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October 26, 2012--------News Archive Return to: News Alerts

Electron micrograph of egg and sperm.

Image: Courtesy of HHMI

WHO Child Growth Charts


Key Genetic Deletions that Contribute to 8% of Male Infertility

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 6% of cases of failed sperm production

by Matt Fearer

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 American Journal of Human
, 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 assisted reproduction. Because of this, we can conclude that its prevalence in the population essentially reflects the rate at which this deletion arises spontaneously in men,"says Page.

"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 Y chromosome," 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 chromosome is made up of several regions of large palindromes—areas of mirror-image 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.
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
. But in
mirrored regions, consensus doesn't really represent
anything. A complete and accurate assembly
of the human genome will answer questions
we do not even know to ask."

David Page
investigator, Howard Hughes Medical Institute.

This work was supported by the National Institutes of Health, the Howard Hughes Medical Institute, and the Singapore Ministry of Health and Agency for Science, Technology, and Research.

David Page's primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a professor of biology at Massachusetts Institute of Technology and an investigator of the Howard Hughes Medical Institute.

Full Citation:
"AZFc Deletions and Spermatogenic Failure: A Population-Based Survey of 20,000 Y Chromosomes"

American Journal of Human Genetics, November 2, 2012 (in print)

Deletions involving the Y chromosome’s AZFc region are the most common known genetic cause of severe spermatogenic failure (SSF). Six recurrent interstitial deletions affecting the region have been reported, but their population genetics are largely unexplored. We assessed the deletions’ prevalence in 20,884 men in five populations and found four of the six deletions (presented here in descending order of prevalence): gr/gr, b2/b3, b1/b3, and b2/b4. One of every 27 men carried one of these four deletions. The 1.6 Mb gr/gr deletion, found in one of every 41 men, almost doubles the risk of SSF and accounts for ∼2% of SSF, although <2% of men with the deletion are affected. The 1.8 Mb b2/b3 deletion, found in one of every 90 men, does not appear to be a risk factor for SSF. The 1.6 Mb b1/b3 deletion, found in one of every 994 men, appears to increase the risk of SSF by a factor of 2.5, although <2% of men with the deletion are affected, and it accounts for only 0.15% of SSF. The 3.5 Mb b2/b4 deletion, found in one of every 2,320 men, increases the risk of SSF 145 times and accounts for ∼6% of SSF; the observed prevalence should approximate the rate at which the deletion arises anew in each generation. We conclude that a single rare variant of major effect (the b2/b4 deletion) and a single common variant of modest effect (the gr/gr deletion) are largely responsible for the AZFc region’s contribution to SSF in the population.

Steven G. Rozen (1,2), Janet D. Marszalek (1,3), Kathryn Irenze (4), Helen Skaletsky (1,3), Laura G. Brown (1,3), Robert D. Oates (5), Sherman J. Silber (6), Kristin Ardlie (4,7), and David C. Page (1,3,8)

1. Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.
2. Duke-NUS Graduate Medical School, Singapore 169857, Singapore.
3. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
4. Genomics Collaborative, SeraCare Life Sciences, Cambridge, MA 02139, USA.
5. Department of Urology, Boston University School of Medicine, Boston Medical Center, Boston, MA 02118, USA.
6. Infertility Center of St. Louis, St. Luke's Hospital, St. Louis, MO 63017, USA.
7. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
8. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Original article: http://wi.mit.edu/news/archive/2012/study-reveals-rate-which-key-genetic-deletions-contribute-male-infertility