Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

'Achilles' heel' in Y chromosome linked to sex disorders

07.09.2009
The unique mechanism behind the evolutionary survival of the human Y chromosome may also be responsible for a range of sex disorders, from failed sperm production to sex reversal to Turner Syndrome.

Roughly six years ago, David Page's lab at Whitehead Institute for Biomedical Research reported the discovery of eight large areas of mirror-imaged genetic sequences, or palindromes, along the Y chromosome.

Because the Y chromosome essentially has no partner with which to swap genes, a process that between ordinary chromosome pairs leads to genetic diversity and the exchange of good genes for damaged ones, it relies on its own palindromes to swap genes with itself. The Y, as it turns out, folds itself in the middle of palindromic regions, thereby pairing identical sequences to allow for potentially beneficial genetic exchange.

At the time, the finding provided explanation for why, despite much-heralded reports to the contrary, the Y chromosome is not doomed to extinction. Now, the Page lab has discovered that the Y's process of self-preservation can randomly go awry, with considerable clinical consequence.

"This is the sequel to the Y chromosome palindrome story," says Page, Whitehead Institute Director and a Howard Hughes Medical Institute investigator.

The latest chapter of the story, whose conclusion is published in the September 4 issue of Cell, began with the intriguing hypothesis that perhaps the Y's process of self-recombination can inadvertently turn the entire chromosome into a palindrome—literally, a mirror-image of itself. The result would be a so-called isodicentric Y chromosome (idicY), an abnormal structure with, as the name implies, two centromeres.

"We began to think seriously about the centromeres and the activity around them. Two centromeres render the chromosome susceptible to damage," says Julian Lange, first author of the Cell paper and a former graduate student in the Page lab. Because of the Y chromosome's well known roles in sex determination and male fertility, Lange began to speculate about the potential clinical impact of the transmission of an idicY during fertilization.

"Because the Y chromosome is not essential to an individual's survival, these isodicentric Ys can persist," says Lange, who, after completing this research at Whitehead, became a postdoctoral fellow at Memorial Sloan-Kettering Cancer Center. "They can be found in the population."

And Lange found them, in the DNA samples of 51 patients screened from a field of nearly 2400 individuals who had come under study over the course of many years because of failed sperm production, structurally abnormal Y chromosomes, or sex reversal. Through sophisticated genetic analysis, it became clear that idicYs were responsible for spermatogenic failure in many of the male patients.

However, 18 of the 51 patients were anatomically female—despite having two copies of the male-determining SRY gene on their idicY chromosomes. Lange and Page began to hypothesize that the feminization they had identified was related to the instability of the idicYs themselves. Suspecting that the level of instability of an idicY increases with the size of the chromosome, they looked for a connection and found something somewhat paradoxical: the larger the Y chromosome, the greater the likelihood of sex reversal.

"We had predicted this correlation, which relates to the overall distance between the centromeres," says Page. "But when we confirmed it with the patient data, we were blown away."

Page believes that this new model for the formation of idicY chromosomes, coupled with the size-instability correlation, suggests a causal link to Turner syndrome, a chromosomal abnormality in girls or women, characterized by the lack of one sex chromosome. Turner syndrome affects an estimated 1 in 2500 females. Page won't yet speculate as to what percentage of Turner syndrome could be caused by this palindrome-to-palindrome recombination, but he does think it's significant.

Written by Matt Fearer

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 Howard Hughes Medical Institute investigator and a professor of biology at Massachusetts Institute of Technology.

Full Citation:

"Isodicentric Y Chromosomes and Sex Disorders as Byproducts of Homologous Recombination that Maintains Palindromes"

Cell, September 4, 2009

Julian Lange (1), Helen Skaletsky (1), Saskia K.M. van Daalen (2), Stephanie L. Embry (3), Cindy M. Korver (2), Laura G. Brown (1), Robert D. Oates (4), Sherman Silber (5), Sjoerd Repping (2), and David C. Page (1).

1. Howard Hughes Medical Institute, Whitehead Institute, and Department of Biology, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA

2. Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Academic Medical Center, University of Amsterdam, the Netherlands

3. Institute for Genome Sciences and Policy, Duke University, Durham, NC 27708, USA

4. Department of Urology, Boston University Medical Center, Boston, MA 02118, USA

5. Infertility Center of St. Louis, St. Luke's Hospital, St. Louis, MO 63107, USA

Nicole Giese | EurekAlert!
Further information:
http://www.wi.mit.edu

More articles from Life Sciences:

nachricht Research team of the HAW Hamburg reanimated ancestral microbe from the depth of the earth
01.03.2017 | Hochschule für Angewandte Wissenschaften Hamburg

nachricht Researchers Imitate Molecular Crowding in Cells
01.03.2017 | Universität Basel

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

Im Focus: Safe glide at total engine failure with ELA-inside

On January 15, 2009, Chesley B. Sullenberger was celebrated world-wide: after the two engines had failed due to bird strike, he and his flight crew succeeded after a glide flight with an Airbus A320 in ditching on the Hudson River. All 155 people on board were saved.

On January 15, 2009, Chesley B. Sullenberger was celebrated world-wide: after the two engines had failed due to bird strike, he and his flight crew succeeded...

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

A better way to measure the stiffness of cancer cells

01.03.2017 | Health and Medicine

Exploring the mysteries of supercooled water

01.03.2017 | Physics and Astronomy

Research team of the HAW Hamburg reanimated ancestral microbe from the depth of the earth

01.03.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>