Disease-Causing Mutations in Healthy People

A large-scale genome sequencing effort identifies mutations with disease-causing potential at higher rates than expected.

By Amanda B. Keener | June 8, 2015


The frequencies of genetic mutations that affect how proteins function are currently based on how often those mutations end up causing detectable disease. According to a study published last week (June 4) in the The American Journal of Human Genetics, mutations with the potential to cause disease only do so about half of the time.

The study, which was part of a large-scale National Institutes of Health (NIH) genome sequencing project called ClinSeq, included more than 950 apparently healthy volunteers between the ages of 45 and 60. All participants carried about 100,000 protein-coding gene variants, but the majority of those variants were harmless. The NIH team found that just more than 100 donors carried potentially disease-causing genetic mutations. When the researchers followed up with 79 of these study participants, they found that although 34 had symptoms of the diseases or had family members with the diseases predicted by their genes, the participants were largely unaware of them.

“It was very startling,” study coathor Leslie Biesecker, chief of the Medical Genomics and Metabolic Genetics Branch at the NIH’s National Human Genome Research Institute told The Washington Post. “To say this is a lot of people is an understatement.”

According to the Washington Post, the results raise the estimated frequency of genetic conditions affecting humans from 0.02 percent to about 3 percent.

“These results show that you can dramatically improve your predictions based on genome sequence information,” Biesecker said in a statement. However, he added, that “in most cases, genes pinpoint a susceptibility, not a fate. It will be a clue for doctors and patients about what you should look for—and how to stop it.”

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Avatar of: amoneret-vautrin


Posts: 1

June 9, 2015

Could I receive  this paper?

D Anne Moneret-Vautrin, emeritus professor

faculty of Medicine

Nancy,  France

Avatar of: S.Pelech-Kinexus


Posts: 7

June 9, 2015

The observation of a high number of potentially disease-causing mutations in apparently healthy volunteers in the ClinSeq study is not new nor surprising.  MacArthur et al. [ 2012 Feb 17;335(6070):823-8.] found that in the individual genomes of about 185 healthy people, there were typically about 100 genuine loss-of-function variants with about 20 genes that were completely inactivated. Apparently, there are a lot of redundancies in gene functionalities, and compensatory changes in gene expression and post-translational modifications in the expressed proteins that can successfully offset many genetic defects in most people.

This capacity of gene and protein networks to adjust for genetic variation accounts for why gene sequencing studies most often do not strongly correlate with the occurrence of the most common types of disease. For example, in a study by Roberts et al. [Sci Transl Med. 2012 May 9; 4(133): 133ra58.] with 53,666 monozygotic twins with similar if not identical genome sequences, when they were analyzed for their afflictions with 24 different diseases, there was no difference in the codevelopment of 23 of these diseases in the identical twins than what was expected in the general population. In a more recent report by Polderman et al. [ 2015 May 18. doi: 10.1038/ng.3285.] looking into the heritability of 17,804 traits from 2,748 other publications that included 14,558,903 twins, it was evident that environmental influences were equally important to genetics in the manifestations of these traits. These traits included the susceptibility to human diseases. 

Outside of specific cancers, genome-wide sequencing as contemplated for the delivery of personalized medicine will only provide insight into the potential cause and most effective treatments for a very limited number of disease cases in the foreseeable future.

Avatar of: tvence


Posts: 1052

Replied to a comment from amoneret-vautrin made on June 9, 2015

June 10, 2015

Thanks for reading, amoneret-vautrin! The abstract is linked above: http://www.cell.com/ajhg/abstract/S0002-9297(15)00150-0

All the best,

Tracy Vence

News Editor, The Scientist



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