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. Two segments of DNA can have shared ancestry because of three phenomena: either a speciation event (orthologs), or a duplication event (paralogs), or else a horizontal (or lateral) gene transfer event (xenologs).

Homology among DNA, RNA, or proteins is typically inferred from their nucleotide or amino acid sequence similarity. Significant similarity is strong evidence that two sequences are related by evolutionary changes from a common ancestral sequence. Alignments of multiple sequences are used to indicate which regions of each sequence are homologous.

The term "percent homology" is often used to mean "sequence similarity", that is the percentage of identical residues (percent identity), or the percentage of residues conserved with similar physicochemical properties (percent similarity), e.g. leucine and isoleucine, is usually used to "quantify the homology." Based on the definition of homology specified above this terminology is incorrect since sequence similarity is the observation, homology is the conclusion. Sequences are either homologous or not. This involves that the term "percent homology" is a misnomer.

As with morphological and anatomical structures, sequence similarity might occur because of convergent evolution, or, as with shorter sequences, by chance, meaning that they are not homologous. Homologous sequence regions are also called conserved. This is not to be confused with conservation in amino acid sequences, where the amino acid at a specific position has been substituted with a different one that has functionally equivalent physicochemical properties.

Partial homology can occur where a segment of the compared sequences has a shared origin, while the rest does not. Such partial homology may result from a gene fusion event.

Proteins are known to conserve their tertiary structure more strongly than their amino acid sequences. Two distantly related proteins can have minimal or even undetectable sequence similarity, yet have highly similar folds that can be compared via structural alignment. Examples of these proteins used to be only discovered by experimental structual determination methods. Modern protein structure prediction methods such as AlphaFold2 allow possible homologs to be identified without wet lab work.

RNA is also known to conserve tertiary structure more strongly than primary structure. RNA secondary structure prediction was found to be helpful in human-to-mouse comparison.

Homologous sequences are orthologous if they are inferred to be descended from the same ancestral sequence separated by a speciation event: when a species diverges into two separate species, the copies of a single gene in the two resulting species are said to be orthologous. Orthologs, or orthologous genes, are genes in different species that originated by vertical descent from a single gene of the last common ancestor. The term "ortholog" was coined in 1970 by the molecular evolutionist Walter Fitch.