An Evolutionarily Conserved Sexual Signature in the Primate Brain

Abstract

The question of a potential biological sexual signature in the human brain is a heavily disputed subject. In order to provide further insight into this issue, we used an evolutionary approach to identify genes with sex differences in brain expression level among primates. We reasoned that expression patterns important to uphold key male and female characteristics may be conserved during evolution. We selected cortex for our studies because this specific brain region is responsible for many higher behavioral functions. We compared gene expression profiles in the occipital cortex of male and female humans (Homo sapiens, a great ape) and cynomolgus macaques (Macaca fascicularis, an old world monkey), two catarrhine species that show abundant morphological sexual dimorphism, as well as in common marmosets (Callithrix Jacchus, a new world monkey) which are relatively sexually monomorphic. We identified hundreds of genes with sex-biased expression patterns in humans and macaques, while fewer than ten were differentially expressed between the sexes in marmosets. In primates, a general rule is that many of the morphological and behavioral sexual dimorphisms seen in polygamous species, such as macaques, are typically less pronounced in monogamous species such as the marmosets. Our observations suggest that this correlation may also be reflected in the extent of sex-biased gene expression in the brain. We identified 85 genes with common sex-biased expression, in both human and macaque and 2 genes, X inactivation-specific transcript (XIST) and Heat shock factor binding protein 1 (HSBP1), that were consistently sex-biased in the female direction in human, macaque, and marmoset. These observations imply a conserved signature of sexual gene expression dimorphism in cortex of primates. Further, we found that the coding region of female-biased genes is more evolutionarily constrained compared to the coding region of both male-biased and non sex-biased brain expressed genes. We found genes with conserved sexual gene expression dimorphism in the occipital cortex of humans, cynomolgus macaques, and common marmosets. Genes within sexual expression profiles may underlie important functional differences between the sexes, with possible importance during primate evolution.

Impact of the X Chromosome and sex on regulatory variation

“…Sex-specific patterns of gene expression have been well studied in the literature across many organisms (Yang et al 2006;Ober et al 2008;Reinius et al 2008;Trabzuni et al 2013). However, beyond differences in mean gene expression levels, differences in expression variation may be attributed to interaction effects of genomic variants and both environmental and biological variables, such as sex (Idaghdour and Awadalla 2012).…”

Sex-Biased Gene Expression and Evolution of the X Chromosome in Nematodes

“…Previous studies have indicated that anywhere between 30 and 60% of metazoan genes may be sex biased Parisi et al 2004;Reinke et al 2004;Yang et al 2006;Reinius et al 2008;Small et al 2009;Innocenti and Morrow 2010;Assis et al 2012;Reinius et al 2012;Thomas et al 2012). Genes with sex-biased expression contribute to both somatic and gonadal sexual dimorphisms Parisi et al 2004;Yang et al 2006;Mank et al 2008a;Reinius et al 2008).As the number of X chromosomes differs between males and females, the X plays a large role in the evolution of sexual dimorphisms (Rice 1984;Mank et al 2008a). Due to both sex-specific natural selection and the unique life cycle of the X chromosome, it is predicted that sex-biased genes should accumulate on the X (Rice 1984).…”

Prenatal sex differences in the human brain

“…1 We hypothesized that the basis of this sex bias is already established in the brain before birth. Here, we show that several genes encoded in the Y-chromosome are expressed in many regions of the male prenatal brain, likely having functional consequences for sex bias during human brain development.…”

“…These genes are not only expressed in the brain before birth but some of them are also known to have sex differences in adult brain, 1,4 whereas others are expressed during infancy, but reduced later on during their lifetime. 5 Intriguingly, SRY, a well-known determinant of testicle development during midgestation, 6 showed no evidence of expression in any of the brain regions analyzed (Figure 1b, and Supplementary Figure 1), suggesting that the main somatic sex determinants may be different for the brain and gonads during human gestation.…”

“…1 Stromalderived factor 1-alpha (SDF-1a), the major chemokine for adult stem cells (SCs), is involved in glucose regulation 3 and is abnormal in diabetes. 4 SDF1 is critical in homing, maintenance and mobilization of adult SCs.…”