Sex-biased genes in the primate brain are associated with human neurological disorders and facilitate rapid molecular evolution

Humans exhibit sex differences in the prevalence and presentation of many psychiatric and neurodevelopmental conditions, including Alzheimer’s disease, autism spectrum disorder (ASD), and schizophrenia; however, the ‘omic’, developmental, and environmental underpinnings of these conditions remain elusive. To illuminate these mechanisms and their interactions, and to identify potential therapies, we need large, sex-specific neurobiological data sets from model organisms whose brains exhibit similar characteristics to those of humans, including comparable sex differences. Among existing models, the rhesus macaque is likely to have the greatest translatability; however, comprehensive analyses of brain sex differences in this species are necessary to demonstrate their relevance to sex-biased human conditions. We present an in-depth investigation of sex differences in the rhesus macaque brain transcriptome (RNA-seq) across 527 samples of 15 regions from 36 free-ranging adult individuals (20F/16M), representing the largest collection of bulk brain gene expression data for this species. We identified hundreds of sex-biased genes throughout the rhesus macaque brain, most of which were shared across regions, suggesting convergent regulatory mechanisms. Similar to studies of human brains, these sex-biased genes are regulated by sex hormones and transcription factors that interact with these hormones, male-biased genes are associated with multiple sex-biased human neurological conditions (e.g., ASD, schizophrenia) and energy metabolism, and female-biased genes are associated with the immune response. We also accurately predicted sex from a relatively small number of genes per region and found that, among genes reported to escape X chromosome inactivation in humans, similar genes are the most predictive of sex both across human tissues and in this dataset. Finally, we demonstrated that sex-biased genes exhibit characteristics that facilitate rapid evolution, including a tendency to be located on the sex chromosomes, more tissue-specific expression, and higher genetic variance for expression. Overall, these findings suggest that the rhesus macaque may be an appropriate model for sex-biased human neurological conditions. 527 bulk tissue transcriptomes derived from a free-ranging population of rhesus macaques. The datataset includes 15 distinct brain regions sampled from 36 males and females spanning the natural adult rhesus macaque age distribution. Please note that the current study represents re-analysis of GSE179328 raw data as following data processing steps: Gene expression counts were quantified from RNA-seq reads using the pseudoalignment method implemented in kallisto. Given that sequence homology across the sex chromosomes present in reference genomes/transcriptome (Mmul_10) can lead to technical mapping errors, we created two modified, sex-specific transcriptomes and separately mapped reads from males and females. Specifically, the Y chromosome was removed from the female-specific transcriptome, and CD99 on the Y chromosome (within the pseudoautosomal region; Hughes et al. 2012 [PMID: 22367542]) was removed from the male-specific transcriptome. Estimated counts and transcripts-per-million (TPM) values were then imported into R v4.0.2 and summarized to genes using the tximport package. and thus the complete raw data can be accesssed from GSE179328 records.