Studies expand understanding of X chromosome

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Studies expand understanding of X chromosome

17 Mar 2005 Medical News Today

NIH-supported research sheds new light on the role of sex chromosomes in health

and disease -

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. ,

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., City, CA.

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, 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 (http://www.ncbi.nih.gov/Genbank) at NIH's National Center

for Biotechnology Information (NCBI); the UCSC Genome Browser

(http://www.genome.ucsc.edu) at the University of California at Santa Cruz; the

Ensembl Genome Browser (http://www.ensembl.org) at the Wellcome Trust Sanger

Institute and the EMBL-European Bioinformatics Institute; the DNA Data Bank of

Japan (http://www.ddbj.nih.ac.jp); and EMBL-Bank

(http://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 http://www.genome.gov and additional information about NIGMS can be

found at http://www.nhgri.nih.gov.