16th March 2005

What Sex did to the X - and Why

A chromosome account of evolution and revolution

What Sex did to the X - and Why; A chromosome account of evolution and revolution

What Sex did to the X - and Why; A chromosome account of evolution and revolution

The human X chromosome is about sex and how it evolved. It also has a unique position in the history of genetics - and the genetics of history.

On Thursday 17 March 2005, an international team led by the Wellcome Trust Sanger Institute, Cambridge, UK publishes in Nature the most complete analysis of this remarkable chromosome. Other major contributions to the sequence came from groups at Baylor College of Medicine, Houston TX, USA, Institute for Molecular Biotechnology, Jena, Germany, Washington University Genome Sequencing Center, St Louis, MO, USA and Max-Planck-Institute for Molecular Genetics, Berlin, Germany.

The landmark 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. For mutations on the X chromosome, the diseases are, most often, diseases of males - and not of humankind.

More than 300 diseases have been mapped to the X chromosome - by far the highest proportion of any chromosome - including Duchenne Muscular Dystrophy (DMD) 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.

"From studying such genes, we can get remarkable insight into disease processes," says Mark Ross, Project Leader at the Wellcome Trust Sanger Institute. "From our study of one gene involved in an X-linked disease, a genetic test was developed and a new pathway that controls the workings of the immune system was discovered."

"But the importance of the sequence goes beyond the biology of individual genes. 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."

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.

"The X chromosome was pivotal in early human genetics because we were able to see clearly how mutations cause disease," said Dr Bentley, 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."

The X chromosome played an important part in developing the methods of genetics in the molecular age. One of the first genes cloned using modern methods was that involved in Duchenne Muscular Dystrophy. For genes such as DMD, diagnosis has been transformed by genomic sequence and we are beginning to see hopes for new treatments based on that understanding.

"The X chromosome has a unique place in biology and medicine. It is the first chromosome to which a human trait was mapped. Its remarkable biology has played a key role in understanding many important genetic causes of human disease," says Dr Mark Walport, Director of the Wellcome Trust. "The freely available sequence analysis is a landmark in our understanding of the role of this chromosome in health and disease. Our task now is to ensure that we translate these research findings into improved healthcare."

There remain many conditions that are associated with genes on the X chromosome for which a genetic basis is lacking. In simple cases, a 'candidate' gene can be identified and tracked down. For more complex diseases, more than one gene may be involved and the hunt is much more difficult and the path littered with false clues and false dawns. However, new methods that make use of the sequence are being developed to identify genes involved in common disease.

"The detailed analysis of the sequence of the human X chromosome is a monumental achievement. This work represents yet another exciting example of what we can learn from the vast trove of sequence data produced by the Human Genome Project and made freely available to researchers around the world," says Francis S. Collins, MD, PhD, director of the National Human Genome Research Institute, which along with the U.S. Department of Energy, led the Human Genome Project in the United States.

The X chromosome has played its part in political history: X-linked human diseases include haemophilia, in which the blood fails to clot properly. Queen Victoria was a 'carrier' of haemophilia and passed it to her own children and, through them, to the Royal families of Europe. It has been argued that inheritance of haemophilia by Alexei, son of the last Tsar of Russia, led indirectly to the Russian Revolution.

This chromosome has also been vital to biomedical history: from the first gene mapped in the human - red-green colour blindness in 1911 - to searching for an understanding of human diseases, this unique chromosome has taught us an enormous amount about genetics and human biology. From the sequence, much knowledge has already been wrested, but there is much more of the X to understand.

Notes to Editors

Additional Materials

Participating Centres

  • The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK
  • Baylor College of Medicine Human Genome Sequencing Center, Department of Molecular and Human Genetics, One Baylor Plaza, Houston, Texas 77030, USA
  • Genomanalyse, Institut fur Molekulare Biotechnologie, Beutenbergstr. 11, 07745 Jena, Germany
  • Washington University Genome Sequencing Center, Box 8501, 4444 Forest Park Avenue, St. Louis, Missouri 63108, USA
  • Max-Planck-Institute for Molecular Genetics, Ihnestrasse 73, 14195 Berlin, Germany
  • Institute for Clinical Molecular Biology, Christian-Albrechts-University, 24105 Kiel, Germany
  • Medizinische Genetik, Ludwig-Maximilian-Universitat, Goethestr. 29, 80336 Munchen, Germany
  • HUGO Gene Nomenclature Committee, The Galton Laboratory, Department of Biology, University College London, Wolfson House, 4 Stephenson Way, London NW1 2HE, UK
  • Department of Biochemistry and Molecular Biology, Pennsylvania State College of Medicine, Hershey, Pennsylvania 17033, USA
  • Advanced Center for Genetic Technology, PE-Applied Biosystems, Foster City, California 94404 USA
  • European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK
  • Institute of Genetics and Biophysics, Adriano Buzzati-Traverso, Via Marconi 12, 80100 Naples, Italy
  • Medical Genetics Section, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK
  • Laboratoire de Genetique et de Physiopathologie des Retards Mentaux, Institut Cochin. Inserm U567, Universite Paris V., 24 rue du Faubourg Saint Jacques, 75014 Paris, France
  • BACPAC Resources, Children's Hospital Oakland Research Institute, 747 52nd Street, Oakland California 94609, USA
  • Molekulare Genomanalyse, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany
  • Institute of Human Genetics, GSF National Research Center for Environment and Health, Ingolstadter Landstr. 1, 85764 Neuherberg, Germany
  • RZPD Resource Center for Genome Research, 14059 Berlin, Germany
  • National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
  • Laboratory of Genetics, National Institute on Aging, NIH, 333 Cassell Drive, Baltimore, Maryland 21224, USA
  • Institute for Genome Sciences & Policy, Duke University, Durham, North Carolina 27708, USA

Publication

  • The DNA sequence of the human X chromosome.

    Ross MT, Grafham DV, Coffey AJ, Scherer S, McLay K, Muzny D, Platzer M, Howell GR, Burrows C, Bird CP, Frankish A, Lovell FL, Howe KL, Ashurst JL, Fulton RS, Sudbrak R, Wen G, Jones MC, Hurles ME, Andrews TD, Scott CE, Searle S, Ramser J, Whittaker A, Deadman R, Carter NP, Hunt SE, Chen R, Cree A, Gunaratne P, Havlak P, Hodgson A, Metzker ML, Richards S, Scott G, Steffen D, Sodergren E, Wheeler DA, Worley KC, Ainscough R, Ambrose KD, Ansari-Lari MA, Aradhya S, Ashwell RI, Babbage AK, Bagguley CL, Ballabio A, Banerjee R, Barker GE, Barlow KF, Barrett IP, Bates KN, Beare DM, Beasley H, Beasley O, Beck A, Bethel G, Blechschmidt K, Brady N, Bray-Allen S, Bridgeman AM, Brown AJ, Brown MJ, Bonnin D, Bruford EA, Buhay C, Burch P, Burford D, Burgess J, Burrill W, Burton J, Bye JM, Carder C, Carrel L, Chako J, Chapman JC, Chavez D, Chen E, Chen G, Chen Y, Chen Z, Chinault C, Ciccodicola A, Clark SY, Clarke G, Clee CM, Clegg S, Clerc-Blankenburg K, Clifford K, Cobley V, Cole CG, Conquer JS, Corby N, Connor RE, David R, Davies J, Davis C, Davis J, Delgado O, Deshazo D, Dhami P, Ding Y, Dinh H, Dodsworth S, Draper H, Dugan-Rocha S, Dunham A, Dunn M, Durbin KJ, Dutta I, Eades T, Ellwood M, Emery-Cohen A, Errington H, Evans KL, Faulkner L, Francis F, Frankland J, Fraser AE, Galgoczy P, Gilbert J, Gill R, Glöckner G, Gregory SG, Gribble S, Griffiths C, Grocock R, Gu Y, Gwilliam R, Hamilton C, Hart EA, Hawes A, Heath PD, Heitmann K, Hennig S, Hernandez J, Hinzmann B, Ho S, Hoffs M, Howden PJ, Huckle EJ, Hume J, Hunt PJ, Hunt AR, Isherwood J, Jacob L, Johnson D, Jones S, de Jong PJ, Joseph SS, Keenan S, Kelly S, Kershaw JK, Khan Z, Kioschis P, Klages S, Knights AJ, Kosiura A, Kovar-Smith C, Laird GK, Langford C, Lawlor S, Leversha M, Lewis L, Liu W, Lloyd C, Lloyd DM, Loulseged H, Loveland JE, Lovell JD, Lozado R, Lu J, Lyne R, Ma J, Maheshwari M, Matthews LH, McDowall J, McLaren S, McMurray A, Meidl P, Meitinger T, Milne S, Miner G, Mistry SL, Morgan M, Morris S, Müller I, Mullikin JC, Nguyen N, Nordsiek G, Nyakatura G, O'Dell CN, Okwuonu G, Palmer S, Pandian R, Parker D, Parrish J, Pasternak S, Patel D, Pearce AV, Pearson DM, Pelan SE, Perez L, Porter KM, Ramsey Y, Reichwald K, Rhodes S, Ridler KA, Schlessinger D, Schueler MG, Sehra HK, Shaw-Smith C, Shen H, Sheridan EM, Shownkeen R, Skuce CD, Smith ML, Sotheran EC, Steingruber HE, Steward CA, Storey R, Swann RM, Swarbreck D, Tabor PE, Taudien S, Taylor T, Teague B, Thomas K, Thorpe A, Timms K, Tracey A, Trevanion S, Tromans AC, d'Urso M, Verduzco D, Villasana D, Waldron L, Wall M, Wang Q, Warren J, Warry GL, Wei X, West A, Whitehead SL, Whiteley MN, Wilkinson JE, Willey DL, Williams G, Williams L, Williamson A, Williamson H, Wilming L, Woodmansey RL, Wray PW, Yen J, Zhang J, Zhou J, Zoghbi H, Zorilla S, Buck D, Reinhardt R, Poustka A, Rosenthal A, Lehrach H, Meindl A, Minx PJ, Hillier LW, Willard HF, Wilson RK, Waterston RH, Rice CM, Vaudin M, Coulson A, Nelson DL, Weinstock G, Sulston JE, Durbin R, Hubbard T, Gibbs RA, Beck S, Rogers J and Bentley DR

    Nature 2005;434;7031;325-37

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The Wellcome Trust Sanger Institute

The Wellcome Trust Sanger Institute, which receives the majority of its funding from the Wellcome Trust, was founded in 1992. The Institute is responsible for the completion of the sequence of approximately one-third of the human genome as well as genomes of model organisms and more than 90 pathogen genomes. In October 2006, new funding was awarded by the Wellcome Trust to exploit the wealth of genome data now available to answer important questions about health and disease.

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The Wellcome Trust and Its Founder

The Wellcome Trust is the most diverse biomedical research charity in the world, spending about £450 million every year both in the UK and internationally to support and promote research that will improve the health of humans and animals. The Trust was established under the will of Sir Henry Wellcome, and is funded from a private endowment, which is managed with long-term stability and growth in mind.

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