I was reading about the genetics of ovarian aging, particularly on the link between breast cancer genes and age at menopause. The below plot is from a 2021 study that looked into rare variant associations with age at natural menopause using exome data of 50k women in the UK Biobank. As you can see, the largest effect sizes were observed for loss of function mutations in two well known breast cancer genes--BRCA2 and CHEK2. I guessed that BRCA2 link to menopause timing should have been known long time ago. I wondered how scientists first recognized that women with BRCA2 mutations had earlier menopause, and the literature turns out fascinating as I expected. You see, it's common for women of reproductive age diagnosed with breast cancer to opt for egg freezing before they start chemotherapy. In early 2010s, specialists who were assisting such women noticed something odd: many of them often failed to respond to the ovarian stimulation procedure. Then they found that it was particularly women with BRCA mutations who were non-responders. This motivated later observational studies which showed that women with BRCA2 mutations often had primary ovarian insufficiency leading to significantly earlier onset of menopause. The biology behind this is also fascinating. BRCA2 encodes a tumor suppressor protein that is critical for maintaining genome integrity. They are part of the protein complex that fix DNA damages. Eggs (and sperm) are gametes produced by meiosis of germ cells and during meiosis DNA undergoes double strand break to enable chromosomal recombination. So, DNA repair process is crucial for production of healthy eggs and sperm. Also, unlike sperms that are produced only after puberty throughout a man's life, eggs are produced during fetal development and get arrested in early meiosis and remains suspended in that state for decades until they get selected for ovulation. So, plenty of time to accumulate mutations. In women with BRCA2 mutations, such mutations don't get fixed and as a result the oocytes get culled through apoptosis. So the women runs out of oocyte reserve faster and reach menopause earlier in life. In the case of CHEK2, you may have noticed that the effect is opposite. Women with CHEK2 mutations attain menopause significantly later in life. This is because CHEK2 encodes a surveillance protein that controls DNA damage check points. When CHEK2 is defective, eggs with damaged DNA get past the checkpoints without triggering apoptosis. So, bad eggs are spared from culling in women with CHEK2 mutations and as a result, their oocyte reserve empties slowly, resulting in significantly later onset of menopause. The impressive fact here is that unlike BRCA2, CHEK2's association with age at menopause in humans wasn't known before (though the effect of CHEK2 loss on fertility itself was known through mice studies). It was only through UK Biobank dataset, scientists first came to recognize the impressive protective effect of CHEK2 mutations on ovarian aging. Ruth, Day, Hussain, Martínez-Marchal, et al. Nature 2021 nature.com/articles/s41586-0…