Research Article: Extraordinary Molecular Evolution in the PRDM9 Fertility Gene

Date Published: December 30, 2009

Publisher: Public Library of Science

Author(s): James H. Thomas, Ryan O. Emerson, Jay Shendure, Pawel Michalak.

Abstract: Recent work indicates that allelic incompatibility in the mouse PRDM9 (Meisetz) gene can cause hybrid male sterility, contributing to genetic isolation and potentially speciation. The only phenotype of mouse PRDM9 knockouts is a meiosis I block that causes sterility in both sexes. The PRDM9 gene encodes a protein with histone H3(K4) trimethyltransferase activity, a KRAB domain, and a DNA-binding domain consisting of multiple tandem C2H2 zinc finger (ZF) domains. We have analyzed human coding polymorphism and interspecies evolutionary changes in the PRDM9 gene. The ZF domains of PRDM9 are evolving very rapidly, with compelling evidence of positive selection in primates. Positively selected amino acids are predominantly those known to make nucleotide specific contacts in C2H2 zinc fingers. These results suggest that PRDM9 is subject to recurrent selection to change DNA-binding specificity. The human PRDM9 protein is highly polymorphic in its ZF domains and nearly all polymorphisms affect the same nucleotide contact residues that are subject to positive selection. ZF domain nucleotide sequences are strongly homogenized within species, indicating that interfinger recombination contributes to their evolution. PRDM9 has previously been assumed to be a transcription factor required to induce meiosis specific genes, a role that is inconsistent with its molecular evolution. We suggest instead that PRDM9 is involved in some aspect of centromere segregation conflict and that rapidly evolving centromeric DNA drives changes in PRDM9 DNA-binding domains.

Partial Text: Allelic incompatibility at the mouse PRDM9 (Meisetz) locus can cause hybrid male sterility due to failure in spermatogenesis [1]. Rare dominant nonsynonymous mutations in human PRDM9 may also cause failure in spermatogenesis (azoospermia, [2]), suggesting similar allelic incompatibility in humans. These data support a role for PRDM9 in an early stage of pre-zygotic hybrid incompatibility, consistent with a role in speciation [1], [3]. Targeted PRDM9 knockout in the mouse causes sterility in both sexes due to a block in meiosis I in both the male and female germ line [4]. The germ line arrest morphology resulting from PRDM9 knockout and from incompatible PRDM9 alleles are identical, suggesting that the incompatible alleles abrogate PRDM9 function [1], [4].

In summary, PRDM9 sequences across mammals show rapid divergence specific to the DNA-binding turn-helix region of their ZF domains and there is an exceptionally high level of nonsynonymous human polymorphism in the same classes of sites. What could account for these patterns? All other domains in PRDM9 are conserved among species, suggesting that a conserved biochemical function is tethered to a rapidly evolving DNA-binding specificity. The expected histone modification activities of PRDM9 (histone deacetylation and histone H3(K4) trimethylation) suggest a role in transcriptional regulation. However transcription factors are generally characterized by highly conserved DNA-binding domains, yet these are the regions where PRDM9 is most rapidly evolving. In contrast to transcriptional regulation, centromere structure and function is associated both with regulated histone modification states [16], [17] and with rapidly evolving DNA sequences [18], [19], [20]. A favored model for the rapid evolution of centromere sequence is the centromere-drive hypothesis, in which selfish centromeres compete to segregate to the oocyte during female meiosis [19], [21]. Centromere drive is potentially deleterious to the host by causing skewed sex ratios or male sterility, effects that may be balanced by observed rapid evolution in genes encoding centromere associated proteins [22].



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