Chromosomal differences aside, males and females differ remarkably with regards to the structure of their genomes. For example, analysis of post-mortem human brains show that around 2.5% of all genes are differentially spliced and expressed between males and females [16], suggesting that the regulatory genome differs between sexes. Indeed, a number of studies across model species (e.g., flies, rodents) show mRNA expression level differences that depend on sex (e.g., [17–19]). To put this in perspective, unrelated human males share 99.9% of their genomes while unrelated males and females share only about 98.5% [16] (although this estimate is somewhat controversial). This could mean that the genome of a human male may be more similar to the genome of a male chimpanzee, sharing around 98.8% (e.g., [20, 21]) than between human males’ and females’ genomes. Despite these differences in the shared genome between males and females, sex differences in disease phenotype/genotype relationships are often not directly studied, even though there are many examples of diseases that differ in prevalence by sex.
