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Sequencing the X Chromosome 3/24/05

Thu, 03/24/2005 - 9:33am
An international team completed the most comprehensive analysis of the X chromosome that shows the origin of the X chromosome and how it has been preserved, while the Y chromosome has degenerated. It also identifies new genes involved in disease and provides, they say, a gold-standard platform for studies to understand, to diagnose and, it is hoped, to treat a huge range of human disease.

The team, which published the work recently in Nature, was led by the Wellcome Trust Sanger Institute, Cambridge, UK, and major contributions to the sequence came from groups at Baylor College of Medicine, Houston, Institute for Molecular Biotechnology, Jena, Germany, Washington University Genome Sequencing Center, St Louis, Mo., and Max-Planck- Institute for Molecular Genetics, Berlin, Germany.

"To date, complex diseases that show a bias in males such as autism, dyslexia, specific language impairment, and attention deficit/hyperactivity disorder have not shown strong evidence for major X-linked genes involved in susceptibility in genetic studies using families,” said Tony Monaco, PhD, director and head of Neurogenetics Group, Wellcome Trust Centre for Human Genetics, Oxford, UK. “However, as the complete sequence of the X chromosome is now available with a high density of single nucleotide polymorphisms (SNPs), association studies for these neurodevelopmental disorders may have more power to identify genes on the X chromosome with variants that increase susceptibility.”

To complete the sequence researchers constructed a map of the X chromosome using predominantly P1-artificial chromosome (PAC) and bacterial artificial chromosome (BAC) clones, assembled into contigs. A total of 1,832 clones were selected from the map for shotgun sequencing. The finished sequence is estimated to be more than 99.99% accurate and covering at least 99.3% of the X chromosome euchromatin.

The complete chromosome was 155,000,000 base pairs in size. A total of 1,098 genes were identified with 399 of those as new. The largest gene, the gene for Duchenne muscular dystrophy, was 2,220,223 base pairs in size. SNPs, 153,146 candidates in all, were mapped onto the X chromosome sequence at the density of one SNP per 1,012 base pairs.

The Y chromosome, is an eroded version of the X chromosome so defects in genes on the X chromosome are often apparent in males because the Y chromosome does not carry corresponding genes to compensate. For mutations on the X chromosome, the diseases are, most often, diseases of males.A detailed comparison of the human X and Y chromosome sequences, carried out in the study, reveals the extent of Y chromosome decay in non-recombining regions. Just 54 genes were found to be shared with Y chromosome.

To understand the evolution of the chromosome, the researchers performed an alignment of the human X and chicken whole genome sequences and found homologies between the human X chromosome and chicken autosomes. They also performed comparisons with other mammalian sequences.

"The X chromosome was pivotal in early human genetics because we were able to see clearly how mutations cause disease," said David Bentley, PhD, head of human genetics at the Institute. "There are many more genetic disorders on the X chromosome where the underlying gene is still to be found. Now we can make use of the finished sequence to find them. These discoveries will have a major impact on our understanding of many fundamental biological processes."

By Elizabeth Tolchin


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