The Y chromosome, which determines the male sex (XY), has been degenerating rapidly throughout human evolution and might eventually disappear. As evolutionary forces continue to chip away at this chromosome, questions arise: What happens if the Y chromosome disappears altogether? 

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Over the past 166 million years, the Y chromosome has lost nearly 95% of its original 1,500 genes, retaining only 106 genes related to testicular development and spermatogenesis. In contrast, the X chromosome, which can recombine during reproduction, contains around 900 genes with diverse functions.[1][2]

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Why is the Y chromosome disappearing?

The early proto-Y chromosome was initially similar to the X chromosome, but through evolutionary processes it lost the ability to recombine, something that is vital for genetic repair.

This lack of recombination leads to the accumulation of harmful mutations, a phenomenon known as Muller’s ratchet, which accelerates gene loss over generations, as described in a report from Genetics.[3] The Y chromosome's structure—characterised by palindromic sequences and weak centromeres—further contributes to its instability, making it prone to age-related mosaic loss of the Y chromosome (mLOY).

In simple terms, it's like a ratchet that only turns one way, with each turn representing another bad mutation. Once the mutation occurs, it can’t be undone, and this causes the Y chromosome to lose its good genes slowly and, over successive generations, ultimately die. 

Furthermore, despite their roles, Y chromosomal genes are not essential for somatic cell survival or proliferation, allowing living cells to continue dividing even after losing the Y chromosome, leading to the accumulation of 45, X cells (cells with 45 chromosomes plus X chromosome instead of the usual 46).[4]

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Health implications

The loss of the Y chromosome in somatic cells is not just an evolutionary curiosity; it has significant health implications. mLOY, the most prevalent form of somatic mosaicism in men, is detected in nearly 20% of those aged 65–85 years and can be identified in blood samples using next-generation sequencing and multiplex PCR techniques.[5]

Alzheimer’s disease

Although the exact connection is still being studied, mLOY has been hypothesised to disrupt immune cell movement through the blood-brain barrier, contributing to the pathogenesis of Alzheimer’s disease (AD).[5]

1. According to a report from the International Journal of Molecular Sciences, mLOY is significantly more prevalent in the microglial cells of AD patients (found in nearly 30% of cases) compared to healthy controls (less than 3%).[6]
2. A Mendelian study found that mLOY risk increases by 80% for each standard deviation increase in the mLOY polygenic risk score (mLOY-PRS). In men with mild cognitive impairment, this accelerated the progression to AD at a 23% faster rate.[5]

Heart disease

The association between mLOY and cardiovascular disease is well-documented. Mechanistically, mLOY may contribute to fibrosis through altered functionality of Y chromosome-deficient cardiac macrophages, exacerbating heart failure.

The link between mLOY and cardiovascular diseases is well-established; consider the following:

1. mLOY has been linked to increased mortality from heart failure and higher cardiovascular risk in experimental models and humans.[2]
2. Studies, including the CARE for HOMe and the 4D study, have shown that men with significant mLOY (>17%) face more than double the risk of death and heart failure within 5 years.[6]

Kidney disease

mLOY has also been observed in hypoxia-prone proximal tubule cells of the kidney, particularly in conditions like end-stage renal disease and neoplastic processes. This chromosomal loss, combined with the kidneys' susceptibility to hypoxic injury, underscores the broader implications of Y chromosome instability.[2]

Cancer

Y chromosome loss is associated with an increased risk of several cancers, including bladder, prostate, and colorectal cancers, as well as mesothelioma and glioblastoma. The loss of critical Y-linked genes, such as KDM5D and CD99, contributes to tumour progression and immune evasion.[2]

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A new sex gene

As evolutionary forces continue to chip away at this chromosome, questions arise: What happens if the Y chromosome disappears altogether? 

There are signs of the emergence of new sex-determining genes and, subsequently, new sex chromosomes. This process, however, would occur over millions of years. 

A 2022 experimental study indicated that essential Y chromosome genes might relocate to other chromosomes.[7] Alternatively, humans might develop entirely new sex-determining genes, potentially leading to new human species, as seen in experimental subjects.[8]

But the Y chromosome might not disappear after all. A study from PLOS Genetics suggests that the Y chromosome’s evolution of palindromic sequences and repetitive gene copies might work in its favour.[9]

They could potentially enable damaged genes to be repaired using undamaged copies, thus escaping Muller’s ratchet and slowing its degradation.

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Clinical strategies

From a clinical standpoint, there is little that can be done to prevent Y chromosome loss over evolutionary timescales. However, there are actionable strategies to slow mLOY in patients. The International Journal of Molecular Sciences report links mLOY to cellular senescence, noting that, “Since the frequency of mLOY in current smokers is significantly higher than that in former smokers, the effect of tobacco smoking on mLOY appears to be reversible. In addition, several other environmental factors, such as polycyclic aromatic hydrocarbons, air pollution, heavy drinking, and obesity, have been linked to the risk of mLOY.”[4]

By reducing exposure to these risk factors through patient counselling, physicians can help mitigate the impact of mLOY on age-related diseases in men.

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Disclaimer: This story is contributed by Alpana Mohta and is a part of our Global Content Initiative, where we feature selected stories from our Global network which we believe would be most useful and informative to our doctor members.