Could X Centromeric Drive Underpin PCOS, Miscarriage and Other Age-Related Reproductive Issues?
PCOS and other reproductive disorders may be linked to X chromosome meiotic drive.
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Female reproductive health is affected by a number of disorders that can seriously impact quality of life.
One of the most prevalent conditions is polycystic ovary syndrome (PCOS), affecting 8-13% of women of reproductive age. Characterized by irregular menstrual cycles, excess androgen levels and ovarian cysts, PCOS is one of the leading causes of infertility. Despite its commonality, the underlying causes of the condition remain poorly understood. Dr. Tom Moore, a principal investigator in the School of Biochemistry and Cell Biology at University College Cork, has proposed a new hypothesis that may explain why human female reproduction is prone to multiple disorders.
The X chromosome is vulnerable to meiotic drive
The X chromosome’s involvement in meiotic drive mechanisms could be a key factor in understanding why certain reproductive disorders are so common and persistent. Meiotic drive refers to a genetic phenomenon where certain genes manipulate the process of meiosis to increase their transmission to the next generation, often at the expense of other genes. In normal meiosis, genes have a 50% chance of being passed on to offspring, but meiotic drive skews this process, allowing "selfish" genes to be inherited more frequently than would be expected by chance. Due to genetic hitchhiking, this can introduce traits that may have detrimental effects on individual fitness.
Antagonistic selection is an evolutionary concept where a genetic trait, which is beneficial in one context but harmful in another, may be passed on to a future generation. This typically occurs when a gene has different effects at different stages of life or under different environmental conditions. In the context of human evolution, antagonistic selection can help explain why certain reproductive disorders, like PCOS, might persist.
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Subscribe for FREE“Genetically-determined deleterious disorders with high heritability are expected to be rare due to selection against the causative DNA variants. However, various modes of antagonistic selection may keep disease-causing variants in the population,” said Moore. “One such antagonistic selective force is meiotic drive, which occurs in both the male and female germlines.”
“In the female germline, drive occurs at meiosis I as homologous chromosome centromeres compete to stay in the oocyte, rather than being segregated to the polar body, which is a genetic dead end.”
Moore’s hypothesis suggests the mammalian X chromosome may be vulnerable to meiotic drive due to the process of X inactivation, whereby one of the two X chromosomes is randomly silenced during early development, in the female germline.
“The current proposal makes the case that the X chromosome is special and may be modified by its competing partner before meiosis I, thereby losing out in the battle to stay in the oocyte,” said Moore.
“I previously proposed a hypothetical meiotic drive mechanism comprising an allele (Suppressor) expressed from the active X chromosome that modifies the inactive X chromosome centromere in primordial germ cells and increases the likelihood of its segregation to the polar body at meiosis I,” Moore wrote.
Meiotic drive is influenced by human X pericentromeric genes
The hypothesis states that the human X pericentromeric region – the section of the X chromosome close to the centromere – contains genes that may potentially be involved in these meiotic mechanisms.
“It is generally accepted that meiotic drive in the female germline explains the rapid evolution of centromeric satellite DNA repeats and their binding proteins,” said Moore. “Unlike autosomal drive systems based on centromeric satellite DNA variants, the X chromosome system is proposed to be far more complex and involves multiple genes that flank the X centromere. Particularly intriguing is the presence of multiple copies of SPIN1 and ZXDC paralogs flanking the X centromere, and the nearby ICCE element which is involved in the X inactivation mechanism.”
He proposes SPIN1 and ZXDC paralogs, along with other X pericentromeric genes, may work together as part of a “multigenic drive system”, which influences what X chromosome ends up in the egg during meiosis.
The prevalence of PCOS and other conditions might be linked to X centromeric drive
“A hypothesis regarding X chromosome centromeric drive first suggested 32 years ago – my PhD thesis – is supported by recent genomic and cell biology findings. This idea has now been developed further and proposes to explain why human female reproduction is prone to multiple disorders that are both common and severe,” said Moore.
Moore proposes the mechanism of X chromosome centromeric meiotic drive may disrupt normal ovarian function and contribute to PCOS and other conditions.
“Deregulation of some of these X pericentromeric genes may explain the occurrence of female reproductive and endocrinological disorders such as PCOS because the evidence suggests that these genes regulate oocyte development, meiotic progression, and the hormones produced by the ovary – all aspects that are deregulated in PCOS,” said Moore.
He also suggests that, as women age, changes in the X chromosome's pericentromeric region may affect the quality of their egg cells, potentially leading to chromosome abnormalities that contribute to miscarriage and menopause.
“Other genes in the X pericentromeric region, if affected by genetic hitchhiking or epigenetic modifications could contribute to a variety of additional conditions if transmitted to progeny, for example, autism, preeclampsia and differences in sexual differentiation,” said Moore.
Reference: Moore T. X centromeric drive may explain the prevalence of polycystic ovary syndrome and other conditions: Genomic structure of the human X chromosome pericentromeric region is consistent with meiotic drive associated with PCOS and other conditions. BioEssays. 2024:2400056. doi: 10.1002/bies.202400056
About the interviewee:
Dr. Tom Moore is a principal investigator in the School of Biochemistry and Cell Biology at University College Cork. He holds a Bachelor of Veterinary Medicine from University College Dublin and earned his doctorate at the University of London. His research focuses on understanding aspects of the evolutionary genetics and physiological mechanisms underlying normal and pathological pregnancy in the mouse and human.
