The evolution of sex differences in disease

It is now becoming widely recognized that there are important sex differences in disease. These include rates of disease incidence, symptoms and age of onset. These differences between the sexes can be seen as a subset of the more general phenomenon of sexual dimorphism of quantitative phenotypes. From a genetic point of view, this is paradoxical, since the vast majority of genetic material is shared between the sexes. How can males and females differ in so many ways and yet have a common genetic code? Traditionally, the modifying action of hormones has been offered as a solution to this paradox, but experiments disentangling the effects of hormones and sex-chromosomes have shown that this cannot be the sole explanation. In this review, I outline current ideas about the evolutionary origins of sex differences in phenotypes, with a particular focus on how sex differences in disease can arise. I also discuss how sex differences in themselves can generate new risk factors for disease, in effect becoming a new environmental factor, as well as briefly reviewing more general evidence for sexually antagonistic selection and genetic variation within humans. Taking an evolutionary view on sex differences in disease provides an opportunity for greater understanding of mechanisms of disease and as such provides a clear motivation for clinicians to explore how therapies may be tailored to the individual in a sex-dependent way.