Towards a comprehensive structural variation map of an individual human genome

Pang, Andy Wing Chun; MacDonald, Jeffrey R.; Pinto, Dalila; Wei, John; Rafiq, Muhammad; Conrad, Donald F.; Park, Hansoo; Hurles, Matthew E.; Lee, Charles; Venter, J. Craig; Kirkness, Ewen F.; Lévy, Samuel; Feuk, Lars; Scherer, Stephen W.

doi:10.1186/gb-2010-11-5-r52

Cited by 291 publications

(275 citation statements)

References 45 publications

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“…Deletions are often associated with diseases (19), and less-common variants generally have a higher impact in driving human diseases (20). In addition, low-frequency CNVs are not well-tagged by SNPs (21) and, therefore, would carry distinct information from previously studied common SNPs that have been evaluated for their potential association with prostate cancer (22). We anticipated that functionally active low-frequency deletions might unravel an as yet unexplored portion of the genetic background.…”

Section: Resultsmentioning

confidence: 99%

Identification of functionally active, low frequency copy number variants at 15q21.3 and 12q21.31 associated with prostate cancer risk

Demichelis

Setlur

Banerjee³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Copy number variants (CNVs) are a recently recognized class of human germ line polymorphisms and are associated with a variety of human diseases, including cancer. Because of the strong genetic influence on prostate cancer, we sought to identify functionally active CNVs associated with susceptibility of this cancer type. We queried low-frequency biallelic CNVs from 1,903 men of Caucasian origin enrolled in the Tyrol Prostate Specific Antigen Screening Cohort and discovered two CNVs strongly associated with prostate cancer risk. The first risk locus (P = 7.7 × 10 −4 , odds ratio = 2.78) maps to 15q21.3 and overlaps a noncoding enhancer element that contains multiple activator protein 1 (AP-1) transcription factor binding sites. Chromosome conformation capture (Hi-C) data suggested direct cis-interactions with distant genes. The second risk locus (P = 2.6 × 10 −3 , odds ratio = 4.8) maps to the α-1,3-mannosyl-glycoprotein 4-β-N-acetylglucosaminyltransferase C (MGAT4C) gene on 12q21.31. In vitro cell-line assays found this gene to significantly modulate cell proliferation and migration in both benign and cancer prostate cells. Furthermore, MGAT4C was significantly overexpressed in metastatic versus localized prostate cancer. These two risk associations were replicated in an independent PSA-screened cohort of 800 men (15q21.3, combined P = 0.006; 12q21.31, combined P = 0.026). These findings establish noncoding and coding germ line CNVs as significant risk factors for prostate cancer susceptibility and implicate their role in disease development and progression.cancer genetics | functionally active DNA loci | cancer predisposition | metabolism | chromosome looping

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Section: Resultsmentioning

confidence: 99%

Identification of functionally active, low frequency copy number variants at 15q21.3 and 12q21.31 associated with prostate cancer risk

Demichelis

Setlur

Banerjee³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…The overall frequency of CNVs identified in nearly 1000 subjects from 261 early/mixed-onset AD families (Table 1) are similar to that described in previous studies utilizing the Affymetrix SNP 6.0 microarray. 23,33 CNV segments that showed o70% overlap with CNPs reported on DGV were analyzed for segregation with disease. These analyses confirmed APP locus duplication previously reported in two EO-FAD families.…”

Section: Resultsmentioning

confidence: 99%

Rare autosomal copy number variations in early-onset familial Alzheimer’s disease

et al. 2013

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“…Copy-number neutrality might also be consistent with a mate-pair event if there are corresponding gains and losses on different alleles for which one allele escaped mate-pair detection. Most importantly, mate-pair analysis detects all manner of SVs that are invisible to arrays, including tandem repeat expansions and gain or loss of mobile genetic elements.Recent descriptions of data from the 1000 Genomes Project and other high-coverage human genome sequences highlight final limitations of both SNP arrays and low-depth mate-pair sequencing (Durbin et al 2010;Pang et al 2010;Sudmant et al 2010). First, it is now clear that the frequency of human population 682 M. F. Arlt et al…”

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confidence: 99%

Comparison of Constitutional and Replication Stress-Induced Genome Structural Variation by SNP Array and Mate-Pair Sequencing

Arlt¹,

Ozdemir²,

Birkeland³

et al. 2011

Genetics

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Copy-number variants (CNVs) are a major source of genetic variation in human health and disease. Previous studies have implicated replication stress as a causative factor in CNV formation. However, existing data are technically limited in the quality of comparisons that can be made between human CNVs and experimentally induced variants. Here, we used two high-resolution strategies-single nucleotide polymorphism (SNP) arrays and mate-pair sequencing-to compare CNVs that occur constitutionally to those that arise following aphidicolin-induced DNA replication stress in the same human cells. Although the optimized methods provided complementary information, sequencing was more sensitive to small variants and provided superior structural descriptions. The majority of constitutional and all aphidicolininduced CNVs appear to be formed via homology-independent mechanisms, while aphidicolin-induced CNVs were of a larger median size than constitutional events even when mate-pair data were considered. Aphidicolin thus appears to stimulate formation of CNVs that closely resemble human pathogenic CNVs and the subset of larger nonhomologous constitutional CNVs. I N recent years, submicroscopic structural variants (SVs) have been found to be widely distributed throughout the human genome where they represent an important component of genetic variation and phenotypic diversity (Iafrate et al. 2004;Sebat et al. 2004;Sharp et al. 2005;Conrad et al. 2010b). These include deletions, duplications, insertions, and inversions, with the majority being copy-number variations (CNVs) discovered in systematic studies using microarrays (Conrad et al. 2010b;. More than 10,000 CNVs have now been described in healthy individuals that represent gains or losses of $1 kb to .1 Mb. CNVs can alter gene expression in affected regions, confer redundancy, and provide substrates for evolution. Spontaneous CNVs are also known to be a major cause of genetic and developmental disorders, including mental retardation, autism, schizophrenia, epilepsy, skeletal defects, and many others (Stankiewicz and Beaudet 2007;Cook and Scherer 2008;Kirov et al. 2009;Tam et al. 2009;Zhang et al. 2009;Miller et al. 2010). Systematic studies of human population CNVs have provided further correlation to human conditions including Crohn's disease, rheumatoid arthritis, and diabetes (Craddock et al. 2010). Related systematic efforts have finally also revealed a high degree of submicroscopic chromosomal structural alterations in cancer (Stratton et al. 2009;Bignell et al. 2010).Despite their importance, there is limited understanding of how SVs arise (Hastings et al. 2009b;Stankiewicz and Lupski 2010). The exceptions are local genome rearrangements that occur by unequal recombination between neighboring low-copy repeated sequences or segmental duplications, a process known as non-allelic homologous recombination (NAHR) (Sasaki et al. 2010). Such events are well described and underlie the specific recurrent alterations responsible for a variety of human microdeletion sy...

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Towards a comprehensive structural variation map of an individual human genome

Abstract: A comprehensive map of structural variation in the human genome provides a reference dataset for analyses of future personal genomes.

Cited by 291 publications

References 45 publications

Identification of functionally active, low frequency copy number variants at 15q21.3 and 12q21.31 associated with prostate cancer risk

Identification of functionally active, low frequency copy number variants at 15q21.3 and 12q21.31 associated with prostate cancer risk

Rare autosomal copy number variations in early-onset familial Alzheimer’s disease

Comparison of Constitutional and Replication Stress-Induced Genome Structural Variation by SNP Array and Mate-Pair Sequencing

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