Study reveals rate at which key genetic deletions contribute to male infertility

October 25, 2012, Whitehead Institute for Biomedical Research

A large-scale analysis of Y chromosomes from more than 20,000 men finds that two spontaneously recurring deletions along a complex region of the Y chromosome are responsible for approximately 8% of cases of failed sperm production.

Although previous research had identified deletions in the region of the Y known as AZFc (for azoospermia factor c) as causing severe spermatogenic failure (SSF), this latest analysis, conducted by Whitehead Institute Director David Page and colleagues, is the first to determine how prevalent these deletions are in the general population.

According to the study, published in the November issue of the , the deletion known as b2/b4 is found in one of every 2,300 men, increases the risk of SSF 145 times, and is responsible for roughly 6% of cases.

"This deletion almost always results in spermatogenic failure, so it would be extremely rare for it to be transmitted from father to son without medically ," says Page. "Because of this, we can conclude that its prevalence in the population essentially reflects the rate at which this deletion arises spontaneously in men."

"Medically relevant population genetics studies are well established for most of the human genome, but this is the first study of this kind for the ," says Steven Rozen, an associate professor at Duke-NUS Graduate Medical School Singapore and first author of the study.

Page notes that this study would not have been possible without the unique sequencing method he developed with collaborators at Washington University in St. Louis to help navigate the structural complexities of the Y chromosome. As Page reported years ago, the Y comprises several regions of large palindromes—areas of mirror-imaged genetic sequences. Such regions render conventional sequencing approaches incapable of detecting extremely subtle genetic differences found hidden among the "mirrors." In response, Page and colleagues developed an approach known as SHIMS (single-haplotype iterative mapping and sequencing) to establish a definitive reference DNA sequence of the Y chromosome.

Such structural complexity is not exclusive to the Y chromosome, however. Smaller "halls of mirrors" can be found scattered throughout the human genome, and these areas are likely to be as unstable and prone to mutation as those on the Y chromosome. While the effects of the known deletions of the AZFc region appear to be limited to sperm production, substantially more harmful health effects are apt to arise from mutations elsewhere. Given the inherent challenges of obtaining accurate and complete DNA sequences of mirrored regions, Page believes that the current reference sequence of the human genome is missing potentially meaningful detail—and that the time has come to apply SHIMS broadly.

"The key to SHIMS starts with the realization that there are areas of the human genome that are almost perfectly mirrored repeated sequences that are greater than 99% identical," says Page, who is also an investigator of the Howard Hughes Medical Institute. "When you assemble a sequence from multiple unrelated chromosomes, as was done with the human genome, you cannot make sense of minute but critical differences."

"The human genome reference is a consensus sequence, which is a politically wonderful outcome," he adds. "But in mirrored regions, consensus doesn't really represent anything. A complete and accurate assembly of the will answer questions we do not even know to ask."

Explore further: Study in roundworm chromosomes may offer new clues to tumor genome development

More information: American Journal of Human Genetics, November 2, 2012

Related Stories

Study in roundworm chromosomes may offer new clues to tumor genome development

April 21, 2011
A study of DNA rearrangements in roundworm chromosomes may offer new insight into large-scale genome duplications that occur in developing tumors.

Recommended for you

Group recreates DNA of man who died in 1827 despite having no body to work with

January 16, 2018
An international team of researchers led by a group with deCODE Genetics, a biopharmaceutical company in Iceland, has partly recreated the DNA of a man who died in 1827, despite having no body to take tissue samples from. ...

The surprising role of gene architecture in cell fate decisions

January 16, 2018
Scientists read the code of life—the genome—as a sequence of letters, but now researchers have also started exploring its three-dimensional organisation. In a paper published in Nature Genetics, an interdisciplinary research ...

How incurable mitochondrial diseases strike previously unaffected families

January 15, 2018
Researchers have shown for the first time how children can inherit a severe - potentially fatal - mitochondrial disease from a healthy mother. The study, led by researchers from the MRC Mitochondrial Biology Unit at the University ...

Genes that aid spinal cord healing in lamprey also present in humans

January 15, 2018
Many of the genes involved in natural repair of the injured spinal cord of the lamprey are also active in the repair of the peripheral nervous system in mammals, according to a study by a collaborative group of scientists ...

The coming of age of gene therapy: A review of the past and path forward

January 11, 2018
After three decades of hopes tempered by setbacks, gene therapy—the process of treating a disease by modifying a person's DNA—is no longer the future of medicine, but is part of the present-day clinical treatment toolkit. ...

Large-scale study to pinpoint genes linked to obesity

January 10, 2018
It's not just diet and physical activity; your genes also determine how easily you lose or gain weight. In a study published in the January issue of Nature Genetics, researchers at the Icahn School of Medicine at Mount Sinai ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.