Scientists at the Wellcome Trust Sanger Institute, Cambridge, UK, and the Institute of Medical Genetics, School of Medicine, Cardiff University, reported in the December 6 online edition of the American Journal of Human Genetics that they had compiled a catalog of deleterious and disease-causing genetic variants in healthy people.
The scientists created the catalog from information obtained by comparing two different datasets: a dataset containing whole-genome sequences from 179 individuals in the 1000 Genomes Pilot Project, and a second with information from the Human Gene Mutation Database (HGMD).
These comprehensive catalogs provide both high-penetrance variants underlying Mendelian disorders (Online Mendelian Inheritance in Man and HGMD) and low-penetrance variants contributing to complex disorders (National Human Genome Research Institute [NHGRI] Catalog of Published Genome-Wide Association Studies).
“For over half a century, medical geneticists have wanted to establish the magnitude of the damage caused by harmful variants in our genomes,” says Yali Xue, Ph.D., lead author from the Wellcome Trust Sanger Institute. “Our study finally brings us closer to understanding the extent of these damaging mutations.”
The researchers found that on average a normal healthy person carries approximately 400 potentially damaging DNA variants and two variants known to be associated directly with disease traits. They showed that one in ten of the individuals studied are expected to develop a genetic disease as a consequence of carrying these variants.
It is has been known that all people carry some damaging genetic variants that appear to cause little or no ill effects, but this research quantifies how many variants an individual has and lists them. The investigators say that figure of 400 is likely to increase as more and more powerful genetic studies discover rare genetic variants more efficiently.
In one in ten people, however, the team could point to a potential clinical effect of the genetic variants 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.
Specifically, the researchers showed that each individual carried 281–515 missense substitutions, 40–85 of which were homozygous, predicted to be highly damaging. They also carried 40–110 variants classified by the HGMD as disease-causing mutations (DMs), 3–24 variants in the homozygous state, and many polymorphisms putatively associated with disease.
The scientists noted that whereas many of these deleterious mutations are likely to represent disease-allele-annotation errors, between 0 and 8 DMs (0–1 homozygous) per individual are predicted to be highly damaging, and some of them provide information of medical relevance.
These analyses emphasize, the authors said, the need for improved annotation of disease alleles both in mutation databases and in the primary literature.
Professor David Cooper, Ph.D, lead author of the study from Cardiff University noted, “We now know that normal healthy people can possess many damaged or even completely inactivated proteins without any noticeable impact on their health.”
Dr. Cooper also noted that it would be “extremely difficult to predict the clinical consequences of a given genetic variant, but databases such as HGMD promise to come into their own as we enter the new era of personalized medicine.”