Large-Scale Copy Number Polymorphism in the Human Genome

Sebat, Jonathan; Lakshmi, B.; Troge, Jennifer; Alexander, Joan; Young, Janet M.; Lundin, Per; Månér, Susanne; Massa, Hillary F.; Walker, Megan; Chi, Maoyen; Navin, Nicholas E.; Lucito, Robert; Healy, John M.; Hicks, James; Ye, Kenny; Reiner, Andrew H.; Gilliam, T. Conrad; Trask, Barbara J.; Patterson, Nick; Zetterberg, Anders; Wigler, Michael

doi:10.1126/science.1098918

Cited by 2,258 publications

(1,794 citation statements)

References 25 publications

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“…[35][36][37][38][39][40][41][42][43] Within our associated region, a segmental duplication is reported, 44 which is situated between the two associated regions on the DRB1*0401-DQA1*03-DQB1*0302 haplotypic background and caused a 223-kb gap not genotyped in our study. This segmental duplication has, to our knowledge, not been studied regarding human diseases.…”

Section: Discussionmentioning

confidence: 58%

Reproducible association with type 1 diabetes in the extended class I region of the major histocompatibility complex

et al. 2009

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The high-risk human leukocyte antigen (HLA)-DRB1, DQA1 and DQB1 alleles cannot explain the entire type 1 diabetes (T1D) association observed within the extended major histocompatibility complex. We have earlier identified an association with D6S2223, located 2.3 Mb telomeric of HLA-A, on the DRB1*03-DQA1*0501-DQB1*0201 haplotype, and this study aimed to fine-map the associated region also on the DRB1*0401-DQA1*03-DQB1*0302 haplotype, characterized by less extensive linkage disequilibrium. To exclude associations secondary to DRB1-DQA1-DQB1 haplotypes, 205 families with at least one parent homozygous for these loci, were genotyped for 137 polymorphisms. We found novel associations on the DRB1*0401-DQA1*03-DQB1*0302 haplotypic background with eight single nucleotide polymorphisms (SNPs) located within or near the PRSS16 gene. In addition, association at the butyrophilin (BTN)-gene cluster, particularly the BTN3A2 gene, was observed by multilocus analyses. We replicated the associations with SNPs in the PRSS16 region and, albeit weaker, to the BTN3A2 region, in an independent material of 725 families obtained from the Type 1 Diabetes Genetics Consortium. It is important to note that these associations were independent of the HLA-DRB1-DQA1-DQB1 genes, as well as of associations observed at HLA-A, -B and -C. Taken together, our results identify PRSS16 and BTN3A2, two genes thought to play important roles in regulating the immune response, as potentially novel susceptibility genes for T1D.

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Section: Discussionmentioning

confidence: 58%

Reproducible association with type 1 diabetes in the extended class I region of the major histocompatibility complex

et al. 2009

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“…This assumption has recently been shattered by studies using high resolution genomic arrays. 11,12 Unexpected levels of copy number variation (CNV) between monozygotic twins provide support for a model of sub-chromosomal genetic divergence after the splitting of the embryo, indicating that the normal genome may be more dynamic than once appreciated. 13 An even more dramatic example of post-conception genomic divergence has recently been described in mammals.…”

Section: Impact Of Genomic Changes On Expressionmentioning

confidence: 99%

Gene expression changes in normal haematopoietic cells

Lionberger¹,

Stirewalt²

2009

Best Practice & Research Clinical Haematology

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The complexity of the healthy hematopoietic system is immense, and as such, one must understand the biology driving normal hematopoietic expression profiles when designing experiments and interpreting expression data that involves normal cells. This chapter seeks to present an organized approach to the use and interpretation of gene profiling in normal hematopoiesis and broadly illustrates the challenges of selecting appropriate controls for high-throughput expression studies.

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“…Yet, a specific but subtle effect mediated by an inversion may become clear only in a longer perspective and detected from the analysis of large and ethnically diverse populations [Stefansson et al, 2005]. In a broader context, inversions are thought to be key players in evolution and account for much of the genomic differences between humans and other primates [Iafrate et al, 2004;Sebat et al, 2004]. Detailed structural analysis of submicroscopic inversion variants indicates that they frequently origin from non-allelic homologous rearrangements between repeated and re-iterated sequences or duplicons [Shaw and Lupski, 2004;Bansal et al, 2007].…”

Section: Introductionmentioning

confidence: 99%

A chromosome 10 variant with a 12 Mb inversion [inv(10)(q11.22q21.1)] identical by descent and frequent in the Swedish population

Entesarian

Carlsson

Mansouri

et al. 2009

American J of Med Genetics Pt A

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We identified a paracentric inversion of chromosome 10 [inv(10)(q11.22q21.1)] in 0.20% of Swedish individuals (15/7,439) referred for cytogenetic analysis. A retrospective analysis of 8,896 karyotypes from amniocenteses in Sweden revealed a carrier frequency of 0.079% (7/8,896) for the inversion. Cloning and detailed analysis of the inversion breakpoint regions show enrichment for interspersed repeat elements and AT-stretches. The centromeric breakpoint coincides with that of a predicted inversion from HapMap data, which suggests that this region is involved in several chromosome 10 variants. No known gene or predicted transcript are disrupted by the inversion which spans approximately 12 Mb. Carriers from four nonrelated Swedish families have identical inversion breakpoints and haplotype analysis confirmed that the rearrangement is identical by descent. Diagnosis was retrieved in 6 out of the 15 carriers referred for cytogenetic analysis. No consistent phenotype was found to be associated with the inversion. Our study demonstrates that the inv(10)(q11.22q21.1) is a rare and inherited chromosome variant with a broad geographical distribution in Sweden.

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Large-Scale Copy Number Polymorphism in the Human Genome

Cited by 2,258 publications

References 25 publications

Reproducible association with type 1 diabetes in the extended class I region of the major histocompatibility complex

Reproducible association with type 1 diabetes in the extended class I region of the major histocompatibility complex

Gene expression changes in normal haematopoietic cells

A chromosome 10 variant with a 12 Mb inversion [inv(10)(q11.22q21.1)] identical by descent and frequent in the Swedish population

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