Analysis of 17 Million SNVs in 650 Tumors from Different Tissues Suggests Differential DNA Mismatch Repair Efficiency Underlies Mutation Rate Variation Across the Human Genome

Copying the large book that it is our genome without mistakes every time a cell divides is a difficult job. Luckily, our cells are well-equipped to proof-read and repair DNA mistakes. Now, two scientists from the EMBL-CRG Systems Biology Unit at the Centre for Genomic Regulation (CRG) in Barcelona, Spain, have published a study showing that mistakes in different parts of our genome are not equally well corrected. This means that some of our genes are more likely to mutate and, therefore, more likely to contribute to disease than others. The scientists analyzed 17 million “single nucleotide variants” (SNVs), i.e., mutations in just one nucleotide (letter) of the DNA sequence, by examining 650 human tumors from different tissues. These were so-called “somatic” mutations, meaning they are not inherited from parents or passed down to children, but, rather, accumulate in our bodies as we age. Such somatic mutations are the main cause of cancer. Many result from the impact of mutagens, such as tobacco smoke or ultraviolet radiation, and others come from naturally occurring mistakes that occur in the process of copying DNA as our tissues renew. Ben Lehner, Ph.D., Senior Group Leader, EMBL-CRG Systems Biology Unit, CRG, and his team had previously described that somatic mutations are much more likely in some parts of the human genome, thus damaging genes that may cause cancer. In a new paper, published online on February 23, 2015 in Nature, Dr. Lehner and his postdoc Fran Supek (photo), Ph.D., provide evidence that this is because genetic mistakes are better repaired in some parts of the genome than in others. This variation was generated by variation in the efficiency of a particular DNA repair mechanism called “mismatch repair,” a sort of a spell-checker that helps fix the errors in the genome after copying has taken place. Drs.
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