Studies Expand Understanding of X Chromosome
NIH-Supported Research Sheds New Light on the Role of Sex Chromosomes
in Health and Disease
Bethesda, Maryland 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 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 (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. |