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Somatic Mutations in Noncoding Regions Common in Adult Blood Cells

NEW YORK— Researchers have found a group of non-oncogenic somatic mutations that are fairly common in blood cells of healthy individuals and some of which could have consequences on blood cell traits.

While previous studies have estimated somatic mutations in coding regions of blood cells and have linked them to physiological changes, not many studies have looked at somatic mutations in noncoding regions, according to the authors of the study, published in Science Advances on Wednesday.

Somatic mutations in noncoding regions are typically non-oncogenic and are believed to have little effect on cellular function, the authors wrote. However, this assumption has not been rigorously tested and may not be true as noncoding regions can actively regulate gene expression through enhancers, splicing, genomic structure, and chromatin configuration, they added.

To understand how common these noncoding mutations are and whether they have any health consequences, researchers studied whole-genome sequencing data from blood samples of 43,693 healthy adults belonging to 37 cohorts that were a part of the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) initiative.

They cataloged all the somatic mutations in the blood samples and identified a class of recurring mutations across individuals which they termed as recurrent non-missense somatic mutations (RNMSMs). These mutations weren't clearly explained by clonal phenomena such as clonal hematopoiesis, the authors noted. 

The researchers were able to home in on a set of 7,131 RNMSMs that were mutated in at least 50 individuals. They also found that every sample had at least one RNMSM mutation, and that the average number of RNMSMs per sample was 28.6.

"Although the majority of somatic variants are individually very rare, a subset are quite common," co-corresponding authors Joshua Weinstock, a biostatistician formerly at University of Michigan School of Public Health, Alexander Bick, assistant professor of medicine at Vanderbilt University Medical Center, and their colleagues wrote in the paper.

The researchers saw that RNMSM burden was positively associated with age, which the authors said was likely because older people have had more time to accumulate mutations. The results showed that an average 50-year-old had 27 RNMSMs.

Subsequent analysis also revealed that eight of the newly identified RNMSMs were significantly associated with blood cell traits such as monocyte count.

Most of these somatic mutations were found to be enriched in the heterochromatin across blood cell types and were present in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment.

The researchers also noted ancestry-based differences in somatic mutations, and surmised that inherited germline mutations could result in an increased likelihood of somatic mutations.

The findings also have implications for cancer biology, the authors noted. In one of their observations, the researchers found that 81 of the somatic mutations called in the Pan-Cancer Analysis of Whole Genomes (PCAWG) project's cancer genomes were present among the blood RNMSMs.

"We observed that 23 of the PCAWG-RNMSMs had at least 100 mutations in our cohort, indicating that a subset of mutations in cancer genomes is prevalent in a population cohort that was not ascertained for cancer," the authors wrote.

The authors said that while this study only looked at somatic mutations in blood samples, it could be extended to almost any other sample type.

Highlighting the limitations of the study, the authors said that the somatic mutations they identified in the blood samples were limited by the sensitivity of the sequencing used. "Some sequencing artifacts have similar properties to somatic mutations, and a subset of somatic mutations are difficult to distinguish from sequencing and mapping artifacts," they wrote.