Sex-Differential Selection and the Evolution of X Inactivation Strategies

Abstract

X inactivation—the transcriptional silencing of one X chromosome copy per female somatic cell—is universal among therian mammals, yet the choice of which X to silence exhibits considerable variation among species. X inactivation strategies can range from strict paternally inherited X inactivation (PXI), which renders females haploid for all maternally inherited alleles, to unbiased random X inactivation (RXI), which equalizes expression of maternally and paternally inherited alleles in each female tissue. However, the underlying evolutionary processes that might account for this observed diversity of X inactivation strategies remain unclear. We present a theoretical population genetic analysis of X inactivation evolution and specifically consider how conditions of dominance, linkage, recombination, and sex-differential selection each influence evolutionary trajectories of X inactivation. The results indicate that a single, critical interaction between allelic dominance and sex-differential selection can select for a broad and continuous range of X inactivation strategies, including unequal rates of inactivation between maternally and paternally inherited X chromosomes. RXI is favored over complete PXI as long as alleles deleterious to female fitness are sufficiently recessive, and the criteria for RXI evolution is considerably more restrictive when fitness variation is sexually antagonistic (i.e., alleles deleterious to females are beneficial to males) relative to variation that is deleterious to both sexes. Evolutionary transitions from PXI to RXI also generally increase mean relative female fitness at the expense of decreased male fitness. These results provide a theoretical framework for predicting and interpreting the evolution of chromosome-wide expression of X-linked genes and lead to several useful predictions that could motivate future studies of allele-specific gene expression variation.

Plastin 3 in health and disease: a matter of balance

“…However, several studies have reported variants that lead to severe skeletal abnormalities among women, resembling the osteoporotic phenotype of men [108,115,[128][129][130]. This huge variation in heterozygous women is suggested to be caused by X-inactivation of the mutant allele or PLS3 escaping X-inactivation which is why women are less severely affected [15,126,129,131,132]. Even though bone morphometry was very heterogeneous [16,126,[133][134][135][136], most male patients showed peripheral fractures, low BMD, VCFs, especially in the thoracic spine, and low bone turnover rate, while only a few developed extraskeletal OI traits [108, 126-128, 131, 137-140], developmental delay [15,127] or neuromuscular abnormalities, like waddling gait [108,126,131,141].…”

X chromosome inactivation and active X upregulation in therian mammals: facts, questions, and hypotheses

“…A recent theoretical population genetic analysis shows that the interaction between allelic dominance and sex-differential selection can generate a broad and continuous range of XCI scenarios, including unequal rates of inactivation between maternal and paternal X chromosomes. rXCI is favored over strict pXCI when alleles deleterious to females are sufficiently recessive (Connallon and Clark, 2013).…”

Evidence for Increased Levels of Positive and Negative Selection on the X Chromosome versus Autosomes in Humans

“…There are currently no experimental data that shed light on the expected h value for X-linked deleterious variants in mammals (Connallon and Clark 2013), although mutation-accumulation experiments for the X chromosome in Drosophila melanogaster are suggestive of dominance coefficient of 0.3 (Mallet et al 2011). Mank et al (2010) suggested h ¼ 0.5 may be a reasonable value to mimic the effects of X inactivation in therian mammals.…”