Y genetic variation and phenotypic diversity in health and disease

Laure K Case, Cory Teuscher

Sexually dimorphic traits arise through the combined effects of sex hormones and sex chromosomes on sex-biased gene expression, and experimental mouse models have been instrumental in determining their relative contribution in modulating sex differences. A role for the Y chromosome (ChrY) in mediating sex differences outside of development and reproduction has historically been overlooked due to its unusual genetic composition and the predominant testes-specific expression of ChrY-encoded genes. However, ample evidence now exists supporting ChrY as a mediator of other physiological traits in males, and genetic variation in ChrY has been linked to several diseases, including heart disease, cancer, and autoimmune diseases in experimental animal models, as well as humans. The genetic and molecular mechanisms by which ChrY modulates phenotypic variation in males remain unknown but may be a function of copy number variation between homologous X-Y multicopy genes driving differential gene expression. Here, we review the literature identifying an association between ChrY polymorphism and phenotypic variation and present the current evidence depicting the mammalian ChrY as a member of the regulatory genome in males and as a factor influencing paternal parent-of-origin effects in female offspring.