Somatic mosaicism for copy number variation in differentiated human tissues

TLDR

Copy‑number variations (CNVs) are a major class of structural genetic variation, yet it is unclear whether they arise somatically, and many CNVs reported as germline may in fact be somatic, potentially contributing to phenotypes that result from somatic processes. The study recommends that biobanks sample multiple tissues to better capture mosaicism in somatic disorder research. The authors examined 34 tissue samples from three individuals, analyzing a minute fraction (≤10⁻⁶) of cells per tissue, and identified at least six CNVs affecting single organs or multiple tissues within the same subject. Somatic mosaic CNVs ranging 82–176 kb, often encompassing known genes, were found in a substantial fraction of cells, indicating that such stochastic CNVs are common and may underlie many human phenotypes.

Abstract

Two major types of genetic variation are known: single nucleotide polymorphisms (SNPs), and a more recently discovered structural variation, involving changes in copy number (CNVs) of kilobase- to megabase-sized chromosomal segments. It is unknown whether CNVs arise in somatic cells, but it is, however, generally assumed that normal cells are genetically identical. We tested 34 tissue samples from three subjects and, having analyzed for each tissue < or =10(-6) of all cells expected in an adult human, we observed at least six CNVs, affecting a single organ or one or more tissues of the same subject. The CNVs ranged from 82 to 176 kb, often encompassing known genes, potentially affecting gene function. Our results indicate that humans are commonly affected by somatic mosaicism for stochastic CNVs, which occur in a substantial fraction of cells. The majority of described CNVs were previously shown to be polymorphic between unrelated subjects, suggesting that some CNVs previously reported as germline might represent somatic events, since in most studies of this kind, only one tissue is typically examined and analysis of parents for the studied subjects is not routinely performed. A considerable number of human phenotypes are a consequence of a somatic process. Thus, our conclusions will be important for the delineation of genetic factors behind these phenotypes. Consequently, biobanks should consider sampling multiple tissues to better address mosaicism in the studies of somatic disorders.