Hot off the presses! Aug 01 Nat Genet

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Latest Articles Include:

• What's so funny about peace, love and understanding?
  - Nat Genet 41(8):861 (2009)
  The Mediterranean Medical Genetics Meeting 2009 at Bilkent University, in Ankara, Turkey, reaffirmed the commitment of a pragmatic group of scientifically excellent researchers to local problem solving and to the vision of borderless global collaboration in human genomics.
• Duplications of noncoding elements 5' of SOX9 are associated with brachydactyly-anonychia
  - Nat Genet 41(8):862-863 (2009)
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• Labile H3.3+H2A.Z nucleosomes mark 'nucleosome-free regions'
  - Nat Genet 41(8):865-866 (2009)
  Chromatin marks, including histone modifications and variants, have become important tools for characterizing epigenomes, yet how they might interact with one another to facilitate gene expression and regulation has remained unclear. A new study maps unstable nucleosomes containing both H3.3 and H2A.Z histone variants to human promoters and regulatory elements and suggests that transient occupancy by double-variant nucleosomes is a general feature of eukaryotic gene regulation.
• Life can be stressful without ATR
  - Nat Genet 41(8):866-868 (2009)
  A new study reports the first mouse model for ATR-mutated Seckel syndrome. The mice show phenotypes recapitulating the human disorder and provide insights into how reduced ATR function affects normal embryonic development by increasing replicative stress, ultimately resulting in an accelerated aging phenotype postnatally.
• Elucidating the role of 8q24 in colorectal cancer
  - Nat Genet 41(8):868-869 (2009)
  Two new reports highlight the power of genome-wide association (GWA) studies to guide the functional annotation of genetic variants contributing to common diseases. The studies show that a common risk variant for colorectal cancer on chromosome 8q24 affects TCF4 binding to an enhancer that interacts with the MYC promoter, providing a mechanistic explanation for the association of this variant with disease risk.
• Research highlights
  - Nat Genet 41(8):870 (2009)
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• Genetic variants at 6p21.33 are associated with susceptibility to follicular lymphoma
  - Nat Genet 41(8):873-875 (2009)
  We conducted genome-wide association studies of non-Hodgkin lymphoma using Illumina HumanHap550 BeadChips to identify subtype-specific associations in follicular, diffuse large B-cell and chronic lymphocytic leukemia/small lymphocytic lymphomas. We found that rs6457327 on 6p21.33 was associated with susceptibility to follicular lymphoma (FL; N = 189 cases, 592 controls) with validation in another 456 FL cases and 2,785 controls (combined allelic P = 4.7 10-11). The region of strongest association overlapped C6orf15 (STG), located near psoriasis susceptibility region 1 (PSORS1).
• A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke
  - Nat Genet 41(8):876-878 (2009)
  We expanded our genome-wide association study on atrial fibrillation (AF) in Iceland, which previously identified risk variants on 4q25, and tested the most significant associations in samples from Iceland, Norway and the United States. A variant in the ZFHX3 gene on chromosome 16q22, rs7193343-T, associated significantly with AF (odds ratio OR = 1.21, P = 1.4 10-10). This variant also associated with ischemic stroke (OR = 1.11, P = 0.00054) and cardioembolic stroke (OR = 1.22, P = 0.00021) in a combined analysis of five stroke samples.
• Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry
  - Nat Genet 41(8):879-881 (2009)
  We conducted meta-analyses of genome-wide association studies for atrial fibrillation (AF) in participants from five community-based cohorts. Meta-analyses of 896 prevalent (15,768 referents) and 2,517 incident (21,337 referents) AF cases identified a new locus for AF (ZFHX3, rs2106261, risk ratio RR = 1.19; P = 2.3 10-7). We replicated this association in an independent cohort from the German AF Network (odds ratio = 1.44; P = 1.6 10-11; combined RR = 1.25; combined P = 1.8 10-15).
• The 8q24 cancer risk variant rs6983267 shows long-range interaction with MYC in colorectal cancer
  - Nat Genet 41(8):882-884 (2009)
  An inherited variant on chromosome 8q24, rs6983267, is significantly associated with cancer pathogenesis. We present evidence that the region harboring this variant is a transcriptional enhancer, that the alleles of rs6983267 differentially bind transcription factor 7-like 2 (TCF7L2) and that the risk region physically interacts with the MYC proto-oncogene. These data provide strong support for a biological mechanism underlying this non-protein-coding risk variant.
• The common colorectal cancer predisposition SNP rs6983267 at chromosome 8q24 confers potential to enhanced Wnt signaling
  - Nat Genet 41(8):885-890 (2009)
  Homozygosity for the G allele of rs6983267 at 8q24 increases colorectal cancer (CRC) risk 1.5 fold. We report here that the risk allele G shows copy number increase during CRC development. Our computer algorithm, Enhancer Element Locator (EEL), identified an enhancer element that contains rs6983267. The element drove expression of a reporter gene in a pattern that is consistent with regulation by the key CRC pathway Wnt. rs6983267 affects a binding site for the Wnt-regulated transcription factor TCF4, with the risk allele G showing stronger binding in vitro and in vivo. Genome-wide ChIP assay revealed the element as the strongest TCF4 binding site within 1 Mb of MYC. An unambiguous correlation between rs6983267 genotype and MYC expression was not detected, and additional work is required to scrutinize all possible targets of the enhancer. Our work provides evidence that the common CRC predisposition associated with 8q24 arises from enhanced responsiveness to Wnt signal! ing.
• A mouse model of ATR-Seckel shows embryonic replicative stress and accelerated aging
  - Nat Genet 41(8):891-898 (2009)
  Although DNA damage is considered a driving force for aging, the nature of the damage that arises endogenously remains unclear. Replicative stress, a source of endogenous DNA damage, is prevented primarily by the ATR kinase. We have developed a mouse model of Seckel syndrome characterized by a severe deficiency in ATR. Seckel mice show high levels of replicative stress during embryogenesis, when proliferation is widespread, but this is reduced to marginal amounts in postnatal life. In spite of this decrease, adult Seckel mice show accelerated aging, which is further aggravated in the absence of p53. Together, these results support a model whereby replicative stress, particularly in utero, contributes to the onset of aging in postnatal life, and this is balanced by the replicative stress–limiting role of the checkpoint proteins ATR and p53.
• Genome-wide association study identifies five susceptibility loci for glioma
  - Nat Genet 41(8):899-904 (2009)
  To identify risk variants for glioma, we conducted a meta-analysis of two genome-wide association studies by genotyping 550K tagging SNPs in a total of 1,878 cases and 3,670 controls, with validation in three additional independent series totaling 2,545 cases and 2,953 controls. We identified five risk loci for glioma at 5p15.33 (rs2736100, TERT; P = 1.50 10-17), 8q24.21 (rs4295627, CCDC26; P = 2.34 10-18), 9p21.3 (rs4977756, CDKN2A-CDKN2B; P = 7.24 10-15), 20q13.33 (rs6010620, RTEL1; P = 2.52 10-12) and 11q23.3 (rs498872, PHLDB1; P = 1.07 10-8). These data show that common low-penetrance susceptibility alleles contribute to the risk of developing glioma and provide insight into disease causation of this primary brain tumor.
• Variants in the CDKN2B and RTEL1 regions are associated with high-grade glioma susceptibility
  - Nat Genet 41(8):905-908 (2009)
  The causes of glioblastoma and other gliomas remain obscure1, 2. To discover new candidate genes influencing glioma susceptibility, we conducted a principal component–adjusted3 genome-wide association study (GWAS) of 275,895 autosomal variants among 692 adult high-grade glioma cases (622 from the San Francisco Adult Glioma Study (AGS) and 70 from the Cancer Genome Atlas (TCGA))4 and 3,992 controls (602 from AGS and 3,390 from Illumina iControlDB (iControls)). For replication, we analyzed the 13 SNPs with P < 10-6 using independent data from 176 high-grade glioma cases and 174 controls from the Mayo Clinic. On 9p21, rs1412829 near CDKN2B had discovery P = 3.4 10-8, replication P = 0.0038 and combined P = 1.85 10-10. On 20q13.3, rs6010620 intronic to RTEL1 had discovery P = 1.5 10-7, replication P = 0.00035 and combined P = 3.40 10-9. For both SNPs, the direction of association was the same in discovery and replication phases.
• New common variants affecting susceptibility to basal cell carcinoma
  - Nat Genet 41(8):909-914 (2009)
  In a follow-up to our previously reported genome-wide association study of cutaneous basal cell carcinoma (BCC)1, we describe here several new susceptibility variants. SNP rs11170164, encoding a G138E substitution in the keratin 5 (KRT5) gene, affects risk of BCC (OR = 1.35, P = 2.1 10-9). A variant at 9p21 near CDKN2A and CDKN2B also confers susceptibility to BCC (rs2151280[C]; OR = 1.19, P = 6.9 10-9), as does rs157935[T] at 7q32 near the imprinted gene KLF14 (OR = 1.23, P = 5.7 10-10). The effect of rs157935[T] is dependent on the parental origin of the risk allele. None of these variants were found to be associated with melanoma or fair-pigmentation traits. A melanoma- and pigmentation-associated variant in the SLC45A2 gene, L374F, is associated with risk of both BCC and squamous cell carcinoma. Finally, we report conclusive evidence that rs401681[C] in the TERT-CLPTM1L locus confers susceptibility to BCC but protects against melanoma.
• Genome-wide association study identifies variants at 9p21 and 22q13 associated with development of cutaneous nevi
  - Nat Genet 41(8):915-919 (2009)
  A high melanocytic nevi count is the strongest known risk factor for cutaneous melanoma. We conducted a genome-wide association study for nevus count using 297,108 SNPs in 1,524 twins, with validation in an independent cohort of 4,107 individuals. We identified strongly associated variants in MTAP, a gene adjacent to the familial melanoma susceptibility locus CDKN2A on 9p21 (rs4636294, combined P = 3.4 10-15), as well as in PLA2G6 on 22q13.1 (rs2284063, combined P = 3.4 10-8). In addition, variants in these two loci showed association with melanoma risk in 3,131 melanoma cases from two independent studies, including rs10757257 at 9p21, combined P = 3.4 10-8, OR = 1.23 (95% CI = 1.15–1.30) and rs132985 at 22q13.1, combined P = 2.6 10-7, OR = 1.23 (95% CI = 1.15–1.30). This provides the first report of common variants associated to nevus number and demonstrates association of these variants with melanoma susceptibility.
• Genome-wide association study identifies three loci associated with melanoma risk
  - Nat Genet 41(8):920-925 (2009)
  We report a genome-wide association study of melanoma conducted by the GenoMEL consortium based on 317K tagging SNPs for 1,650 selected cases and 4,336 controls, with replication in an additional two cohorts (1,149 selected cases and 964 controls from GenoMEL, and a population-based case-control study in Leeds of 1,163 cases and 903 controls). The genome-wide screen identified five loci with genotyped or imputed SNPs reaching P < 5 10-7. Three of these loci were replicated: 16q24 encompassing MC1R (combined P = 2.54 10-27 for rs258322), 11q14-q21 encompassing TYR (P = 2.41 10-14 for rs1393350) and 9p21 adjacent to MTAP and flanking CDKN2A (P = 4.03 10-7 for rs7023329). MC1R and TYR are associated with pigmentation, freckling and cutaneous sun sensitivity, well-recognized melanoma risk factors. Common variants within the 9p21 locus have not previously been associated with melanoma. Despite wide variation in allele frequency, these genetic variants show notable homog! eneity of effect across populations of European ancestry living at different latitudes and show independent association to disease risk.
• Sequence variants in the CLDN14 gene associate with kidney stones and bone mineral density
  - Nat Genet 41(8):926-930 (2009)
  Kidney stone disease is a common condition. To search for sequence variants conferring risk of kidney stones, we conducted a genome-wide association study in 3,773 cases and 42,510 controls from Iceland and The Netherlands. We discovered common, synonymous variants in the CLDN14 gene that associate with kidney stones (OR = 1.25 and P = 4.0 10-12 for rs219780[C]). Approximately 62% of the general population is homozygous for rs219780[C] and is estimated to have 1.64 times greater risk of developing the disease compared to noncarriers. The CLDN14 gene is expressed in the kidney and regulates paracellular permeability at epithelial tight junctions. The same variants were also found to associate with reduced bone mineral density at the hip (P = 0.00039) and spine (P = 0.0077).
• De novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot
  - Nat Genet 41(8):931-935 (2009)
  Tetralogy of Fallot (TOF), the most common severe congenital heart malformation, occurs sporadically, without other anomaly, and from unknown cause in 70% of cases. Through a genome-wide survey of 114 subjects with TOF and their unaffected parents, we identified 11 de novo copy number variants (CNVs) that were absent or extremely rare (<0.1%) in 2,265 controls. We then examined a second, independent TOF cohort (n = 398) for additional CNVs at these loci. We identified CNVs at chromosome 1q21.1 in 1% (5/512, P = 0.0002, OR = 22.3) of nonsyndromic sporadic TOF cases. We also identified recurrent CNVs at 3p25.1, 7p21.3 and 22q11.2. CNVs in a single subject with TOF occurred at six loci, two that encode known (NOTCH1, JAG1) disease-associated genes. Our findings predict that at least 10% (4.5–15.5%, 95% confidence interval) of sporadic nonsyndromic TOF cases result from de novo CNVs and suggest that mutations within these loci might be etiologic in other cases of TOF.
• Mutations affecting the secretory COPII coat component SEC23B cause congenital dyserythropoietic anemia type II
  - Nat Genet 41(8):936-940 (2009)
  Congenital dyserythropoietic anemias (CDAs) are phenotypically and genotypically heterogeneous diseases1, 2, 3, 4. CDA type II (CDAII) is the most frequent CDA. It is characterized by ineffective erythropoiesis and by the presence of bi- and multinucleated erythroblasts in bone marrow, with nuclei of equal size and DNA content, suggesting a cytokinesis disturbance5. Other features of the peripheral red blood cells are protein and lipid dysglycosylation and endoplasmic reticulum double-membrane remnants4, 6. Development of other hematopoietic lineages is normal. Individuals with CDAII show progressive splenomegaly, gallstones and iron overload potentially with liver cirrhosis or cardiac failure. Here we show that the gene encoding the secretory COPII component SEC23B is mutated in CDAII. Short hairpin RNA (shRNA)-mediated suppression of SEC23B expression recapitulates the cytokinesis defect. Knockdown of zebrafish sec23b also leads to aberrant erythrocyte development. O! ur results provide in vivo evidence for SEC23B selectivity in erythroid differentiation and show that SEC23A and SEC23B, although highly related paralogous secretory COPII components, are nonredundant in erythrocyte maturation.
• H3.3/H2A.Z double variant–containing nucleosomes mark 'nucleosome-free regions' of active promoters and other regulatory regions
  - Nat Genet 41(8):941-945 (2009)
  To understand how chromatin structure is organized by different histone variants, we have measured the genome-wide distribution of nucleosome core particles (NCPs) containing the histone variants H3.3 and H2A.Z in human cells. We find that a special class of NCPs containing both variants is enriched at 'nucleosome-free regions' of active promoters, enhancers and insulator regions. We show that preparative methods used previously in studying nucleosome structure result in the loss of these unstable double-variant NCPs. It seems likely that this instability facilitates the access of transcription factors to promoters and other regulatory sites in vivo. Other combinations of variants have different distributions, consistent with distinct roles for histone variants in the modulation of gene expression.
• A transposon-based chromosomal engineering method to survey a large cis-regulatory landscape in mice
  - Nat Genet 41(8):946-952 (2009)
  A large cis-regulatory landscape is a common feature of vertebrate genomes, particularly at key developmental gene loci with finely tuned expression patterns. Existing genetic tools for surveying large genomic regions of interest spanning over hundreds of kilobases are limited. Here we propose a chromosomal engineering strategy exploiting the local hopping trait of the Sleeping Beauty transposon in the mouse genome. We generated embryonic stem cells with a targeted integration of the transposon vector, carrying an enhancer-detecting lacZ reporter and loxP cassette, into the developmentally critical Pax1 gene locus, followed by efficient local transpositions, nested deletion formation and derivation of embryos by tetraploid complementation. Comparative reporter expression analysis among different insertion/deletion embryos substantially facilitated long-range cis-regulatory element mapping in the genomic neighborhood and demonstrated the potential of the transposon-base! d approach as a versatile tool for exploration of defined genomic intervals of functional or clinical relevance, such as disease-associated microdeletions.