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Cardiff-Cambridge collaboration identifies 400 potentially damaging DNA variants in healthy people

17 December 2012

Researchers at Cardiff and Cambridge Universities have found that a healthy person carries, on average, approximately 400 potentially damaging DNA variants and two variants known to be associated directly with disease. The joint study, published in the American Journal of Human Genetics, showed that one in ten people is likely to develop a genetic disease as a consequence of carrying these variants.

It has been known for decades that all people carry some damaging genetic variants that appear to cause little or no ill effect. However, this is the first time that researchers have been able to quantify how many such variants each of us has, and to list them. This average figure of 400 is likely to increase as more and more powerful genetic studies discover rare genetic variants more efficiently. However, such research also brings to the fore ethical questions surrounding anonymous studies and what to do with incidental findings.

To perform their analysis, the Cardiff-Cambridge team cross-compared two existing datasets. The availability of whole genome sequences derived from 179 people enrolled in the 1000 Genomes Pilot Project, allowed scientists to draw up a detailed catalogue of human disease-causing mutations. Samples for this study were taken from individuals who were unlikely to have any overt genetic disease. This DNA sequence information was then directly compared with data from the Human Gene Mutation Database (HGMD), a comprehensive collection of published data on gene mutations underlying or associated with human inherited disease ( which has been developed over the last 15 years at Cardiff University’s Institute of Medical Genetics.

"In the majority of people we found to have a potential disease-causing mutation, the genetic condition is actually quite mild, or would only become apparent in the later decades of life," says Professor David Cooper, lead author of the study from Cardiff University. "We now know that normal healthy people can possess many damaged or even completely inactivated proteins without any noticeable impact on their health. It is extremely difficult to be able to predict the clinical consequences of a given genetic variant. So databases such as HGMD promise to come into their own as we enter the new era of personalized medicine."

"For over half a century, medical geneticists have wanted to establish the magnitude of the damage caused by harmful variants in our genomes," says Dr Yali Xue, one of the authors from the Wellcome Trust Sanger Institute. "Our study finally brings us closer to understanding the extent of these damaging mutations."

In many cases, the disease or damaged variants were single genetic variants with a recessive mode of inheritance that are unlikely to cause any harm to the carrier. A recessive genetic variant will only exert its effect when two copies - one on each of a pair of homologous chromosomes - are present. In one in ten people, however, the team could point to a potential clinical effect of the genetic variants. This is because these people either carry two copies of a specific recessive disease variant, or alternatively a dominant genetic variant. Dominant disease genetic variants can give rise to a disease trait when even a single copy is present.

A variety of databases of disease-causing mutations have been created over the past 25 years. However, they are generally small and gene-specific. HGMD is unique in that it attempts to collate all reported gene mutations underlying or associated with human inherited disease, currently 135,000 different lesions in 5,200 different genes. HGMD has more than 58,000 registered users worldwide but is nevertheless still far from complete in terms of the data it seeks to collect. Reported gene mutations are likely to represent only the tip of a very large iceberg. Disease variants are generally rare and comprehensive searches for such mutations in many populations have scarcely begun. Although originally established for the scientific study of mutational mechanisms in human genes, over the last decade HGMD has acquired a much broader utility for researchers, physicians, clinicians and genetic counsellors as well as for companies specializing in biopharmaceuticals, bioinformatics and personalised genomics.


Notes to Editors

Publication details:

Deleterious- and Disease-Allele Prevalence in Healthy Individuals: Insights from Current Predictions, Mutation Databases, and Population-Scale Resequencing
Yali Xue, Yuan Chen, Qasim Ayub, et al
American Journal of Human Genetics
2012; 91(6):1022-1032.
A copy of the paper can be accessed here: 10.1016/j.ajhg.2012.10.015

For further information or to arrange a media interview, please contact:

Tomas Llewelyn Barrett
Public Relations
Cardiff University
Tel: 029 20 875 596