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.2008 Dec;25(12):2589-600.
doi: 10.1093/molbev/msn200. Epub 2008 Sep 9.

New genes originated via multiple recombinational pathways in the beta-globin gene family of rodents

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New genes originated via multiple recombinational pathways in the beta-globin gene family of rodents

Federico G Hoffmann et al. Mol Biol Evol.2008 Dec.

Abstract

Species differences in the size or membership composition of multigene families can be attributed to lineage-specific additions of new genes via duplication, losses of genes via deletion or inactivation, and the creation of chimeric genes via domain shuffling or gene fusion. In principle, it should be possible to infer the recombinational pathways responsible for each of these different types of genomic change by conducting detailed comparative analyses of genomic sequence data. Here, we report an attempt to unravel the complex evolutionary history of the beta-globin gene family in a taxonomically diverse set of rodent species. The main objectives were: 1) to characterize the genomic structure of the beta-globin gene cluster of rodents; 2) to assign orthologous and paralogous relationships among duplicate copies of beta-like globin genes; and 3) to infer the specific recombinational pathways responsible for gene duplications, gene deletions, and the creation of chimeric fusion genes. Results of our comparative genomic analyses revealed that variation in gene family size among rodent species is mainly attributable to the differential gain and loss of later expressed beta-globin genes via unequal crossing-over. However, two distinct recombinational mechanisms were implicated in the creation of chimeric fusion genes. In muroid rodents, a chimeric gamma/epsilon fusion gene was created by unequal crossing-over between the embryonic epsilon- and gamma-globin genes. Interestingly, this gamma/epsilon fusion gene was generated in the same fashion as the "anti-Lepore" 5'-delta-(beta/delta)-beta-3' duplication mutant in humans (the reciprocal exchange product of the pathological hemoglobin Lepore deletion mutant). By contrast, in the house mouse, Mus musculus, a chimeric beta/delta fusion pseudogene was created by a beta-globin --> delta-globin gene conversion event. Although the gamma/epsilon and beta/delta fusion genes share a similar chimeric gene structure, they originated via completely different recombinational pathways.

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Figures

F<sc>IG</sc>. 1.—
FIG. 1.—
Genomic structure of the β-globin cluster in rodents and two outgroup species—human and rabbit. The depicted phylogenetic relationships are based on a loose consensus of recent studies (Murphy et al. 2001; Steppan et al. 2004; Prasad et al. 2008). The orientation of the clusters is from 5′ (on the left) to 3′ (on the right).
F<sc>IG</sc>. 2.—
FIG. 2.—
Maximum likelihood phylograms depicting relationships among embryonic β-like globin genes of rodents. The phylogeny reconstructions were based on 1 kb of 5′-flanking sequence (left column), coding sequence (center column), and 1 kb of 3′-flanking sequence (right column). Note that the guinea pig HBGps pseudogene is excluded from the analyses because the 3′ portion of the coding region has been deleted. Measures of support for the relevant nodes are presented as bootstrap values (above the nodes) and as Bayesian posterior probabilities (below the nodes).
F<sc>IG</sc>. 3.—
FIG. 3.—
Maximum likelihood phylograms depicting relationships among HBB genes of rodents. The phylogeny reconstructions were based on 1 kb of 5′-flanking sequence (left column), coding sequence (center column), and 1 kb of 3′-flanking sequence (right column). Measures of support for the relevant nodes are presented as bootstrap values (above the nodes) and as Bayesian posterior probabilities (below the nodes).
F<sc>IG</sc>. 4.—
FIG. 4.—
Orthologous relationships among β-like globin genes of rodents, rabbit, and human, as inferred from comparative analyses of 5′- and 3′-flanking sequences. Solid boxes denote putatively functional genes, open boxes denote pseudogenes, and crosses denote gene deletions. Vertical lines are used to indicate 1:1 orthologous relationships.
F<sc>IG</sc>. 5.—
FIG. 5.—
Dot plots of sequence similarity between the HBD and HBB genes of rabbit,Oryctolagus (horizontal axis) and their presumptive orthologs inMus (A, vertical axis) andRattus (B, vertical axis). The pairwise comparisons were based on a chromosomal region that contained the HBB-T1 genes and HBD-like pseudogenes of both rodent species.
F<sc>IG</sc>. 6.—
FIG. 6.—
Dot plot of a chromosomal fragment spanning the β-globin gene cluster on Chromosome 7 of house mouse (Mus musculus, strain C57BL/6) and the syntenic region on Chromosome 1 of rat (Rattus norvegicus), with masked repeats. The polygon with magenta outline encloses a locally alignable chromosomal region that provides evidence for a 1:1 orthologous relationship between HBDps ofRattus and HBD(β/δ)-T2ps ofMus. Specifically, the pattern of pairwise sequence matches suggests that HBDps ofRattus is a 1:1 ortholog of the ancestral HBD-T2 gene ofMus, the 5′ end of which was later overwritten by a short conversion tract derived from HBB-T1 sometime after the divergence betweenRattus andMus.
F<sc>IG</sc>. 7.—
FIG. 7.—
Alternative models for the evolution of the mouse β-globin gene cluster. Three alternative pathways are illustrated for the derivation of theMus musculus (BALB/c) β-globin gene cluster from the ancestral gene arrangement in the stem lineage of rodents (see text for details). (A) The HH84 model outlined by Hardies et al. (1984) and Hill et al. (1984); (B) The HM93 model outlined by Hardison and Miller (1993); and (C) Our proposed model based on inferences drawn from a comparative genomic analysis of the β-globin gene cluster in multiple rodent taxa. Note that the HM93 model did not specify whether the creation of the HBD(β/δ)-T2ps fusion gene was attributable to interparalog gene conversion or unequal crossing-over, although the fusion event is depicted as a result of HBB → HBDps gene conversion (panelB, step 6).
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