If you search “Y chromosome degradation” online, you will quickly find articles about the gradual loss of the Y chromosome on an evolutionary scale. Over the last 166 million years, the smallest mammalian chromosome – the male sex chromosome – has been slowly losing a large number of genes at a rate of about 10 genes per million years. Today, it contains about 50 genes in humans, down from the 900 it started with, all of which are crucial for male development. However, this genetic loss does not mean that the Y chromosome is disappearing entirely, nor does it suggest that men are going extinct. Rather, it simply reflects natural selection, a process where organisms better adapted to their environment survive and pass on their advantageous traits to future generations. As part of this, genes that are no longer useful can slowly be lost from a population over time. To put this timescale into perspective, Homo sapiens (modern humans) are only thought to have appeared in the fossil record 200,000 to 300,000 years ago, whereas our close relatives, chimpanzees, showed up about 8 million years ago. In comparison to the amount of genetic development the Y chromosome has undergone over its 166 million year evolution, the genetic change of modern humans has been relatively minimal even for the sex chromosome.
While the evolutionary loss of genes from the Y chromosome has taken place over hundreds of millions of years, scientists have discovered that some men experience a much more rapid and dramatic form of Y chromosome loss, not over millennia, but within their own lifetime.
This phenomenon involves the complete disappearance of the Y chromosome from some of the body’s cells and is linked to a variety of health concerns, particularly as men age. It’s estimated that around 20% of the male population have this Y loss, though many may never know. The scientific term for this is mosaic loss of chromosome Y, or mLOY for short. The word “mosaic” comes from the fact that some of the body’s cells will retain the chromosome; others will lose it. But why does this occur, and what does it imply for men’s health?
mLOY is most commonly seen in older men because our bodies become less and less effective at maintaining and repairing our cells as we age. Over a lifetime, the basic cell machinery that is needed to copy our DNA into new cells can accidentally build in errors, leading to accumulation of damage to the DNA. This damage can interfere with normal cellular function and, being so small, the Y chromosome is particularly vulnerable to damage during replication and repair, explaining its loss in certain cell types over time. As with most complex health conditions, mLOY occurs due to a combination of environmental and genetic factors. Over 100 genetic variants have been identified and linked to mLOY, many of which affect the cell’s ability to repair and maintain DNA. Some of these same genes are also involved in cancer, which can also be related to the accumulation of DNA damage. Certain lifestyle choices present major risk factors too. Tobacco smoking, exposure to air pollution, high alcohol intake, and obesity are all associated with increased likelihood of mLOY. The condition is most commonly seen in the stem cells responsible for making different types of blood cells and is often an indicator of age-related disease, such as cardiovascular disease or Alzheimer’s, as well as a shorter lifespan. While extremely rare, mLOY has also been observed in younger men, in these cases it is associated with subfertility and developmental defects. Early-onset mLOY can negatively affect, and even completely halt, sperm production in young men resulting in male infertility. If the condition develops during early childhood, it can result in shorter stature due to insufficient levels of an important growth protein made by a gene found on the Y chromosome. However, it is important to remember that this condition is very rarely seen before the age of 50, and a sign of the condition developing at an earlier age, is solely due to genetic factors.
The fundamental difference in sex chromosomes between males and females may provide an explanation for the well-documented gap seen in longevity between the sexes. According to the World Health Organisation (WHO), global female life expectancy is 74.2 years, around five years longer than the 69.8 year average for males. This is comparable to the UK figures: 82.8 years for women, and only 78.8 for men. Women have two X chromosomes whereas men have one X and one Y. Crucially, the X chromosome is larger, much more stable, and carries far more genes than its Y counterpart. The Y chromosome, being both small and singular in men, lacks a genetic backup. Women, on the other hand, have that second copy, and although it’s inactivated, it can still act as a genetic safety net: if one X chromosome carries a harmful mutation, the other often compensates by providing a kind of genetic redundancy that men don’t have.
There have been many theories as to why women tend to live longer than men – women generally “eat healthier”, they “see the doctor more”, and “drink and smoke less”. While these behavioural explanations may hold some truth, this theory does not fully account for the fact that we see this longevity gap in virtually every country regardless of culture, wealth or healthcare access. We also see the female life expectancy outdoing the male in most mammals too. Since neither monkeys nor bears smoke cigarettes, this points to something more universal among mammals – DNA. This fundamental biological contributor, along with the gradual, mosaic loss of the Y chromosome over a man’s lifetime, begins to show us how chromosomal differences could make men more susceptible to age-related disease and earlier mortality. Without a backup, and with increasing genomic instability, men may simply be more vulnerable to the genetic wear and tear of aging.
Mosaic loss of the Y chromosome may not serve as a marker of aging, but also a direct contributor to the biological inequality in lifespan between the sexes, potentially answering the highly debated question of why women tend to live significantly longer than men.
Article written by Angelica Leach, a second year Biological Sciences student who hopes to share the complex and intricate alignment between genetics, lifestyle and human health.
Article edited by Eleanor Stamp, a Neuroscience PhD student at the Institute of Genetics and Cancer, University of Edinburgh, and an Online News Editor for EUSci.
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