Study helps uncover why some females may be more susceptible to disease April 29, 2021 Findings from a University of Dundee study help to explain why some females may be more predisposed to disease, suffer worse outcomes of virus infection such as Covid-19, or why they respond differently to drug therapies. Alejandro Brenes Researchers from the University’s School of Life Sciences have discovered that the control of genes on X chromosomes in females can cause much wider effects on cells than previously realised. Female mammals, including humans, have two X chromosomes (XX), while males have only one, plus a Y chromosome (XY). The X chromosome contains over 1,000 genes which are vital for cell development, however a double dose of X chromosome gene products can be lethal. To balance this, one of the two X chromosomes in female cells is shut down. This process, known as X chromosome inactivation (XCI), ensures that females, like males, have the correct levels of gene activity produced by X chromosomes in cells. In the study, published in Cell Reports, Alejandro Brenes and colleagues show that issues with the XCI process in female cells can cause major changes in protein levels. Proteins are the main targets of almost all drugs and differences in the levels of proteins expressed in a cell are frequently responsible for many different types of disease, including cancer. The findings from the study allow for a better understanding of mechanisms that can cause disease and may point to new drug development. “This study has revealed major consequences for the female cells if the XCI mechanism is defective” said Brenes. “By analysing a collection of human stem cells from both healthy male and female donors, we found that a defective XCI increased the levels of thousands of proteins from all chromosomes, many of which are known markers of disease. “The data can help to explain why some people may be more likely to develop specific types of disease, suffer worse outcomes of virus infection, such as Covid-19, or vary in how they respond to treatments and therapy. The results could also be important for the safe development of stem cell therapies. It also highlights the importance of sex specific studies, as there are still many uncharacterised differences between females and males that need to be better understood in order to advance precision medicine.” Erosion of human X chromosome inactivation causes major remodeling of the iPSC proteome authored by Alejandro J. Brenes, Harunori Yoshikawa, Dalila Bensaddek, Bogdan Mirauta, Daniel Seaton, Jens L. Hukelmann, Hao Jiang, Oliver Stegle and Angus I. Lamond is available to read in Cell Reports now.