NK cell receptor repertoires evolve under increased constraint butare not more diverse in menstruating mammals

Abstract

The immune system plays key roles in the mammalian uterine cycle, particularly for menstruation, a dramatic tissue renewal mechanism independently acquired four times in eutherians. These roles specifically involve NK cells through the expression of surface killer cell immunoglobulin-like receptors (KIRs) and killer cell lectin-like receptors (KLRs), respectively part of the immunoglobulin-like and lectin-like gene superfamilies with poorly resolved phylogenetic histories. Acquisition of menstruation in primates seemingly coincides with a large expansion of the KIR family, suggesting that gains and losses in NK cell receptor families may have been crucial for the evolution of menstruation. To test this hypothesis, we performed an in-depth analysis of the evolutionary histories of the KIR and KLR gene families across 41 mammalian genomes, including all four clades that acquired menstruation. Our results reveal the existence of undescribed KIR and KLR genes across many mammalian species, including elephants, armadillos, rhinoceroses, and leaf-nosed bats, as well as a novel subfamily within the KLR phylogeny. Altogether, we identify more than twice as many NK cell receptor genes across mammals than currently reported in reference genomes. Further, we show that the KIR gene family has experienced intensified purifying selection in menstruating species compared to non-menstruating species, suggesting specific evolutionary pressures related to menstruation. Our data, however, do not support that menstruation coincides with expansions or contractions in NK cell receptor repertoires, except in primates, highlighting both shared and lineage-specific immune adaptations to rapidly evolving reproductive biology. Significance statementThe evolutionary history of the uterus in mammals is complex, with many traits acquired convergently. One of these traits is menstruation. There has, historically, been a dearth of research to better understand this physiological mechanism within an evolutionary context. Here, we tested whether two families of natural killer cell receptors, known to be implicated in successful human and murine pregnancies, have evolved in concert with acquisitions of menstruation in mammals. Our findings indicate that the immune system likely does not play the same role in catarrhine menstruation as in menstruation in other clades, such as bats and rodents. We also reconstructed the history of this trait and performed a thorough inventory of these receptor gene families across a wide range of mammals, including the identification of unreported expansions. This study places menstruation within an evolutionary context and provides a foundation to better understand the interactions between the mammalian immune system and uterus.