Rhesus macaque as a model for sex-biased neurological diseases
Authors: Leticia Rodríguez-Montes, Henrik Kaessmann
Journal: Cell Genomics (2024)

Sexual dimorphism, differences between males and females of the same species, is widespread in mammals. However, good animal models to study human sexually dimorphic phenotypes are currently lacking. In this issue, DeCasien et al.1DeCasien A.R. Chiou K.L. Testard C. Mercer A. Negrón-Del Valle J.E. Bauman Surratt S.E. González O. Stock M.K. Ruiz-Lambides A.V. Martinez M.I. et al.Evolutionary and biomedical implications of sex differences in the primate brain transcriptome.Cell Genomics. 2022; 4100589Google Scholar explore the potential of rhesus macaque as a model for investigating sexually dimorphic traits in the human brain. Sexual dimorphism, differences between males and females of the same species, is widespread in mammals. However, good animal models to study human sexually dimorphic phenotypes are currently lacking. In this issue, DeCasien et al.1DeCasien A.R. Chiou K.L. Testard C. Mercer A. Negrón-Del Valle J.E. Bauman Surratt S.E. González O. Stock M.K. Ruiz-Lambides A.V. Martinez M.I. et al.Evolutionary and biomedical implications of sex differences in the primate brain transcriptome.Cell Genomics. 2022; 4100589Google Scholar explore the potential of rhesus macaque as a model for investigating sexually dimorphic traits in the human brain. In many mammals, males and females look phenotypically different. This phenomenon is known as sexual dimorphism and includes differences in morphology, physiology, and behavior between individuals from each of the sexes. Some sexually dimorphic traits are evident to the naked eye, like the existence of antlers in male deer. Others are not visible, but equally important, such as differences in immune response. Sexual dimorphism does not only manifest in homeostatic conditions but also in disease. In humans, sex differences in the prevalence, progression, and severity of different neurological conditions have been described. For example, depression2Eid R.S. Gobinath A.R. Galea L.A.M. Sex differences in depression: Insights from clinical and preclinical studies.Prog. Neurobiol. 2019; 176: 86-102https://doi.org/10.1016/j.pneurobio.2019.01.006Crossref PubMed Scopus (235) Google Scholar or Alzheimer's disease3Hebert L.E. Weuve J. Scherr P.A. Evans D.A. Alzheimer disease in the United States (2010–2050) estimated using the 2010 census.Neurology. 2013; 80: 1778-1783https://doi.org/10.1212/WNL.0b013e31828726f5Crossref PubMed Scopus (1988) Google Scholar are more common in females, whereas attention deficit hyperactivity disorder4Bálint S. Czobor P. Komlósi S. Mészáros A. Simon V. Bitter I. Attention deficit hyperactivity disorder (ADHD): gender- and age-related differences in neurocognition.Psychol. Med. 2009; 39: 1337-1345https://doi.org/10.1017/S0033291708004236Crossref PubMed Scopus (113) Google Scholar or autism spectrum disorders5Ferri S.L. Abel T. Brodkin E.S. Sex Differences in Autism Spectrum Disorder: a Review.Curr. Psychiatry Rep. 2018; 20: 9https://doi.org/10.1007/s11920-018-0874-2Crossref PubMed Scopus (205) Google Scholar show a higher prevalence in males. Moreover, our scientific knowledge on sex differences has been historically scarce. In the past, preclinical research mostly used male animals for experimentation, and clinical trials predominantly included male participants.6Labots G. Jones A. de Visser S.J. Rissmann R. Burggraaf J. Gender differences in clinical registration trials: is there a real problem?.Br. J. Clin. Pharmacol. 2018; 84: 700-707https://doi.org/10.1111/bcp.13497Crossref PubMed Scopus (62) Google Scholar This was based on the assumption that findings would apply equally to both sexes and that adjusting treatments based on differences in male and female sizes would be enough to treat both men and women. However, it is now clear that many diseases show differences between the sexes, and certain medical treatments have effects specific to one sex.7Klein S.L. Flanagan K.L. Sex differences in immune responses.Nat. Rev. Immunol. 2016; 16: 626-638https://doi.org/10.1038/nri.2016.90Crossref PubMed Scopus (3367) Google Scholar Previous studies have highlighted the fast turnover of sex differences across species, specifically in terms of sex-related transcriptomic differences.8Naqvi S. Godfrey A.K. Hughes J.F. Goodheart M.L. Mitchell R.N. Page D.C. Conservation, acquisition, and functional impact of sex-biased gene expression in mammals.Science. 2019; 365: eaaw7317https://doi.org/10.1126/science.aaw7317Crossref PubMed Scopus (122) Google Scholar,9Rodríguez-Montes L. Ovchinnikova S. Yuan X. Studer T. Sarropoulos I. Anders S. Kaessmann H. Cardoso-Moreira M. Sex-biased gene expression across mammalian organ development and evolution.Science. 2023; 382eadf1046https://doi.org/10.1126/science.adf1046Crossref PubMed Scopus (8) Google Scholar This poses a challenge when investigating human sexual dimorphism in typical non-human model organisms (like the mouse, which last shared a common ancestor with humans ∼90 million years ago), as most gene expression sex differences are species specific. In this issue of Cell Genomics, DeCasien et al.1DeCasien A.R. Chiou K.L. Testard C. Mercer A. Negrón-Del Valle J.E. Bauman Surratt S.E. González O. Stock M.K. Ruiz-Lambides A.V. Martinez M.I. et al.Evolutionary and biomedical implications of sex differences in the primate brain transcriptome.Cell Genomics. 2022; 4100589Google Scholar explore the suitability of using a closer evolutionary relative of humans, the rhesus macaque (an Old World monkey that diverged ∼30 million years ago from the lineage leading to humans), as an animal model to study sexually dimorphic phenotypes in the human brain by comparing sex-related differences in gene expression across various brain regions between these two species. To quantify sexual dimorphism, it is common to use sex-biased genes as a proxy. These are genes with expression levels that differ between males and females or genes exclusively expressed in one of the sexes. In their study, DeCasien et al. quantify sex-biased gene expression in different regions of the macaque brain and compare it to sex-biased expression in the human brain. The authors collected an extensive gene expression dataset, which included 527 samples representing 15 brain regions from 36 adult macaques (20 females, 16 males). In agreement with previous studies,8Naqvi S. Godfrey A.K. Hughes J.F. Goodheart M.L. Mitchell R.N. Page D.C. Conservation, acquisition, and functional impact of sex-biased gene expression in mammals.Science. 2019; 365: eaaw7317https://doi.org/10.1126/science.aaw7317Crossref PubMed Scopus (122) Google Scholar,9Rodríguez-Montes L. Ovchinnikova S. Yuan X. Studer T. Sarropoulos I. Anders S. Kaessmann H. Cardoso-Moreira M. Sex-biased gene expression across mammalian organ development and evolution.Science. 2023; 382eadf1046https://doi.org/10.1126/science.adf1046Crossref PubMed Scopus (8) Google Scholar they found an overall rapid turnover of sex-biased gene expression, but also that part of the sex differences in gene expression observed in macaque resemble those found in humans (Figure 1). The latter observation is consistent with the macaque being one of our closer evolutionary relatives and a more relevant model for studying human-specific traits than other more evolutionarily distant animal models like the mouse. The authors also identified conserved regulatory mechanisms responsible for these transcriptomic differences in both species, mostly mediated by sex hormones, like estrogens. Sex differences in gene expression at the bulk tissue level could reflect differential expression of genes in the same cell types between the sexes, differences in the cell type proportions between males and females, and/or genes being expressed in different cell types between the sexes. DeCasien et al. use deconvolution methods to show that considering differences in cell composition between the sexes influences the results of their analysis. For example, the enrichment for microglial markers in female-biased genes potentially reflects differences in the abundance of microglial cells in certain brain regions between males and females.10Schwarz J.M. Sholar P.W. Bilbo S.D. Sex differences in microglial colonization of the developing rat brain.J. Neurochem. 2012; 120: 948-963https://doi.org/10.1111/j.1471-4159.2011.07630.xCrossref PubMed Scopus (486) Google Scholar These observations reinforce the need to combine large transcriptomic datasets with expression data at single-cell resolution in future studies to address transcriptomic sex differences. Only then will it be possible to distinguish between the different scenarios that give rise to sex-biased gene expression. The sex-biased genes identified by DeCasien et al. tend to be tissue specific and exhibit greater genetic variance, two characteristics that could be involved in the rapid turnover of sex-biased expression across species. Most importantly, the authors also report that sex-biased genes are involved in similar processes in both human and macaque and are related to some of the same diseases known to have sex-biased prevalence, particularly in autism spectrum disorders. Given the early onset of this condition, typically diagnosed at around 2–5 years of age in humans, it will be key to extend this comparative study to individuals from earlier developmental stages. This would allow for a more comprehensive assessment of whether macaque is a suitable model for studying sex differences in the development of autism spectrum disorders in humans. Collectively, the results presented by DeCasien et al. offer valuable insights into the biological processes driving sex-biased gene expression and disease and suggest that macaque is a promising model for studying sex differences in human neurological diseases. This work was supported by a fellowship from Joachim Herz Stiftung to L.R.-M. and a Sinergia grant (CRSII5_189970) and European Research Council grant (615253, OntoTransEvol) to H.K. The authors declare no competing interests. Evolutionary and biomedical implications of sex differences in the primate brain transcriptomeDeCasien et al.Cell GenomicsJune 27, 2024In BriefDeCasien, Chiou, and colleagues demonstrate that human and rhesus macaque brains exhibit similar sex differences in gene expression and that these shared patterns overlap with genetic risk for a sex-biased condition (autism). These findings suggest that this model species may be appropriate for studying sex-biased human brain conditions. Full-Text PDF Open Access