Abstract
We asked if essentiality for either fertility or viability differentially affects sequence evolution of human testis proteins. Based on murine knockout data, we classified a set of 965 proteins expressed in human seminiferous tubules into three categories: proteins essential for prepubertal survival (“lethality proteins”), associated with male sub- or infertility (“male sub-/infertility proteins”), and nonessential proteins. In our testis protein dataset, lethality genes evolved significantly slower than nonessential and male sub-/infertility genes, which is in line with other authors’ findings. Using tissue specificity, connectivity in the protein-protein interaction (PPI) network, and multifunctionality as proxies for evolutionary constraints, we found that of the three categories, proteins linked to male sub- or infertility are least constrained. Lethality proteins, on the other hand, are characterized by broad expression, many PPI partners, and high multifunctionality, all of which points to strong evolutionary constraints. We conclude that compared with lethality proteins, those linked to male sub- or infertility are nonetheless indispensable, but evolve under more relaxed constraints. Finally, adaptive evolution in response to postmating sexual selection could further accelerate evolutionary rates of male sub- or infertility proteins expressed in human testis. These findings may become useful for in silico detection of human sub-/infertility genes.
Highlights
Genes associated with male sub- or infertility had significantly higher dS estimate contrasts nonsynonymous (dN) than lethality genes, while the difference regarding dS was nonsignificant; this result corresponds to the findings reported by Torgerson et al.[8]
It became evident that proteins associated with male sub- or infertility and those potentially related to the risk of prepubertal death display different patterns regarding their evolutionary conservation, network connectivity, multifunctionality, and tissue-specificity
While proteins linked to prepubertal death were strongly conserved, more widely expressed, highly connected and multifunctional, the category associated with male sub- or infertility evolved more rapidly, had strongly tissue-biased expression, and exhibited low connectivity and relatively reduced numbers of biological processes
Summary
We hypothesized that lethality proteins evolve under stronger purifying selection due to their functional importance and increased evolutionary constraints. Relaxation of constraints as well as sexual selection might accelerate sequence evolution of more specialized[8], but important sub-/infertility proteins. Numbers of PPI partners, expression breadth, and multifunctionality are known to correlate with pleiotropy[22,23] and have been previously used to quantify levels of pleiotropy (see, e.g., refs 24 and 25). Before comparing the three protein categories – lethality, sub-/infertility, and nonessential proteins – regarding their evolutionary rates and constraints, we evaluated the interrelations among dN/dS, node degree, multifunctionality, and tissue specificity within our human testis dataset employing rank correlations. We were able to examine the interdependencies among essentiality, evolutionary constraints, and rates of sequence evolution in a set of human testis proteins
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