Inside infertility: The Y chromosome 9/10/03. By Giles Newton Deletions in the Y chromosome can lead to infertility. Mark Jobling is turning to fertile men to find out why such deletions occur.

The Y chromosome is the bastion of maleness. Inherit a Y chromosome from your father, and you will be male. Yet the passage of the Y chromosome through the generations can come to a grinding halt if the Y chromosome is damaged during the production of sperm – the man inheriting the disrupted Y may well be infertile.

Indeed, male infertility is surprisingly common – it is estimated that 7.5 per cent of men have reduced fertility or are completely infertile. In up to a quarter of cases, this infertility is due to deletions in the Y chromosome, leading the loss of genes involved in sperm production.

At the University of Leicester, Wellcome Trust Senior Research Fellow Mark Jobling is investigating why and how such deletions occur – research fuelled by his interest in the quirks and paradoxes of the Y chromosome. "The Y chromosome is fascinating because it's weird," he says. "It breaks all the rules of human genetics: it has only a few genes, it is full of repeated DNA, and it does not recombine as only the tips of the Y pair up with the X."

This lack of recombination is key to the Y chromosome's allure for geneticists. While other chromosomes pair up and swap DNA during the formation of sex cells (eggs and sperm), the majority of the Y chromosome has been left to its own devices during evolution – and indeed during the production of every Y-chromosome-carrying sperm. Millions of years ago, the forerunners of the X and Y used to exchange DNA, but at some point the Y lost this ability and has traveled on a solitary evolutionary path ever since, carrying a dwindling collection of genes.

The huge regions of repeated DNA that dominate the Y chromosome are therefore free to accumulate extraordinary rearrangements by recombining with themselves. "If you look at the Y chromosomes of several different men under the microscope, they often appear different," says Dr Jobling. "You see all sorts of funny-looking Ys: some with extra bits, some with bits swapped around or inverted, and others apparently missing bits. Some of these rearrangements appear harmless; others lead to infertility."

Since the mid-1990s, it has been known that rearrangements can cause infertility, and three regions, termed AZFa, b and c (AZF standing for azoospermia factor), have been identified. All three regions contain genes essential for the production of sperm.

AZFa is quite well understood. Two direct repeats are separated by a region of DNA that includes at least two genes. If the repeats pair up and recombine incorrectly, deletions or duplications can occur. Duplications of AZFa appear to have little impact on fertility, but deletions lead to Sertoli cell-only syndrome, where there is a complete lack of germ cells in the testes and hence no sperm are produced.

The AZFb and AZFc regions are larger, less well understood, and contain enormous repeat regions. "These regions are very complex and puzzling," says Dr Jobling. "Deletions lead to all sorts of outcomes: men with a reduced number of sperm, men whose sperm develop only part way, and men with a complete lack of sperm. Then there is the famous extreme of one guy with no AZFc region at all. But he had six sons, who were all infertile. So it's very difficult to link genetic changes to outcomes in a simple way, and these regions are still very difficult to study."

Sifting sperm

Insights into the AZF regions have come from studies of infertile men, but research has been hampered by the small number of patients available for study.

More crucially, researchers are really interested in the fathers of the infertile men with deleted Ys, and the events that occurred in the sperm-production process.

"Each patient is the chance result of one sperm, with a deleted Y, fertilising an egg and producing a man with infertility," says Dr Jobling. "Unfortunately for us – but not for men in general – these deletion events are rare."

Dr Jobling is therefore going straight to the sperm-production process, and looking for Y chromosomes with deletions in the sperm of fertile men. "We're looking at the AZFa region, and we know roughly that deletions occur in about 1 in 100 000 sperm. So if we look at the millions and millions of sperm that a single fertile man can produce, we can identify these rare deletion molecules and analyse them in detail. We can then find out what kinds of rearrangements were being produced in the testes, the frequency of those events, and how they are affected by the general Y chromosome background."

Comparing the results from one man with those of another, with a different Y chromosome, will show the significance of particular arrangements of repeats, and of sequences within repeats." We can start to learn about what factors in the sequence affect the processes of rearrangement, and whether there are Y chromosome haplotypes that increase the likelihood of infertility."

Dr Jobling argues that the study of Y chromosome rearrangements has a wider relevance – and not only to his own studies on a form of sex reversal – where the SRY 'maleness gene' is transferred to the X chromosome, resulting in XX males. "Repeats are found on all of the other chromosomes," he points out. "Rearrangements between these sequences, leading to deletions and duplications, can lead to human disease – such as the neurological disorder Charcot–Marie–Tooth disease. But these other chromosomes are much harder to study because the repeats can be swapped around by recombination. If we can understand the dynamics of rearrangements on the much simpler Y, we can start to look at the more complex processes throughout the human genome."

Links

Professor Mark Jobling, University of Leicester, research page