Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers map of genetic variations implicated in disease

27.01.2006


Finding the variants that human history has favoured



Sequence differences in less than 0.2% of the 3-billion-base human genome play a vital role in a bewildering variety of human disease. Today, researchers from the Wellcome Trust Sanger Institute and the Cambridge University’s Cambridge Institute for Medical Research, together with international colleagues report in PLoS Genetics their detailed maps of differences implicated in disease as well as genes that are unchanged in recent human history.

The Major Histocompatibility Complex (MHC) consists of hundreds of genes on human chromosome 6 that are important in most autoimmune conditions, when our biological defences turn on our own systems. The MHC has the major role in type 1 diabetes and rheumatoid arthritis. The MHC is also pivotal in response to infection, including malaria and AIDS.


Genes in the MHC can differ dramatically between people, and the differences among us affect medical events as diverse as tissue transplant rejection, arthritis, asthma and disease resistance. A detailed study of this region in different people will shed light on which genes are most important.

"We analysed the entire MHC region in detail from three individuals that carried different susceptibility to disease," explained Dr Stephan Beck, leader of the team at the Wellcome Trust Sanger Institute. Key differences were then further analysed in a much larger population of 140 DNA samples.

"Within the sea of over 20,000 sequence variations across the 4 million MHC bases, we found one island of stability," continued Dr Beck. "A region of 160,000 bases that is up to 200-fold less variant between chromosomes sharing part of the same HLA type, suggesting these individuals most likely shared a common ancestor as recently as 50,000 years ago."

Swapping of ancestral sequence blocks is a potential mechanism (identity-by-descent) whereby certain gene combinations, which presumably have favoured immunological advantage (e.g. resistance to infectious disease), can spread across haplotypes and populations.

Professor John Trowsdale, at the Department of Pathology, University of Cambridge, said, "The region, called DR-DQ, where we find this island of stability is one of the most variable in our genome, yet in some people it has been ’fixed’. We suggest that ancestral DR-DQ blocks have been shuffled into different MHC backgrounds and subsequently expanded in frequency across European populations.

"These ’fixed’ haplotypes might then have expanded because they protected against infection and disease. We hope to show, in further studies, whether this stable region was a key to disease resistance in our recent past."

The study further described over 300 amino acid changing variants in gene sequences. These variants are strong candidates for functional studies to understand the role of variation in MHC-associated disease.

Autoimmune disease affects about 3 million people in the UK. The three haplotypes studied here display different susceptibilities to diseases such as type 1 diabetes, myasthenia gravis and multiple sclerosis.

For some common autoimmune diseases the MHC provides by far the largest genetic contribution by a single chromosome region. For example, the MHC accounts for at least 30% of the familial aggregation in type 1 diabetes and rheumatoid arthritis.

"Data generated by projects such as the MHC Haplotype Project will feed into the recently announced Wellcome Trust Case-Control Consortium," explained Professor John Todd, Professor of Medical Genetics at the Cambridge Institute for Medical Research, "and the WTCCC search for the genetic signposts for eight common diseases will be accelerated by the new markers reported here. At an ever increasing rate, we are developing the necessary tools and sample collections to make a real difference to the study, diagnosis and, we hope, treatment of diseases such as TB, coronary heart disease, diabetes and rheumatoid arthritis."

The MHC Haplotype Project is creating a public resource to assist the discovery of genetic factors influencing these medical traits and to shed light on the evolution of the MHC. Access to complete sequences across several MHC haplotypes that exhibit differences in disease susceptibility will help researchers to home in on specific variants (susceptibility alleles) and to rule out regions contributing to a given disease.

Haplotypes and the MHC

Haplotypes are combinations of gene and sequence variants that tend to occur together in an individual genome. This may be purely fortuitous, or it may reflect selection of given combinations (they have been successful in the past), or it may reflect a population bottleneck, where only a few, perhaps similar, genomes have contributed to the further population growth.

The MHC is among the most gene-dense regions of the human genome and the most variable, as might be expected from a region involved in fighting infection (as well as other functions). Over evolutionary time, the MHC has been driven to become the most variable region of our genome.

The MHC Haplotype Project is studying in fine detail the sequence of eight of the most common human haplotypes, selected for conferring protection against or susceptibility to common disease. The detailed analysis of the third of these eight is reported here and compared with the two previously described.

The COX haplotype has been associated with susceptibility to a wide range of diseases, including type 1 diabetes, systemic lupus erythematosus and myasthenia gravis. The PGF haplotype provides protection against type 1 diabetes and predisposes to other diseases such as multiple sclerosis and systemic lupus erythematosus. The QBL haplotype is positively associated with Graves’ disease and type 1 diabetes.

Dr. Don Powell | EurekAlert!
Further information:
http://www.plos.org
http://www.sanger.ac.uk

More articles from Life Sciences:

nachricht Flow of cerebrospinal fluid regulates neural stem cell division
21.05.2018 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt

nachricht Chemists at FAU successfully demonstrate imine hydrogenation with inexpensive main group metal
21.05.2018 | Friedrich-Alexander-Universität Erlangen-Nürnberg

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Explanation for puzzling quantum oscillations has been found

So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics

Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...

Im Focus: Dozens of binaries from Milky Way's globular clusters could be detectable by LISA

Next-generation gravitational wave detector in space will complement LIGO on Earth

The historic first detection of gravitational waves from colliding black holes far outside our galaxy opened a new window to understanding the universe. A...

Im Focus: Entangled atoms shine in unison

A team led by Austrian experimental physicist Rainer Blatt has succeeded in characterizing the quantum entanglement of two spatially separated atoms by observing their light emission. This fundamental demonstration could lead to the development of highly sensitive optical gradiometers for the precise measurement of the gravitational field or the earth's magnetic field.

The age of quantum technology has long been heralded. Decades of research into the quantum world have led to the development of methods that make it possible...

Im Focus: Computer-Designed Customized Regenerative Heart Valves

Cardiovascular tissue engineering aims to treat heart disease with prostheses that grow and regenerate. Now, researchers from the University of Zurich, the Technical University Eindhoven and the Charité Berlin have successfully implanted regenerative heart valves, designed with the aid of computer simulations, into sheep for the first time.

Producing living tissue or organs based on human cells is one of the main research fields in regenerative medicine. Tissue engineering, which involves growing...

Im Focus: Light-induced superconductivity under high pressure

A team of scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg investigated optically-induced superconductivity in the alkali-doped fulleride K3C60under high external pressures. This study allowed, on one hand, to uniquely assess the nature of the transient state as a superconducting phase. In addition, it unveiled the possibility to induce superconductivity in K3C60 at temperatures far above the -170 degrees Celsius hypothesized previously, and rather all the way to room temperature. The paper by Cantaluppi et al has been published in Nature Physics.

Unlike ordinary metals, superconductors have the unique capability of transporting electrical currents without any loss. Nowadays, their technological...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Save the date: Forum European Neuroscience – 07-11 July 2018 in Berlin, Germany

02.05.2018 | Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

Unique scope of UV LED technologies and applications presented in Berlin: ICULTA-2018

12.04.2018 | Event News

 
Latest News

Supersonic waves may help electronics beat the heat

18.05.2018 | Power and Electrical Engineering

Keeping a Close Eye on Ice Loss

18.05.2018 | Information Technology

CrowdWater: An App for Flood Research

18.05.2018 | Information Technology

VideoLinks
Science & Research
Overview of more VideoLinks >>>