The role of sex-chromosome genes in health and disease

Sex-chromosome aneuploidies are the most common chromosome abnormalities, and include Turner (single X chromosome; XO), Klinefelter (XXY) and Jacob (XYY) syndrome. Humans with these conditions are generally infertile. In the lab we research how sex chromosome aneuploidies contribute to infertility, using in vivo and in vitro models of these syndromes.

We discovered that during reprogramming of fibroblasts from mouse models of Jacob or Klinefelter syndrome the extra sex chromosome was lost. The resulting diploid induced pluripotent stem cells could be used to produce healthy and fertile offspring. This approach represented the first therapy to overcome infertility in sex chromosome trisomic models.

We are also interested in X-chromosome inactivation and X-chromosome upregulation, which together ensure X-chromosome dosage compensation in male and female cells. We showed that in mouse and human, X-chromosome gene output differs between the germ cells and somatic cells, and between sexes. This unexpected outcome provides new perspectives on sex chromosome infertility.

We are also interested in harnessing the unique inheritance of the sex chromosomes in the paternal line; i.e. the paternal X chromosome is always inherited by daughters, and the Y by sons. We use CRISPR-Cas9 genome editing to generate sex-chromosome specific transgenic mouse lines.