The X factor, and why the sexes are so different
Tim Radford, science editor
Thursday March 17, 2005
The Guardian
Scientists have deciphered the chromosome that explains the difference between men and women and holds the secrets to at least 300 inherited diseases.
Chromosome X could reveal the precise machinery behind mental retardation, autism, colour blindness, muscular dystrophy, a host of other diseases - and even the colour pattern of calico cats. Haemophilia - an inherited condition linked to a gene on the X chromosome - played a role in the Russian revolution of 1917. Other X-linked genes, involved in gout, obesity, blindness, deafness, anaemia, cleft palate, epilepsy, leukaemia and infertility, affect the lives of millions.
"The X chromosome is probably - I would say definitely - the most extraordinary in the human genome in terms of its inheritance pattern, in terms of its unique biology and in terms of its association with human disease," said Mark Ross of the Wellcome Trust Sanger Institute at Cambridge, who led the British team in the international effort to analyse the 155m letters of DNA code, containing more than 1,100 genes, published in Nature today.
Humans inherit two copies of 22 chromosomes, one from each parent. But only women have two X chromosomes, and males are defined by having a Y chromosome and only one X. If there are errors or mutations on that X chromosome, then male carriers are more at risk, because they do not have a spare copy. The Y chromosome may once have been almost identical to the X: geneticists now see the Y as a poor, stunted thing, with very few remaining genes. But analysis of the X chromosome will throw light on the evolution of sex in mammal history, around 300m years ago.
It has already begun to explain why so many inherited diseases seem to afflict boys rather than girls. The identification of the genetic machinery with an estimated 300 inherited diseases already offers practical counselling, and could lead to treatments for conditions such as Duchenne muscular dystrophy.
"The X chromosome was pivotal in early human genetics because we were able to see clearly how mutations cause disease," said David Bentley, also of the Sanger Centre.
"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."
One of the first conditions linked to the X chromosome was haemophilia, in which the blood fails to clot. This was passed to the Russian royal line through Queen Victoria's daughter. Alexei, son of the last tsar of Russia, had haemophilia. Anxiety about his condition led his parents into close contact with the monk Rasputin, a link that is supposed to have helped precipitate the 1917 revolution and the fall of the Romanovs.
The X chromosome was also linked, more than 40 years ago, to the coat colouring of tortoiseshell or calico cats. These colour patterns are found only in female cats. The theory is that - to avoid a double dose of genetic proteins - one of the two chromosomes in every female is switched off, or made inactive. A British researcher, Mary Lyon, in 1961 suggested that this switching off occurred at random, leading to either normal or mutant colour patterns in female cats.
"In seeing what goes wrong, we really begin to understand those biological processes of the normal body much better," said Dr Bentley. "It really is a successful fusion of medicine and genome science that gives us a chance to explain that level of detail."
Researchers have already identified 168 of the estimated 300 genetic diseases linked to the X chromosome. Six - from night blindness to ocular albinism - affect the eyes. Other conditions show up in the ears, the skin, the kidney, the muscle, the joints, the nervous system, the face, the heart, the blood and the kidney. There are at least six X-linked diseases of the immune system, and seven involving metabolism. Asperger's syndrome, autism, and mental retardation - afflicting 2-3% of the population, but adding up to 8% of health spending - are also X-linked conditions.
The complete sequence for the chromosome allows scientists for the first time to begin to explore the machinery behind mental retardation: the cruel mutations that lead to low IQ in children - again, mostly boys. The knowledge is already being used to advise prospective parents.
"What we would like to do is find the remainder of the genes on the X chromosome that are responsible for mental retardation. There is likely to be as many as 100 different genes on the X chromosome that can result in it," said Mike Stratton of the Sanger Institute. "We should not forget that the understanding of these genes may allow us to intervene to prevent their onset."
