GoKawiilCholesterol-lowering statins are among the most widely prescribed drugs in the world. They can have side effects, however, including muscle pain that affects twice as many women as men. When Karen Reue, a geneticist at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA), set out to discover why, she expected that the answer would lie in the sex hormones, such as oestrogen and testosterone, which are produced by the ovaries and testes.
The ‘crazy rule-defying’ genes that determine sex
But her data pointed to a different culprit: the X chromosome. Whether they had female or male gonads, mice with two Xs were more susceptible to statin-induced side effects1. “I was amazed when we got our results,” says Reue. “It was just clear-cut as could be.” A single gene on the X chromosome was the main contributor to the difference in how female mice respond to the drug. Her work has even pointed to a potential way to mitigate the side effects in women. Fish oil contains a fatty acid called DHA, which is depleted in women taking the drugs, and the supplement reverses some of the metabolic side effects of statins in female mice.
Reue’s findings are just one of a wave of discoveries showing that genes on the sex chromosomes, and how they are regulated, can have a substantial impact on health and disease. Women usually have two X chromosomes, men an X and a Y. In women, one of the X chromosomes is typically ‘silenced’ to ensure that both sexes have a roughly equivalent number of X-linked genes expressing proteins in each cell. But some genes manage to escape the silencing process.
Sex redefined
Although these escapees have been known about for a while, the fundamental nature of their influence is only now emerging, says Edith Heard, who studies X-chromosome inactivation at the Francis Crick Institute in London. Escape genes on the X chromosome — and Y genes as well — are revealing themselves to be key contributors to observed sex differences in conditions such as autoimmunity, cancer, cardiovascular disease, metabolic disease, dementia and autism and other neurodevelopmental disorders. These genes are also spotlighting the yawning gap in our understanding of women’s health. “Female biology has been neglected for so long,” says Heard. “Finally, we actually have the tools to find out what is different in an XX and an XY context other than just the hormones.”
The origins of X and Y
Human sex differentiation might look simple, but it is deeply complicated, emerging from the collective action of genes, sex chromosomes and hormones. Variations in any of these can mean that individuals might develop a mix of female-typical and male-typical traits, resulting in a spectrum of outcomes in the population. In individuals with typical development, some sex traits, such as gonad type, are a one-or-the-other affair, whereas others, such as gene-expression patterns or disease risk, appear in ranges that are biased towards one sex. And although some sex differences are permanent, others can change over time. Further complicating things is gender — the societal roles and expectations associated with an individual’s sex — and gender identity, which might not align with a person’s sex.
Why women’s brains are more resilient: it could be their ‘silent’ X chromosome
What is clear is that a main cause of sex differences stems from the unequal sets of genes on the X and Y chromosomes. According to the conventional view on sex differentiation, the presence or absence of a gene called SRY, which is found only on the Y chromosome, determines whether individuals develop testes or ovaries. Then the gonads take over, directing changes in the rest of the body through the secretion of hormones — before birth, during puberty and beyond.
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