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Studies Expand Understanding of X Chromosome

NIH-Supported Research Sheds New Light on the Role Of Sex Chromosomes in Health and Disease

Image of DNA Double Helix BETHESDA, Md., Wed., March 16, 2005 - The National Institutes of Health (NIH) hailed the first comprehensive analysis of the sequence of the human X chromosome, saying that this provides sweeping new insights into the evolution of sex chromosomes and the biological differences between males and females. These studies, a detailed analysis of the X chromosome's DNA sequence and a survey of its gene activity, are published in the current issue of the journal Nature.

"These detailed analyses of the X chromosome represent a monumental achievement for biology and medicine. They are exciting examples of what is being learned from the vast trove of sequence data produced by the Human Genome Project and made freely available to researchers around the world," said Francis S. Collins, M.D., Ph.D., director of National Human Genome Research Institute (NHGRI), part of NIH, which led the U.S. component of the Human Genome Project along with the Department of Energy.

The sequencing work on the X chromosome was carried out as part of the Human Genome Project at the Wellcome Trust Sanger Institute in Hinxton, England; Baylor College of Medicine, Houston; Washington University School of Medicine, St. Louis; the Max Planck Institute for Molecular Genetics, Berlin; the Institute of Molecular Biotechnology, Jena, Germany; and Applied Biosystems, Inc., Foster

In the first study, an international team of more than 250 genomic researchers led by the Wellcome Trust Sanger Institute described an analysis of the complete DNA sequence of the human X chromosome. In humans and other mammals, sexual identity is governed by a pair of chromosomes referred to as "X" and "Y." Females have two X chromosomes, while males have one X chromosome and one Y chromosome.

One of the central goals of the effort to analyze the human genome is the identification of all genes, which are generally defined as stretches of DNA that code for particular proteins. The new analysis confirmed the existence of 1,098 protein-coding genes on the X chromosome. Only 54 of the 1,098 genes have functional counterparts on the much smaller Y chromosome, which has been described as an "eroded" version of the X chromosome. Interestingly, almost 10 percent of the genes on the X chromosome are part of a somewhat mysterious family of "cancer-testis antigens," which are normally expressed in the testis but also appear in certain cancers, making them possible targets for immunotherapy.

The X chromosome's gene density is among the lowest for the human chromosomes that have been analyzed to date. Researchers say this may reflect a low density of genes on the ancestral chromosome that gave rise to the X chromosome, or it may indicate that genes coding for key proteins that are required in double dose were transferred from the X chromosome to other chromosomes during the course of mammalian evolution.

Despite its relatively low gene density, the X chromosome holds a prominent place in the study and understanding of human disease. This arises from the fact that any defects in genes on the X chromosome are often apparent in males because the Y does not carry corresponding genes to compensate. More than 300 diseases already have been mapped to the X chromosome, and though the X chromosome contains only 4 percent of all human genes, it accounts for almost 10 percent of inherited diseases caused by a single gene, which doctors often refer to as Mendelian disorders. These "X-linked" disorders include red-green color blindness, hemophilia, varied forms of mental retardation and Duchenne muscular dystrophy.

"From studying such genes, we can get remarkable insight into disease processes. But the importance of the sequence goes beyond individual genes. We have also gained a deep insight into the way evolution has shaped the chromosomes that determine our gender to give them unique properties," said Mark Ross, Ph.D., project leader at the Wellcome Trust Sanger Institute.

The research team compared the human X chromosome to the genome sequences of a variety of other organisms, including dog, rat, mouse and chicken. They found that the gene order of the human and dog X chromosomes were virtually identical. Comparing gene order in the human and rodent sequences showed several segments had reshuffled in the rodent lineage, and an interesting, 9 million base pair region appears to have been deleted from the rodent chromosome after humans and rodents diverged from their common ancestor.

Of particular interest was the comparison of the human X chromosome to the sequence of the chicken. Most of the genes on the short arm of the human X are found on chicken chromosome 1, and most of the genes on the long arm of the human X are found on chicken chromosome 4. These findings support the idea that mammalian X and Y chromosomes evolved from an "ordinary" ancestral pair of identical chromosomes.

The second study, which was supported by the NIH's National Institute of General Medical Sciences, focused on the activity of a large set of genes on the X chromosome. Researchers at the Duke University Institute for Genome Sciences & Policy in Durham, N.C., and Pennsylvania State University in University Park surveyed the activity, or expression, of 471 genes on the X chromosomes of 40 women. To their surprise, they found that each woman's X chromosomes showed a unique pattern of gene expression.

More than 45 years ago, researchers discovered that most genes on one copy of a female's X chromosome are switched off - a modification known as X-inactivation. This mechanism thus reduced the level of female expression of genes on the X chromosome to the same level as that in an XY male. Initially, it was thought the process resulted in a complete inactivation, or "silencing," of all of the genes on that copy of the chromosome in a female. However, in the late 1980s, researchers learned that some fraction of the genes remain active. The new work extends those findings to the complete set of X-linked genes.

Specifically, the researchers determined that due to the incomplete nature of X-inactivation, at least 15 percent of genes on the X chromosome produced proteins at higher, often variable, levels in females than in males. Furthermore, in some women but not in others, an additional 10 percent of the X-linked genes are expressed at variable levels.

Much more work is needed to explore the implications of the new findings for human health and disease. However, Duke's Huntington Willard, Ph.D., senior author of the study, said, "We now know that up to 25 percent of the X chromosome can be uniquely expressed in one sex relative to the other. Such differences should be recognized as a potential factor to explain sex-specific traits, both in complex disease as well as normal gender differences."

In October 2004, the International Human Genome Sequencing Consortium published its scientific description of the finished human genome sequence in Nature. Detailed annotations and analyses have already been published for chromosomes 5, 6, 7, 9, 10, 13, 14, 16, 19, 20, 21, 22 and Y. Publications describing the remaining chromosomes are forthcoming. The sequence of the X chromosome, as well as the rest of the human genome sequence, can be accessed through the following public databases: GenBank (www.ncbi.nih.gov/Genbank) at NIH's National Center for Biotechnology Information (NCBI); the UCSC Genome Browser (www.genome.ucsc.edu) at the University of California at Santa Cruz; the Ensembl Genome Browser (www.ensembl.org) at the Wellcome Trust Sanger Institute and the EMBL-European Bioinformatics Institute; the DNA Data Bank of Japan (www.ddbj.nig.ac.jp); and EMBL-Bank (www.ebi.ac.uk/embl/index.html) at the European Molecular Biology Laboratory's Nucleotide Sequence Database.

NHGRI and NIGMS are among the 27 institutes and centers at NIH, an agency of the Department of Health and Human Services. Additional information about NHGRI can be found at www.genome.gov and additional information about NIGMS can be found at www.nigms.nih.gov.

For more information, contact:

Geoff Spencer, NHGRI
(301) 402-0911

Ann Dieffenbach, NIGMS
(301) 496-7301

Last updated: August 01, 2012