Rapid Evolution of a Homeodomain: Evidence for Positive Selection

Abstract

One often-noted feature of homeobox genes is the conservation of the homeodomain among orthologous genes from distantly related species. This sequence conservation is presumed to reflect functional conservation, which indeed has been demonstrated in several cases. We analyzed the evolution of an orphan homeobox gene, Pem, which is expressed preferentially in male and female reproductive tissue. Sequence analysis of 12 species of mice and rats indicated that the Pem gene has evolved at a remarkably high rate. The most rapidly evolving region of the Pem protein is the amino portion of the homeodomain, including the flexible N-terminal arm, helices I and II, and the linker regions between the helices. In contrast, the third helix, which is known to mediate base-specific DNA contacts in other homeodomains, is conserved in the Pem protein. Analysis of the ratio of nonsynonymous and synonymous codon substitution rates within the Pem homeodomain suggested that its divergence was driven by adaptive selection. The rate of nonsynonymous substitutions in Pem was higher than that of the sex-determination gene Sry, which also appears to have undergone directional selection over a short evolutionary period. Despite the rapid evolution of the Pem gene, we detected no Pem polymorphisms and observed no variation in the homeobox sequence among closely related Mus species. This suggests that purifying episodes followed phases in which selection pressure drove the rapid divergence of this locus. We propose that transcription factors that function in reproductive events can be subject to rapid adaptive selection.

The humanRHOXgene cluster: target genes and functional analysis of gene variants in infertile men

“…These alterations, in turn, can lead to modified binding properties of already existing target genes or enable novel interactions with different cofactors to regulate a new set of targets. The c.202G>A mutation impacts the region upstream of the homeodomain, a region that is known to be a protein-protein interaction domain in other homeobox proteins (19,23). Our finding that the c.202G>A mutation is present with a similar frequency in the control group indicates that this mutation alone is not sufficient to cause severe oligozoospermia.…”

“…3A). This encodes the homeodomain N-terminal region, which is of interest given that this region is involved in protein-protein interactions that modulate homebox transcription factor target gene specificity and transcription rate (19,23). We suggest that mutations in this region might disrupt functional interactions of RHOX proteins with other proteins (such as heterodimeric transcription factor partners) and might even allow RHOX proteins to gain new functional properties.…”

Positive Darwinian selection drives the evolution of several female reproductive proteins in mammals

“…O ne of the striking features that has emerged from the study of reproduction is diversity (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Diversity has been observed in several morphological traits that are involved in reproduction, including sperm (14) and reproductive organ (15) morphology.…”

“…Recently, male-derived molecules involved in reproduction have been shown to be extraordinarily divergent between closely related species (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). These molecules include proteins involved in signaling between males and females (3)(4)(5), fertilization (6)(7)(8)(9)(10)(11), sperm chromosome condensation (1,12), and sex-specific transcription (16,17). However, only the divergence of molecules from males has been shown to be driven by positive selection.…”

“…The ratio of the two rates, d N ͞d S , denoted herein, measures the magnitude and direction of selective pressure on a protein, with ϭ 1, Ͻ1, and Ͼ1 indicating neutral evolution, purifying selection, and positive diversifying selection, respectively. This criterion has been used to demonstrate rapid evolution of male reproductive proteins in a variety of invertebrate and vertebrate species (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Recently, Wyckoff et al (1) used the ratio and other criteria to demonstrate the rapid evolution of male reproductive proteins in primates.…”