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Home | Pregnancy Timeline | News Alerts | News Archive July 25, 2013



The X chromosome

Upgraded reference in hand, the Page lab discovered that the mouse and human X
chromosomes have nearly 95% of their X-linked, single-copy genes in common.

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Shocker: The 'female' X chromosome key to sperm production

Painstaking new analysis of the genetic sequence of the X chromosome—long perceived as the "female" counterpart to the male-associated Y chromosome—reveals that large portions of the X have evolved to play a specialized role in sperm production.

by Matt Fearer

This surprising finding, reported by Whitehead Institute scientists in a paper published online this week in the journal Nature Genetics, is paired with another unexpected outcome: despite its reputation as the most stable chromosome of the genome, the X has actually been undergoing relatively swift change. Taken together, these results suggest that it's time to reexamine the biological and medical importance of the X chromosome.

"We view this as the double life of the X chromosome," says Whitehead Institute Director David Page, whose lab conducted this latest research.

"The X is the most famous, most intensely studied chromosome in all of human genetics. And the story of the X has been the story of X-linked recessive diseases, such as color blindness, hemophilia, and Duchenne's muscular dystrophy. But there's another side to the X, a side that is rapidly evolving and seems to be attuned to the reproductive needs of males."

David Page, primary investigator, Whitehead Institute Director

Page's lab, best known for its pioneering investigations of the Y chromosome, embarked on a rigorous comparison of the mouse and human X chromosomes, in part to test the longstanding biological belief that X chromosomes genes are conserved and shared across mammals.

However, to render a valid comparison, the lab had to amplify the human X sequences originally assembled from the X chromosomes of at least 16 people. This composite of  X chromosomes was filled with errors and gaps and failed to capture so-called ampliconic* or amplified nucleotide regions containing virtually identical segments — but preventing recognition of tiny, important differences.

To clean up the sequences, the lab used a method Page developed with collaborators at Washington University in St. Louis. to navigate every structural complexity of the Y chromosome. As Page reported roughly a decade ago, the Y contains several regions of large palindromes—areas of mirror-imaged gene sequences. Such regions defy conventional sequencing which cannot detect subtle gene differences hidden among the "mirrors." In response, Page and colleagues devised SHIMS (single-haplotype iterative mapping and sequencing) and created a definitive DNA reference sequence of the Y.

Using SHIMS, the lab greatly improved the human X reference sequence, assembling three large amplicons, identifying previously unknown palindromes, and ultimately shortening the entire length of the sequence by eliminating four major gaps. These important finds will now be incorporated into the reference sequence of the human X for use by the greater scientific community.

Upgraded reference in hand, the lab discovered that the mouse and human X chromosomes have nearly 95% of their X-linked, single-copy genes in common.

Almost all of these genes are expressed in both sexes. However, the lab identified approximately 340 genes that are not shared between the two species. Most of these genes reside in ampliconic regions of the X and appear to have been acquired independently during the 80 million years since mouse and human diverged from a common ancestor.

Expression analyses reveals that these X genes are active almost exclusively in testicular germ cells, where, at a minimum, they likely contribute to sperm production. Further exploration of these X-ampliconic regions and their associated genes is warranted.

"This is a collection of genes that has largely eluded medical geneticists," says Jacob Mueller, a postdoctoral researcher in Page's lab and first author of the Nature Genetics paper. "None of these genes has been associated with a Mendellian trait. Now that we're confident of the assembly and gene content of these highly repetitive regions on the X chromosome, we can start to dissect their biological significance."

Adds Page: "These genes are more likely to have roles in diseases that are related to reproduction, infertility, perhaps even testis cancer. There's a whole other book to be written about this aspect of the X."

Research results were published in Nature Genetics, online publication, July 21, 2013

Nature Genetics (2013) doi:10.1038/ng.2705
Received 11 February 2013 Accepted 20 June 2013 Published online 21 July 2013
We compared the human and mouse X chromosomes to systematically test Ohno's law, which states that the gene content of X chromosomes is conserved across placental mammals1. First, we improved the accuracy of the human X-chromosome reference sequence through single-haplotype sequencing of ampliconic regions. The new sequence closed gaps in the reference sequence, corrected previously misassembled regions and identified new palindromic amplicons. Our subsequent analysis led us to conclude that the evolution of human and mouse X chromosomes was bimodal. In accord with Ohno's law, 94–95% of X-linked single-copy genes are shared by humans and mice; most are expressed in both sexes. Notably, most X-ampliconic genes are exceptions to Ohno's law: only 31% of human and 22% of mouse X-ampliconic genes had orthologs in the other species. X-ampliconic genes are expressed predominantly in testicular germ cells, and many were independently acquired since divergence from the common ancestor of humans and mice, specializing portions of their X chromosomes for sperm production.

*the ampliconic class displays extraordinarily high sequence similarity to other sequences of the same region, has higher gene density than the X-degenerate class, and its genes are found in multiple copies and are expressed almost exclusively in the \testes
. http://phylogenous.wordpress.com/2010/08/04/y-chromsome-v-the-ampliconic-sequence-class/

This work is supported by the National Institutes of Health (grants HG00257 and HD064753).

David Page's primary affiliation is with Whitehead Institute, 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:
"Independent specialization of the human and mouse X chromosomes for the male germline"

Jacob L. Mueller (1), Helen Skaletsky (1,2), Laura G. Brown (1,2), Sara Zaghlul (1), Susan Rock (4), Tina Graves (4), Katherine Auger (5), Wesley C. Warren (4), Richard K. Wilson (4), David C. Page (1,2,3).

1. Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.

2. Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

3. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

4. The Genome Institute, Washington University School of Medicine, St. Louis, MO, USA.

5. The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

Original press release:http://wi.mit.edu/news/archive/2013/sex-chromosome-shocker-female-x-key-contributor-sperm-production