Servin B.,French National Institute for Agricultural Research |
Faraut T.,French National Institute for Agricultural Research |
Iannuccelli N.,French National Institute for Agricultural Research |
Zelenika D.,Center National Of Genotypage |
Milan D.,French National Institute for Agricultural Research
BMC Genomics | Year: 2012
Background: The release of the porcine genome sequence offers great perspectives for Pig genetics and genomics, and more generally will contribute to the understanding of mammalian genome biology and evolution. The process of producing a complete genome sequence of high quality, while facilitated by high-throughput sequencing technologies, remains a difficult task. The porcine genome was sequenced using a combination of a hierarchical shotgun strategy and data generated with whole genome shotgun. In addition to the BAC contig map used for the clone-by-clone approach, genomic mapping resources for the pig include two radiation hybrid (RH) panels at two different resolutions. These two panels have been used extensively for the physical mapping of pig genes and markers prior to the availability of the pig genome sequence.Results: In order to contribute to the assembly of the pig genome, we genotyped the two radiation hybrid (RH) panels with a SNP array (the Illumina porcineSNP60 array) and produced high density physical RH maps for each pig autosome. We first present the methods developed to obtain high density RH maps with 38,379 SNPs from the SNP array genotyping. We then show how they were useful to identify problems in a draft of the pig genome assembly, and how the RH maps enabled the problems to be corrected in the porcine genome sequence. Finally, we used the RH maps to predict the position of 2,703 SNPs and 1,328 scaffolds currently unplaced on the porcine genome assembly.Conclusions: A complete process, from genotyping of a high density SNP array on RH panels, to the construction of genome-wide high density RH maps, and finally their exploitation for validating and improving a genome assembly is presented here. The study includes the cross-validation of RH based findings with independent information from genetic data and comparative mapping with the Human genome. Several additional resources are also provided, in particular the predicted genomic location of currently unplaced SNPs and associated scaffolds summing up to a total of 72 megabases, that can be useful for the exploitation of the pig genome assembly. © 2012 Servin et al.; licensee BioMed Central Ltd.
Athanasiadis G.,Hospital Of La Santa Creu I Sant Pau |
Sabater-Lleal M.,Karolinska University Hospital |
Buil A.,University of Geneva |
Souto J.C.,Autonomous University of Barcelona |
And 6 more authors.
Journal of Thrombosis and Haemostasis | Year: 2013
Background: β2-Glycoprotein I (β2-GPI), also designated apolipoprotein H, is a 50-kDa protein that circulates in blood at high concentrations, playing important roles in autoimmune diseases, hemostasis, atherogenesis, and angiogenesis, as well as in host defense against bacteria and in protein/cellular waste removal. Plasma β2-GPI levels have a significant genetic component (heritability of ~ 80%). Objectives: To present the results of a genome-wide association study for plasma β2-GPI levels in a set of extended pedigrees from the Genetic Analysis of Idiopathic Thrombophilia (GAIT) Project. Patients/Methods: A total of 306 individuals for whom β2-GPI plasma measurements were available were typed for 307 984 single-nucleotide polymorphisms (SNPs) with the Infinium 317k Beadchip (Illumina). Association with the β2-GPI phenotype was investigated through variance component analysis, and the most significant results were followed up for association with coronary artery disease (CAD) in an independent in silico analysis involving 5765 CAD cases from the PROCARDIS Project and 7264 controls from the PROCARDIS Project and the Wellcome Trust Case Control Consortium (WTCCC) collection. Results: After correction for multiple testing, three SNPs located in/around two genes (ELF5 and SCUBE2) reached genome-wide significance. Moreover, an SNP in the APOH gene showed suggestive association with the β2-GPI phenotype. Some of the identified genes are plausible biological candidates, as they are actually or potentially involved in inflammatory processes. Conclusions: Our results represent a first step towards identifying common variants reflecting the genetic architecture influencing plasma β2-GPI levels, and warrant further validation by functional experiments, as the functions of some of the discovered loci are still unknown. © 2013 International Society on Thrombosis and Haemostasis.
Belostotsky R.,Shaare Zedek Medical Center |
Seboun E.,University Pierre and Marie Curie |
Seboun E.,French Institute of Health and Medical Research |
Idelson G.H.,Shaare Zedek Medical Center |
And 13 more authors.
American Journal of Human Genetics | Year: 2010
Primary hyperoxaluria (PH) is an autosomal-recessive disorder of endogenous oxalate synthesis characterized by accumulation of calcium oxalate primarily in the kidney. Deficiencies of alanine-glyoxylate aminotransferase (AGT) or glyoxylate reductase (GRHPR) are the two known causes of the disease (PH I and II, respectively). To determine the etiology of an as yet uncharacterized type of PH, we selected a cohort of 15 non-PH I/PH II patients from eight unrelated families with calcium oxalate nephrolithiasis for high-density SNP microarray analysis. We determined that mutations in an uncharacterized gene, DHDPSL, on chromosome 10 cause a third type of PH (PH III). To overcome the difficulties in data analysis attributed to a state of compound heterozygosity, we developed a strategy of "heterozygosity mapping" - a search for long heterozygous patterns unique to all patients in a given family and overlapping between families, followed by reconstruction of haplotypes. This approach enabled us to determine an allelic fragment shared by all patients of Ashkenazi Jewish descent and bearing a 3 bp deletion in DHDPSL. Overall, six mutations were detected: four missense mutations, one in-frame deletion, and one splice-site mutation. Our assumption is that DHDPSL is the gene encoding 4-hydroxy-2-oxoglutarate aldolase, catalyzing the final step in the metabolic pathway of hydroxyproline. © 2010 The American Society of Human Genetics.
Purper-Ouakil D.,French Institute of Health and Medical Research |
Ramoz N.,French Institute of Health and Medical Research |
Lepagnol-Bestel A.-M.,Center National Of Genotypage |
Gorwood P.,French Institute of Health and Medical Research |
Simonneau M.,French Institute of Health and Medical Research
Pediatric Research | Year: 2011
Attention deficit/hyperactivity disorder (ADHD), a prevalent neurodevelopmental disorder, has been associated with various structural and functional CNS abnormalities but findings about neurobiological mechanisms linking genes to brain phenotypes are just beginning to emerge. Despite the high heritability of the disorder and its main symptom dimensions, common individual genetic variants are likely to account for a small proportion of the phenotype's variance. Recent findings have drawn attention to the involvement of rare genetic variants in the pathophysiology of ADHD, some being shared with other neurodevelopmental disorders. Traditionally, neurobiological research on ADHD has focused on catecholaminergic pathways, the main target of pharmacological treatments. However, more distal and basic neuronal processes in relation with cell architecture and function might also play a role, possibly accounting for the coexistence of both diffuse and specific alterations of brain structure and activation patterns. This article aims to provide an overview of recent findings in the rapidly evolving field of ADHD neurobiology with a focus on novel strategies regarding pathophysiological analyses. Copyright © 2011 International Pediatric Research Foundation, Inc.
Gandotra S.,University of Cambridge |
Le Dour C.,University Pierre and Marie Curie |
Bottomley W.,Wellcome Trust Sanger Institute |
Cervera P.,University Pierre and Marie Curie |
And 17 more authors.
New England Journal of Medicine | Year: 2011
Perilipin is the most abundant adipocyte-specific protein that coats lipid droplets, and it is required for optimal lipid incorporation and release from the droplet. We identified two heterozygous frameshift mutations in the perilipin gene (PLIN1) in three families with partial lipodystrophy, severe dyslipidemia, and insulin-resistant diabetes. Subcutaneous fat from the patients was characterized by smaller-than-normal adipocytes, macrophage infiltration, and fibrosis. In contrast to wild-type perilipin, mutant forms of the protein failed to increase triglyceride accumulation when expressed heterologously in preadipocytes. These findings define a novel dominant form of inherited lipodystrophy and highlight the serious metabolic consequences of a primary defect in the formation of lipid droplets in adipose tissue. Copyright © 2011 Massachusetts Medical Society.
Momozawa Y.,University of Liège |
Mni M.,University of Liège |
Nakamura K.,University of Liège |
Coppieters W.,University of Liège |
And 25 more authors.
Nature Genetics | Year: 2011
Genome-wide association studies (GWAS) have identified dozens of risk loci for many complex disorders, including Crohn's disease. However, common disease-associated SNPs explain at most ∼20% of the genetic variance for Crohn's disease. Several factors may account for this unexplained heritability, including rare risk variants not adequately tagged thus far in GWAS. That rare susceptibility variants indeed contribute to variation in multifactorial phenotypes has been demonstrated for colorectal cancer, plasma high-density lipoprotein cholesterol levels, blood pressure, type 1 diabetes, hypertriglyceridemia and, in the case of Crohn's disease, for NOD2 (refs. 14,15). Here we describe the use of high-throughput resequencing of DNA pools to search for rare coding variants influencing susceptibility to Crohn's disease in 63 GWAS-identified positional candidate genes. We identify low frequency coding variants conferring protection against inflammatory bowel disease in IL23R, but we conclude that rare coding variants in positional candidates do not make a large contribution to inherited predisposition to Crohn's disease. © 2011 Nature America, Inc. All rights reserved.
Center National Of Genotypage and Hoffmann-La Roche | Date: 2012-12-19
The present application provides polynucleotides comprising 5-tails with sequence segments useful for the detection of target nucleic acid sequences, and methods for their use in detecting target nucleic acids. The polynucleotides are used to amplify a subsequence of a target nucleic acid in the presence of one or more ribonucleotides. The ribonucleotides are incorporated into amplification products at regular intervals complementary to the 5-tail sequence segments. Cleavage of amplification products at the bond immediately 3 to incorporated ribonucleotides produces detectably distinct fragments indicative of the presence or absence of a target nucleic acid.
Travis R.C.,University of Oxford |
Reeves G.K.,University of Oxford |
Green J.,University of Oxford |
Bull D.,University of Oxford |
And 7 more authors.
The Lancet | Year: 2010
Background: Information is scarce about the combined effects on breast cancer incidence of low-penetrance genetic susceptibility polymorphisms and environmental factors (reproductive, behavioural, and anthropometric risk factors for breast cancer). To test for evidence of gene-environment interactions, we compared genotypic relative risks for breast cancer across the other risk factors in a large UK prospective study. Methods: We tested gene-environment interactions in 7610 women who developed breast cancer and 10 196 controls without the disease, studying the effects of 12 polymorphisms (FGFR2-rs2981582, TNRC9-rs3803662, 2q35-rs13387042, MAP3K1-rs889312, 8q24-rs13281615, 2p-rs4666451, 5p12-rs981782, CASP8-rs1045485, LSP1-rs3817198, 5q-rs30099, TGFB1-rs1982073, and ATM-rs1800054) in relation to prospectively collected information about ten established environmental risk factors (age at menarche, parity, age at first birth, breastfeeding, menopausal status, age at menopause, use of hormone replacement therapy, body-mass index, height, and alcohol consumption). Findings: After allowance for multiple testing none of the 120 comparisons yielded significant evidence of a gene-environment interaction. By contrast with previous suggestions, there was little evidence that the genotypic relative risks were affected by use of hormone replacement therapy, either overall or for oestrogen-receptor-positive disease. Only one of the 12 polymorphisms was correlated with any of the ten other risk factors: carriers of the high-risk C allele of MAP3K1-rs889312 were significantly shorter than non-carriers (mean height 162·4 cm [95% CI 162·1-162·7] vs 163·1 cm [162·9-163·2]; p=0·01 after allowance for multiple testing). Interpretation: Risks of breast cancer associated with low-penetrance susceptibility polymorphisms do not vary significantly with these ten established environmental risk factors. Funding: Cancer Research UK and the UK Medical Research Council. © 2010 Elsevier Ltd. All rights reserved.
Liang L.,Harvard University |
Morar N.,Imperial College London |
Dixon A.L.,Imperial College London |
Lathrop G.M.,Center National Of Genotypage |
And 3 more authors.
Genome Research | Year: 2013
Gene expression levels can be an important link DNA between variation and phenotypic manifestations. Our previous map of global gene expression, based on ∼400K single nucleotide polymorphisms (SNPs) and 50K transcripts in 400 sib pairs from the MRCA family panel, has been widely used to interpret the results of genome-wide association studies (GWASs). Here, we more than double the size of our initial data set with expression data on 550 additional individuals from the MRCE family panel using the Illumina whole-genome expression array. We have used new statistical methods for dimension reduction to account for nongenetic effects in estimates of expression levels, and we have also included SNPs imputed from the 1000 Genomes Project. Our methods reduced false-discovery rates and increased the number of expression quantitative trait loci (eQTLs) mapped either locally or at a distance (i.e., in cis or trans) from 1534 in the MRCA data set to 4452 (with <5% FDR). Imputation of 1000 Genomes SNPs further increased the number of eQTLs to 7302. Using the same methods and imputed SNPs in the newly acquired MRCE data set, we identified eQTLs for 9000 genes. The combined results identify strong local and distant effects for transcripts from 14,177 genes. Our eQTL database based on these results is freely available to help define the function of disease-associated variants. © 2013, Published by Cold Spring Harbor Laboratory Press.
Julier C.,French Institute of Health and Medical Research |
Julier C.,University Paris Diderot |
Julier C.,Center National Of Genotypage |
Nicolino M.,University of Lyon |
Nicolino M.,French Institute of Health and Medical Research
Orphanet Journal of Rare Diseases | Year: 2010
Wolcott-Rallison syndrome (WRS) is a rare autosomal recessive disease, characterized by neonatal/early-onset non-autoimmune insulin-requiring diabetes associated with skeletal dysplasia and growth retardation. Fewer than 60 cases have been described in the literature, although WRS is now recognised as the most frequent cause of neonatal/early-onset diabetes in patients with consanguineous parents. Typically, diabetes occurs before six months of age, and skeletal dysplasia is diagnosed within the first year or two of life. Other manifestations vary between patients in their nature and severity and include frequent episodes of acute liver failure, renal dysfunction, exocrine pancreas insufficiency, intellectual deficit, hypothyroidism, neutropenia and recurrent infections. Bone fractures may be frequent. WRS is caused by mutations in the gene encoding eukaryotic translation initiation factor 2 kinase 3 (EIF2AK3), also known as PKR-like endoplasmic reticulum kinase (PERK). PERK is an endoplasmic reticulum (ER) transmembrane protein, which plays a key role in translation control during the unfolded protein response. ER dysfunction is central to the disease processes. The disease variability appears to be independent of the nature of the EIF2AK3 mutations, with the possible exception of an older age at onset; other factors may include other genes, exposure to environmental factors and disease management. WRS should be suspected in any infant who presents with permanent neonatal diabetes associated with skeletal dysplasia and/or episodes of acute liver failure. Molecular genetic testing confirms the diagnosis. Early diagnosis is recommended, in order to ensure rapid intervention for episodes of hepatic failure, which is the most life threatening complication. WRS should be differentiated from other forms of neonatal/early-onset insulin-dependent diabetes based on clinical presentation and genetic testing. Genetic counselling and antenatal diagnosis is recommended for parents of a WRS patient with confirmed EIF2AK3 mutation. Close therapeutic monitoring of diabetes and treatment with an insulin pump are recommended because of the risk of acute episodes of hypoglycaemia and ketoacidosis. Interventions under general anaesthesia increase the risk of acute aggravation, because of the toxicity of anaesthetics, and should be avoided. Prognosis is poor and most patients die at a young age. Intervention strategies targeting ER dysfunction provide hope for future therapy and prevention. © 2010 Julier and Nicolino; licensee BioMed Central Ltd.