Dataset Information

Characterization of large structural genetic mosaicism in human autosomes.

ABSTRACT: Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 × 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.

SUBMITTER: Machiela MJ

PROVIDER: S-EPMC4375431 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Characterization of large structural genetic mosaicism in human autosomes.

Machiela Mitchell J MJ Zhou Weiyin W Sampson Joshua N JN Dean Michael C MC Jacobs Kevin B KB Black Amanda A Brinton Louise A LA Chang I-Shou IS Chen Chu C Chen Constance C Chen Kexin K Cook Linda S LS Crous Bou Marta M De Vivo Immaculata I Doherty Jennifer J Friedenreich Christine M CM Gaudet Mia M MM Haiman Christopher A CA Hankinson Susan E SE Hartge Patricia P Henderson Brian E BE Hong Yun-Chul YC Hosgood H Dean HD Hsiung Chao A CA Hu Wei W Hunter David J DJ Jessop Lea L Kim Hee Nam HN Kim Yeul Hong YH Kim Young Tae YT Klein Robert R Kraft Peter P Lan Qing Q Lin Dongxin D Liu Jianjun J Le Marchand Loic L Liang Xiaolin X Lissowska Jolanta J Lu Lingeng L Magliocco Anthony M AM Matsuo Keitaro K Olson Sara H SH Orlow Irene I Park Jae Yong JY Pooler Loreall L Prescott Jennifer J Rastogi Radhai R Risch Harvey A HA Schumacher Fredrick F Seow Adeline A Setiawan Veronica Wendy VW Shen Hongbing H Sheng Xin X Shin Min-Ho MH Shu Xiao-Ou XO VanDen Berg David D Wang Jiu-Cun JC Wentzensen Nicolas N Wong Maria Pik MP Wu Chen C Wu Tangchun T Wu Yi-Long YL Xia Lucy L Yang Hannah P HP Yang Pan-Chyr PC Zheng Wei W Zhou Baosen B Abnet Christian C CC Albanes Demetrius D Aldrich Melinda C MC Amos Christopher C Amundadottir Laufey T LT Berndt Sonja I SI Blot William J WJ Bock Cathryn H CH Bracci Paige M PM Burdett Laurie L Buring Julie E JE Butler Mary A MA Carreón Tania T Chatterjee Nilanjan N Chung Charles C CC Cook Michael B MB Cullen Michael M Davis Faith G FG Ding Ti T Duell Eric J EJ Epstein Caroline G CG Fan Jin-Hu JH Figueroa Jonine D JD Fraumeni Joseph F JF Freedman Neal D ND Fuchs Charles S CS Gao Yu-Tang YT Gapstur Susan M SM Patiño-Garcia Ana A Garcia-Closas Montserrat M Gaziano J Michael JM Giles Graham G GG Gillanders Elizabeth M EM Giovannucci Edward L EL Goldin Lynn L Goldstein Alisa M AM Greene Mark H MH Hallmans Goran G Harris Curtis C CC Henriksson Roger R Holly Elizabeth A EA Hoover Robert N RN Hu Nan N Hutchinson Amy A Jenab Mazda M Johansen Christoffer C Khaw Kay-Tee KT Koh Woon-Puay WP Kolonel Laurence N LN Kooperberg Charles C Krogh Vittorio V Kurtz Robert C RC LaCroix Andrea A Landgren Annelie A Landi Maria Teresa MT Li Donghui D Liao Linda M LM Malats Nuria N McGlynn Katherine A KA McNeill Lorna H LH McWilliams Robert R RR Melin Beatrice S BS Mirabello Lisa L Peplonska Beata B Peters Ulrike U Petersen Gloria M GM Prokunina-Olsson Ludmila L Purdue Mark M Qiao You-Lin YL Rabe Kari G KG Rajaraman Preetha P Real Francisco X FX Riboli Elio E Rodríguez-Santiago Benjamín B Rothman Nathaniel N Ruder Avima M AM Savage Sharon A SA Schwartz Ann G AG Schwartz Kendra L KL Sesso Howard D HD Severi Gianluca G Silverman Debra T DT Spitz Margaret R MR Stevens Victoria L VL Stolzenberg-Solomon Rachael R Stram Daniel D Tang Ze-Zhong ZZ Taylor Philip R PR Teras Lauren R LR Tobias Geoffrey S GS Viswanathan Kala K Wacholder Sholom S Wang Zhaoming Z Weinstein Stephanie J SJ Wheeler William W White Emily E Wiencke John K JK Wolpin Brian M BM Wu Xifeng X Wunder Jay S JS Yu Kai K Zanetti Krista A KA Zeleniuch-Jacquotte Anne A Ziegler Regina G RG de Andrade Mariza M Barnes Kathleen C KC Beaty Terri H TH Bierut Laura J LJ Desch Karl C KC Doheny Kimberly F KF Feenstra Bjarke B Ginsburg David D Heit John A JA Kang Jae H JH Laurie Cecilia A CA Li Jun Z JZ Lowe William L WL Marazita Mary L ML Melbye Mads M Mirel Daniel B DB Murray Jeffrey C JC Nelson Sarah C SC Pasquale Louis R LR Rice Kenneth K Wiggs Janey L JL Wise Anastasia A Tucker Margaret M Pérez-Jurado Luis A LA Laurie Cathy C CC Caporaso Neil E NE Yeager Meredith M Chanock Stephen J SJ

American journal of human genetics 20150301 3

Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS s ...[more]

PMID: 25748358

Similar Datasets

Project description:BackgroundCaM (calmodulin) mutations are associated with congenital arrhythmia susceptibility (calmodulinopathy) and are most often de novo. In this report, we sought to broaden the genotype-phenotype spectrum of calmodulinopathies with 2 novel calmodulin mutations and to investigate mosaicism in 2 affected families.MethodsCaM mutations were identified in 4 independent cases by DNA sequencing. Biochemical and electrophysiological studies were performed to determine functional consequences of each mutation.ResultsGenetic studies identified 2 novel CaM variants (CALM3-E141K in 2 cases; CALM1-E141V) and one previously reported CaM pathogenic variant (CALM3-D130G) among 4 probands with shared clinical features of prolonged QTc interval (range 505-725 ms) and documented ventricular arrhythmia. A fatal outcome occurred for 2 of the cases. The parents of all probands were asymptomatic with normal QTc duration. However, 2 of the families had multiple affected offspring or multiple occurrences of intrauterine fetal demise. The mother from the family with recurrent intrauterine fetal demise exhibited the CALM3-E141K mutant allele in 25% of next-generation sequencing reads indicating somatic mosaicism, whereas CALM3-D130G was present in 6% of captured molecules of the paternal DNA sample, also indicating mosaicism. Two novel mutations (E141K and E141V) impaired Ca2+ binding affinity to the C-domain of CaM. Human-induced pluripotent stem cell-derived cardiomyocytes overexpressing mutant or wild-type CaM showed that both mutants impaired Ca2+-dependent inactivation of L-type Ca2+ channels and prolonged action potential duration.ConclusionsWe report 2 families with somatic mosaicism associated with arrhythmogenic calmodulinopathy, and demonstrate dysregulation of L-type Ca2+ channels by 2 novel CaM mutations affecting the same residue. Parental mosaicism should be suspected in families with unexplained fetal arrhythmia or fetal demise combined with a documented CaM mutation.

Project description:BACKGROUND:Pigmentary mosaicism constitutes a heterogeneous group of skin pigmentation alterations associated with multisystem involvement. The aim of this study was to establish a complete cytogenetic and molecular characterization of PM patients, emphasizing on searching for possible low chromosomal mosaicism and on establishing an accurate genotype-phenotype correlation. RESULTS:A total of 73 patients were included (3?months to 18?years of age), 52% male and 48% female. Observed in 69 (95%) patients, the most frequent pattern of pigmentation was fine and whorled BL, which was associated with disseminated skin extent in 41 (59%) patients. Central nervous system (84%) alterations were the most frequent observed in the group of patients, followed by the musculoskeletal (53%) and ophthalmologic (27%) alterations. Considering the pattern of pigmentation, no significant differences in association with skin extent or extracutaneous manifestations were detected. Following a strict cytogenetic analysis strategy, screening metaphases from three different tissues (peripheral blood, hyperpigmented and hypopigmented skin) we found that 23/73 patients had chromosomal abnormalities classified as follows: 1) Mosaic with 2 or more different cell lines with structural alterations n =?19; 2) Polyploidy (mosaic) n =?1 and 3) Alterations in all cells in three different tissues n =?3. SNP array, array CGH and FISH were useful for the complete characterization of the chromosomal aberrations, for the detection of microdeletions in patients with normal karyotype but with strong clinical suspicious of chromosomal alteration, and for a better establishment of genotype-phenotype correlation. In 2 patients we found genes associated with some of the extracutaneous manifestations (SHH, MNX1, PPP2R2C). CONCLUSIONS:This group of 73 patients finely described is the largest series of patients with pigmentary mosaicism reported worldwide. As we showed in this study, the followed analysis strategy allowed the detection of cytogenetic and molecular abnormalities, and made possible the establishment of genotype-phenotype associations in some patients. An important limitation of our study was the analysis of fibroblasts cultures instead of melanocytes and keratinocytes. In some cases the direct molecular DNA analysis of skin biopsy could be another choice.

Dataset Information

Characterization of large structural genetic mosaicism in human autosomes.

Publications

Characterization of large structural genetic mosaicism in human autosomes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets