Adaptive Functional Divergence among Triplicated [Alpha]-Globin Genes in Rodents

By Storz, Jay F.; Hoffmann, Federico G. et al. | Genetics, March 2008 | Go to article overview

Adaptive Functional Divergence among Triplicated [Alpha]-Globin Genes in Rodents


Storz, Jay F., Hoffmann, Federico G., Opazo, Juan C., Moriyama, Hideaki, Genetics


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 α-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 5'-end of the α-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 3'-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 α-globin genes in Rattus and Peromyscus, the red blood cells of both rodent species contain a mixture of functionally distinct α-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.

THE duplication of protein-codinggenes, followed by functional changes in one or both daughter copies, is thought to play a fundamental role in the evolution of new developmental and physiological pathways (Ohno et al. 1968; Ohno 1970; Kimura and Ohta 1974; Li 1983). However, the role of positive Darwinian selection in driving the functional divergence of duplicated genes remains controversial (Hughes 1994, 1999; Lynch and Force 2000; Lynch et al. 2001; Zhang 2003; Lynch and Katju 2004; Lynch 2007). One of the fundamental questions is whether the mutations that are responsible for the initial retention and subsequent divergence of newly created gene duplicates are typically advantageous or degenerative. According to the subfunctionalization model, the accumulation of degenerative mutations in one or both gene duplicates leads to a complementary loss of paralog-specific subfunctions (Force et al. 1999; Stoltzfus 1999; Lynch and Force 2000; Lynch 2007). The gene duplicates are then retained by purifying selectionbecause inactivation of either paralog results in loss of the ancestral gene function.

According to the neofunctionalizationmodel ofOhno (1970), the functional redundancy of duplicated genes entails a relaxation of purifying selection that results in the accumulation ofmutations that are effectively neutral as long as the other paralog continues to perform the essential tasks of the ancestral, single-copy gene. In the vast majority of cases, the redundant gene duplicate will eventually be rendered functionless by inactivating mutations. In rare cases, the redundant gene copy will escape pseudogenization by fixing one or more mutations that fortuitously adapt the encoded protein to a new or modified function. An alternative model for the evolution of novel protein functions, suggested by Hughes (1994, 1999),PiatigorskyandWistow(1991), andPiatigorsky (2007), invokes the presence of functional divergence prior to gene duplication and does not require an initial relaxation of functional constraint. …

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Adaptive Functional Divergence among Triplicated [Alpha]-Globin Genes in Rodents
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