Adaptive Functional Divergence Among Triplicated α-Globin Genes in Rodents

Abstract

The functional divergence of duplicated genes is thought to play an important role in the evolution of new developmental and physiological pathways, but the role of positive selection in driving this process remains controversial. The objective of this study was to test whether amino acid differences among triplicated a-globin paralogs of the Norway rat (Rattus norvegicus) and the deer mouse (Peromyscus maniculatus) are attributable to a relaxation of purifying selection or to a history of positive selection that has adapted the gene products to new or modified physiological tasks. In each rodent species, the two paralogs at the 59-end of the a-globin gene cluster (HBA-T1 and HBA-T2) are evolving in concert and are therefore identical or nearly identical in sequence. However, in each case, the HBA-T1 and HBA-T2 paralogs are distinguished from the third paralog at the 39-end of the gene cluster (HBA-T3) by multiple amino acid substitutions. An analysis of genomic sequence data from several rodent species revealed that the HBA-T3 genes of Rattus and Peromyscus originated via independent, lineage-specific duplication events. In the independently derived HBA-T3 genes of both species, a likelihood analysis based on a codon-substitution model revealed that accelerated rates of amino acid substitution are attributable to positive directional selection, not to a relaxation of purifying selection. As a result of functional divergence among the triplicated a-globin genes in Rattus and Peromyscus, the red blood cells of both rodent species contain a mixture of functionally distinct a-chain hemoglobin isoforms that are predicted to have different oxygen-binding affinities. In P. maniculatus, a species that is able to sustain physiological function under conditions of chronic hypoxia at high altitude, the coexpression of distinct hemoglobin isoforms with graded oxygen affinities is expected to broaden the permissible range of arterial oxygen tensions for pulmonary/tissue oxygen transport.

Copy number polymorphism in the α-globin gene cluster of European rabbit (Oryctolagus cuniculus)

“…The pattern of gene turnover has been especially well characterized in the a-globin gene cluster of mammals (Zimmer et al, 1980;Hoffmann et al, 2008a;Storz et al, 2008). Electrophoretic surveys of genetic variation at the HBA locus in natural and domestic populations of the European rabbit had previously revealed a pattern that was consistent with the existence of a single HBA gene, as reported by Cheng et al (1986).…”

“…Comparative genomic studies have revealed extensive variation in the size and membership composition of the a-and b-globin gene families in mammals (Hoffmann et al, 2008a, b;Storz et al, 2008;Opazo et al, , b, 2009. In principle, studies of gene copy number variation within species could provide insights into the evolutionary forces that have shaped the observed copy number variation among species.…”

Relaxed functional constraints on triplicate α-globin gene in the bank vole suggest a different evolutionary history from other rodents

“…In addition to the bank vole sequences, we also included published sequences of a-globin genes from the species analysed by Storz et al (2008), that is, P. maniculatus, R. norvegicus and M. musculus. As in the study of Storz et al (2008), a sequence of the single HBA gene of the guinea pig (Cavia porcellus) was used as outgroup (Fabre et al, 2012).…”

“…As in the study of Storz et al (2008), a sequence of the single HBA gene of the guinea pig (Cavia porcellus) was used as outgroup (Fabre et al, 2012).…”

“…However, the a-globin genes of two rodents, the Norway rat (Rattus norvegicus) and the deer mouse (Peromyscus maniculatus), are a striking exception to this general pattern. Each species possesses three copies of adult a-globin genes, where two of the paralogues (HBA-T1 and HBA-T2) have almost identical sequences because of concerted evolution, whereas the third paralogue (HBA-T3) shows differences at multiple amino acid sites, predicted to produce changes in oxygen-binding affinity (for details see Hoffmann et al, 2008;Storz et al, 2008). The HBA-T3 paralogue was inferred to originate independently in Rattus and in Peromyscus, and in each species the high rate of protein evolution has been attributed to positive directional selection rather than relaxed purifying selection .…”