence assembly refers to aligning and merging fragments from a longer DNA sequence in order to reconstruct the original sequence.
• De novo sequence assemblers — De novo sequence assemblers are a type of program that assembles short nucleotide sequences into longer ones without the use of a reference genome. These are most commonly used in bioinformatic studies to assemble genomes or transcriptomes.
• De Bruijn graph — In graph theory, an n-dimensional De Bruijn graph of m symbols is a directed graph representing overlaps between sequences of symbols.
• Eulerian path — In graph theory, an Eulerian trail is a trail in a finite graph that visits every edge exactly once. Similarly, an Eulerian circuit or Eulerian cycle is an Eulerian trail that starts and ends on the same vertex.
• N50, L50, and related statistics — In computational biology, N50 and L50 are statistics of a set of contig or scaffold lengths. The N50 is similar to a mean or median of lengths, but has greater weight given to the longer contigs.
• Scaffolding (bioinformatics) — Scaffolding is a technique used in bioinformatics. It is defined as follows: Link together a non-contiguous series of genomic sequences into a scaffold, consisting of sequences separated by gaps of known length.
• Hybrid genome assembly — In bioinformatics, hybrid genome assembly refers to utilizing various sequencing technologies to achieve the task of assembling a genome from fragmented, sequenced DNA resulting from shotgun sequencing.
• Whole genome sequencing — Whole genome sequencing (WGS), also known as full genome sequencing or just genome sequencing, is the process of determining the entirety of the DNA sequence of an organism’s genome at a single time.

E.5.3 Mapping and variant calling

• Sequence alignment — In bioinformatics, a sequence alignment is a way of arranging the sequences of DNA, RNA, or protein to identify regions of similarity that may be a consequence of functional, structural, or evolutionary relationships between the sequences.
• Burrows–Wheeler transform — The Burrows–Wheeler transform (BWT) rearranges a character string into runs of similar characters, in a manner that can be reversed to recover the original string.
• FASTQ format — FASTQ format is a text-based format for storing both a biological sequence and its corresponding quality scores. Both the sequence letter and quality score are each encoded with a single ASCII character for brevity.
• SAM (file format) — Sequence Alignment Map (SAM) is a text-based format originally for storing biological sequences aligned to a reference sequence developed by Heng Li and Bob Handsaker et al.
• SNV calling from NGS data — SNV calling from NGS data is any of a range of methods for identifying the existence of single nucleotide variants (SNVs) from the results of next generation sequencing (NGS) experiments.
• Variant Call Format — The Variant Call Format or VCF is a standard text file format used in bioinformatics for storing gene sequence or DNA sequence variations.
• Structural variation — Genomic structural variation is the variation in structure of an organism’s chromosome, such as deletions, duplications, copy-number variants, insertions, inversions and translocations.

E.5.4 Gene prediction

• Gene prediction — In computational biology, gene prediction or gene finding refers to the process of identifying the regions of genomic DNA that encode genes.
• Open reading frame — In molecular biology and genetics, reading frames are defined as spans of DNA sequence between the start and stop codons.
• Hidden Markov model — In probability theory, a hidden Markov model (HMM) is a Markov model in which the observations are dependent on a latent Markov process. An HMM requires that there be an observable process whose outcomes depend on the outcomes of in a known way.
• RNA splicing — RNA splicing is a process in molecular biology where a newly-made precursor messenger RNA (pre-mRNA) transcript is transformed into a mature messenger RNA (mRNA). It works by removing all the introns and splicing back together exons.
• GENSCAN — In bioinformatics, GENSCAN is a program to identify complete gene structures in genomic DNA. It is a GHMM-based program that can be used to predict the location of genes and their exon-intron boundaries in genomic sequences from a variety of organisms.
• GeneMark — GeneMark is a generic name for a family of ab initio gene prediction algorithms and software programs developed at the Georgia Institute of Technology in Atlanta.
• Genome project — Genome projects are scientific endeavours that ultimately aim to determine the complete genome sequence of an organism and to annotate protein-coding genes and other important genome-encoded features.

E.5.5 Metagenomics

• Metagenomics — Metagenomics is the study of all genetic material from all organisms in a particular environment, providing insights into their composition, diversity, and functional potential.
• 16S ribosomal RNA — 16S ribosomal RNA is the RNA component of the 30S subunit of a prokaryotic ribosome. It binds to the Shine-Dalgarno sequence and provides most of the SSU structure.
• Operational taxonomic unit — An operational taxonomic unit (OTU) is an operational definition used to classify groups of closely related individuals. The term was originally introduced in 1963 by Robert R. Sokal and Peter H. A.
• Amplicon sequence variant — An amplicon sequence variant (ASV) is any one of the inferred single DNA sequences recovered from a high-throughput analysis of marker genes.
• Binning (metagenomics) — In metagenomics, binning is the computational process of grouping assembled contigs and assigning them to their separate genomes of origin.
• Metagenome-assembled genome — Metagenomics is the study of all genetic material from all organisms in a particular environment, providing insights into their composition, diversity, and functional potential.

E.5.6 Regulatory and epigenomic sequencing data

• ChIP sequencing — ChIP-sequencing, also known as ChIP-seq, is a method used to analyze protein interactions with DNA. ChIP-seq combines chromatin immunoprecipitation (ChIP) with massively parallel DNA sequencing to identify the binding sites of DNA-associated proteins.
• ATAC-seq — ATAC-seq is a laboratory technique used in molecular biology to assess genome-wide chromatin accessibility.
• Bisulfite sequencing — Bisulfite sequencing (also known as bisulphite sequencing) is the use of bisulfite treatment of DNA before routine sequencing to determine the pattern of methylation. DNA methylation was the first discovered epigenetic mark, and remains the most studied.
• DNA methylation — DNA methylation is a biological process by which methyl groups are added to the DNA molecule. Methylation can change the activity of a DNA segment without changing the sequence.
• Cross-linking immunoprecipitation — Cross-linking and immunoprecipitation is a method used in molecular biology that combines UV crosslinking with immunoprecipitation in order to identify RNA binding sites of proteins on a transcriptome-wide scale, thereby increasing our understanding of post-transcriptional regulatory networks.

E.5.7 Human genetics: finding disease genes and variants

• Genome-wide association study — In genomics, a genome-wide association study, is an observational study of a genome-wide set of genetic variants in different individuals to see if any variant is associated with a trait.
• Linkage disequilibrium — Linkage disequilibrium, often abbreviated to LD, is a term in population genetics referring to the association of genes, usually linked genes, in a population. It has become an important tool in medical genetics and other fields.
• Polygenic score — In genetics, a polygenic score (PGS) is a number that summarizes the estimated effect of many genetic variants on an individual’s phenotype.
• Missing heritability problem — In genetics, the missing heritability problem refers to a difference between heritability estimates obtained from early genome-wide association studies (GWAS) and heritability estimates from twin and family data across many physical and mental traits, including diseases, behaviors, and other phenotypes.
• Exome sequencing — Exome sequencing, also known as whole exome sequencing (WES), is a genomic technique for sequencing all of the protein-coding regions of genes in a genome. It consists of two steps: the first step is to select only the subset of DNA that encodes proteins.
• Genetic linkage — Genetic linkage is the tendency of DNA sequences that are close together on a chromosome to be inherited together during the meiosis phase of sexual reproduction.

E.6 Genomes

Wikipedia articles for Chapter 6.

E.6.1 Background: genes, genomes and cells

• DNA — Deoxyribonucleic acid is a polymer composed of two polynucleotide chains that coil around each other to form a double helix.
• RNA — Ribonucleic acid (RNA) is a polymeric molecule that is essential for most biological functions, either by performing the function itself or by forming a template for the production of proteins. RNA and deoxyribonucleic acid (DNA) are nucleic acids.
• Gene — In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce RNA.
• Central dogma of molecular biology — The central dogma of molecular biology deals with the flow of genetic information within a biological system. It is often stated as “DNA makes RNA, and RNA makes protein”, although this is not its original meaning.
• Transcription (biology) — Transcription is the process of duplicating a segment of DNA into RNA for the purpose of gene expression. Some segments of DNA are transcribed into RNA molecules that can encode proteins, called messenger RNA (mRNA).
• Translation (biology) — Translation is the process in biological cells in which proteins are produced using RNA molecules as templates. The generated protein is a sequence of amino acids determined by the sequence of nucleotides in the RNA.
• Genetic code — Genetic code is a set of rules used by living cells to translate information encoded within genetic material into proteins.
• Model organism — A model organism is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the model organism will provide insight into the workings of other organisms.

E.6.2 From the first genome projects

• Genome project — Genome projects are scientific endeavours that ultimately aim to determine the complete genome sequence of an organism and to annotate protein-coding genes and other important genome-encoded features.
• Human Genome Project — The Human Genome Project (HGP) was an international scientific research project with the goal of determining the base pairs that make up human DNA, and of identifying, mapping and sequencing all of the genes of the human genome from both a physical and a functional standpoint.
• Shotgun sequencing — In genetics, shotgun sequencing is a method used for sequencing random DNA strands. It is named by analogy with the rapidly expanding, quasi-random shot grouping of a shotgun.
• Bermuda Principles — The Bermuda Principles set out rules for the rapid and public release of DNA sequence data.
• Genome size — Genome size is the total amount of DNA contained within one copy of a single complete genome. It is typically measured in terms of mass in picograms or less frequently in daltons, or as the total number of nucleotide base pairs, usually in megabases.
• C-value — C-value is the amount, in picograms, of DNA contained within a haploid nucleus or one half the amount in a diploid somatic cell of a eukaryotic organism.
• Polyploidy — Polyploidy is a condition in which the cells of an organism have more than two paired sets of (homologous) chromosomes.

E.6.3 Differences across the tree of life

• Prokaryote — A prokaryote, less commonly spelled procaryote, is a cellular organism that lacks a distinct cell nucleus or other membrane-bound organelles.
• Bacterial genome — Bacterial genomes are generally smaller and less varied in size between species when compared with genomes of eukaryotes. Bacterial genomes can range in size anywhere from about 130 kbp to over 14 Mbp.
• Operon — In genetics, an operon is a functioning unit of DNA containing a cluster of genes under the control of a single promoter.
• GC skew — GC skew is when the nucleotides guanine and cytosine are over- or under-abundant in a particular region of DNA or RNA. GC skew is also a statistical method for measuring strand-specific guanine overrepresentation.
• Intron — An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word intron is derived from the term intragenic region, i.e., a region inside a gene.
• Paleopolyploidy — Paleopolyploidy is the result of genome duplications which occurred at least several million years ago (MYA). Such an event could either double the genome of a single species (autopolyploidy) or combine those of two species (allopolyploidy).
• Symbiogenesis — Symbiogenesis, also known as the endosymbiotic theory or serial endosymbiotic theory,) is the leading scientific theory for the evolutionary origin of eukaryotes from prokaryotic ancestors.
• Mitochondrial DNA — Mitochondrial DNA is the DNA located in the mitochondria organelles in a eukaryotic cell that converts chemical energy from organic compounds into adenosine triphosphate (ATP).

E.6.4 Genomes in populations

• Pan-genome — In the fields of molecular biology and genetics, a pan-genome is the entire set of genes from all strains within a clade. More generally, it is the union of all the genomes of a clade.
• Genetic drift — Genetic drift is the change in the frequency of an existing allele in a population due to chance.
• Effective population size — The effective population size (Ne) is the size of an idealised population that would experience the same rate of genetic drift as the real population.
• Drift-barrier hypothesis — The drift-barrier hypothesis is an evolutionary hypothesis formulated by Michael Lynch in 2010 as an application of mutation-selection balance to mutation rates.
• Recent African origin of modern humans — The recent African origin of modern humans or the “Out of Africa” theory (OOA) holds that present-day humans outside Africa descend mainly from a single expansion of anatomically modern humans from Africa about 70,000–50,000 years ago.
• Neanderthal genome project — The Neanderthal genome project is an effort, founded in July 2006, of a group of scientists to sequence the Neanderthal genome.
• Interbreeding between archaic and modern humans — Interbreeding between archaic humans and anatomically modern humans took place during the Middle Paleolithic and early Upper Paleolithic.
• Denisovan — The Denisovans or Denisova hominins are an extinct species or subspecies of archaic human that ranged across Asia during the Middle to Late Pleistocene, approximately 200,000–32,000 years ago. Most of what is known about Denisovans comes from DNA evidence.

E.6.5 Repeats and the 3D genome

• Transposable element — Transposable elements (TEs), also known as transposons, jumping genes, or mobile genetic elements, are DNA sequences that can change their position, or translocate, within a genome.
• Retrotransposon — Retrotransposons are mobile elements which move in the host genome by converting their transcribed RNA into DNA through reverse transcription.
• Alu element — An Alu element is a short stretch of DNA originally characterized by the action of the Arthrobacter luteus (Alu) restriction endonuclease. Alu elements are the most abundant transposable elements in the human genome, present in excess of one million copies.
• Selfish genetic element — Selfish genetic elements are genetic segments that can enhance their own transmission at the expense of other genes in the genome, even if this has no positive or a net negative effect on organismal fitness.
• Tandem repeat — In genetics, tandem repeats occur in DNA when a pattern of one or more nucleotides is repeated and the repetitions are directly adjacent to each other, e.g. ATTCG ATTCG ATTCG, in which the sequence ATTCG is repeated three times.
• Satellite DNA — Satellite DNA, also known as highly repetitive DNA, consists of very large arrays of tandemly repeating, non-coding DNA. Satellite DNA is the main component of functional centromeres, and form the main structural constituent of heterochromatin.
• Segmental duplication — Low copy repeats (LCRs), also known as segmental duplications (SDs), or duplicons, are DNA sequences with high levels of sequence identity, present in multiple locations within a genome.
• Chromatin — Chromatin is a complex of DNA and protein responsible for condensing and packaging chromosomal DNA. Chromatin is found in both bacterial and eukaryotic cells.
• Chromosome conformation capture — Chromosome conformation capture techniques are a set of molecular biology methods used to analyze the spatial organization of chromatin in a cell.
• Topologically associating domain — A topologically associating domain (TAD) is a self-interacting genomic region, meaning that DNA sequences within a TAD physically interact with each other more frequently than with sequences outside the TAD.

E.6.6 RNA genes and regulatory elements

• Non-coding RNA — A non-coding RNA (ncRNA) is a functional RNA molecule that is not translated into a protein. The DNA sequence from which a functional non-coding RNA is transcribed is often called a non-coding gene or an RNA gene.
• MicroRNA — Micro ribonucleic acid are small, single-stranded, non-coding RNA molecules containing 21–23 nucleotides.
• Long non-coding RNA — Long non-coding RNAs are a type of RNA, generally defined as transcripts of more than 200 nucleotides that are not translated into protein.
• Enhancer (genetics) — In genetics, an enhancer is a short region of DNA that can be bound by proteins (activators) to increase the likelihood that transcription of a particular gene will occur. These proteins are usually referred to as transcription factors.
• Non-coding DNA — Non-coding DNA (ncDNA) sequences are components of an organism’s DNA that do not encode protein sequences. Some non-coding DNA is transcribed into functional non-coding RNA molecules.
• Junk DNA — Junk DNA is a DNA sequence that has no known biological function.
• ENCODE — The Encyclopedia of DNA Elements (ENCODE) is a public research project which aims “to build a comprehensive parts list of functional elements in the human genome.”

E.6.7 Gene order, synteny and genome rearrangements

• Synteny — In genetics, the term synteny refers to two related concepts:In classical genetics, synteny describes the physical co-localization of genetic loci on the same chromosome within an individual or species.
• Chromosomal rearrangement — In genetics, a chromosomal rearrangement is a mutation that is a type of chromosome abnormality involving a change in the structure of the native chromosome.
• Dot plot (bioinformatics) — In bioinformatics a dot plot is a graphical method for comparing two biological sequences and identifying regions of close similarity after sequence alignment. It is a type of recurrence plot.
• Comparative genomics — Comparative genomics is a branch of biological research that examines genome sequences across a spectrum of species, spanning from humans and mice to a diverse array of organisms from bacteria to chimpanzees.
• Chromosomal inversion — An inversion is a chromosome rearrangement in which a segment of a chromosome becomes inverted within its original position.

E.6.8 Pseudogenes, new genes and small proteins

• Pseudogene — Pseudogenes are nonfunctional segments of DNA that resemble functional genes. Pseudogenes can be formed from both protein-coding genes and non-coding genes.
• De novo gene birth — De novo gene birth is the process by which new genes evolve from non-coding DNA. De novo genes represent a subset of novel genes, and may be protein-coding or instead act as RNA genes.
• Orphan gene — Orphan genes, ORFans, or taxonomically restricted genes are genes that lack a detectable homologue outside of a given species or lineage. Most genes have known homologues.
• Small open reading frame — In molecular biology and genetics, reading frames are defined as spans of DNA sequence between the start and stop codons.
• Retrogene — Gene duplication is a mechanism through which new genetic material is generated during molecular evolution. It can be defined as any duplication of a region of DNA that contains a gene.

E.7 Expression analysis

Wikipedia articles for Chapter 7.

E.7.1 The first genome-wide methods: microarrays

• DNA microarray — A DNA microarray is a collection of microscopic DNA spots attached to a solid surface. Scientists use DNA microarrays to measure the expression levels of large numbers of genes simultaneously or to genotype multiple regions of a genome.
• Gene expression profiling — In the field of molecular biology, gene expression profiling is the measurement of the activity of thousands of genes at once, to create a global picture of cellular function.
• Serial analysis of gene expression — Serial Analysis of Gene Expression (SAGE) is a transcriptomic technique used by molecular biologists to produce a snapshot of the messenger RNA population in a sample of interest in the form of small tags that correspond to fragments of those transcripts.
• Quantile normalization — In statistics, quantile normalization is a technique for making two distributions identical in statistical properties.
• MA plot — Within computational biology, an MA plot is an application of a Bland–Altman plot for visual representation of genomic data.
• Affymetrix — Affymetrix is now Applied Biosystems, a brand of DNA microarray products sold by Thermo Fisher Scientific that originated with an American biotechnology research and development and manufacturing company of the same name.
• Microarray analysis techniques — Microarray analysis techniques are used in interpreting the data generated from experiments on DNA, RNA, and protein microarrays, which allow researchers to investigate the expression state of a large number of genes – in many cases, an organism’s entire genome – in a single experiment.

E.7.2 RNA sequencing

• RNA-Seq — RNA-Seq is a next-generation sequencing (NGS) technique used to quantify and identify RNA molecules in a biological sample, providing a snapshot of the transcriptome at a specific time.
• Transcriptomics technologies — Transcriptomics technologies are the techniques used to study an organism’s transcriptome, the sum of all of its RNA transcripts. The information content of an organism is recorded in the DNA of its genome and expressed through transcription.
• Alternative splicing — Alternative splicing, alternative RNA splicing, or differential splicing is an alternative splicing process during gene expression that allows a single gene to produce different splice variants.
• Expectation–maximization algorithm — In statistics, an expectation–maximization (EM) algorithm is an iterative method to find (local) maximum likelihood or maximum a posteriori (MAP) estimates of parameters in statistical models, where the model depends on unobserved latent variables.
• Batch effect — In molecular biology, a batch effect occurs when non-biological factors in an experiment cause changes in the data produced by the experiment.

E.7.3 Testing and statistics

• Negative binomial distribution — In probability theory and statistics, the negative binomial distribution, also called a Pascal distribution, is a discrete probability distribution that models the number of failures in a sequence of independent and identically distributed Bernoulli trials before a specified/constant/fixed number of successes occur.
• Generalized linear model — In statistics, a generalized linear model (GLM) is a flexible generalization of ordinary linear regression.
• P-value — In null-hypothesis significance testing, the p-value is the probability of obtaining test results at least as extreme as the result actually observed, under the assumption that the null hypothesis is correct.
• Multiple comparisons problem — Multiple comparisons, multiplicity or multiple testing problem occurs when many statistical tests are performed on the same dataset.
• False discovery rate — In statistics, the false discovery rate (FDR) is a method of conceptualizing the rate of type I errors in null hypothesis testing when conducting multiple comparisons.
• Hierarchical clustering — In data mining and statistics, hierarchical clustering is a method of cluster analysis that seeks to build a hierarchy of clusters.
• Principal component analysis — Principal component analysis (PCA) is a linear dimensionality reduction technique with applications in exploratory data analysis, visualization and data preprocessing.
• T-distributed stochastic neighbor embedding — t-distributed stochastic neighbor embedding (t-SNE) is a statistical method for visualizing high-dimensional data by giving each datapoint a location in a two or three-dimensional map.

E.7.4 From gene lists to biology

• Gene set enrichment analysis — Gene set enrichment analysis (GSEA) (also called functional enrichment analysis or pathway enrichment analysis) is a method to identify classes of genes or proteins that are over-represented in a large set of genes or proteins, and may have an association with different phenotypes (e.g. different organism growth patterns or diseases).
• Gene Ontology — The Gene Ontology (GO) is a major bioinformatics initiative to unify the representation of gene and gene product attributes across all species.
• Hypergeometric distribution — In probability theory and statistics, the hypergeometric distribution is a discrete probability distribution that describes the probability of successes in draws, without replacement, from a finite population of size that contains exactly objects with that feature, where in each draw is either a success or a failure.
• Gene co-expression network — A gene co-expression network (GCN) is an undirected graph, where each node corresponds to a gene, and a pair of nodes is connected with an edge if there is a significant co-expression relationship between them.
• Weighted correlation network analysis — Weighted correlation network analysis, also known as weighted gene co-expression network analysis (WGCNA), is a widely used data mining method especially for studying biological networks based on pairwise correlations between variables.
• Expression quantitative trait loci — An expression quantitative trait locus (eQTL) is a type of quantitative trait locus (QTL), a genomic locus that is associated with phenotypic variation for a specific, quantifiable trait.
• Human Protein Atlas — The Human Protein Atlas (HPA) is a Swedish-based program started in 2003 with the aim to map all the human proteins in cells, tissues and organs using integration of various omics technologies, including antibody-based imaging, mass spectrometry-based proteomics, transcriptomics and systems biology.

E.7.5 Single-cell genomics

• Single-cell transcriptomics — Single-cell transcriptomics refers to the quantification and analysis of the transcriptomes of individual cells.
• Single-cell sequencing — Single-cell sequencing examines the nucleic acid sequence information from individual cells with optimized next-generation sequencing technologies, providing a higher resolution of cellular differences and a better understanding of the function of an individual cell in the context of its microenvironment.
• Unique molecular identifier — Unique molecular identifiers (UMIs), or molecular barcodes (MBC) are short sequences or molecular “tags” added to DNA fragments in some next generation sequencing library preparation protocols to identify the input DNA molecule.
• CITE-Seq — CITE-Seq is a method for performing RNA sequencing along with gaining quantitative and qualitative information on surface proteins with available antibodies on a single cell level.
• RNA velocity — RNA velocity is a way of measuring the changes in gene expression. It is derived from ratio of spliced to unspliced RNA in the cell over time. Monitoring this value over time allows to see if the gene of interest is induced or repressed.
• Spatial transcriptomics — Spatial transcriptomics, or spatially resolved transcriptomics, is a method that captures positional context of transcriptional activity within intact tissue.
• Foundation model — In artificial intelligence, a foundation model (FM), also known as large x model, is a machine learning or deep learning model trained on vast datasets so that it can be applied across a wide range of use cases.
• Human Cell Atlas — The Human Cell Atlas is a global project to describe all cell types in the human body, to understand human health and for diagnosing, monitoring, and treating disease.

E.7.6 Single-cell sequencing and cancer evolution

• Somatic evolution in cancer — Somatic evolution is the accumulation of mutations and epimutations in somatic cells during a lifetime, and the effects of those mutations and epimutations on the fitness of those cells.
• Tumour heterogeneity — Tumour heterogeneity describes the observation that different tumour cells can show distinct morphological and phenotypic profiles, including cellular morphology, gene expression, metabolism, motility, proliferation, and metastatic potential.
• Cancer stem cell — Cancer stem cells (CSCs) are cancer cells that possess characteristics associated with normal stem cells, specifically the ability to give rise to all cell types found in a particular cancer sample.
• Single-cell sequencing — Single-cell sequencing examines the nucleic acid sequence information from individual cells with optimized next-generation sequencing technologies, providing a higher resolution of cellular differences and a better understanding of the function of an individual cell in the context of its microenvironment.
• Copy number variation — Copy number variation (CNV) is a phenomenon in which sections of the genome are repeated and the number of repeats in the genome varies between individuals.
• Phylogenetic tree — A phylogenetic tree or phylogeny is a graphical representation which shows the evolutionary history between a set of species or taxa during a specific time.
• Infinite sites model — The Infinite sites model (ISM) is a mathematical model of molecular evolution first proposed by Motoo Kimura in 1969. Like other mutation models, the ISM provides a basis for understanding how mutation develops new alleles in DNA sequences.

E.8 Proteomics

Wikipedia articles for Chapter 8.

E.8.1 Mass spectrometry methods

• Proteomics — Proteomics is the large-scale study of proteins. The proteome is the entire set of proteins produced or modified by an organism or system.
• Mass spectrometry — Mass spectrometry (MS) is an analytical technique that is used to measure the mass-to-charge ratio of ions. The results are presented as a mass spectrum, a plot of intensity as a function of the mass-to-charge ratio.
• Liquid chromatography–mass spectrometry — Liquid chromatography–mass spectrometry (LC–MS) is an analytical chemistry technique that combines the physical separation capabilities of liquid chromatography with the mass analysis capabilities of mass spectrometry (MS).
• Electrospray ionization — Electrospray ionization (ESI) is a technique used in mass spectrometry to produce ions using an electrospray in which a high voltage is applied to a liquid to create an aerosol.
• Matrix-assisted laser desorption/ionization — In mass spectrometry, matrix-assisted laser desorption/ionization (MALDI) is an ionization technique that uses a laser energy-absorbing matrix to create ions from large molecules with minimal fragmentation.
• Orbitrap — In mass spectrometry, Orbitrap is an ion trap mass analyzer consisting of an outer barrel-like electrode and a coaxial inner spindle-like electrode that traps ions in an orbital motion around the spindle.
• Tandem mass spectrometry — Tandem mass spectrometry, also known as MS/MS or MS2, is a technique in instrumental analysis where two or more stages of analysis using one or more mass analyzers are performed with an additional reaction step in between these analyses to increase their abilities to analyse chemical samples.
• Collision-induced dissociation — Collision-induced dissociation (CID), also known as collisionally activated dissociation (CAD), is a mass spectrometry technique to induce fragmentation of selected ions in the gas phase.
• Bottom-up proteomics — Bottom-up proteomics is a common method to identify proteins and characterize their amino acid sequences and post-translational modifications by proteolytic digestion of proteins prior to analysis by mass spectrometry.
• Top-down proteomics — Top-down proteomics is a method of protein identification capable of identifying and quantitating unique proteoforms through the analysis of intact proteins. The name is derived from the similar approach to DNA sequencing.
• Data-independent acquisition — In mass spectrometry, data-independent acquisition (DIA) is a method of molecular structure determination in which all ions within a selected m/z range are fragmented and analyzed in a second stage of tandem mass spectrometry.
• Stable isotope labeling by amino acids in cell culture — Stable isotope labeling by amino acids in cell culture (SILAC) is a technique based on mass spectrometry that detects differences in protein abundance among samples using non-radioactive isotopic labeling. It is a popular method for quantitative proteomics.
• Isobaric labeling — Isobaric labeling is a mass spectrometry strategy used in quantitative proteomics. Peptides or proteins are labeled with chemical groups that have nominally identical mass (isobaric), but vary in terms of distribution of heavy isotopes in their structure.
• Label-free quantification — Label-free quantification is a method in mass spectrometry that aims to determine the relative amount of proteins in two or more biological samples.

E.8.2 Algorithms for peptide identification

• Shotgun proteomics — Shotgun proteomics refers to the use of bottom-up proteomics techniques in identifying proteins in complex mixtures using a combination of high performance liquid chromatography combined with mass spectrometry.
• Tandem mass spectrometry — Tandem mass spectrometry, also known as MS/MS or MS2, is a technique in instrumental analysis where two or more stages of analysis using one or more mass analyzers are performed with an additional reaction step in between these analyses to increase their abilities to analyse chemical samples.
• Peptide mass fingerprinting — Peptide mass fingerprinting (PMF), also known as protein fingerprinting, is an analytical technique for protein identification in which the unknown protein of interest is first cleaved into smaller peptides, whose absolute masses can be accurately measured with a mass spectrometer such as MALDI-TOF or ESI-TOF.
• Mascot (software) — Mascot is a software search engine that uses mass spectrometry data to identify proteins from peptide sequence databases. Mascot is widely used by research facilities around the world.
• De novo peptide sequencing — In mass spectrometry, de novo peptide sequencing is the method in which a peptide amino acid sequence is determined from tandem mass spectrometry.
• Proteogenomics — Proteogenomics is a field of biological research that utilizes a combination of proteomics, genomics, and transcriptomics to aid in the discovery and identification of peptides.
• Edman degradation — Edman degradation, developed by Pehr Edman, is a method of sequencing amino acids in a peptide. In this method, the amino-terminal residue is labeled and cleaved from the peptide without disrupting the peptide bonds between other amino acid residues.

E.8.3 Statistics and error control

• False discovery rate — In statistics, the false discovery rate (FDR) is a method of conceptualizing the rate of type I errors in null hypothesis testing when conducting multiple comparisons.
• Q-value (statistics) — In statistical hypothesis testing, specifically multiple hypothesis testing, the q-value in the Storey procedure provides a means to estimate the positive false discovery rate (pFDR).
• Multiple comparisons problem — Multiple comparisons, multiplicity or multiple testing problem occurs when many statistical tests are performed on the same dataset.
• Weak supervision — Weak supervision is a paradigm in machine learning, the relevance and notability of which increased with the advent of large language models due to the large amount of data required to train them.
• Support vector machine — In machine learning, a support vector machine (SVM) or support vector network is a supervised max-margin model with associated learning algorithms that analyze data for classification and regression analysis.
• Shotgun proteomics — Shotgun proteomics refers to the use of bottom-up proteomics techniques in identifying proteins in complex mixtures using a combination of high performance liquid chromatography combined with mass spectrometry.
• Label-free quantification — Label-free quantification is a method in mass spectrometry that aims to determine the relative amount of proteins in two or more biological samples.

E.8.4 Proteomics beyond protein abundance

• Post-translational modification — Post-translational modifications (PTMs) are the covalent processes of changing proteins following their synthesis, and release from ribosomes.
• Phosphoproteomics — Phosphoproteomics is a branch of proteomics that identifies, catalogs, and characterizes proteins containing a phosphate group as a posttranslational modification.
• Protein–protein interaction — Protein–protein interactions (PPIs) are physical contacts of high specificity established between two or more protein molecules as a result of biochemical events steered by interactions that include electrostatic forces, hydrogen bonding and the hydrophobic effect.
• Tandem affinity purification — Tandem affinity purification (TAP) is an immunoprecipitation-based purification technique for studying protein–protein interactions. The goal is to extract from a cell only the protein of interest, in complex with any other proteins it interacted with.
• Proximity labeling — Enzyme-catalyzed proximity labeling (PL), also known as proximity-based labeling, is a laboratory technique that labels biomolecules, usually proteins or RNA, proximal to a protein of interest.
• Hydrogen–deuterium exchange — Hydrogen–deuterium exchange is a chemical reaction in which a covalently bonded hydrogen atom is replaced by a deuterium atom, or vice versa.
• Thermal shift assay — A thermal shift assay (TSA) measures the stability of a protein by the change in its thermal denaturation temperature. This is done under varying conditions, such as variations in drug concentration, buffer formulation, redox potential, or sequence mutation.
• Mass spectrometry imaging — Mass spectrometry imaging (MSI) is a technique used in mass spectrometry to visualize the spatial distribution of molecules, as biomarkers, metabolites, peptides or proteins by their molecular masses.

E.8.5 Proteomics without mass spectrometry

• Human Protein Atlas — The Human Protein Atlas (HPA) is a Swedish-based program started in 2003 with the aim to map all the human proteins in cells, tissues and organs using integration of various omics technologies, including antibody-based imaging, mass spectrometry-based proteomics, transcriptomics and systems biology.
• Immunohistochemistry — Immunohistochemistry is a form of immunostaining. It involves the process of selectively identifying antigens in cells and tissue, by exploiting the principle of antibodies binding specifically to antigens in biological tissues.
• Antibody — An antibody (Ab), or immunoglobulin (Ig), is a large protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as those that exist on bacteria and virus cells, including those that cause disease.
• Proximity extension assay — The proximity extension assay (PEA) is a method for detecting and quantifying the amount of many specific proteins present in a biological sample such as serum or plasma.
• Aptamer — Aptamers are oligomers of artificial ssDNA, RNA, XNA, or peptide that bind a specific target molecule, or family of target molecules.
• Mass cytometry — Mass cytometry is a high-dimensional single-cell analysis technique that integrates flow cytometry with time of flight mass spectrometry. It is used for the determination of the properties of cells (cytometry).
• Protein sequencing — Protein sequencing is the practical process of determining the amino acid sequence of all or part of a protein or peptide. This may serve to identify the protein or characterize its post-translational modifications.
• Nanopore sequencing — Nanopore sequencing is a third generation approach used in the sequencing of biopolymers — specifically, polynucleotides in the form of DNA or RNA.

E.8.6 Repositories and standards

• Proteomics Identifications Database — The PRIDE is a public data repository of mass spectrometry-based proteomics data, and is maintained by the European Bioinformatics Institute as part of the Proteomics Team.
• PeptideAtlas — PeptideAtlas is a proteomics data resource that gathers tandem mass spectrometry datasets from around the world, reprocesses them with the Trans-Proteomic Pipeline, and makes the combined result freely available to the community.
• Proteomics Standards Initiative — The Proteomics Standards Initiative (PSI) is a working group of the Human Proteome Organization. It aims to define data standards for proteomics to facilitate data comparison, exchange and verification.
• Mass spectrometry data format — Mass spectrometry is a scientific technique for measuring the mass-to-charge ratio of ions.
• Human Proteome Organization — The Human Proteome Organization (HUPO) is an international consortium of national proteomics research associations, government researchers, academic institutions, and industry partners.
• Human Proteome Project — The Human Proteome Project (HPP) is a collaborative effort coordinated by the Human Proteome Organization. Its stated goal is to experimentally observe all of the proteins produced by the sequences translated from the human genome.

E.9 Protein structure

Wikipedia articles for Chapter 9.

E.9.1 CASP: a blind test of structure prediction

• CASP — Critical Assessment of Structure Prediction (CASP), sometimes called Critical Assessment of Protein Structure Prediction, is a community-wide, worldwide experiment for protein structure prediction taking place every two years since 1994.
• Global distance test — The global distance test (GDT), also written as GDT_TS to represent “total score”, is a measure of similarity between two protein structures with known amino acid correspondences but different tertiary structures.
• Template modeling score — In bioinformatics, the template modeling score or TM-score is a measure of similarity between two protein structures.
• Root-mean-square deviation of atomic positions — In bioinformatics, the root mean square deviation of atomic positions, or simply root mean square deviation (RMSD), is the measure of the average distance between the atoms (usually the backbone atoms) of superimposed molecules.
• Protein structure prediction — Protein structure prediction is the inference of the three-dimensional structure of a protein from its amino acid sequence—that is, the prediction of its secondary and tertiary structure from primary structure.
• Critical Assessment of Prediction of Interactions — Critical Assessment of PRediction of Interactions (CAPRI) is a community-wide experiment in modelling the molecular structure of protein complexes, otherwise known as protein–protein docking.

E.9.2 Background: amino acids, energetics and enzymes

• Amino acid — Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins.
• Proteinogenic amino acid — Proteinogenic amino acids are amino acids that are incorporated biosynthetically into proteins during translation from RNA. The word “proteinogenic” means “protein creating”.
• Peptide bond — In organic chemistry, a peptide bond is an amide type of covalent chemical bond linking two consecutive alpha-amino acids from C1 of one alpha-amino acid and N2 of another, along a peptide or protein chain.
• Gibbs free energy — In thermodynamics, the Gibbs free energy is a thermodynamic potential that can be used to calculate the maximum amount of work, other than pressure–volume work, that may be performed by a thermodynamically closed system at constant temperature and pressure.
• Dissociation constant — In chemistry, biochemistry, and pharmacology, a dissociation constant (KD) is a specific type of equilibrium constant that measures the propensity of a larger object to separate (dissociate) reversibly into smaller components, as when a complex falls apart into its component molecules, or when a salt splits up into its component ions.
• Enzyme — An enzyme is a biological macromolecule, usually a protein, that acts as a biological catalyst, accelerating chemical reactions without being consumed in the process. The molecules on which enzymes act are called substrates, which are converted into products.
• Enzyme catalysis — Enzyme catalysis is the increase in the rate of a process by an “enzyme”, a biological molecule. Most enzymes are proteins, and most such processes are chemical reactions.
• Michaelis–Menten kinetics — In biochemistry, Michaelis–Menten kinetics, named after Leonor Michaelis and Maud Menten, is the simplest case of enzyme kinetics, applied to enzyme-catalysed reactions involving the transformation of one substrate into one product.

E.9.3 Protein structure and how it is determined

• Protein structure — Protein structure is the three-dimensional arrangement of atoms in an amino acid-chain molecule. Proteins are polymers – specifically polypeptides – formed from sequences of amino acids, which are the monomers of the polymer.
• Protein secondary structure — Protein secondary structure is the local spatial conformation of the polypeptide backbone excluding the side chains. The two most common secondary structural elements are alpha helices and beta sheets, though beta turns and omega loops occur as well.
• Ramachandran plot — In biochemistry, a Ramachandran plot, originally developed in 1963 by G. N. Ramachandran, C. Ramakrishnan, and V.
• X-ray crystallography — X-ray crystallography is the experimental science of determining the atomic and molecular structure of a crystal, in which the structure causes a beam of incident X-rays to diffract in specific directions.
• R-factor (crystallography) — In crystallography, the R-factor is a measure of the disagreement between the crystallographic model and the experimental X-ray diffraction data - lower the R value lower is the disagreement or better is the agreement.
• Protein nuclear magnetic resonance spectroscopy — Nuclear magnetic resonance spectroscopy of proteins is a field of structural biology in which NMR spectroscopy is used to obtain information about the structure and dynamics of proteins, and also nucleic acids, and their complexes.
• Cryogenic electron microscopy — Cryogenic electron microscopy (cryo-EM) is a transmission electron microscopy technique applied to samples cooled to cryogenic temperatures.
• Single particle analysis — Single particle analysis is a group of related computerized image processing techniques used to analyze images from transmission electron microscopy (TEM).

E.9.4 Protein folding

• Protein folding — Protein folding is the physical process by which a protein, after synthesis by a ribosome as a linear chain of amino acids, changes from an unstable random coil into a more ordered three-dimensional structure.
• Anfinsen’s dogma — Anfinsen’s dogma, also known as the thermodynamic hypothesis, is a postulate in molecular biology.
• Levinthal’s paradox — Levinthal’s paradox is a thought experiment in the field of computational protein structure prediction that concerns the mechanism through which peptides reach a stable native configuration, given the large amount of folding conformations.
• Folding funnel — The folding funnel hypothesis is a specific version of the energy landscape theory of protein folding, which assumes that a protein’s native state corresponds to its free energy minimum under the solution conditions usually encountered in cells.
• Hydrophobic effect — The hydrophobic effect is the observed tendency of nonpolar substances to aggregate in an aqueous solution and to be excluded by water.
• Molten globule — In molecular biology, the term molten globule (MG) refers to protein states that are more or less compact, but are lacking the specific tight packing of amino acid residues which creates the solid state-like tertiary structure of completely folded proteins.
• Chaperone (protein) — In molecular biology, molecular chaperones are proteins that assist the conformational folding or unfolding of proteins or macromolecular protein complexes.

E.9.5 Structure comparison and evolution

• Structural alignment — Structural alignment attempts to establish homology between two or more polymer structures based on their shape and three-dimensional conformation. This process is usually applied to protein tertiary structures but can also be used for large RNA molecules.
• Structural alignment software — This list of structural comparison and alignment software is a compilation of software tools and web portals used in pairwise or multiple structural comparison and structural alignment.
• Root-mean-square deviation of atomic positions — In bioinformatics, the root mean square deviation of atomic positions, or simply root mean square deviation (RMSD), is the measure of the average distance between the atoms (usually the backbone atoms) of superimposed molecules.
• Template modeling score — In bioinformatics, the template modeling score or TM-score is a measure of similarity between two protein structures.
• Protein fold — A protein superfamily is the largest grouping (clade) of proteins for which common ancestry can be inferred. Usually this common ancestry is inferred from structural alignment and mechanistic similarity, even if no sequence similarity is evident.
• Protein domain — In molecular biology, a protein domain is a region of a protein’s polypeptide chain that is self-stabilizing and folds independently from the rest. Each domain forms a compact, folded three-dimensional structure.
• Protein superfamily — A protein superfamily is the largest grouping (clade) of proteins for which common ancestry can be inferred. Usually this common ancestry is inferred from structural alignment and mechanistic similarity, even if no sequence similarity is evident.

E.9.6 Protein structure databases

• Protein Data Bank — The Protein Data Bank (PDB) is a database for the three-dimensional structural data of large biological molecules such as proteins and nucleic acids, which is overseen by the Worldwide Protein Data Bank (wwPDB).
• Structural Classification of Proteins database — The Structural Classification of Proteins (SCOP) database is a largely manual classification of protein structural domains based on similarities of their structures and amino acid sequences.
• CATH database — The CATH Protein Structure Classification database is a free, publicly available online resource that provides information on the evolutionary relationships of protein domains.
• Evolutionary Classification of Protein Domains — The Evolutionary Classification of Protein Domains (ECOD) is a biological database that classifies protein domains available from the Protein Data Bank. The ECOD tries to determine the evolutionary relationships between proteins.
• AlphaFold Protein Structure Database — AlphaFold is an artificial intelligence (AI) program developed by DeepMind, a subsidiary of Alphabet, which performs predictions of protein structure. It is designed using deep learning techniques.
• Protein domain — In molecular biology, a protein domain is a region of a protein’s polypeptide chain that is self-stabilizing and folds independently from the rest. Each domain forms a compact, folded three-dimensional structure.

E.9.7 Protein structure prediction

• Protein structure prediction — Protein structure prediction is the inference of the three-dimensional structure of a protein from its amino acid sequence—that is, the prediction of its secondary and tertiary structure from primary structure.
• Homology modeling — Homology modeling, also known as comparative modeling of protein, refers to constructing an atomic-resolution model of the “target” protein from its amino acid sequence and an experimental three-dimensional structure of a related homologous protein.
• Threading (protein sequence) — In molecular biology, protein threading, also known as fold recognition, is a method of protein modeling which is used to model those proteins which have the same fold as proteins of known structures, but do not have homologous proteins with known structure.
• De novo protein structure prediction — In computational biology, de novo protein structure prediction refers to an algorithmic process by which protein tertiary structure is predicted from its amino acid primary sequence.
• Direct coupling analysis — Direct coupling analysis or DCA is an umbrella term comprising several methods for analyzing sequence data in computational biology.
• Protein contact map — A protein contact map represents the distance between all possible amino acid residue pairs of a three-dimensional protein structure using a binary two-dimensional matrix.
• AlphaFold — AlphaFold is an artificial intelligence (AI) program developed by DeepMind, a subsidiary of Alphabet, which performs predictions of protein structure. It is designed using deep learning techniques.
• Intrinsically disordered proteins — In molecular biology, an intrinsically disordered protein (IDP) is a protein that lacks a fixed or ordered three-dimensional structure, typically in the absence of its macromolecular interaction partners, such as other proteins or RNA.

E.9.8 Protein language models and structure

• Large language model — A large language model (LLM) is an AI model trained on a vast amount of text for natural language processing tasks, especially language generation. LLMs can typically generate, summarize, translate, and analyze text in many contexts.
• Transformer (deep learning architecture) — In deep learning, the transformer is a family of artificial neural network architectures based on the multi-head attention mechanism, in which input data such as text, images, or audio is converted to a sequence of numerical representations called tokens, and each token is converted into a vector through an embedding layer.
• BERT (language model) — Bidirectional encoder representations from transformers (BERT) is a language model introduced in October 2018 by researchers at Google. It learns to represent text as a sequence of vectors using self-supervised learning.
• Word embedding — In natural language processing, a word embedding is a representation of a word. The embedding is used in text analysis.
• Multiple sequence alignment — Multiple sequence alignment (MSA) is the process or the result of sequence alignment of three or more biological sequences, generally protein, DNA, or RNA.
• Metagenomics — Metagenomics is the study of all genetic material from all organisms in a particular environment, providing insights into their composition, diversity, and functional potential.
• AlphaFold — AlphaFold is an artificial intelligence (AI) program developed by DeepMind, a subsidiary of Alphabet, which performs predictions of protein structure. It is designed using deep learning techniques.

E.9.9 Membrane proteins

• Membrane protein — Membrane proteins are common proteins that are part of, or interact with, biological membranes. Membrane proteins fall into several broad categories depending on their location.
• Transmembrane protein — A transmembrane protein is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane.
• Transmembrane domain — A transmembrane domain is a membrane-spanning protein domain. TMDs may consist of one or several alpha-helices or a transmembrane beta barrel.
• Membrane topology — Topology of a transmembrane protein refers to locations of N- and C-termini of membrane-spanning polypeptide chain with respect to the inner or outer sides of the biological membrane occupied by the protein.
• Hydrophobicity scales — Hydrophobicity scales are values that define the relative hydrophobicity or hydrophilicity of amino acid residues. The more positive the value, the more hydrophobic are the amino acids located in that region of the protein.
• Translocon — The translocon is a general term for a protein channel in biological membranes that functions to move polypeptides across the membrane or insert them into the lipid bilayer.
• Beta barrel — In protein structures, a beta barrel (β barrel) is a beta sheet composed of tandem repeats that twists and coils to form a closed toroidal structure in which the first strand is bonded to the last strand.
• Bacterial outer membrane — The bacterial outer membrane is found in gram-negative bacteria. Gram-negative bacteria form two lipid bilayers in their cell envelopes - an inner membrane (IM) that encapsulates the cytoplasm, and an outer membrane (OM) that encapsulates the periplasm.

E.9.10 Dynamics and docking

• Molecular dynamics — Molecular dynamics (MD) is a computer simulation method for analyzing the physical movements of atoms and molecules. The atoms and molecules are allowed to interact for a fixed period of time, giving a view of the dynamic “evolution” of the system.
• Force field (chemistry) — In the context of chemistry, molecular physics, physical chemistry, and molecular modelling, a force field is a computational model that is used to describe the forces between atoms within molecules or between molecules as well as in crystals.
• Protein dynamics — In molecular biology, proteins are generally thought to adopt unique structures determined by their amino acid sequences. However, proteins are not strictly static objects, but rather populate ensembles of conformations.
• Normal mode — A normal mode of a dynamical system is a pattern of motion in which all parts of the system move sinusoidally with the same frequency and with a fixed phase relation. The free motion described by the normal modes takes place at fixed frequencies.
• Anisotropic Network Model — The Anisotropic Network Model (ANM) is a simple yet powerful tool made for normal mode analysis of proteins, which has been successfully applied for exploring the relation between function and dynamics for many proteins.
• Gaussian network model — The Gaussian network model (GNM) is a representation of a biological macromolecule as an elastic mass-and-spring network to study, understand, and characterize the mechanical aspects of its long-time large-scale dynamics.
• Docking (molecular) — In the field of molecular modeling, docking is a method which predicts the preferred orientation of one molecule to a second when a ligand and a target are bound to each other to form a stable complex.
• Scoring functions for docking — In the fields of computational chemistry and molecular modelling, scoring functions are mathematical functions used to approximately predict the binding affinity between two molecules after they have been docked.

E.9.11 Protein design

• Protein design — Protein design is the rational design of new protein molecules to design novel activity, behavior, or purpose, and to advance basic understanding of protein function.
• Protein engineering — Protein engineering is the process of developing useful or valuable proteins through the design and production of unnatural polypeptides, often by altering amino acid sequences found in nature.
• Diffusion model — In machine learning, diffusion models, also known as diffusion-based generative models or score-based generative models, are a class of latent variable generative models.
• Rosetta@home — Rosetta@home is a volunteer computing project researching protein structure prediction on the Berkeley Open Infrastructure for Network Computing (BOINC) platform, run by the Baker lab.
• Protein folding — Protein folding is the physical process by which a protein, after synthesis by a ribosome as a linear chain of amino acids, changes from an unstable random coil into a more ordered three-dimensional structure.

E.10 Protein function

Wikipedia articles for Chapter 10.

E.10.1 Definitions of function

• Gene Ontology — The Gene Ontology (GO) is a major bioinformatics initiative to unify the representation of gene and gene product attributes across all species.
• Ontology (information science) — In information science, an ontology encompasses a representation, formal naming, and definitions of the categories, properties, and relations between the concepts, data, or entities that pertain to one, many, or all domains of discourse.
• Enzyme Commission number — The Enzyme Commission number is a numerical classification scheme for enzymes, based on the chemical reactions they catalyze.
• Enzyme — An enzyme is a biological macromolecule, usually a protein, that acts as a biological catalyst, accelerating chemical reactions without being consumed in the process. The molecules on which enzymes act are called substrates, which are converted into products.
• Moonlighting protein — Protein moonlighting is a phenomenon by which a protein can perform more than one function. It is an example of gene sharing.
• Protein function prediction — Protein function prediction methods are techniques that bioinformatics researchers use to assign biological or biochemical roles to proteins. These proteins are usually ones that are poorly studied or predicted based on genomic sequence data.

E.10.2 Function prediction

• Protein function prediction — Protein function prediction methods are techniques that bioinformatics researchers use to assign biological or biochemical roles to proteins. These proteins are usually ones that are poorly studied or predicted based on genomic sequence data.
• Sequence homology — Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life.
• Homology (biology) — In biology, homology is similarity in anatomical structures or genes between organisms of different taxa due to shared ancestry, regardless of current functional differences.
• Protein domain — In molecular biology, a protein domain is a region of a protein’s polypeptide chain that is self-stabilizing and folds independently from the rest. Each domain forms a compact, folded three-dimensional structure.
• InterPro — InterPro is a database of protein families, protein domains and functional sites in which identifiable features found in known proteins can be applied to new protein sequences in order to functionally characterise them.
• Phylogenetic profiling — Phylogenetic profiling is a bioinformatics technique in which the joint presence or joint absence of two traits across large numbers of species is used to infer a meaningful biological connection, such as involvement of two different proteins in the same biological pathway.
• Operon — In genetics, an operon is a functioning unit of DNA containing a cluster of genes under the control of a single promoter.
• Short linear motif — In molecular biology short linear motifs (SLiMs), linear motifs or minimotifs are short stretches of protein sequence that mediate protein–protein interaction.

E.10.3 Subcellular localisation

• Protein targeting — Protein targeting or protein sorting is the biological mechanism by which proteins are transported to their appropriate destinations within or outside the cell.
• Signal peptide — A signal peptide is a short peptide present at the N-terminus of most newly synthesized proteins that are destined toward the secretory pathway.
• Signal recognition particle — The signal recognition particle (SRP) is an abundant, cytosolic, universally conserved ribonucleoprotein that recognizes and targets specific proteins to the endoplasmic reticulum in eukaryotes and the plasma membrane in prokaryotes.
• Transit peptide — A signal peptide is a short peptide present at the N-terminus of most newly synthesized proteins that are destined toward the secretory pathway.
• Mitochondrial targeting sequence — A target peptide is a short peptide consensus sequence that directs the transport of a protein to a specific region in the cell, including the nucleus, mitochondria, endoplasmic reticulum (ER), chloroplast, apoplast, peroxisome and plasma membrane.
• Nuclear localization sequence — A nuclear localization sequence, or signal (NLS) is an amino acid sequence motif that ‘tags’ a protein for import into the cell nucleus by nuclear transport.
• Protein subcellular localization prediction — Protein subcellular localization prediction involves the prediction of where a protein resides in a cell, its subcellular localization.

E.10.4 Predicting the effects of mutations

• Missense mutation — In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution.
• Multiplexed Assays of Variant Effect — Multiplexed Assays of Variant Effect (MAVE) is a method used to determine sequence-function relationships, identify variants that alter protein structure, stability, or activity, and characterize regulatory elements.
• ClinVar — ClinVar is a public archive with free access to reports on the relationships between human genetic variations and phenotypes, with supporting evidence. The database includes germline and somatic variants of any size, type or genomic location.
• Variant of uncertain significance — A variant of uncertain significance (VUS) is a genetic variant that has been identified through genetic testing but whose significance to the function or health of an organism is not known.

E.10.5 Benchmarking function prediction

• Critical Assessment of Function Annotation — The Critical Assessment of Function Annotation (CAFA) is an ongoing community-driven experiment designed to evaluate computational methods for protein function prediction.
• Protein function prediction — Protein function prediction methods are techniques that bioinformatics researchers use to assign biological or biochemical roles to proteins. These proteins are usually ones that are poorly studied or predicted based on genomic sequence data.
• Precision and recall — In classification, precision and recall are performance metrics that apply to data retrieved from a collection, corpus or sample space.
• Open-world assumption — The closed-world assumption (CWA), in a formal system of logic used for knowledge representation, is the presumption that a statement that is true is also known to be true. Therefore, by the contrapositive, what is not currently known to be true must be false.

E.10.6 Experimental determination of function

• Forward genetics — Forward genetics is a molecular genetics approach of determining the genetic basis responsible for a phenotype.
• Reverse genetics — Reverse genetics is a method in molecular genetics that is used to help understand the function(s) of a gene by analysing the phenotypic effects caused by genetically engineering specific nucleic acid sequences within the gene.
• CRISPR gene editing — CRISPR gene editing is a genetic engineering technique in molecular biology by which the genomes of living organisms may be modified. It is based on a simplified version of the bacterial CRISPR-Cas9 antiviral defense system.
• Genetic screen — A genetic screen or mutagenesis screen is an experimental technique used to identify and select individuals who possess a phenotype of interest in a mutagenized population. Hence a genetic screen is a type of phenotypic screen.
• Gene knockout — Gene knockouts are a widely used genetic engineering technique that involves the targeted removal or inactivation of a specific gene within an organism’s genome.
• Essential gene — Essential genes are indispensable genes for organisms to grow and reproduce offspring under certain environment. However, being essential is highly dependent on the circumstances in which an organism lives.

E.11 Protein–protein interactions

Wikipedia articles for Chapter 11.

E.11.1 Experimental methods

• Protein–protein interaction — Protein–protein interactions (PPIs) are physical contacts of high specificity established between two or more protein molecules as a result of biochemical events steered by interactions that include electrostatic forces, hydrogen bonding and the hydrophobic effect.
• Two-hybrid screening — Two-hybrid screening is a molecular biology technique used to discover protein–protein interactions (PPIs) and protein–DNA interactions by testing for physical interactions between two proteins or a single protein and a DNA molecule, respectively.
• Tandem affinity purification — Tandem affinity purification (TAP) is an immunoprecipitation-based purification technique for studying protein–protein interactions. The goal is to extract from a cell only the protein of interest, in complex with any other proteins it interacted with.
• Co-immunoprecipitation — Immunoprecipitation (IP) is the technique of precipitating a protein antigen out of solution using an antibody that specifically binds to that particular protein.
• Protein-fragment complementation assay — Within the field of molecular biology, a protein-fragment complementation assay, or PCA, is a method for the identification and quantification of protein–protein interactions.
• Synthetic lethality — Synthetic lethality is defined as a type of genetic interaction where the combination of two genetic events results in cell death or death of an organism.
• Epistasis — Epistasis is a phenomenon in genetics in which the effect of a mutation on a trait is dependent on the presence or absence of mutations at different loci, that may be on the same gene (intragenic) or on different genes, called modifier genes.
• Gene regulatory network — A gene regulatory network (GRN) is a collection of molecular regulators that interact with each other and with other substances in the cell to govern the gene expression levels of mRNA and proteins which, in turn, determine the function of the cell.

E.11.2 Networks

• Interactome — In molecular biology, an interactome is the whole set of molecular interactions in a particular cell. The term specifically refers to physical interactions among molecules but can also describe sets of indirect interactions among genes.
• Biological network — A biological network is a method of representing systems as complex sets of binary interactions or relations between various biological entities. In general, networks or graphs are used to capture relationships between entities or objects.
• Scale-free network — A scale-free network is a network whose degree distribution follows a power law, at least asymptotically. That is, the fraction P(k) of nodes in the network having k connections to other nodes goes for large values of k as
• Small-world network — A small-world network is a graph characterized by a high clustering coefficient and low distances. In an example of a social network, high clustering implies the high probability that two friends of one person are friends themselves.
• Clustering coefficient — In graph theory, a clustering coefficient is a measure of the degree to which nodes in a graph tend to cluster together.
• Network motif — Network motifs are recurrent and statistically significant subgraphs or patterns of a larger graph.
• STRING — In molecular biology, STRING is a biological database and web resource of known and predicted protein–protein interactions.
• Network medicine — Network medicine is the application of network science towards identifying, preventing, and treating diseases. This field focuses on using network topology and network dynamics towards identifying diseases and developing medical drugs.
• Systems biology — Systems biology is the computational and mathematical analysis and modeling of complex biological systems.
• Flux balance analysis — In biochemistry and systems biology, flux balance analysis (FBA) is a mathematical method for simulating the metabolism of cells or entire unicellular organisms, such as E. coli or yeast, using genome-scale reconstructions of metabolic networks.

E.11.3 Prediction methods

• Protein–protein interaction prediction — Protein–protein interaction prediction is a field combining bioinformatics and structural biology in an attempt to identify and catalog physical interactions between pairs or groups of proteins.
• Phylogenetic profiling — Phylogenetic profiling is a bioinformatics technique in which the joint presence or joint absence of two traits across large numbers of species is used to infer a meaningful biological connection, such as involvement of two different proteins in the same biological pathway.
• Direct coupling analysis — Direct coupling analysis or DCA is an umbrella term comprising several methods for analyzing sequence data in computational biology.
• Docking (molecular) — In the field of molecular modeling, docking is a method which predicts the preferred orientation of one molecule to a second when a ligand and a target are bound to each other to form a stable complex.
• Protein–protein docking — Macromolecular docking is the computational modelling of the quaternary structure of complexes formed by two or more interacting biological macromolecules.
• Critical Assessment of Prediction of Interactions — Critical Assessment of PRediction of Interactions (CAPRI) is a community-wide experiment in modelling the molecular structure of protein complexes, otherwise known as protein–protein docking.
• AlphaFold — AlphaFold is an artificial intelligence (AI) program developed by DeepMind, a subsidiary of Alphabet, which performs predictions of protein structure. It is designed using deep learning techniques.
• Biomolecular condensate — In biochemistry, biomolecular condensates are a class of membrane-less organelles and organelle subdomains, which carry out specialized functions within the cell.

E.12 Machine learning

Wikipedia articles for Chapter 12.

E.12.1 Basics

• Machine learning — Machine learning (ML) is a field of study in artificial intelligence concerned with the development and study of statistical algorithms that can learn from data and generalize to unseen data, and thus perform tasks without being explicitly programmed.
• Overfitting — In mathematical modeling, overfitting is the production of an analysis that corresponds too closely or exactly to a particular set of data and may therefore fail to fit to additional data or predict future observations reliably.
• Bias–variance tradeoff — In statistics and machine learning, the bias–variance tradeoff describes the relationship between a model’s complexity, the accuracy of its predictions, and how well it can make predictions on previously unseen data that were not used to train the model.
• Cross-validation (statistics) — Cross-validation, sometimes called rotation estimation or out-of-sample testing, is any of various similar model validation techniques for assessing how the results of a statistical analysis will generalize to an independent data set.
• Leakage (machine learning) — In statistics and machine learning, leakage refers to the use of information during model training that would not be available at prediction time.
• Precision and recall — In classification, precision and recall are performance metrics that apply to data retrieved from a collection, corpus or sample space.
• Receiver operating characteristic — A receiver operating characteristic curve, or ROC curve, is a graphical plot that illustrates the performance of a binary classifier model at varying threshold values.
• Phi coefficient — In statistics, the phi coefficient, also known as the mean square contingency coefficient or Yule coefficient of correlation and commonly denoted by φ or rφ, is a measure of association between two binary variables.

E.12.2 A short history of machine learning in bioinformatics

• Perceptron — In machine learning, the perceptron is an algorithm for supervised learning of binary classifiers. A binary classifier is a function that can decide whether or not an input, represented by a vector of numbers, belongs to some specific class.
• Artificial neural network — In machine learning, a neural network (NN) or artificial neural network (ANN) is a computational model inspired by the structure and functions of biological neural networks.
• Backpropagation — In machine learning, backpropagation is a gradient computation method commonly used for training a neural network in computing parameter updates.
• Hidden Markov model — In probability theory, a hidden Markov model (HMM) is a Markov model in which the observations are dependent on a latent Markov process. An HMM requires that there be an observable process whose outcomes depend on the outcomes of in a known way.
• Support vector machine — In machine learning, a support vector machine (SVM) or support vector network is a supervised max-margin model with associated learning algorithms that analyze data for classification and regression analysis.
• Kernel method — In machine learning, kernel machines are a class of algorithms for pattern analysis, whose best known member is the support-vector machine (SVM). These methods involve using linear classifiers to solve nonlinear problems.
• Random forest — Random forests or random decision forests is an ensemble learning method for classification, regression and other tasks that works by creating a multitude of decision trees during training.
• Gradient boosting — Gradient boosting is a machine learning technique based on boosting in a functional space, where the target is pseudo-residuals instead of residuals as in traditional boosting.

E.12.3 Deep learning

• Deep learning — In machine learning, deep learning (DL) focuses on utilizing multilayered neural networks to perform tasks such as classification, regression, and representation learning.
• Stochastic gradient descent — Stochastic gradient descent is an iterative method for optimizing an objective function with suitable smoothness properties.
• Convolutional neural network — A convolutional neural network (CNN) is a type of feedforward neural network that learns features via filter optimization.
• Recurrent neural network — In artificial neural networks, recurrent neural networks (RNNs) are designed for processing sequential data, such as text, speech, and time series, where the order of elements is important.
• Long short-term memory — Long short-term memory (LSTM) is a type of recurrent neural network (RNN) aimed at mitigating the vanishing gradient problem commonly encountered by traditional RNNs.
• Transformer (deep learning architecture) — In deep learning, the transformer is a family of artificial neural network architectures based on the multi-head attention mechanism, in which input data such as text, images, or audio is converted to a sequence of numerical representations called tokens, and each token is converted into a vector through an embedding layer.
• Graph neural network — Graph neural networks (GNNs) are artificial neural networks designed for tasks whose inputs are graphs.
• Explainable artificial intelligence — Within artificial intelligence (AI), explainable AI (XAI), generally overlapping with interpretable AI, interpretable machine learning and explainable machine learning (XML), is a field of research that explores methods that provide humans with the ability of intellectual oversight over AI algorithms.

E.12.4 Generative models

• Generative model — Generative models are a class of computational models frequently used for classification.
• Autoregressive model — In statistics, an autoregressive (AR) model is a modelled representation of a type of random process. It can be used to describe time-varying processes from many natural and artificial sources.
• Autoencoder — An autoencoder is a type of artificial neural network used to learn efficient codings of unlabeled data.
• Variational autoencoder — In machine learning, a variational autoencoder (VAE) is an artificial neural network architecture introduced by Diederik P. Kingma and Max Welling in 2013. It is part of the families of probabilistic graphical models and variational Bayesian methods.
• Generative adversarial network — A generative adversarial network (GAN) is a class of machine learning frameworks and a prominent framework for approaching generative AI. The concept was initially developed by Ian Goodfellow and his colleagues at Université de Montréal in June 2014.
• Diffusion model — In machine learning, diffusion models, also known as diffusion-based generative models or score-based generative models, are a class of latent variable generative models.

E.12.5 Foundation models

• Foundation model — In artificial intelligence, a foundation model (FM), also known as large x model, is a machine learning or deep learning model trained on vast datasets so that it can be applied across a wide range of use cases.
• Self-supervised learning — Self-supervised learning (SSL) is a paradigm in machine learning where a model is trained on a task using the data itself to generate supervisory signals, rather than relying on externally-provided labels.
• Transfer learning — Transfer learning (TL) is a technique in machine learning (ML) in which knowledge learned from a task is re-used in order to boost performance on a related task.
• Fine-tuning (deep learning) — In deep learning, fine-tuning is the process of adapting a computational model trained for one task to perform a different, usually more specific, task.
• Neural scaling law — In machine learning, a neural scaling law is an empirical scaling law that describes how neural network performance changes as key factors are scaled up or down.
• Retrieval-augmented generation — Retrieval-augmented generation (RAG) is a technique that enables large language models (LLMs) to retrieve and incorporate new information from external data sources. With RAG, LLMs first refer to a specified set of documents, then respond to user queries.

E.12.6 AI in research practice

• Artificial intelligence — Artificial intelligence (AI) is the capability of computational systems to perform tasks typically associated with human intelligence, such as learning, reasoning, problem-solving, perception, and decision-making.
• Large language model — A large language model (LLM) is an AI model trained on a vast amount of text for natural language processing tasks, especially language generation. LLMs can typically generate, summarize, translate, and analyze text in many contexts.
• Generative artificial intelligence — Generative artificial intelligence (GenAI) is a subfield of artificial intelligence (AI) that uses generative models to generate text, images, videos, audio, computer code or other forms of digital data.
• Reinforcement learning from human feedback — In machine learning, reinforcement learning from human feedback (RLHF) is a technique to align an intelligent agent with human preferences.
• Hallucination (artificial intelligence) — In the field of artificial intelligence (AI), a hallucination or artificial hallucination is a response generated by AI that contains false or misleading information presented as fact.
• Ethics of artificial intelligence — The ethics of artificial intelligence covers a broad range of topics within AI that are considered to have particular ethical stakes.

E.12.7 Integrating data

• Multiomics — Multiomics, multi-omics, integrative omics, “panomics” or “pan-omics” is a biological analysis approach in which the data consists of multiple “omes”, such as the genome, epigenome, transcriptome, proteome, metabolome, exposome, and microbiome ; in other words, the use of multiple omics technologies to study life in a concerted way.
• Data integration — Data integration is the process of combining, sharing, or synchronizing data from multiple sources to provide users with a unified view. There are a wide range of possible applications for data integration, from commercial to scientific.
• Canonical correlation — In statistics, canonical-correlation analysis (CCA), also called canonical variates analysis, is a way of inferring information from cross-covariance matrices.
• Mendelian randomization — In epidemiology, Mendelian randomization is a method using measured variation in genes to examine the causal effect of an exposure on an outcome.
• Causal inference — Causal inference is the process of determining the independent, actual effect of a particular phenomenon that is a component of a larger system.

E.13 Image analysis and models of cells

Wikipedia articles for Chapter 13.

E.13.1 Images as data

• Microscopy — Microscopy is the technical field of using microscopes to view subjects too small to be seen with the naked eye.
• Fluorescence microscope — A fluorescence microscope is an optical microscope that uses fluorescence instead of, or in addition to scattering, reflection, and attenuation or absorption, to study the properties of organic or inorganic substances.
• Confocal microscopy — Confocal microscopy is an optical imaging technique for increasing optical resolution and contrast of a micrograph by means of using a spatial pinhole to block out-of-focus light in image formation.
• Image segmentation — In digital image processing and computer vision, image segmentation is the process of partitioning a digital image into multiple image segments, also known as image regions or image objects.
• Watershed (image processing) — In the study of image processing, a watershed is a transformation defined on a grayscale image. The name refers metaphorically to a geological watershed, or drainage divide, which separates adjacent drainage basins.
• Fiji (software) — Fiji is an open source image processing package based on ImageJ2.
• CellProfiler — CellProfiler is free, open-source software designed to enable biologists without training in computer vision or programming to quantitatively measure phenotypes from thousands of images automatically.

E.13.2 Deep learning for images

• Convolutional neural network — A convolutional neural network (CNN) is a type of feedforward neural network that learns features via filter optimization.
• U-Net — U-Net is a convolutional neural network that was developed for image segmentation.
• Vision transformer — A vision transformer (ViT) is a transformer designed for computer vision. A ViT decomposes an input image into a series of patches, serializes each patch into a vector, and maps it to a smaller dimension with a single matrix multiplication.
• Self-supervised learning — Self-supervised learning (SSL) is a paradigm in machine learning where a model is trained on a task using the data itself to generate supervisory signals, rather than relying on externally-provided labels.
• Segment Anything — Segment Anything is a series of open-source computer vision foundation models developed by Meta AI for image and video segmentation.
• ImageNet — The ImageNet project is a large visual database designed for use in visual object recognition software research.

E.13.3 Image-based profiling

• High-content screening — High-content screening (HCS), also known as high-content analysis (HCA) or cellomics, is a method that is used in biological research and drug discovery to identify substances such as small molecules, peptides, or RNAi that alter the phenotype of a cell in a desired manner.
• Cell Painting — The cell painting assay is a high-content, high-throughput imaging technique used to capture a wide array of cellular phenotypes in response to diverse perturbations.
• Phenotypic screening — Phenotypic screening is a type of screening used in biological research and drug discovery to identify substances such as small molecules, peptides, or RNAi that alter the phenotype of a cell or an organism in a desired manner.
• Mechanism of action — In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect.

E.13.4 Protein localisation from images

• Human Protein Atlas — The Human Protein Atlas (HPA) is a Swedish-based program started in 2003 with the aim to map all the human proteins in cells, tissues and organs using integration of various omics technologies, including antibody-based imaging, mass spectrometry-based proteomics, transcriptomics and systems biology.
• Immunofluorescence — Immunofluorescence (IF) is a light microscopy-based technique that allows detection and localization of a wide variety of target biomolecules within a cell or tissue at a quantitative level.
• Subcellular localization — The cells of eukaryotic organisms are elaborately subdivided into functionally-distinct membrane-bound compartments.
• Green fluorescent protein — The green fluorescent protein (GFP) is a protein that exhibits green fluorescence when exposed to light in the blue to ultraviolet range.
• Protein tag — Protein tags are peptide sequences genetically grafted onto a recombinant protein. Tags are attached to proteins for various purposes.

E.13.5 Tissues: multiplexed imaging and computational pathology

• Digital pathology — Digital pathology is a sub-field of pathology that focuses on managing and analyzing information generated from digitized specimen slides.
• Spatial transcriptomics — Spatial transcriptomics, or spatially resolved transcriptomics, is a method that captures positional context of transcriptional activity within intact tissue.
• Mass cytometry — Mass cytometry is a high-dimensional single-cell analysis technique that integrates flow cytometry with time of flight mass spectrometry. It is used for the determination of the properties of cells (cytometry).
• Multiple instance learning — In machine learning, multiple-instance learning (MIL) is a type of supervised learning. Instead of receiving a set of instances which are individually labeled, the learner receives a set of labeled bags, each containing many instances.
• Histopathology — Histopathology is the microscopic examination of tissue in order to study the manifestations of disease.
• H&E stain — Hematoxylin and eosin stain is one of the principal tissue stains used in histology. It is the most widely used stain in medical diagnosis and is often the gold standard.

E.13.6 Cell atlases and virtual cells

• Human Cell Atlas — The Human Cell Atlas is a global project to describe all cell types in the human body, to understand human health and for diagnosing, monitoring, and treating disease.
• Virtual cell — A cellular model or virtual cell is a computational model of aspects of a biological cell, for the purposes of in silico research.
• Foundation model — In artificial intelligence, a foundation model (FM), also known as large x model, is a machine learning or deep learning model trained on vast datasets so that it can be applied across a wide range of use cases.
• Perturb-seq — Perturb-seq refers to a high-throughput method of performing single cell RNA sequencing (scRNA-seq) on pooled genetic perturbation screens.
• Chan Zuckerberg Initiative — The Chan Zuckerberg Initiative (CZI) is an organization established and owned by Facebook founder Mark Zuckerberg and his wife Priscilla Chan with an investment of 99 percent of the couple’s wealth from their Facebook shares over their lifetime.

E.13.7 Whole-cell models and cryo-electron tomography

• Cryogenic electron tomography — Cryogenic electron tomography (cryoET) is an imaging technique used to reconstruct high-resolution (~1–4 nm) three-dimensional volumes of samples, often biological macromolecules and cells. cryoET is a specialized application of transmission electron cryomicroscopy (CryoTEM) in which samples are imaged as they are tilted, resulting in a series of 2D images that can be combined to produce a 3D reconstruction, similar to a CT scan of the human body.
• Mycoplasma genitalium — Mycoplasma genitalium is a sexually transmitted, small pathogenic bacterium that lives on the mucous epithelial cells of the urinary and genital tracts in humans. Medical journals in 2007 and 2015 reported that Mgen had become more common.
• Minimal genome — Minimal genome is the theoretical smallest set of genes sufficient for life to exist and propagate under nutrient-rich and stress-free conditions.
• Molecular dynamics — Molecular dynamics (MD) is a computer simulation method for analyzing the physical movements of atoms and molecules. The atoms and molecules are allowed to interact for a fixed period of time, giving a view of the dynamic “evolution” of the system.
• Systems biology — Systems biology is the computational and mathematical analysis and modeling of complex biological systems.