Fundamentals of Bioinformatics - Ogurtsov A.N. 2013

Methods of Bioinformatics Analysis
Phylogenetic Analysis
Homology

The term "homology" literally means common descent from an ancestor. Descendants of a common ancestor typically exhibit similarities across multiple traits, which are referred to as homologous traits.

For a long time, the terms "homology" and "similarity" were used as interchangeable synonyms—despite the fact that they are formally distinct (see also Section 4.2, Example 3).

Similarity is a measure of likeness or difference and is independent of the source of that likeness. Similarity can be observed among currently available data and does not imply any historical hypothesis.

In contrast, statements of homology are based entirely on speculative inferences about historical events that are practically unobservable. While the degree of similarity can be quantified, homology is primarily a qualitative measure.

Homologous Proteins are proteins whose descent from a common ancestor has been established. If protein folds are similar but their primary sequences differ, such folds are considered analogous.

Consider, for example, the tubulin protein family—proteins that form the microtubules of the Cytoskeleton. According to a simplified scheme (Figure 63), ancestral Eukaryotic Cells possessed only a single tubulin Gene, which underwent duplication early in evolutionary history (see [7], Section 13.2).

Subsequent divergence of the various copies of the ancestral tubulin gene gave rise to the precursor genes of today's $\alpha$- and $\beta$-tubulins. As various species diverged from these ancestral eukaryotic cells, each of these gene sequences also diverged, thereby giving rise to the slightly different forms of $\alpha$- and $\beta$-tubulins found in every Organism today.

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Figure 63 - Evolution of various tubulin genes during eukaryote evolution

Comparative analysis of nucleotide sequences in DNA and Amino acid sequences in proteins necessitated an expansion of the traditional concept of homology. In sequence analysis, it is customary to distinguish between orthology and paralogy.

Homologous sequences are termed orthologous if their divergence was driven by a speciation event: if a gene exists in a species that diverges to form two species, the copies of this gene in the daughter species are called orthologs.

Homologous sequences are termed paralogous if their divergence was driven by Gene Duplication: if a gene is duplicated within a single organism As a result of a chromosomal mutation, its copies are called paralogs.

Orthologs typically perform identical or similar Functions. This is not always true for paralogs. Due to the absence of Selection pressure on one copy of a duplicated gene, that copy is free to accumulate further Mutations, which can lead to The Emergence of novel functions (see also Section 12.4).

In the case of tubulin, the $\alpha$- and $\beta$-tubulin gene sequences are paralogous, having diverged as a result of gene duplication. Conversely, the tubulin gene sequences that arose through speciation—such as $\alpha$-tubulin genes across different species, or $\beta$-tubulin genes across different species—are orthologous. By assessing the degree of similarity among tubulins present in various organisms today, one can determine their evolutionary relationship (Figure 64). The figure shows a phylogenetic scheme, specifically a cladogram, representing the relationships and relatedness among tubulin sequences.

Figure 64 - Phylogenetic scheme (cladogram) showing the relationships among tubulin gene sequences

A phylogenetic scheme is a diagram representing putative genealogical (evolutionary) relationships among individuals, populations, or taxa of various levels across historical time; the "branching" points on the diagram correspond to hypothetical moments of The formation of new forms (divergence).

A cladogram is a Phylogenetic Tree that contains no information about branch lengths (see Figures 21, 22, and 64).

If, however, branch lengths convey information about the magnitude of a specific parameter, such a tree is called a phylogram (or phenogram). For instance, a phylogram in which branch lengths represent evolutionary time is called a chronogram (see, e.g., Figure 20).

Among the Three types of genetic relationship—homology, orthology, and paralogy—orthologous sequences are the most likely to encode the same Protein Functions.

When decoding and analyzing Biological Sequences, results must be cross-checked against all available sources of biological information.

The analytical process is complicated by the fact that sequence similarity is sometimes restricted to only a portion of an alignment, such as when studying modular proteins. Modules can be viewed as subsets of Protein domains; they are independent folding units that pack together and often serve as structural elements for the assembly of a protein molecule (see Section 6.5). Acting as Building Blocks of the overall architecture, they can be utilized to transmit a rich palette of the parent protein's diverse functions—both through multiple combinations of a single module and via combinations of different modules to form structural mosaics. The widespread occurrence of modules is largely driven by gene rearrangement processes, rather than solely by gene duplication and fusion.