Sequencing of X chromosome helps treat genetic disorders

The mysteries of both human sex chromosomes have now been laid bare with the publication of the sequence of the human X chromosome in the March 17 issue of Nature.

Scientists at the Wellcome Trust Sanger Institute in England led the effort to sequence the X, with significant contributions from WUSTL’s Genome Sequencing Center (GSC).

Women have two X chromosomes; men have an X and a Y chromosome.

The GSC collaborated with the Whitehead Institute at Massachusetts Institute of Technology to publish the sequence of the smaller Y chromosome in June 2003.

The Y chromosome features unusual sequences of coding designed to preserve the function of its genes.

The X chromosome, by contrast, is sized much closer to the other human chromosomes not involved in sex determination, which are collectively known as autosomes.

But the X chromosome also is interesting to many scientists because of its role in gender and because it contains a high number of genes linked to inherited genetic disorders.

“Some of these disease genes, like the gene for hemophilia, are recessive mutations,” said Bob Fulton, a GSC research associate. “That means if you have one good copy of the gene and one bad copy, you’re a carrier for the disease.

“That also means men, who have only one copy of the X chromosome, are much more likely to get the disorders than women, who have two copies of the X chromosome.”

When a gene mutates on autosomes, a normal version of the gene found on the second copy of the autosome is often able to compensate. In males, though, there’s only one copy of the X chromosome, so no normal copies of the gene can compensate.

This baring of mutation’s effects first led scientists to associate genes with chromosomes in 1910, when a scientist found that a mutation that gives fruit flies white eyes shows up disproportionately in male fruit flies and is linked to inheritance of the X chromosome.

Females can suffer from inherited disorders or changes linked to genes on the X chromosome, but they often have to get two damaged or altered copies of the gene.

Scientists cloned the first human disease genes for muscular dystrophy and an immune system disorder, called chronic granulomatous disease, from the X chromosome in the early 1980s.

Scientists have now associated more than 300 diseases with the X chromosome, proportionally the highest of any chromosome so far.

Other conditions linked to the X chromosome include color blindness and cleft palate.

The X chromosome genome sequence has already allowed researchers to isolate more than 40 genes involved in medical conditions and disorders, which improve their ability to diagnose the disorders and potentially open up new avenues for development of treatments.

GSC researchers contributed base-pair sequencing data included in the published X chromosome sequence and also contributed heavily to a tool known as the “finger-print map.”

Chromosomes are far too large for automated gene sequencing machines, therefore researchers chop up multiple copies of the chromosome into pieces prior to sequencing.

The fingerprint map is a way to determine where those pieces came from on the chromosome by comparing many different pieces of varying lengths.

Other sex chromosomes being sequenced at the GSC include the mouse and chimp Y chromosomes and the chicken sex chromosomes, which are different from other sex chromosomes and known as the Z and W chromosomes.