BioWorld International Correspondent
LONDON - The X chromosome - unique in the human genome - now has revealed its secrets, if only in code form. The sequence of the X chromosome promises to deliver answers to the mysteries of many inherited diseases, as well as eventually making it possible to develop therapies for those conditions.
Analysis of the sequence has identified regions coding for almost 1,100 genes. It also unveils the evolution of the X chromosome, and how the X chromosome has been preserved while the Y chromosome has degenerated.
An international team led by the Wellcome Trust Sanger Institute in Cambridge, UK, published the analysis in Nature last week, in a paper titled "The DNA sequence of the human X chromosome." Other groups that made major contributions to the sequence were Baylor College of Medicine in Houston; the Institute for Molecular Biotechnology in Jena, Germany; Washington University Genome Sequencing Center in St Louis; and the Max Planck Institute for Molecular Genetics in Berlin.
Allan Bradley, director of the Sanger Institute, said, "We are already seeing clinical benefits, and the sequence will stimulate research into the unusual biology of the X chromosome."
While female humans inherit an X chromosome from both parents, males inherit a single X chromosome from their mothers and a Y chromosome from their fathers. As a result, any defects in genes on the X chromosome often are apparent in males because the short Y chromosome does not carry corresponding genes to compensate.
In females, there is a need to shut down the genes on one of the X chromosomes to avoid females producing twice as much protein from those genes as males, a phenomenon called X chromosome inactivation.
A companion paper in the same issue of Nature by Laura Carrel, of Pennsylvania State University College of Medicine in Hershey, and Huntington Willard, of Duke University in Durham, N.C., provides a catalog of the inactivation state of X-linked genes.
That paper, titled "X-inactivation profile reveals extensive variability in X-linked gene expression in females," concludes that about three-quarters of X chromosome genes in females are permanently silent, while about 15 percent are never inactivated. Those genes are, therefore, expressed at twice the level in females as in males. The remainder are expressed in some inactive X chromosomes but not in others - leading to variable gene expression in females that could have clinical consequences.
More than 300 diseases already have been mapped to the X chromosome, including Duchenne's muscular dystrophy (DMD) and hemophilia. The genome sequence has been used to help isolate more than 40 genes that are involved in medical conditions including cleft palate and blindness.
Mark Ross, project leader at the Sanger Institute, said, "From studying such genes, we can get remarkable insight into disease processes."
Kay Davies, a leading researcher in muscular dystrophy at the University of Oxford, said: "There are still questions about the DMD locus, which the sequence will help us answer. It has a very high rate of new mutations and part of the gene is deleted with high frequency. We are still trying to understand the complex genetics of this, the largest gene in the human genome."
Martin Bobrow, of the Cambridge Institute for Medical Research, has worked for many years on the diagnosis and mechanisms of X-linked diseases, including X-linked lymphoproliferative disease, muscular dystrophies and Alport syndrome, which leads to kidney failure.
"Although we have known the genes for many of these conditions for a while," he said, "we still do not know much about how these genes are controlled, and this may be critical information if new therapies are to be developed. The sequence of the X chromosome will contribute directly to this, and an accurate catalog of genes will make that task much easier."
Davies added that the sequence opens up many new avenues of research.
"For me, the finished sequence provides an opportunity to look for genes involved in intellectual disability, many of which have been mapped to the X chromosome," Davies said. "Researchers can examine all the candidate genes to analyze them for mutations. The fragile X syndrome is well known, but there are others, such as the FRAXE site, associated with milder mental impairment. The sequence of this gene will be vital in understanding its role and that of the related ALF gene family, which is involved in leukemia and other disorders."