Showing papers by "Wellcome Trust Centre for Human Genetics published in 2011"
TL;DR: A measure of dependence for two-variable relationships: the maximal information coefficient (MIC), which captures a wide range of associations both functional and not, and for functional relationships provides a score that roughly equals the coefficient of determination of the data relative to the regression function.
Abstract: Identifying interesting relationships between pairs of variables in large data sets is increasingly important. Here, we present a measure of dependence for two-variable relationships: the maximal information coefficient (MIC). MIC captures a wide range of associations both functional and not, and for functional relationships provides a score that roughly equals the coefficient of determination (R2) of the data relative to the regression function. MIC belongs to a larger class of maximal information-based nonparametric exploration (MINE) statistics for identifying and classifying relationships. We apply MIC and MINE to data sets in global health, gene expression, major-league baseball, and the human gut microbiota and identify known and novel relationships.
2,414 citations
TL;DR: These sequences provide a starting point for a new era in the functional analysis of a key model organism and show that the molecular nature of functional variants and their position relative to genes vary according to the effect size of the locus.
Abstract: We report genome sequences of 17 inbred strains of laboratory mice and identify almost ten times more variants than previously known. We use these genomes to explore the phylogenetic history of the laboratory mouse and to examine the functional consequences of allele-specific variation on transcript abundance, revealing that at least 12% of transcripts show a significant tissue-specific expression bias. By identifying candidate functional variants at 718 quantitative trait loci we show that the molecular nature of functional variants and their position relative to genes vary according to the effect size of the locus. These sequences provide a starting point for a new era in the functional analysis of a key model organism.
1,453 citations
TL;DR: A read mapper, Stampy, which uses a hybrid mapping algorithm and a detailed statistical model to achieve both speed and sensitivity, particularly when reads include sequence variation, which results in a higher useable sequence yield and improved accuracy compared to that of existing software.
Abstract: High-volume sequencing of DNA and RNA is now within reach of any research laboratory and is quickly becoming established as a key research tool. In many workflows, each of the short sequences ("reads") resulting from a sequencing run are first "mapped" (aligned) to a reference sequence to infer the read from which the genomic location derived, a challenging task because of the high data volumes and often large genomes. Existing read mapping software excel in either speed (e.g., BWA, Bowtie, ELAND) or sensitivity (e.g., Novoalign), but not in both. In addition, performance often deteriorates in the presence of sequence variation, particularly so for short insertions and deletions (indels). Here, we present a read mapper, Stampy, which uses a hybrid mapping algorithm and a detailed statistical model to achieve both speed and sensitivity, particularly when reads include sequence variation. This results in a higher useable sequence yield and improved accuracy compared to that of existing software.
1,184 citations
TL;DR: The results show that trio-based exome sequencing is a powerful approach for identifying new candidate genes for ASDs and suggest that de novo mutations may contribute substantially to the genetic etiology of ASDs.
Abstract: Evidence for the etiology of autism spectrum disorders (ASDs) has consistently pointed to a strong genetic component complicated by substantial locus heterogeneity. We sequenced the exomes of 20 individuals with sporadic ASD (cases) and their parents, reasoning that these families would be enriched for de novo mutations of major effect. We identified 21 de novo mutations, 11 of which were protein altering. Protein-altering mutations were significantly enriched for changes at highly conserved residues. We identified potentially causative de novo events in 4 out of 20 probands, particularly among more severely affected individuals, in FOXP1, GRIN2B, SCN1A and LAMC3. In the FOXP1 mutation carrier, we also observed a rare inherited CNTNAP2 missense variant, and we provide functional support for a multi-hit model for disease risk. Our results show that trio-based exome sequencing is a powerful approach for identifying new candidate genes for ASDs and suggest that de novo mutations may contribute substantially to the genetic etiology of ASDs.
1,116 citations
TL;DR: Endometriosis impairs HRQoL and work productivity across countries and ethnicities, yet women continue to experience diagnostic delays in primary care, and a higher index of suspicion is needed to expedite specialist assessment of symptomatic women.
1,007 citations
TL;DR: Global gene expression analysis demonstrated that exogenous IRF5 upregulated or downregulated expression of established phenotypic markers of M1 or M2 macrophages, respectively, suggesting a critical role for IRf5 in M1 macrophage polarization and defining a previously unknown function forIRF5 as a transcriptional repressor.
Abstract: Polymorphisms in the gene encoding the transcription factor IRF5 that lead to higher mRNA expression are associated with many autoimmune diseases. Here we show that IRF5 expression in macrophages was reversibly induced by inflammatory stimuli and contributed to the plasticity of macrophage polarization. High expression of IRF5 was characteristic of M1 macrophages, in which it directly activated transcription of the genes encoding interleukin 12 subunit p40 (IL-12p40), IL-12p35 and IL-23p19 and repressed the gene encoding IL-10. Consequently, those macrophages set up the environment for a potent T helper type 1 (T(H)1)-T(H)17 response. Global gene expression analysis demonstrated that exogenous IRF5 upregulated or downregulated expression of established phenotypic markers of M1 or M2 macrophages, respectively. Our data suggest a critical role for IRF5 in M1 macrophage polarization and define a previously unknown function for IRF5 as a transcriptional repressor.
991 citations
Medical Research Council1, University of Oxford2, National Institute for Health Research3, Structural Genomics Consortium4, University of Bristol5, University of Bath6, University of Queensland7, National Institutes of Health8, Cedars-Sinai Medical Center9, University of Toronto10, University of Alberta11, Memorial University of Newfoundland12, University of Leeds13, Norfolk and Norwich University Hospital14, Repatriation General Hospital15, University of Porto16, Sapienza University of Rome17, QIMR Berghofer Medical Research Institute18, Second Military Medical University19, Telethon Institute for Child Health Research20, Wellcome Trust Sanger Institute21, University of London22, Trinity College, Dublin23, Cardiff University24, Wellcome Trust25, Wellcome Trust Centre for Human Genetics26, St George's, University of London27, King's College London28, Churchill Hospital29, University of Leicester30, University of Cambridge31, University College London32, Moorfields Eye Hospital33, University of Texas Health Science Center at Houston34, Princess Alexandra Hospital35
TL;DR: In this paper, the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 x 10(-8) in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all their datasets (p < 5x 10(-6) overall, with support in each of the three datasets studied).
Abstract: Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 x 10(-8) in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 x 10(-6) overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.
798 citations
TL;DR: A strong genetic component to inter-individual variation in DNA methylation profiles is demonstrated, and there was an enrichment of SNPs that affect both methylation and gene expression, providing evidence for shared mechanisms in a fraction of genes.
Abstract: DNA methylation is an essential epigenetic mechanism involved in gene regulation and disease, but little is known about the mechanisms underlying inter-individual variation in methylation profiles. Here we measured methylation levels at 22,290 CpG dinucleotides in lymphoblastoid cell lines from 77 HapMap Yoruba individuals, for which genome-wide gene expression and genotype data were also available. Association analyses of methylation levels with more than three million common single nucleotide polymorphisms (SNPs) identified 180 CpG-sites in 173 genes that were associated with nearby SNPs (putatively in cis, usually within 5 kb) at a false discovery rate of 10%. The most intriguing trans signal was obtained for SNP rs10876043 in the disco-interacting protein 2 homolog B gene (DIP2B, previously postulated to play a role in DNA methylation), that had a genome-wide significant association with the first principal component of patterns of methylation; however, we found only modest signal of trans-acting associations overall. As expected, we found significant negative correlations between promoter methylation and gene expression levels measured by RNA-sequencing across genes. Finally, there was a significant overlap of SNPs that were associated with both methylation and gene expression levels. Our results demonstrate a strong genetic component to inter-individual variation in DNA methylation profiles. Furthermore, there was an enrichment of SNPs that affect both methylation and gene expression, providing evidence for shared mechanisms in a fraction of genes.
761 citations
TL;DR: Genetic differences between Arabidopsis thaliana accessions underlie the plant’s extensive phenotypic variation, and until now these have been interpreted largely in the context of the annotated reference accession Col-0.
Abstract: Genetic differences between Arabidopsis thaliana accessions underlie the plant's extensive phenotypic variation, and until now these have been interpreted largely in the context of the annotated reference accession Col-0. Here we report the sequencing, assembly and annotation of the genomes of 18 natural A. thaliana accessions, and their transcriptomes. When assessed on the basis of the reference annotation, one-third of protein-coding genes are predicted to be disrupted in at least one accession. However, re-annotation of each genome revealed that alternative gene models often restore coding potential. Gene expression in seedlings differed for nearly half of expressed genes and was frequently associated with cis variants within 5 kilobases, as were intron retention alternative splicing events. Sequence and expression variation is most pronounced in genes that respond to the biotic environment. Our data further promote evolutionary and functional studies in A. thaliana, especially the MAGIC genetic reference population descended from these accessions.
656 citations
TL;DR: Using chromatin immunoprecipitation linked to high throughput sequencing, HIF-binding sites across the genome are identified, indicating that these sites operate over long genomic intervals, and epigenetic regulation of chromatin may have an important role in defining the response to hypoxia.
638 citations
TL;DR: Significantly elevated risks of VTE were found, in all three populations studied, in people with a hospital record of admission for autoimmune haemolytic anaemia, chronic active hepatitis, dermatomyositis/polymyositis, type 1 diabetes mellitus, multiple sclerosis, myasthenia gravis, myxoedema, pemphigus/pemphIGoid, polyarteritis nodosa, psoriasis, rheumatoid arthritis, Sj
Abstract: Venous thromboembolism (VTE) is a common complication during and after a hospital admission. Although it is mainly considered a complication of surgery, it often occurs in people who have not undergone surgery, with recent evidence suggesting that immune-mediated diseases may play a role in VTE risk. We, therefore, decided to study the risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in people admitted to hospital with a range of immune-mediated diseases. We analysed databases of linked statistical records of hospital admissions and death certificates for the Oxford Record Linkage Study area (ORLS1:1968 to 1998 and ORLS2:1999 to 2008) and the whole of England (1999 to 2008). Rate ratios for VTE were determined, comparing immune-mediated disease cohorts with comparison cohorts. Significantly elevated risks of VTE were found, in all three populations studied, in people with a hospital record of admission for autoimmune haemolytic anaemia, chronic active hepatitis, dermatomyositis/polymyositis, type 1 diabetes mellitus, multiple sclerosis, myasthenia gravis, myxoedema, pemphigus/pemphigoid, polyarteritis nodosa, psoriasis, rheumatoid arthritis, Sjogren's syndrome, and systemic lupus erythematosus. Rate ratios were considerably higher for some of these diseases than others: for example, for systemic lupus erythematosus the rate ratios were 3.61 (2.36 to 5.31) in the ORLS1 population, 4.60 (3.19 to 6.43) in ORLS2 and 3.71 (3.43 to 4.02) in the England dataset. People admitted to hospital with immune-mediated diseases may be at an increased risk of subsequent VTE. Our findings need independent confirmation or refutation; but, if confirmed, there may be a role for thromboprophylaxis in some patients with these diseases.
TL;DR: The discovery of a cross-strain dependency on a single extracellular receptor–ligand pair for erythrocyte invasion by P. falciparum provides a focus for new anti-malarial therapies.
Abstract: Erythrocyte invasion by Plasmodium falciparum is central to the pathogenesis of malaria. Invasion requires a series of extracellular recognition events between erythrocyte receptors and ligands on the merozoite, the invasive form of the parasite. None of the few known receptor-ligand interactions involved are required in all parasite strains, indicating that the parasite is able to access multiple redundant invasion pathways. Here, we show that we have identified a receptor-ligand pair that is essential for erythrocyte invasion in all tested P. falciparum strains. By systematically screening a library of erythrocyte proteins, we have found that the Ok blood group antigen, basigin, is a receptor for PfRh5, a parasite ligand that is essential for blood stage growth. Erythrocyte invasion was potently inhibited by soluble basigin or by basigin knockdown, and invasion could be completely blocked using low concentrations of anti-basigin antibodies; importantly, these effects were observed across all laboratory-adapted and field strains tested. Furthermore, Ok(a-) erythrocytes, which express a basigin variant that has a weaker binding affinity for PfRh5, had reduced invasion efficiencies. Our discovery of a cross-strain dependency on a single extracellular receptor-ligand pair for erythrocyte invasion by P. falciparum provides a focus for new anti-malarial therapies.
Washington University in St. Louis1, Human Genome Sequencing Center2, Wellcome Trust Centre for Human Genetics3, University of Oxford4, Pompeu Fabra University5, University of Washington6, Howard Hughes Medical Institute7, Wellcome Trust Sanger Institute8, European Bioinformatics Institute9, University of Illinois at Urbana–Champaign10, University of California, Santa Cruz11, Pennsylvania State University12, University of Porto13, Universidade Nova de Lisboa14, University of Bari15, University of Bologna16, Louisiana State University17, Institute for Systems Biology18, Indiana University19, University of Oviedo20, Comenius University in Bratislava21, Cornell University22, Columbia University23, Stanford University24, University of Arizona25, Aarhus University26, Children's Hospital Oakland Research Institute27
TL;DR: The orang-utan species, Pongo abelii and Pongo pygmaeus, are the most phylogenetically distant great apes from humans, thereby providing an informative perspective on hominid evolution and a primate polymorphic neocentromere, found in both Pongo species are described.
Abstract: 'Orang-utan' is derived from a Malay term meaning 'man of the forest' and aptly describes the southeast Asian great apes native to Sumatra and Borneo. The orang-utan species, Pongo abelii (Sumatran) and Pongo pygmaeus (Bornean), are the most phylogenetically distant great apes from humans, thereby providing an informative perspective on hominid evolution. Here we present a Sumatran orang-utan draft genome assembly and short read sequence data from five Sumatran and five Bornean orang-utan genomes. Our analyses reveal that, compared to other primates, the orang-utan genome has many unique features. Structural evolution of the orang-utan genome has proceeded much more slowly than other great apes, evidenced by fewer rearrangements, less segmental duplication, a lower rate of gene family turnover and surprisingly quiescent Alu repeats, which have played a major role in restructuring other primate genomes. We also describe a primate polymorphic neocentromere, found in both Pongo species, emphasizing the gradual evolution of orang-utan genome structure. Orang-utans have extremely low energy usage for a eutherian mammal, far lower than their hominid relatives. Adding their genome to the repertoire of sequenced primates illuminates new signals of positive selection in several pathways including glycolipid metabolism. From the population perspective, both Pongo species are deeply diverse; however, Sumatran individuals possess greater diversity than their Bornean counterparts, and more species-specific variation. Our estimate of Bornean/Sumatran speciation time, 400,000 years ago, is more recent than most previous studies and underscores the complexity of the orang-utan speciation process. Despite a smaller modern census population size, the Sumatran effective population size (N(e)) expanded exponentially relative to the ancestral N(e) after the split, while Bornean N(e) declined over the same period. Overall, the resources and analyses presented here offer new opportunities in evolutionary genomics, insights into hominid biology, and an extensive database of variation for conservation efforts.
TL;DR: Adult mouse LSK cells unable to undergo autophagy contain fewer HSCs, accumulate mitochondria, and fail to reconstitute lethally irradiated mice.
Abstract: The role of autophagy, a lysosomal degradation pathway which prevents cellular damage, in the maintenance of adult mouse hematopoietic stem cells (HSCs) remains unknown Although normal HSCs sustain life-long hematopoiesis, malignant transformation of HSCs leads to leukemia Therefore, mechanisms protecting HSCs from cellular damage are essential to prevent hematopoietic malignancies In this study, we crippled autophagy in HSCs by conditionally deleting the essential autophagy gene Atg7 in the hematopoietic system This resulted in the loss of normal HSC functions, a severe myeloproliferation, and death of the mice within weeks The hematopoietic stem and progenitor cell compartment displayed an accumulation of mitochondria and reactive oxygen species, as well as increased proliferation and DNA damage HSCs within the Lin(-)Sca-1(+)c-Kit(+) (LSK) compartment were significantly reduced Although the overall LSK compartment was expanded, Atg7-deficient LSK cells failed to reconstitute the hematopoietic system of lethally irradiated mice Consistent with loss of HSC functions, the production of both lymphoid and myeloid progenitors was impaired in the absence of Atg7 Collectively, these data show that Atg7 is an essential regulator of adult HSC maintenance
National Institutes of Health1, University of Cambridge2, National University of Singapore3, Ealing Hospital4, Imperial College London5, University of Oklahoma6, University of Oxford7, University of Geneva8, Aga Khan University9, The Heart Research Institute10, Indian Council of Medical Research11, Heart of England NHS Foundation Trust12, University of Birmingham13, Singapore National Eye Center14, National Health Service15, King's College London16, Agency for Science, Technology and Research17, University of Kelaniya18, Wellcome Trust Sanger Institute19, University of Melbourne20, Beijing Genomics Institute21, University of Michigan22, Queen Mary University of London23, University of Exeter24, University of Colombo25, University of Oklahoma Health Sciences Center26, University of California, San Francisco27, Baker IDI Heart and Diabetes Institute28, National Institute for Health Research29, Wellcome Trust Centre for Human Genetics30, Imperial College Healthcare31
TL;DR: A genome-wide association study of type-2 diabetes in individuals of South Asian ancestry provides additional insight into mechanisms underlying T2D and shows the potential for new discovery from genetic association studies in South Asians.
Abstract: John Chambers and colleagues report a genome-wide association study for type 2 diabetes in individuals of south Asian ancestry. They identify six loci newly associated with type 2 diabetes.
TL;DR: Findings indicate that classic sweeps were not a dominant mode of human adaptation over the past ~250,000 years and amino acid and putative regulatory sites are not significantly enriched in alleles that are highly differentiated between populations.
Abstract: Efforts to identify the genetic basis of human adaptations from polymorphism data have sought footprints of "classic selective sweeps" (in which a beneficial mutation arises and rapidly fixes in the population).Yet it remains unknown whether this form of natural selection was common in our evolution. We examined the evidence for classic sweeps in resequencing data from 179 human genomes. As expected under a recurrent-sweep model, we found that diversity levels decrease near exons and conserved noncoding regions. In contrast to expectation, however, the trough in diversity around human-specific amino acid substitutions is no more pronounced than around synonymous substitutions. Moreover, relative to the genome background, amino acid and putative regulatory sites are not significantly enriched in alleles that are highly differentiated between populations. These findings indicate that classic sweeps were not a dominant mode of human adaptation over the past ~250,000 years.
TL;DR: Mechanical analysis revealed that fumarate modifies cysteine residues within the Kelch-like ECH-associated protein 1 (KEAP1), abrogating its ability to repress the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-mediated antioxidant response pathway, suggesting a role for Nrf2 dysregulation in FH-associated cysts and tumors.
TL;DR: This protocol describes how to perform basic statistical analysis in a population-based genetic association case-control study and uses popular tools for handling single-nucleotide polymorphism data in order to carry out tests of association and visualize and interpret results.
Abstract: This protocol describes how to perform basic statistical analysis in a population-based genetic association case-control study. The steps described involve the (i) appropriate selection of measures of association and relevance of disease models; (ii) appropriate selection of tests of association; (iii) visualization and interpretation of results; (iv) consideration of appropriate methods to control for multiple testing; and (v) replication strategies. Assuming no previous experience with software such as PLINK, R or Haploview, we describe how to use these popular tools for handling single-nucleotide polymorphism data in order to carry out tests of association and visualize and interpret results. This protocol assumes that data quality assessment and control has been performed, as described in a previous protocol, so that samples and markers deemed to have the potential to introduce bias to the study have been identified and removed. Study design, marker selection and quality control of case-control studies have also been discussed in earlier protocols. The protocol should take ~1 h to complete.
TL;DR: The role of cis-regulatory variation in three human tissues: lymphoblastoid cell lines, skin, and fat is explored and it is proposed that continuous estimates of the proportion of tissue-shared signals and direct comparison of the magnitude of effect on the fold change in expression are essential properties that jointly provide a biologically realistic view of tissues-specificity.
Abstract: While there have been studies exploring regulatory variation in one or more tissues, the complexity of tissue-specificity in multiple primary tissues is not yet well understood. We explore in depth the role of cis-regulatory variation in three human tissues: lymphoblastoid cell lines (LCL), skin, and fat. The samples (156 LCL, 160 skin, 166 fat) were derived simultaneously from a subset of well-phenotyped healthy female twins of the MuTHER resource. We discover an abundance of cis-eQTLs in each tissue similar to previous estimates (858 or 4.7% of genes). In addition, we apply factor analysis (FA) to remove effects of latent variables, thus more than doubling the number of our discoveries (1,822 eQTL genes). The unique study design (Matched Co-Twin Analysis—MCTA) permits immediate replication of eQTLs using co-twins (93%–98%) and validation of the considerable gain in eQTL discovery after FA correction. We highlight the challenges of comparing eQTLs between tissues. After verifying previous significance threshold-based estimates of tissue-specificity, we show their limitations given their dependency on statistical power. We propose that continuous estimates of the proportion of tissue-shared signals and direct comparison of the magnitude of effect on the fold change in expression are essential properties that jointly provide a biologically realistic view of tissue-specificity. Under this framework we demonstrate that 30% of eQTLs are shared among the three tissues studied, while another 29% appear exclusively tissue-specific. However, even among the shared eQTLs, a substantial proportion (10%–20%) have significant differences in the magnitude of fold change between genotypic classes across tissues. Our results underline the need to account for the complexity of eQTL tissue-specificity in an effort to assess consequences of such variants for complex traits.
QIMR Berghofer Medical Research Institute1, Peninsula College of Medicine and Dentistry2, Broad Institute3, Harvard University4, Montreal Heart Institute5, University of Michigan6, Karolinska Institutet7, University of Maryland, Baltimore8, St Thomas' Hospital9, Wellcome Trust Centre for Human Genetics10, Washington University in St. Louis11, Boston Children's Hospital12, University of Oxford13, University of Melbourne14
TL;DR: It is shown that in the absence of population structure and other technical artefacts, but in the presence of polygenic inheritance, substantial genomic inflation is expected, and its magnitude depends on sample size, heritability, linkage disequilibrium structure and the number of causal variants.
Abstract: Population structure, including population stratification and cryptic relatedness, can cause spurious associations in genome-wide association studies (GWAS). Usually, the scaled median or mean test statistic for association calculated from multiple single-nucleotide-polymorphisms across the genome is used to assess such effects, and 'genomic control' can be applied subsequently to adjust test statistics at individual loci by a genomic inflation factor. Published GWAS have clearly shown that there are many loci underlying genetic variation for a wide range of complex diseases and traits, implying that a substantial proportion of the genome should show inflation of the test statistic. Here, we show by theory, simulation and analysis of data that in the absence of population structure and other technical artefacts, but in the presence of polygenic inheritance, substantial genomic inflation is expected. Its magnitude depends on sample size, heritability, linkage disequilibrium structure and the number of causal variants. Our predictions are consistent with empirical observations on height in independent samples of ~4000 and ~133,000 individuals.
TL;DR: The results suggest that stratifying tumor responses according to CINstatus should be considered within the context of clinical trials to minimize the confounding effects of tumor CIN status on drug sensitivity.
Abstract: Aneuploidy is associated with poor prognosis in solid tumors. Spontaneous chromosome missegregation events in aneuploid cells promote chromosomal instability (CIN) that may contribute to the acquisition of multidrug resistance in vitro and heighten risk for tumor relapse in animal models. Identification of distinct therapeutic agents that target tumor karyotypic complexity has important clinical implications. To identify distinct therapeutic approaches to specifically limit the growth of CIN tumors, we focused on a panel of colorectal cancer (CRC) cell lines, previously classified as either chromosomally unstable (CIN(+)) or diploid/near-diploid (CIN(-)), and treated them individually with a library of kinase inhibitors targeting components of signal transduction, cell cycle, and transmembrane receptor signaling pathways. CIN(+) cell lines displayed significant intrinsic multidrug resistance compared with CIN(-) cancer cell lines, and this seemed to be independent of somatic mutation status and proliferation rate. Confirming the association of CIN rather than ploidy status with multidrug resistance, tetraploid isogenic cells that had arisen from diploid cell lines displayed lower drug sensitivity than their diploid parental cells only with increasing chromosomal heterogeneity and isogenic cell line models of CIN(+) displayed multidrug resistance relative to their CIN(-) parental cancer cell line derivatives. In a meta-analysis of CRC outcome following cytotoxic treatment, CIN(+) predicted worse progression-free or disease-free survival relative to patients with CIN(-) disease. Our results suggest that stratifying tumor responses according to CIN status should be considered within the context of clinical trials to minimize the confounding effects of tumor CIN status on drug sensitivity.
Sébastien Jacquemont1, Alexandre Reymond, Flore Zufferey, Louise Harewood +179 more•Institutions (11)
TL;DR: In this article, the reciprocal duplication is associated with being clinically underweight, which is the main sign of a series of heterogeneous clinical conditions including failure to thrive, feeding and eating disorder and/or anorexia nervosa.
Abstract: Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index (BMI) ≤ 18.5 kg per m(2) in adults and ≤ -2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive, feeding and eating disorder and/or anorexia nervosa. In contrast to obesity, few genetic variants underlying these clinical conditions have been reported. We previously showed that hemizygosity of a ∼600-kilobase (kb) region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities. Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers (including 132 novel cases and 108 unrelated carriers) from individuals clinically referred for developmental or intellectual disabilities (DD/ID) or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance.
QIMR Berghofer Medical Research Institute1, Peninsula College of Medicine and Dentistry2, Harvard University3, Broad Institute4, Montreal Heart Institute5, University of Michigan6, Karolinska Institutet7, University of Maryland, Baltimore8, St Thomas' Hospital9, Wellcome Trust Centre for Human Genetics10, Washington University in St. Louis11, Boston Children's Hospital12, University of Oxford13, University of Melbourne14
TL;DR: In this paper, the authors show that in the absence of population structure and other technical artefacts, but in the presence of polygenic inheritance, substantial genomic inflation is expected, its magnitude depends on sample size, heritability, linkage disequilibrium structure and the number of causal variants.
Abstract: Population structure, including population stratification and cryptic relatedness, can cause spurious associations in genome-wide association studies (GWAS). Usually, the scaled median or mean test statistic for association calculated from multiple single-nucleotide-polymorphisms across the genome is used to assess such effects, and 'genomic control' can be applied subsequently to adjust test statistics at individual loci by a genomic inflation factor. Published GWAS have clearly shown that there are many loci underlying genetic variation for a wide range of complex diseases and traits, implying that a substantial proportion of the genome should show inflation of the test statistic. Here, we show by theory, simulation and analysis of data that in the absence of population structure and other technical artefacts, but in the presence of polygenic inheritance, substantial genomic inflation is expected. Its magnitude depends on sample size, heritability, linkage disequilibrium structure and the number of causal variants. Our predictions are consistent with empirical observations on height in independent samples of ~4000 and ~133,000 individuals.
TL;DR: This phylogeny makes sense of the shared characteristics of Xenoturbellida and Acoelomorpha, and implies the loss of various deuterostome characters in the Xenobiology including coelomic cavities, through gut and gill slits.
Abstract: Xenoturbellida and Acoelomorpha are marine worms with contentious ancestry. Both were originally associated with the flatworms (Platyhelminthes), but molecular data have revised their phylogenetic positions, generally linking Xenoturbellida to the deuterostomes and positioning the Acoelomorpha as the most basally branching bilaterian group(s). Recent phylogenomic data suggested that Xenoturbellida and Acoelomorpha are sister taxa and together constitute an early branch of Bilateria. Here we assemble three independent data sets-mitochondrial genes, a phylogenomic data set of 38,330 amino-acid positions and new microRNA (miRNA) complements-and show that the position of Acoelomorpha is strongly affected by a long-branch attraction (LBA) artefact. When we minimize LBA we find consistent support for a position of both acoelomorphs and Xenoturbella within the deuterostomes. The most likely phylogeny links Xenoturbella and Acoelomorpha in a clade we call Xenacoelomorpha. The Xenacoelomorpha is the sister group of the Ambulacraria (hemichordates and echinoderms). We show that analyses of miRNA complements have been affected by character loss in the acoels and that both groups possess one miRNA and the gene Rsb66 otherwise specific to deuterostomes. In addition, Xenoturbella shares one miRNA with the ambulacrarians, and two with the acoels. This phylogeny makes sense of the shared characteristics of Xenoturbellida and Acoelomorpha, such as ciliary ultrastructure and diffuse nervous system, and implies the loss of various deuterostome characters in the Xenacoelomorpha including coelomic cavities, through gut and gill slits.
Texas Biomedical Research Institute1, University of Dundee2, Wellcome Trust Centre for Human Genetics3, National Institute for Health Research4, University of Oxford5, South London and Maudsley NHS Foundation Trust6, King's College London7, University of Queensland8, Princess Alexandra Hospital9, University of London10, University College London11, Trinity College, Dublin12, Cardiff University13, Wellcome Trust Sanger Institute14, Wellcome Trust15, Queen Mary University of London16, Leicester Royal Infirmary17, St George's, University of London18, University of Cambridge19, Glenfield Hospital20, University of Leicester21, University of Edinburgh22, Peninsula College of Medicine and Dentistry23, University of Exeter24, Ninewells Hospital25
TL;DR: It is concluded that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMP-activated protein kinase, and variation in this gene alters glycemic response to meetformin.
Abstract: Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We report a genome-wide association study for glycemic response to metformin in 1,024 Scottish individuals with type 2 diabetes with replication in two cohorts including 1,783 Scottish individuals and 1,113 individuals from the UK Prospective Diabetes Study. In a combined meta-analysis, we identified a SNP, rs11212617, associated with treatment success (n = 3,920, P = 2.9 × 10(-9), odds ratio = 1.35, 95% CI 1.22-1.49) at a locus containing ATM, the ataxia telangiectasia mutated gene. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMP-activated protein kinase in response to metformin. We conclude that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMP-activated protein kinase, and variation in this gene alters glycemic response to metformin.
TL;DR: An overview of genetics, clinical and molecular progress recently performed in understanding the basis of HPGL/PCC tumorigenesis is reported.
Texas Biomedical Research Institute1, University of Dundee2, Wellcome Trust Centre for Human Genetics3, National Institute for Health Research4, University of Oxford5, King's College London6, South London and Maudsley NHS Foundation Trust7, University of Queensland8, Princess Alexandra Hospital9, University of London10, University College London11, Trinity College, Dublin12, Cardiff University13, Wellcome Trust Sanger Institute14, Wellcome Trust15, Leicester Royal Infirmary16, Queen Mary University of London17, St George's, University of London18, University of Cambridge19, Glenfield Hospital20, University of Leicester21, University of Edinburgh22, University of Exeter23, Peninsula College of Medicine and Dentistry24, Ninewells Hospital25
TL;DR: A genome-wide association study for glycemic response to metformin in 1,024 Scottish individuals with type 2 diabetes with replication in two cohorts including 1,783 Scottish individuals and 1,113 individuals from the UK Prospective Diabetes Study.
Abstract: Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We report a genome-wide association study for glycemic response to metformin in 1,024 Scottish individuals with type 2 diabetes with replication in two cohorts including 1,783 Scottish individuals and 1,113 individuals from the UK Prospective Diabetes Study. In a combined meta-analysis, we identified a SNP, rs11212617, associated with treatment success (n = 3,920, P = 2.9 P×-9, odds ratio = 1.35, 95% CI 1.22-1.49) at a locus containing ATM, the ataxia telangiectasia mutated gene. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMP-activated protein kinase in response to metformin. We conclude that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMP-activated protein kinase, and variation in this gene alters glycemic response to metformin. © 2011 Nature America, Inc. All rights reserved.
TL;DR: A new simulation algorithm based on a successful resampling method, HAPGEN, that can simulate multiple nearby disease SNPs on the same chromosome is introduced and expands the range of disease models that current simulators offer.
Abstract: Motivation: Performing experiments with simulated data is an inexpensive approach to evaluating competing experimental designs and analysis methods in genome-wide association studies. Simulation based on resampling known haplotypes is fast and efficient and can produce samples with patterns of linkage disequilibrium (LD), which mimic those in real data. However, the inability of current methods to simulate multiple nearby disease SNPs on the same chromosome can limit their application. Results: We introduce a new simulation algorithm based on a successful resampling method, HAPGEN, that can simulate multiple nearby disease SNPs on the same chromosome. The new method, HAPGEN2, retains many advantages of resampling methods and expands the range of disease models that current simulators offer. Availability: HAPGEN2 is freely available from http://www.stats.ox.ac.uk/~marchini/software/gwas/gwas.html. Contact: zhan@well.ox.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online.
TL;DR: It is inferred that insertion of retrotransposons causes more than half of SVs, and 24 SVs are identified that disrupt coding exons, acting as rare variants of large effect on gene function.
Abstract: Structural variation is widespread in mammalian genomes and is an important cause of disease, but just how abundant and important structural variants (SVs) are in shaping phenotypic variation remains unclear. Without knowing how many SVs there are, and how they arise, it is difficult to discover what they do. Combining experimental with automated analyses, we identified 711,920 SVs at 281,243 sites in the genomes of thirteen classical and four wild-derived inbred mouse strains. The majority of SVs are less than 1 kilobase in size and 98% are deletions or insertions. The breakpoints of 160,000 SVs were mapped to base pair resolution, allowing us to infer that insertion of retrotransposons causes more than half of SVs. Yet, despite their prevalence, SVs are less likely than other sequence variants to cause gene expression or quantitative phenotypic variation. We identified 24 SVs that disrupt coding exons, acting as rare variants of large effect on gene function. One-third of the genes so affected have immunological functions.
TL;DR: A novel transethnic meta‐analysis methodology that takes account of the expected similarity in allelic effects between the most closely related populations, while allowing for heterogeneity between more diverse ethnic groups is proposed.
Abstract: The detection of loci contributing effects to complex human traits, and their subsequent fine-mapping for the location of causal variants, remains a considerable challenge for the genetics research community. Meta-analyses of genomewide association studies, primarily ascertained from European-descent populations, have made considerable advances in our understanding of complex trait genetics, although much of their heritability is still unexplained. With the increasing availability of genomewide association data from diverse populations, transethnic meta-analysis may offer an exciting opportunity to increase the power to detect novel complex trait loci and to improve the resolution of fine-mapping of causal variants by leveraging differences in local linkage disequilibrium structure between ethnic groups. However, we might also expect there to be substantial genetic heterogeneity between diverse populations, both in terms of the spectrum of causal variants and their allelic effects, which cannot easily be accommodated through traditional approaches to meta-analysis. In order to address this challenge, I propose novel transethnic meta-analysis methodology that takes account of the expected similarity in allelic effects between the most closely related populations, while allowing for heterogeneity between more diverse ethnic groups. This approach yields substantial improvements in performance, compared to fixed-effects meta-analysis, both in terms of power to detect association, and localization of the causal variant, over a range of models of heterogeneity between ethnic groups. Furthermore, when the similarity in allelic effects between populations is well captured by their relatedness, this approach has increased power and mapping resolution over random-effects meta-analysis.