Comparison of the beta-like globin gene families of rabbits and humans indicates that the gene cluster 5'-epsilon-gamma-delta-beta-3' predates the mammalian radiation.

Abstract

The members of the rabbit and human P-like globin gene families have been compared both by a computer-generated dot matrix graphical analysis of each entire gene and by calculating divergences in the coding regions. The rabbit-human gene pairs P~-E, p3-y, vp2-6, and p 1 -p were identified as orthologous on the basis of sequence similarities found in flanking and intervening sequences as well as by quantitative divergence calculations. The orthologous genes are in the same order on the chromosome in each species, which suggests that an ancestral family with the arrangement S-a-y-6-p-3 preceded the mammalian radiation. Descendants of ancestral E have diverged more slowly than other P-like genes and are expressed only in embryonic life. Descendants of ancestral y and p diverged at a higher rate and are expressed at wider range of developmental times. Descendants of 6 have undergone nonreciprocal recombination at a high frequency and are often pseudogenes. Paralogous comparisons among the rabbit P-like globin genes show that the p4-p3 and w/32-p1 pairs are most similar and that p4 and p3 are more closely related to pl than to wp2. This fits with a branching pattern where the primordial p split into a ncestral a/y and 6/p genes, which later split into a and y or 6 and p, respectively. Rabbit genes p4 and p 1 acquired similar 3' untranslated regions after the E/Y split but prior to the mammalian radiation, presumably via a gene conversion event. The 5' end of j32 apparently converted with pl after the radiation, and afterward it became a pseudogene.

Repeated Evolution of Chimeric Fusion Genes in the β-Globin Gene Family of Laurasiatherian Mammals

“…In contrast, functionally intact copies of the reciprocal HBD / HBB fusion gene appear to be completely absent. Second, contrary to conventional wisdom that the HBD gene is a vestigial relict that is always either inactivated or expressed at negligible levels (Martin et al 1983; Hardies et al 1984; Hardison 1984; Hardison and Margot 1984; Koop et al 1989; Prychitko et al 2005), we identified a surprisingly large number of laurasiatherian taxa in which the β-type subunits of adult-expressed Hb contain HBD -like primary structures. Taken together, our results confirm that the retention and ascendancy of genes with HBD -like coding sequence require the retention of HBB -like promoter sequence via unequal crossing-over or the secondary acquisition of HBB -like promoter sequence via gene conversion.…”

“…The rationale for conducting phylogenetic analyses on each of these different data partitions is that interparalog gene conversion between tandemly duplicated globin genes is typically restricted to coding sequence, so noncoding flanking sequence typically records the most accurate history of gene duplication and species divergence (Hardison and Gelinas 1986; Hoffmann and Storz 2007; Storz et al 2007, 2008, 2009, 2010, 2012; Hoffmann et al 2008a, 2008b; Opazo et al 2008a, 2008b, 2009; Runck et al 2009, 2010). In the case of mammalian HBD , ectopic recombinational exchanges are typically restricted to the 5′-end of the gene as HBB → HBD conversion events typically overwrite exon 1, intron 1, and exon 2 of the HBD recipient sequence (Hardies et al 1984; Hardison 1984; Hardison and Margot 1984; Prychtiko et al 2005; Hoffmann et al 2008a; Opazo et al 2008b, 2009). Thus, sequence variation in intron 2 and the 3′-flanking region is best suited to the task of assigning orthology, and comparisons of 5′- and 3′-flanking regions can reveal whether chimeric fusion genes were created via unequal crossing-over or gene conversion (Hoffmann et al 2008b; Opazo et al 2009).…”

“…Interspecific variation in the size and membership composition of the β-globin gene family is attributable to lineage-specific gene gains via duplication and lineage-specific gene losses via deletion or inactivation (Hoffmann et al 2008b; Opazo et al 2008a, 2008b; Storz et al 2011, 2013; Hardison 2012). The HBD and HBB paralogs represent the products of a tandem gene duplication that occurred in the stem lineage of placental mammals (Goodman et al 1984; Hardison 1984; Opazo et al 2008a, 2008b; Hoffmann et al 2010). In humans and other mammals that have been investigated to date, HBB is typically expressed at a much higher level than HBD because it is under the transcriptional control of a stronger basal promoter (Poncz et al 1983; Antoniou and Grosveld 1990; Hardison 2001).…”

“…1), and these exchanges appear to be highly asymmetric, as the coding region of HBD has been converted by the downstream HBB gene in multiple lineages, particularly in the 5′-coding region (Jeffreys et al 1982; Martin et al 1983; Goodman et al 1984; Hardies et al 1984; Hardison 1984; Hardison and Margot 1984; Koop et al 1989; Tagle et al 1991; Prychitko et al 2005; Hoffmann et al 2008a; Opazo et al 2008a). However, these events typically result in HBD coding sequence that is fused to HBB -like upstream sequence that does not extend to the HBB CCAAT promoter element (Hardies et al 1984; Koop et al 1989), so that expression levels of the resultant fusion gene are not altered.…”

Revealing Mammalian Evolutionary Relationships by Comparative Analysis of Gene Clusters

“…However, many approaches to defining orthology also use genomic context as a guide (reviewed in Dewey 2011). Some of the earliest work on assigning orthology in gene clusters used alignments in flanking DNA sequences as a guide, specifically to avoid confusion introduced by gene conversion events (Hardison 1984; Hardies et al 1984; Hardison and Gelinas 1986; Hardison and Miller 1993). These and subsequent studies showed that the aligning flanking sequences also harbor gene regulatory modules, such as distal enhancers.…”