Evolutionary and biomedical implications of sex differences in the primate brain transcriptome

Abstract

Humans exhibit sex differences in the prevalence of many neurodevelopmental and neurodegenerative conditions. To better understand the translatability of a critical nonhuman primate model, the rhesus macaque, we generated one of the largest multi-brain region bulk transcriptional datasets for this species and characterized sex-biased gene expression patterns. We demonstrate that these patterns are similar to those in humans and are associated with overlapping regulatory mechanisms, biological processes, and genes implicated in sex-biased human disorders, including autism. We also show that sex-biased genes exhibit greater genetic variance for expression and more tissue-specific expression patterns, which may facilitate the rapid evolution of sex-biased genes. Our findings provide insights into the biological mechanisms underlying sex-biased disease and validate the rhesus macaque model for the study of these conditions.

The biology of aging in a social world: insights from free-ranging rhesus macaques

“…By contrast, after Hurricane Maria, broad connections to the wider social group were more important than investing in existing key relationships such as with kin (Testard et al, 2021). Social status did not predict gross brain structure (Testard et al, 2022) but did predict brain gene expression profiles (Chiou, Decasien et al, 2022). These examples from the Cayo Santiago population demonstrate that, depending on the context, needs, and biological system, certain dimensions of sociality might be more important than others in predicting biological variation and survival.…”

“…Further, in the blood, transcriptomic signatures of chronic social stress in rhesus macaques are shared with signatures of advancing age in humans (Snyder-Mackler et al, 2014). Previous studies of the Cayo Santiago rhesus macaques have also illustrated that social status and age show overlapping transcriptional variance in the brain and immune cell composition in the blood (Chiou, Decasien et al, 2022; Rosado et al, 2021). However, the extent to which social adversity recapitulates age more broadly, across molecular mechanisms, types of adversity, and different organs, is still unknown.…”

“…Although biological sex has historically been ignored in many animal model studies (with a bias towards male-only study designs), the inclusion of both males and females in research is now a priority for many funding agencies (e.g., NIH policy on SABV). Given that the Cayo Santiago population includes approximately equal numbers of males and females, and recent work confirms that rhesus macaques and humans exhibit similar sex differences in the brain transcriptome (Decasien, Chiou et al, 2022), this creates a unique opportunity to consider the potential impacts of biological sex on our variables of interest.…”

“…In the Cayo Santiago study system, cross-sectional sampling of tissues from rhesus macaques removed as part of population management circumvents these limitations. Recent work profiling the transcriptomes of 15 brain regions acquired from healthy adult Cayo Santiago rhesus macaques revealed numerous brain-region specific and multi-region signatures of age (Chiou, Decasien et al, 2022). Many of these multi-region (i.e., “whole-brain”) age-associated genes were also identified in humans as markers of a diseased state in Alzheimer’s disease.…”

“…Notably, brain structure varied specifically with the number of affiliative social connections, but not other key dimensions of sociality such as social status or position in the social network, as was also the case for certain immune markers (Pavez-Fox et al, 2021). Although an effect of social status could not be detected at a gross neuroanatomical level (Testard et al, 2022), patterns of gene expression in the brain varied with social status and age in a parallel fashion (Chiou, Decasien et al, 2022). Specifically, high-ranking females exhibited younger transcriptomic ages across the brain.…”