Nucleotide Sequence Analysis of the Lemur P-Globin Gene Family: Evidence for Major Rate Fluctuations in Globin Polypeptide Evolution’

Lemur P-related globin genes have been isolated and sequenced. Orthology of pro-simian and human E-, y-, and P-related globin genes was established by dot-matrix analysis. All of these lemur globin genes potentially encode functional P-related globin polypeptides, though precisely when the y-globin gene is expressed remains unknown. The organization of the 18-kb brown lemur P-globin gene cluster (5' a-r-[m-s]-P 3') is consistent with its evolution by contraction via unequal crossing-over from the putative ancestral mammalian P_globin gene cluster (5' a-y-t@-p 3'). The dwarf lemur nonadult globin genes are arranged as in the brown lemur. Similar levels of synonymous (silent) nucleotide substitutions and noncoding DNA sequence differences have accumulated between species in all of these genes, suggesting a uniform rate of noncoding DNA divergence throughout primate P-globin gene clusters. These differences are comparable with those observed in the nonfunctional vq pseudogene and have therefore accumulated at the presumably maximal neutral rate. In contrast, nonsynonymous (replacement) nucleotide substitutions show a significant heterogeneity in distribution for both the same gene in different lineages and different genes in the same lineage. These major fluctuations in replacement but not silent substitution rates cannot be attributed to changes in mutation rate, suggesting that changes in the rate of globin polypeptide evolution in primates is not governed solely by variable mutation rates. Introduction The regulated expression of the vertebrate a.-and P-globin gene clusters results in the synthesis of several different forms of hemoglobin at different stages of development. The P-globin gene cluster has been well characterized in a number of species from different mammalian orders (for review, see Collins and Weissman 1984). Primates have been studied in the greatest detail, to reveal the possible evolutionary events that led to contemporary cluster organizations in this lineage (Efstratiadis et 1. similar cluster arrangement is found in the great apes and old-world monkeys, whose common ancestor occurred 20-40 Myr ago (Banie et al. 198 1). In contrast, the owl monkey (Lotus trivirgatus, a new-world monkey) and several lemurs (prosimians) all have shorter P-globin gene clusters (Barrie et al. 198 1). The owl monkey P-globin gene cluster is arranged 5' ~-y-vq-&p 3' (Harris et al. 1984), and the brown lemur cluster contains single a-, 'y-, and P-related globin genes plus a hybrid vq-8~globin pseudogene (Barrie et al. 198 1; Jeffi-eys et al. 1982; Harris et al. 1984). The ancestral primate P-globin gene cluster was probably arranged 5' a+~~-8-p 3', as still …