Positional orthology: putting genomic evolutionary relationships into context

Abstract

Orthology is a powerful refinement of homology that allows us to describe more precisely the evolution of genomes and understand the function of the genes they contain. However, because orthology is not concerned with genomic position, it is limited in its ability to describe genes that are likely to have equivalent roles in different genomes. Because of this limitation, the concept of 'positional orthology' has emerged, which describes the relation between orthologous genes that retain their ancestral genomic positions. In this review, we formally define this concept, for which we introduce the shorter term 'toporthology', with respect to the evolutionary events experienced by a gene's ancestors. Through a discussion of recent studies on the role of genomic context in gene evolution, we show that the distinction between orthology and toporthology is biologically significant. We then review a number of orthology prediction methods that take genomic context into account and thus that may be used to infer the important relation of toporthology.

Figure 1:

An example of the limitations of the orthology concept. A segmental duplication creates two copies of gene Y in species B. Gene YA is orthologous to both YB1 and YB2. However, we would like to distinguish the (YA, YB1) relationship from the (YA, YB2) relationship because YA and YB1 are most representative of the ancestral copy of Y.

Figure 2:

A hypothetical evolutionary scenario in which we distinguish between classes of orthologs. (A) A speciation event occurs, creating species A and B. The genome of species A undergoes an undirected duplication (a tandem duplication of gene YA) followed by an inversion. Meanwhile, a directed duplication (a segmental duplication of gene YB) followed by a whole genome duplication event occurs within species B. (B) The evolutionary tree for the descendants of gene Y. The top V-shaped split represents a speciation event, while the rectangular splits represent duplications. For the one directed duplication in the tree, the arrow points towards the target copy of the duplication event. (C) The evolutionary terms used to describe the relationship between each pair of extant genes. Note that the inversion event in species A does not impact the evolutionary relationships.

Figure 3:

The three classes of orthology prediction methods that take genomic context into account. (A) Methods that consider the conservation of local gene order or gene neighborhood into account would predict Y and Y1 to be toporthologs because they have two neighbors in common, whereas Y and Y2 only have one common neighbor (where we only consider immediately adjacent neighbors). (B) Methods based on gene order evolution models infer toporthology by finding an assignment between the gene sets that minimizes the number of evolutionary events required to explain the genomes. Assignment of Y and Y2 as toporthologs (scenario 2) requires four events (three inversions and one duplication), whereas assignment of Y and Y1 as toporthologs (scenario 1) only requires two events (one inversion and one duplication). Thus, Y and Y1 would be predicted as toporthologs by these methods. (C) Whole-genome alignment methods disregard gene boundaries and find colinear orthologous segments between genomes (the shaded blocks). From this alignment, we would infer that Y and Y1 are toporthologs because they fall within in the same block.