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1.
BMC Evol Biol ; 17(1): 88, 2017 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-28335724

RESUMO

BACKGROUND: India is a patchwork of tribal and non-tribal populations that speak many different languages from various language families. Indo-European, spoken across northern and central India, and also in Pakistan and Bangladesh, has been frequently connected to the so-called "Indo-Aryan invasions" from Central Asia ~3.5 ka and the establishment of the caste system, but the extent of immigration at this time remains extremely controversial. South India, on the other hand, is dominated by Dravidian languages. India displays a high level of endogamy due to its strict social boundaries, and high genetic drift as a result of long-term isolation which, together with a very complex history, makes the genetic study of Indian populations challenging. RESULTS: We have combined a detailed, high-resolution mitogenome analysis with summaries of autosomal data and Y-chromosome lineages to establish a settlement chronology for the Indian Subcontinent. Maternal lineages document the earliest settlement ~55-65 ka (thousand years ago), and major population shifts in the later Pleistocene that explain previous dating discrepancies and neutrality violation. Whilst current genome-wide analyses conflate all dispersals from Southwest and Central Asia, we were able to tease out from the mitogenome data distinct dispersal episodes dating from between the Last Glacial Maximum to the Bronze Age. Moreover, we found an extremely marked sex bias by comparing the different genetic systems. CONCLUSIONS: Maternal lineages primarily reflect earlier, pre-Holocene processes, and paternal lineages predominantly episodes within the last 10 ka. In particular, genetic influx from Central Asia in the Bronze Age was strongly male-driven, consistent with the patriarchal, patrilocal and patrilineal social structure attributed to the inferred pastoralist early Indo-European society. This was part of a much wider process of Indo-European expansion, with an ultimate source in the Pontic-Caspian region, which carried closely related Y-chromosome lineages, a smaller fraction of autosomal genome-wide variation and an even smaller fraction of mitogenomes across a vast swathe of Eurasia between 5 and 3.5 ka.


Assuntos
Genética Populacional , Migração Humana , Ásia Ocidental , Cromossomos Humanos Y , Clima , DNA Mitocondrial/genética , Feminino , Variação Genética , Estudo de Associação Genômica Ampla , Projeto Genoma Humano , Humanos , Índia/etnologia , Masculino
2.
Hum Mol Genet ; 24(19): 5464-74, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26173456

RESUMO

Homozygous loss of function (HLOF) variants provide a valuable window on gene function in humans, as well as an inventory of the human genes that are not essential for survival and reproduction. All humans carry at least a few HLOF variants, but the exact number of inactivated genes that can be tolerated is currently unknown­as are the phenotypic effects of losing function for most human genes. Here, we make use of 1432 whole exome sequences from five European populations to expand the catalogue of known human HLOF mutations; after stringent filtering of variants in our dataset, we identify a total of 173 HLOF mutations, 76 (44%) of which have not been observed previously. We find that population isolates are particularly well suited to surveys of novel HLOF genes because individuals in such populations carry extensive runs of homozygosity, which we show are enriched for novel, rare HLOF variants. Further, we make use of extensive phenotypic data to show that most HLOFs, ascertained in population-based samples, appear to have little detectable effect on the phenotype. On the contrary, we document several genes directly implicated in disease that seem to tolerate HLOF variants. Overall HLOF genes are enriched for olfactory receptor function and are expressed in testes more often than expected, consistent with reduced purifying selection and incipient pseudogenisation.


Assuntos
Mutação , População Branca/genética , Exoma , Frequência do Gene , Homozigoto , Humanos , Fenótipo , Seleção Genética
3.
PLoS Genet ; 10(4): e1004234, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24743097

RESUMO

Many existing cohorts contain a range of relatedness between genotyped individuals, either by design or by chance. Haplotype estimation in such cohorts is a central step in many downstream analyses. Using genotypes from six cohorts from isolated populations and two cohorts from non-isolated populations, we have investigated the performance of different phasing methods designed for nominally 'unrelated' individuals. We find that SHAPEIT2 produces much lower switch error rates in all cohorts compared to other methods, including those designed specifically for isolated populations. In particular, when large amounts of IBD sharing is present, SHAPEIT2 infers close to perfect haplotypes. Based on these results we have developed a general strategy for phasing cohorts with any level of implicit or explicit relatedness between individuals. First SHAPEIT2 is run ignoring all explicit family information. We then apply a novel HMM method (duoHMM) to combine the SHAPEIT2 haplotypes with any family information to infer the inheritance pattern of each meiosis at all sites across each chromosome. This allows the correction of switch errors, detection of recombination events and genotyping errors. We show that the method detects numbers of recombination events that align very well with expectations based on genetic maps, and that it infers far fewer spurious recombination events than Merlin. The method can also detect genotyping errors and infer recombination events in otherwise uninformative families, such as trios and duos. The detected recombination events can be used in association scans for recombination phenotypes. The method provides a simple and unified approach to haplotype estimation, that will be of interest to researchers in the fields of human, animal and plant genetics.


Assuntos
Haplótipos/genética , Mapeamento Cromossômico/métodos , Efeito de Coortes , Família , Genótipo , Humanos , Modelos Genéticos , Linhagem , Fenótipo , Recombinação Genética/genética
4.
Hum Genet ; 135(3): 309-26, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26781090

RESUMO

There are two very different interpretations of the prehistory of Island Southeast Asia (ISEA), with genetic evidence invoked in support of both. The "out-of-Taiwan" model proposes a major Late Holocene expansion of Neolithic Austronesian speakers from Taiwan. An alternative, proposing that Late Glacial/postglacial sea-level rises triggered largely autochthonous dispersals, accounts for some otherwise enigmatic genetic patterns, but fails to explain the Austronesian language dispersal. Combining mitochondrial DNA (mtDNA), Y-chromosome and genome-wide data, we performed the most comprehensive analysis of the region to date, obtaining highly consistent results across all three systems and allowing us to reconcile the models. We infer a primarily common ancestry for Taiwan/ISEA populations established before the Neolithic, but also detected clear signals of two minor Late Holocene migrations, probably representing Neolithic input from both Mainland Southeast Asia and South China, via Taiwan. This latter may therefore have mediated the Austronesian language dispersal, implying small-scale migration and language shift rather than large-scale expansion.


Assuntos
Povo Asiático/genética , DNA Mitocondrial/genética , Genoma Humano , Sudeste Asiático , Cromossomos Humanos Y/genética , Bases de Dados Genéticas , Feminino , Estudos de Associação Genética , Loci Gênicos , Humanos , Masculino , Modelos Genéticos , Filogenia , Filogeografia , Polimorfismo de Nucleotídeo Único , Reprodutibilidade dos Testes
5.
Nat Commun ; 12(1): 24, 2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-33402679

RESUMO

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.


Assuntos
Anorexia Nervosa/genética , Glicemia/metabolismo , Intolerância à Glucose/genética , Proteínas Substratos do Receptor de Insulina/genética , Resistência à Insulina/genética , Insulina/sangue , Fatores de Transcrição Kruppel-Like/genética , Adulto , Anorexia Nervosa/sangue , Anorexia Nervosa/etnologia , Anorexia Nervosa/fisiopatologia , Jejum/sangue , Feminino , Expressão Gênica , Loci Gênicos , Estudo de Associação Genômica Ampla , Intolerância à Glucose/sangue , Intolerância à Glucose/etnologia , Intolerância à Glucose/fisiopatologia , Humanos , Proteínas Substratos do Receptor de Insulina/sangue , Fatores de Transcrição Kruppel-Like/sangue , Masculino , Pessoa de Meia-Idade , Fenótipo , Caracteres Sexuais , Fatores Sexuais , Relação Cintura-Quadril , População Branca
6.
J Mol Biol ; 364(4): 582-98, 2006 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-17027853

RESUMO

Nucleosome positioning signals embedded within the DNA sequence have the potential to influence the detailed structure of the higher-order chromatin fibre. In two previous studies of long stretches of DNA, encompassing the chicken beta-globin and ovine beta-lactoglobulin genes, respectively, we mapped the relative affinity of every site for the core histone octamer. In both cases a periodic arrangement of the in vitro positioning sites suggests that they might influence the folding of a nucleosome chain into higher-order structure; this hypothesis was borne out in the case of the beta-lactoglobulin gene, where the distribution of the in vitro positioning sites is related to the positions nucleosomes actually occupy in sheep liver cells. Here, we have exploited the in vitro nucleosome positioning datasets to simulate nucleosomal organisation using in silico approaches. We use the high-resolution, quantitative positioning maps to define a one-dimensional positioning energy lattice, which can be populated with a defined number of nucleosomes. Monte Carlo techniques are employed to simulate the behaviour of the model at equilibrium to produce a set of configurations, which provide a probability-based occupancy map. Employing a variety of techniques we show that the occupancy maps are a sensitive function of the histone octamer density (nucleosome repeat length) and find that a minimal change in this property can produce dramatic localised changes in structure. Although simulations generally give rise to regular periodic nucleosomal arrangements, they often show octamer density-dependent discontinuities, which tend to co-localise with sequences that adopt distinctive chromatin structure in vivo. Furthermore, the overall organisation of simulated chromatin structures are more closely related to the situation in vivo than is the original in vitro positioning data, particularly at a nucleosome density corresponding to the in vivo state. Although our model is simplified, we argue that it provides a unique insight into the influence that DNA sequence can have in determining chromatin structure and could serve as a useful basis for the incorporation of other parameters.


Assuntos
Cromatina/química , Simulação por Computador , Histonas/metabolismo , Sequência de Bases , Sítios de Ligação , DNA , Bases de Dados de Ácidos Nucleicos , Modelos Biológicos , Modelos Moleculares , Método de Monte Carlo , Nucleossomos/química
7.
Nat Genet ; 48(10): 1279-83, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27548312

RESUMO

We describe a reference panel of 64,976 human haplotypes at 39,235,157 SNPs constructed using whole-genome sequence data from 20 studies of predominantly European ancestry. Using this resource leads to accurate genotype imputation at minor allele frequencies as low as 0.1% and a large increase in the number of SNPs tested in association studies, and it can help to discover and refine causal loci. We describe remote server resources that allow researchers to carry out imputation and phasing consistently and efficiently.


Assuntos
Genótipo , Haplótipos , Polimorfismo de Nucleotídeo Único , Alelos , Técnicas Genéticas , Estudo de Associação Genômica Ampla , Humanos , Internet , Valores de Referência
9.
Nat Genet ; 46(11): 1173-86, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25282103

RESUMO

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/ß-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.


Assuntos
Estatura/genética , Variação Genética/genética , Polimorfismo de Nucleotídeo Único/genética , População Branca/genética , Adulto , Análise de Variância , Genética Populacional , Estudo de Associação Genômica Ampla/métodos , Humanos , Análise de Sequência com Séries de Oligonucleotídeos
10.
Lancet Diabetes Endocrinol ; 2(9): 719-29, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24974252

RESUMO

BACKGROUND: Low plasma 25-hydroxyvitamin D (25[OH]D) concentration is associated with high arterial blood pressure and hypertension risk, but whether this association is causal is unknown. We used a mendelian randomisation approach to test whether 25(OH)D concentration is causally associated with blood pressure and hypertension risk. METHODS: In this mendelian randomisation study, we generated an allele score (25[OH]D synthesis score) based on variants of genes that affect 25(OH)D synthesis or substrate availability (CYP2R1 and DHCR7), which we used as a proxy for 25(OH)D concentration. We meta-analysed data for up to 108 173 individuals from 35 studies in the D-CarDia collaboration to investigate associations between the allele score and blood pressure measurements. We complemented these analyses with previously published summary statistics from the International Consortium on Blood Pressure (ICBP), the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and the Global Blood Pressure Genetics (Global BPGen) consortium. FINDINGS: In phenotypic analyses (up to n=49 363), increased 25(OH)D concentration was associated with decreased systolic blood pressure (ß per 10% increase, -0·12 mm Hg, 95% CI -0·20 to -0·04; p=0·003) and reduced odds of hypertension (odds ratio [OR] 0·98, 95% CI 0·97-0·99; p=0·0003), but not with decreased diastolic blood pressure (ß per 10% increase, -0·02 mm Hg, -0·08 to 0·03; p=0·37). In meta-analyses in which we combined data from D-CarDia and the ICBP (n=146 581, after exclusion of overlapping studies), each 25(OH)D-increasing allele of the synthesis score was associated with a change of -0·10 mm Hg in systolic blood pressure (-0·21 to -0·0001; p=0·0498) and a change of -0·08 mm Hg in diastolic blood pressure (-0·15 to -0·02; p=0·01). When D-CarDia and consortia data for hypertension were meta-analysed together (n=142 255), the synthesis score was associated with a reduced odds of hypertension (OR per allele, 0·98, 0·96-0·99; p=0·001). In instrumental variable analysis, each 10% increase in genetically instrumented 25(OH)D concentration was associated with a change of -0·29 mm Hg in diastolic blood pressure (-0·52 to -0·07; p=0·01), a change of -0·37 mm Hg in systolic blood pressure (-0·73 to 0·003; p=0·052), and an 8·1% decreased odds of hypertension (OR 0·92, 0·87-0·97; p=0·002). INTERPRETATION: Increased plasma concentrations of 25(OH)D might reduce the risk of hypertension. This finding warrants further investigation in an independent, similarly powered study. FUNDING: British Heart Foundation, UK Medical Research Council, and Academy of Finland.


Assuntos
Colestanotriol 26-Mono-Oxigenase/genética , Hipertensão/prevenção & controle , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Polimorfismo de Nucleotídeo Único , Deficiência de Vitamina D/prevenção & controle , Vitamina D/análogos & derivados , Adulto , Índice de Massa Corporal , Família 2 do Citocromo P450 , Feminino , Predisposição Genética para Doença , Humanos , Hipertensão/sangue , Hipertensão/genética , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Fenótipo , Ensaios Clínicos Controlados Aleatórios como Assunto , Vitamina D/administração & dosagem , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/genética
11.
J Mol Biol ; 425(22): 4206-22, 2013 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-23871836

RESUMO

Using high-throughput sequencing, we have mapped sequence-directed nucleosome positioning in vitro on four plasmid DNAs containing DNA fragments derived from the genomes of sheep, drosophila, human and yeast. Chromatins were prepared by reconstitution using chicken, frog and yeast core histones. We also assembled yeast chromatin in which histone H3 was replaced by the centromere-specific histone variant, Cse4. The positions occupied by recombinant frog and native chicken histones were found to be very similar. In contrast, nucleosomes containing the canonical yeast octamer or, in particular, the Cse4 octamer were assembled at distinct populations of locations, a property that was more apparent on particular genomic DNA fragments. The factors that may contribute to this variation in nucleosome positioning and the implications of the behavior are discussed.


Assuntos
Histonas/metabolismo , Nucleossomos/metabolismo , Animais , Anuros , Sítios de Ligação , Galinhas , DNA/química , DNA/metabolismo , Histonas/química , Nucleossomos/química , Plasmídeos/química , Plasmídeos/metabolismo , Ligação Proteica , Leveduras/genética , Leveduras/metabolismo
12.
PLoS One ; 8(7): e68604, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23874685

RESUMO

The analysis of less common variants in genome-wide association studies promises to elucidate complex trait genetics but is hampered by low power to reliably detect association. We show that addition of population-specific exome sequence data to global reference data allows more accurate imputation, particularly of less common SNPs (minor allele frequency 1-10%) in two very different European populations. The imputation improvement corresponds to an increase in effective sample size of 28-38%, for SNPs with a minor allele frequency in the range 1-3%.


Assuntos
Exoma/genética , Estudo de Associação Genômica Ampla/métodos , Frequência do Gene/genética , Genoma Humano/genética , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único/genética , População Branca
13.
Nat Genet ; 45(11): 1345-52, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24097064

RESUMO

Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.


Assuntos
HDL-Colesterol/genética , LDL-Colesterol/genética , Doença da Artéria Coronariana/sangue , Triglicerídeos/sangue , Triglicerídeos/genética , Transporte Biológico , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/genética , Humanos , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Triglicerídeos/metabolismo
14.
Nat Genet ; 45(11): 1274-1283, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24097068

RESUMO

Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.


Assuntos
Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/genética , Lipídeos/sangue , Lipídeos/genética , Povo Asiático/genética , População Negra/genética , HDL-Colesterol/sangue , HDL-Colesterol/genética , LDL-Colesterol/sangue , LDL-Colesterol/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Triglicerídeos/sangue , Triglicerídeos/genética , População Branca/genética
15.
J Mol Biol ; 417(3): 152-64, 2012 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-22310051

RESUMO

We have mapped sequence-directed nucleosome positioning on genomic DNA molecules using high-throughput sequencing. Chromatins, prepared by reconstitution with either chicken or frog histones, were separately digested to mononucleosomes using either micrococcal nuclease (MNase) or caspase-activated DNase (CAD). Both enzymes preferentially cleave internucleosomal (linker) DNA, although they do so by markedly different mechanisms. MNase has hitherto been very widely used to map nucleosomes, although concerns have been raised over its potential to introduce bias. Having identified the locations and quantified the strength of both the chicken or frog histone octamer binding sites on each DNA, the results obtained with the two enzymes were compared using a variety of criteria. Both enzymes displayed sequence specificity in their preferred cleavage sites, although the nature of this selectivity was distinct for the two enzymes. In addition, nucleosomes produced by CAD nuclease are 8-10 bp longer than those produced with MNase, with the CAD cleavage sites tending to be 4-5 bp further out from the nucleosomal dyad than the corresponding MNase cleavage sites. Despite these notable differences in cleavage behaviour, the two nucleases identified essentially equivalent patterns of nucleosome positioning sites on each of the DNAs tested, an observation that was independent of the histone type. These results indicate that biases in nucleosome positioning data collected using MNase are, under our conditions, not significant.


Assuntos
Desoxirribonucleases/química , Desoxirribonucleases/metabolismo , Nuclease do Micrococo/química , Nuclease do Micrococo/metabolismo , Nucleossomos/metabolismo , Mapeamento por Restrição/métodos , Animais , Sítios de Ligação , Galinhas/genética , Cromatina/metabolismo , Histonas/genética , Histonas/metabolismo , Lactoglobulinas , Modelos Moleculares , Nucleossomos/genética , Conformação Proteica , Ranidae/genética
16.
Nat Genet ; 44(9): 981-90, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22885922

RESUMO

To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of additional common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis.


Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Genes/fisiologia , Predisposição Genética para Doença/genética , Humanos , Desequilíbrio de Ligação , Masculino , Paquistão/epidemiologia , Polimorfismo de Nucleotídeo Único/fisiologia , Fatores Sexuais
17.
Nat Genet ; 44(9): 991-1005, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22885924

RESUMO

Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.


Assuntos
Glicemia/genética , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Redes e Vias Metabólicas/genética , Locos de Características Quantitativas , Adulto , Animais , Glicemia/metabolismo , Jejum/sangue , Jejum/metabolismo , Feminino , Frequência do Gene , Humanos , Insulina/sangue , Masculino , Camundongos , Concentração Osmolar , Locos de Características Quantitativas/fisiologia
18.
J Mol Biol ; 390(2): 292-305, 2009 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-19427325

RESUMO

We have mapped in vitro nucleosome positioning on the sheep beta-lactoglobulin gene using high-throughput sequencing to characterise the DNA sequences recovered from reconstituted nucleosomes. This methodology surpasses previous approaches for coverage, accuracy and resolution and, most importantly, offers a simple yet rapid and relatively inexpensive method to characterise genomic DNA sequences in terms of nucleosome positioning capacity. We demonstrate an unambiguous correspondence between in vitro and in vivo nucleosome positioning around the promoter of the gene; identify discrete, sequence-specific nucleosomal structures above the level of the canonical core particle-a feature that has implications for regulatory protein access and higher-order chromatin packing; and reveal new insights into the involvement of periodically organised dinucleotide sequence motifs of the type GG and CC and not AA and TT, as determinants of nucleosome positioning-an observation that supports the idea that the core histone octamer can exploit different patterns of sequence organisation, or structural potential, in the DNA to bring about nucleosome positioning.


Assuntos
Sítios de Ligação , DNA/metabolismo , Nucleossomos/metabolismo , Animais , DNA/química , DNA/genética , Histonas/metabolismo , Lactoglobulinas/genética , Ligação Proteica , Análise de Sequência de DNA , Ovinos
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