X chromosome unveiled

17/3/05. By the Wellcome Trust Sanger Institute

New insights into the role of sex chromosomes in health and disease

On 17 March 2005, an international team led by the Wellcome Trust Sanger Institute published in the journal Nature an analysis of the remarkable X chromosome.

The study shows how we got an X chromosome and how it has been preserved (while the Y chromosome has degenerated). It also identifies new genes involved in disease and provides a gold-standard platform for studies to understand, to diagnose and, it is hoped, to treat a huge range of human disease.

The human X chromosome has a different biology to all others. Whereas females have two X chromosomes, males have only one X chromosome and a Y chromosome, which is an eroded version of the X chromosome, containing only a few genes.

The consequences are dramatic; any defects in genes on the X chromosome are often apparent in males because the Y chromosome does not carry corresponding genes to compensate.

These remarkable chromosomes evolved from humble beginnings as an 'ordinary' pair of identical chromosomes. It is thought that changes to a gene on one of the pair created the key switch in the pathway to male development and set in train the degeneration of this chromosome. As this emerging Y chromosome eroded, maintaining the integrity of the X chromosome was essential. When the integrity is compromised in human males, disease often results.

Human chromosomes. A DNA ‘paint’ identifies sequences on the X chromosome (yellow) and a small region at the tip of the Y chromosome. Image courtesy Dr Nigel Carter, Wellcome Trust Sanger Institute.

The new study confirmed the existence of 1098 protein-coding genes on the X chromosome. Only 54 of these genes have functional counterparts on the much smaller Y chromosome, which has only 76 known genes altogether and has been described as an 'eroded' version of the X chromosome.

More than 300 diseases have been mapped to the X chromosome - by far the highest proportion of any chromosome - including Duchenne muscular dystrophy and haemophilia.

The genome sequence has been used in the isolation of more than 40 genes that are involved in medical conditions, including cleft palate and blindness.

Background: Haemophilia A and B

Background: Duchenne and Becker muscular dystrophy

Interestingly, almost 10 per cent 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 importance of the sequence goes beyond the biology of individual genes," says Dr Mark Ross, Project Leader at the Wellcome Trust Sanger Institute. "We have also gained a deep insight into the evolution and biology of the whole chromosome. We can see the way evolution has shaped the chromosomes that determine our gender to give them their unique properties."

Adapted from a press release by the Wellcome Trust Sanger Institute.

X chromosome unveiled

Further reading