Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Somatic mosaicism for copy number variation in differentiated human tissues

ABSTRACT: 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)

ORGANISM(S): Homo sapiens

SUBMITTER: Carl Bruder

PROVIDER: E-GEOD-9598 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Somatic mosaicism for copy number variation in differentiated human tissues.

Piotrowski Arkadiusz A Bruder Carl E G CE Andersson Robin R Diaz de Ståhl Teresita T Menzel Uwe U Sandgren Johanna J Poplawski Andrzej A von Tell Desiree D Crasto Chiquito C Bogdan Adam A Bartoszewski Rafal R Bebok Zsuzsa Z Krzyzanowski Maciej M Jankowski Zbigniew Z Partridge E Christopher EC Komorowski Jan J Dumanski Jan P JP

Human mutation 20080901 9

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 ...[more]

PMID: 18570184

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Project description:Human-induced pluripotent stem cells (iPSCs) are derived from differentiated somatic cells using defined factors and provide a renewable source of autologous cells for cell therapy. Many reprogramming methods have been employed to generate human iPSCs, including the use of integrating vectors and non-integrating vectors. Maintenance of the genomic integrity of iPSCs is highly desirable if the cells are to be used in clinical applications. Here, using the Affymetrix Cytoscan HD array, we investigated the genomic aberration profiles of 19 human cell lines: 5 embryonic stem cell (ESC) lines, 6 iPSC lines derived using integrating vectors (“integrating iPSC lines”), 6 iPSC lines derived using non-integrating vectors (“non-integrating iPSC lines”), and the 2 parental cell lines from which the iPSCs were derived. The genome-wide copy number variation (CNV), loss of heterozygosity (LOH) and mosaicism patterns of integrating and non-integrating iPSC lines were investigated. The maximum sizes of CNVs in the genomes of the integrating iPSC lines were 20 times higher than those of the non-integrating iPSC lines. Moreover, the total number of CNVs was much higher in integrating iPSC lines than in other cell lines. The average numbers of novel CNVs with a low degree of overlap with the DGV and of likely pathogenic CNVs with a high degree of overlap with the ISCA database were highest in integrating iPSC lines. Different SNP calls revealed that, using the parental cell genotype as a reference, integrating iPSC lines displayed more single nucleotide variations and mosaicism than did non-integrating iPSC lines. This study describes the genome stability of human iPSCs generated using either a DNA-integrating or non-integrating reprogramming method, of the corresponding somatic cells, and of hESCs. Our results highlight the importance of using a high-resolution method to monitor genomic aberrations in iPSCs intended for clinical applications to avoid any negative effects of reprogramming or cell culture. 19 human cell lines: 5 embryonic stem cell (ESC) lines, 6 iPSC lines derived using integrating vectors (“integrating iPSC lines”), 6 iPSC lines derived using non-integrating vectors (“non-integrating iPSC lines”), and the 2 parental cell lines from which the iPSCs were derived.

Project description:Chromosomal structural variation can cause alterations in gene dosage and gene regulation between genomes. Structural variants producing a change in the number of copies of a genomic region are termed copy number variants (CNVs). CNVs have been demonstrated to have causative effects on both Mendelian and complex traits, including susceptibility to infectious diseases. We are interested in mapping CNVs to domesticated chicken breeds to help determine structural variation between genomes that influences economically important traits. For this study, Fayoumi, Leghorn, Line A broiler and Line B broiler chicken were chosen. Fayoumi and Leghorn chickens were selected as these two breeds harbor different responses certain pathogens like Avian Influenza Virus and coccidiosis; Broiler Line A and Line B indivduals were chosen as they harbor different intestinal colonization loads to the bacterium Campylobacter jejuni. Campylobacter genetic Line A and genetic Line B are from a commercial producer have been previously described as either resistant (Line A) or susceptible (Line B). Highly inbred chicken lines Fayoumi M15.2 (n=6) and Leghorn GHs6 (n=6) and broilers from Line A (n=24 individuals in pools of 4) and Line B (n=24 individuals in pools of 4)were subjected to array Comparative Genomic Hybridization (aCGH). Each sample was normalized to a Red Jungle Fowl reference. CNVs for each individual and between lines were determined. The major goal of this study was to discover and characterize CNVs in chickens to further narrow in on Quantitative Trait Loci (QTLs) affecting disease response. For the test DNA in Fayoumi and Leghorn, samples from 6 inbred Fayoumi and 6 inbred Leghorn individuals were used; For the test DNA in the Campylobacter genetic lines, samples from 24 individual broilers of Line A (in pools of 4) and 24 individual broilers of Line B (in pools of 4) were used. For the reference DNA, Red Jungle Fowl line UCD001 was used from a self-self hybridization.

Dataset Information

Somatic mosaicism for copy number variation in differentiated human tissues

Publications

Somatic mosaicism for copy number variation in differentiated human tissues.

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