Rapid evolution and copy number variation of primate RHOXF2, an X-linked homeobox gene involved in male reproduction and possibly brain function

Abstract

<p>Abstract</p> <p>Background</p> <p>Homeobox genes are the key regulators during development, and they are in general highly conserved with only a few reported cases of rapid evolution. <it>RHOXF2 </it>is an X-linked homeobox gene in primates. It is highly expressed in the testicle and may play an important role in spermatogenesis. As male reproductive system is often the target of natural and/or sexual selection during evolution, in this study, we aim to dissect the pattern of molecular evolution of <it>RHOXF2 </it>in primates and its potential functional consequence.</p> <p>Results</p> <p>We studied sequences and copy number variation of <it>RHOXF2 </it>in humans and 16 nonhuman primate species as well as the expression patterns in human, chimpanzee, white-browed gibbon and rhesus macaque. The gene copy number analysis showed that there had been parallel gene duplications/losses in multiple primate lineages. Our evidence suggests that 11 nonhuman primate species have one <it>RHOXF2 </it>copy, and two copies are present in humans and four Old World monkey species, and at least 6 copies in chimpanzees. Further analysis indicated that the gene duplications in primates had likely been mediated by endogenous retrovirus (ERV) sequences flanking the gene regions. In striking contrast to non-human primates, humans appear to have homogenized their two <it>RHOXF2 </it>copies by the ERV-mediated non-allelic recombination mechanism. Coding sequence and phylogenetic analysis suggested multi-lineage strong positive selection on <it>RHOXF2 </it>during primate evolution, especially during the origins of humans and chimpanzees. All the 8 coding region polymorphic sites in human populations are non-synonymous, implying on-going selection. Gene expression analysis demonstrated that besides the preferential expression in the reproductive system, <it>RHOXF2 </it>is also expressed in the brain. The quantitative data suggests expression pattern divergence among primate species.</p> <p>Conclusions</p> <p><it>RHOXF2 </it>is a fast-evolving homeobox gene in primates. The rapid evolution and copy number changes of <it>RHOXF2 </it>had been driven by Darwinian positive selection acting on the male reproductive system and possibly also on the central nervous system, which sheds light on understanding the role of homeobox genes in adaptive evolution.</p