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Extensive genetic variation in somatic human tissues.

ABSTRACT: Genetic variation between individuals has been extensively investigated, but differences between tissues within individuals are far less understood. It is commonly assumed that all healthy cells that arise from the same zygote possess the same genomic content, with a few known exceptions in the immune system and germ line. However, a growing body of evidence shows that genomic variation exists between differentiated tissues. We investigated the scope of somatic genomic variation between tissues within humans. Analysis of copy number variation by high-resolution array-comparative genomic hybridization in diverse tissues from six unrelated subjects reveals a significant number of intraindividual genomic changes between tissues. Many (79%) of these events affect genes. Our results have important consequences for understanding normal genetic and phenotypic variation within individuals, and they have significant implications for both the etiology of genetic diseases such as cancer and for immortalized cell lines that might be used in research and therapeutics.

SUBMITTER: O'Huallachain M

PROVIDER: S-EPMC3497787 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Extensive genetic variation in somatic human tissues.

O'Huallachain Maeve M Karczewski Konrad J KJ Karczewski Konrad J KJ Weissman Sherman M SM Urban Alexander Eckehart AE Snyder Michael P MP

Proceedings of the National Academy of Sciences of the United States of America 20121005 44

Genetic variation between individuals has been extensively investigated, but differences between tissues within individuals are far less understood. It is commonly assumed that all healthy cells that arise from the same zygote possess the same genomic content, with a few known exceptions in the immune system and germ line. However, a growing body of evidence shows that genomic variation exists between differentiated tissues. We investigated the scope of somatic genomic variation between tissues ...[more]

PMID: 23043118

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Project description:Genetic variation is responsible for the generation of phenotypic diversity, including susceptibility to disease. Two major types of 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. Variation caused by CNVs has exceeded the amount of SNP-based differences expected to exist between two unrelated humans. Furthermore, many CNVs have been associated with disease predisposition. It is unknown whether CNVs arise in somatic cells, but it is, however, generally assumed that normal cells are genetically identical. Here we show that CNVs are frequent in healthy somatic cells of adult humans. We tested 34 tissue samples from three subjects and, having analyzed for each tissue <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 82-176 kb, often encompassing known genes, potentially affecting gene function. Our results point to a paradigm shift in the genetics of somatic cells and indicate that humans are commonly affected by somatic mosaicism for stochastic CNVs, which occur in a substantial fraction of cells. A considerable number of phenotypes and diseases affecting humans 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 in order to better address mosaicism in the studies of somatic disorders. Furthermore, forensic medicine laboratories should be sensitized to the issue of underestimated frequency of somatic CNV mosaicism. Keywords: copy number variation (CNV), phenotype diversity, somatic cells 31 experiments; each experiment consists of two hybridizations, i.e. regular and dye-swap (62 hybridizations in total); cerebellum from corresponding subject was used as a reference; additionally 12 control self-self hybridizations are included (cerrebellum vs self)

Dataset Information

Extensive genetic variation in somatic human tissues.

Publications

Extensive genetic variation in somatic human tissues.

Similar Datasets

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