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).[1]

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.
Gene phylogeny as red and blue branches within grey species
phylogeny. Top: An ancestral gene duplication produces two
paralogs (histone H1.1 and 1.2). A speciation event produces
orthologs in the two daughter species (human and chimpanzee).
Bottom: in a separate species (E. coli), a gene has a similar function
(histone-like nucleoid-structuring protein) but has a separate
evolutionary origin and so is an analog.

Contents
Identity, similarity, and conservation
Orthology
Databases of orthologous genes
Paralogy
Regulation
Paralogous chromosomal regions
Ohnology
Xenology
Homoeology
Gametology
See also
References

Identity, similarity, and conservation

The term "percent homology" is often used to mean "sequence similarity." 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.
 A sequence alignment of mammalian histone proteins. Sequences are the middle
120-180 amino acid residues of the proteins. Residues that are conserved across all
sequences are highlighted in grey. The key below denotes conserved sequence (*),
conservative mutations (:), semi-conservative mutations (.), and non-conservative
mutations ( ).[2]

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.

Orthology
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.[3]

For instance, the plant Flu regulatory protein is present both in

Arabidopsis (multicellular higher plant) and Chlamydomonas
(single cell green algae). The Chlamydomonas version is more
complex: it crosses the membrane twice rather than once, contains
additional domains and undergoes alternative splicing. However it
can fully substitute the much simpler Arabidopsis protein, if
transferred from algae to plant genome by means of genetic
engineering. Significant sequence similarity and shared functional
domains indicate that these two genes are orthologous genes,[4] inherited from the shared ancestor.
Top: An ancestral gene duplicates to produce two
paralogs (Genes A and B). A speciation event
produces orthologs in the two daughter species.
Bottom: in a separate species, an unrelated gene
has a similar function (Gene C) but has a
separate evolutionary origin and so is an analog.

Orthology is strictly defined in terms of ancestry. Given that the exact ancestry of genes in different organisms is difficult to
ascertain due to gene duplication and genome rearrangement events, the strongest evidence that two similar genes are orthologous
is usually found by carrying out phylogenetic analysis of the gene lineage. Orthologs often, but not always, have the same
function.[5]
Orthologous sequences provide useful information in taxonomic classification and phylogenetic studies of organisms. The pattern
of genetic divergence can be used to trace the relatedness of organisms. Two organisms that are very closely related are likely to
display very similar DNA sequences between two orthologs. Conversely, an organism that is further removed evolutionarily from
another organism is likely to display a greater divergence in the sequence of the orthologs being studied.

Databases of orthologous genes

Given their tremendous importance for biology and bioinformatics, orthologous genes have been organized in several specialized
databases that provide tools to identify and analyze orthologous gene sequences. These resources employ approaches that can be
generally classified into those that use heuristic analysis of all pairwise sequence comparisons, and those that use phylogenetic
methods. Sequence comparison methods were first pioneered in the COGs database in 1997.[6] These methods have been
extended and automated in the following databases:

eggNOG[7]
GreenPhylDB[8] for plants
InParanoid[9] focuses on pairwise ortholog relationships
OHNOLOGS (http://ohnologs.curie.fr/)[10][11] is a repository of the genes retained from whole genome
duplications in the vertebrate genomes including human and mouse.
OMA
OrthoDB[12] appreciates that the orthology concept is relative to different speciation points by providing a
hierarchy of orthologs along the species tree.
OrthoInspector (http://lbgi.igbmc.fr/orthoinspectorv3/)[13] is a repository of orthologous genes for 4753 organisms
covering the three domains of life
OrthologID[14]
OrthoMaM[15] for mammals
OrthoMCL[16]
Roundup[17]
Tree-based phylogenetic approaches aim to distinguish speciation from gene duplication events by comparing gene trees with
species trees, as implemented in databases such as:

LOFT[18]
TreeFam[19]
A third category of hybrid approaches uses both heuristic and phylogenetic methods to construct clusters and determine trees, for
example:

EnsemblCompara GeneTrees[20]
HomoloGene[21]
Ortholuge[22]

Paralogy
Paralogous genes are genes that are related via duplication events in the last common ancestor (LCA) of the species being
compared. They result from the mutation of duplicated genes during separate speciation events. When descendants from the LCA
share mutated homologs of the original duplicated genes then those genes are considered paralogs.[1]

As an example, in the LCA, one gene (gene A) may get duplicated to make a separate similar gene (gene B), those two genes will
continue to get passed to subsequent generations. During speciation, one environment will favor a mutation in gene A (gene A1),
producing a new species with genes A1 and B. Then in a separate speciation event, one environment will favor a mutation in gene
B (gene B1) giving rise to a new species with genes A and B1. The descendants’ genes A1 and B1 are paralogous to each other
because they are homologs that are related via a duplication event in the last common ancestor of the two species.[1]

Additional classifications of paralogs include alloparalogs (out-paralogs) and symparalogs (in-paralogs). Alloparalogs are
paralogs that evolved from gene duplications that preceded the given speciation event. In other words, alloparalogs are paralogs
that evolved from duplication events that happened in the LCA of the organisms being compared. The example above is an
example alloparalogy. Symparalogs are paralogs that evolved from gene duplication of paralogous genes in subsequent speciation
events. From the example above, if the descendant with genes A1 and B underwent another speciation event where gene A1
duplicated, the new species would have genes B, A1a, and A1b. In this example, genes A1a and A1b are symparalogs.[1]

Paralogous genes can shape the structure of whole genomes and

thus explain genome evolution to a large extent. Examples include
the Homeobox (Hox) genes in animals. These genes not only
underwent gene duplications within chromosomes but also whole
genome duplications. As a result Hox genes in most vertebrates are
clustered across multiple chromosomes with the HoxA-D clusters
being the best studied.[23]

Another example are the globin genes which encode myoglobin

and hemoglobin and are considered to be ancient paralogs.
Similarly, the four known classes of hemoglobins (hemoglobin A,
hemoglobin A2, hemoglobin B, and hemoglobin F) are paralogs of
each other. While each of these proteins serves the same basic
function of oxygen transport, they have already diverged slightly in
function: fetal hemoglobin (hemoglobin F) has a higher affinity for
oxygen than adult hemoglobin. Function is not always conserved,
however. Human angiogenin diverged from ribonuclease, for Vertebrate Hox genes are organized in sets of
example, and while the two paralogs remain similar in tertiary paralogs. Each Hox cluster (HoxA, HoxB, etc.) is
on a different chromosome. For instance, the
structure, their functions within the cell are now quite different.
human HoxA cluster is on chromosome 7. The
mouse HoxA cluster shown here has 11
It is often asserted that orthologs are more functionally similar than
paralogous genes (2 are missing).[23]
paralogs of similar divergence, but several papers have challenged
this notion.[24][25][26]

Regulation
Paralogs are often regulated differently, e.g. by having different tissue-specific expression patterns (see Hox genes). However,
they can also be regulated differently on the protein level. For instance, Bacillus subtilis encodes two paralogues of glutamate
dehydrogenase: GudB is constitutively transcribed whereas RocG is tightly regulated. In their active, oligomeric states, both
enzymes show similar enzymatic rates. However, swaps of enzymes and promoters cause severe fitness losses, thus indicating
promoter–enzyme coevolution. Characterization of the proteins shows that, compared to RocG, GudB's enzymatic activity is
highly dependent on glutamate and pH.[27]

Paralogous chromosomal regions

Sometimes, large regions of chromosomes share gene content similar to other chromosomal regions within the same genome.[28]
They are well characterised in the human genome, where they have been used as evidence to support the 2R hypothesis. Sets of
duplicated, triplicated and quadruplicated genes, with the related genes on different chromosomes, are deduced to be remnants
from genome or chromosomal duplications. A set of paralogy regions is together called a paralogon.[29] Well-studied sets of
paralogy regions include regions of human chromosome 2, 7, 12 and 17 containing Hox gene clusters, collagen genes, keratin
genes and other duplicated genes,[30] regions of human chromosomes 4, 5, 8 and 10 containing neuropeptide receptor genes, NK
class homeobox genes and many more gene families,[31][32][33] and parts of human chromosomes 13, 4, 5 and X containing the
ParaHox genes and their neighbors.[34] The Major histocompatibility complex (MHC) on human chromosome 6 has paralogy
regions on chromosomes 1, 9 and 19.[35] Much of the human genome seems to be assignable to paralogy regions.[36]

Ohnology
Ohnologous genes are paralogous genes that have originated by a
process of whole-genome duplication. The name was first given in
honour of Susumu Ohno by Ken Wolfe.[37] Ohnologues are useful
for evolutionary analysis because all ohnologues in a genome have
been diverging for the same length of time (since their common
A whole genome duplication event produces a
origin in the whole genome duplication). Ohnologues are also
genome with two ohnolog copies of each gene.
known to show greater association with cancers, dominant genetic
disorders, and pathogenic copy number
variations.[38][39][40][41][42]

Xenology
Homologs resulting from horizontal gene transfer between two
organisms are termed xenologs. Xenologs can have different
functions, if the new environment is vastly different for the
A speciation event produces orthologs of a gene
horizontally moving gene. In general, though, xenologs typically
in the two daughter species. A horizontal gene
have similar function in both organisms. The term was coined by
transfer event from one species to another adds
Walter Fitch.[3] a xenolog of the gene to its genome.

Homoeology
Homoeologous (also spelled homeologous) chromosomes or parts
of chromosomes are those brought together following inter-species
hybridization and allopolyploidization, and whose relationship was
completely homologous in an ancestral species. In allopolyploids,
the homologous chromosomes within each parental sub-genome
should pair faithfully during meiosis, leading to disomic
inheritance; however in some allopolyploids, the homoeologous
A speciation event produces orthologs of a gene
chromosomes of the parental genomes may be nearly as similar to in the two daughter species. Subsequent
one another as the homologous chromosomes, leading to hybridisation of those species generates a hybrid
tetrasomic inheritance (four chromosomes pairing at meiosis), genome with a homoeolog copy of each gene
intergenomic recombination, and reduced fertility. from both species.

Gametology
Gametology denotes the relationship between homologous genes on non-recombining, opposite sex chromosomes. The term was
coined by García-Moreno and Mindell.[43] 2000. Gametologs result from the origination of genetic sex determination and barriers
to recombination between sex chromosomes. Examples of gametologs include CHDW and CHDZ in birds.[43]
See also
Deep homology
EggNOG (database)
OrthoDB
Orthologous MAtrix (OMA)
Protein family
Protein superfamily
TreeFam
Syntelog

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