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1.
BMC Plant Biol ; 21(1): 364, 2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376143

RESUMO

BACKGROUND: Improving the overall production of rice with high quality is a major target of breeders. Mining potential yield-related loci have been geared towards developing efficient rice breeding strategies. In this study, one single-locus genome-wide association studies (SL-GWAS) method (MLM) in conjunction with five multi-locus genome-wide association studies (ML-GWAS) approaches (mrMLM, FASTmrMLM, pLARmEB, pKWmEB, and ISIS EM-BLASSO) were conducted in a panel consisting of 529 rice core varieties with 607,201 SNPs. RESULTS: A total of 152, 106, 12, 111, and 64 SNPs were detected by the MLM model associated with the five yield-related traits, namely grain length (GL), grain width (GW), grain thickness (GT), thousand-grain weight (TGW), and yield per plant (YPP), respectively. Furthermore, 74 significant quantitative trait nucleotides (QTNs) were presented across at least two ML-GWAS methods to be associated with the above five traits successively. Finally, 20 common QTNs were simultaneously discovered by both SL-GWAS and ML-GWAS methods. Based on genome annotation, gene expression analysis, and previous studies, two candidate key genes (LOC_Os09g02830 and LOC_Os07g31450) were characterized to affect GW and TGW, separately. CONCLUSIONS: These outcomes will provide an indication for breeding high-yielding rice varieties in the immediate future.


Assuntos
Estudo de Associação Genômica Ampla , Oryza/crescimento & desenvolvimento , Oryza/genética , Desequilíbrio de Ligação , Fenótipo , Melhoramento Vegetal , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
2.
Nat Commun ; 12(1): 5071, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417470

RESUMO

Identification of causal variants and genes underlying genome-wide association study (GWAS) loci is essential to understand the biology of alcohol use disorder (AUD) and drinks per week (DPW). Multi-omics integration approaches have shown potential for fine mapping complex loci to obtain biological insights to disease mechanisms. In this study, we use multi-omics approaches, to fine-map AUD and DPW associations at single SNP resolution to demonstrate that rs56030824 on chromosome 11 significantly reduces SPI1 mRNA expression in myeloid cells and lowers risk for AUD and DPW. Our analysis also identifies MAPT as a candidate causal gene specifically associated with DPW. Genes prioritized in this study show overlap with causal genes associated with neurodegenerative disorders. Multi-omics integration analyses highlight, genetic similarities and differences between alcohol intake and disordered drinking, suggesting molecular heterogeneity that might inform future targeted functional and cross-species studies.


Assuntos
Alcoolismo/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genômica , Doenças Neurodegenerativas/genética , Encéfalo/metabolismo , Epigênese Genética , Feto/metabolismo , Redes Reguladoras de Genes , Loci Gênicos , Marcadores Genéticos , Humanos , Desequilíbrio de Ligação/genética , Análise da Randomização Mendeliana , Mapeamento Físico do Cromossomo , Regiões Promotoras Genéticas/genética , Locos de Características Quantitativas/genética
3.
Int J Mol Sci ; 22(11)2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34199768

RESUMO

Single mutations can confer resistance to antibiotics. Identifying such mutations can help to develop and improve drugs. Here, we systematically screen for candidate quinolone resistance-conferring mutations. We sequenced highly diverse wastewater E. coli and performed a genome-wide association study (GWAS) to determine associations between over 200,000 mutations and quinolone resistance phenotypes. We uncovered 13 statistically significant mutations including 1 located at the active site of the biofilm dispersal gene bdcA and 6 silent mutations in the aminoacyl-tRNA synthetase valS. The study also recovered the known mutations in the topoisomerases gyrase (gyrA) and topoisomerase IV (parC). In summary, we demonstrate that GWAS effectively and comprehensively identifies resistance mutations without a priori knowledge of targets and mode of action. The results suggest that mutations in the bdcA and valS genes, which are involved in biofilm dispersal and translation, may lead to novel resistance mechanisms.


Assuntos
Farmacorresistência Bacteriana/genética , Proteínas de Escherichia coli/genética , Escherichia coli/genética , Mutação/genética , Quinolonas/farmacologia , Valina-tRNA Ligase/genética , Águas Residuárias/microbiologia , Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Escherichia coli/isolamento & purificação , Loci Gênicos , Estudo de Associação Genômica Ampla , Desequilíbrio de Ligação/genética , Modelos Moleculares , Fenótipo , Filogenia
4.
Front Immunol ; 12: 620847, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248929

RESUMO

Ticks cause substantial production losses for beef and dairy cattle. Cattle resistance to ticks is one of the most important factors affecting tick control, but largely neglected due to the challenge of phenotyping. In this study, we evaluate the pooling of tick resistance phenotyped reference populations from multi-country beef cattle breeds to assess the possibility of improving host resistance through multi-trait genomic selection. Data consisted of tick counts or scores assessing the number of female ticks at least 4.5 mm length and derived from seven populations, with breed, country, number of records and genotyped/phenotyped animals being respectively: Angus (AN), Brazil, 2,263, 921/1,156, Hereford (HH), Brazil, 6,615, 1,910/2,802, Brangus (BN), Brazil, 2,441, 851/851, Braford (BO), Brazil, 9,523, 3,062/4,095, Tropical Composite (TC), Australia, 229, 229/229, Brahman (BR), Australia, 675, 675/675, and Nguni (NG), South Africa, 490, 490/490. All populations were genotyped using medium density Illumina SNP BeadChips and imputed to a common high-density panel of 332,468 markers. The mean linkage disequilibrium (LD) between adjacent SNPs varied from 0.24 to 0.37 across populations and so was sufficient to allow genomic breeding values (GEBV) prediction. Correlations of LD phase between breeds were higher between composites and their founder breeds (0.81 to 0.95) and lower between NG and the other breeds (0.27 and 0.35). There was wide range of estimated heritability (0.05 and 0.42) and genetic correlation (-0.01 and 0.87) for tick resistance across the studied populations, with the largest genetic correlation observed between BN and BO. Predictive ability was improved under the old-young validation for three of the seven populations using a multi-trait approach compared to a single trait within-population prediction, while whole and partial data GEBV correlations increased in all cases, with relative improvements ranging from 3% for BO to 64% for TC. Moreover, the multi-trait analysis was useful to correct typical over-dispersion of the GEBV. Results from this study indicate that a joint genomic evaluation of AN, HH, BN, BO and BR can be readily implemented to improve tick resistance of these populations using selection on GEBV. For NG and TC additional phenotyping will be required to obtain accurate GEBV.


Assuntos
Cruzamento , Bovinos/genética , Resistência à Doença/genética , Genoma , Genômica/métodos , Infestações por Carrapato/veterinária , Carrapatos/fisiologia , Animais , Brasil , Bovinos/fisiologia , Feminino , Genótipo , Desequilíbrio de Ligação , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único , Característica Quantitativa Herdável , África do Sul , Infestações por Carrapato/genética
5.
Nat Genet ; 53(8): 1125-1134, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34312540

RESUMO

Autism is a highly heritable complex disorder in which de novo mutation (DNM) variation contributes significantly to risk. Using whole-genome sequencing data from 3,474 families, we investigate another source of large-effect risk variation, ultra-rare variants. We report and replicate a transmission disequilibrium of private, likely gene-disruptive (LGD) variants in probands but find that 95% of this burden resides outside of known DNM-enriched genes. This variant class more strongly affects multiplex family probands and supports a multi-hit model for autism. Candidate genes with private LGD variants preferentially transmitted to probands converge on the E3 ubiquitin-protein ligase complex, intracellular transport and Erb signaling protein networks. We estimate that these variants are approximately 2.5 generations old and significantly younger than other variants of similar type and frequency in siblings. Overall, private LGD variants are under strong purifying selection and appear to act on a distinct set of genes not yet associated with autism.


Assuntos
Transtorno do Espectro Autista/genética , Predisposição Genética para Doença , Proteínas/genética , Transtorno Autístico/genética , Evolução Molecular , Dosagem de Genes , Haplótipos , Humanos , Desequilíbrio de Ligação , Modelos Genéticos , Mutação , Linhagem , Polimorfismo de Nucleotídeo Único , Mapas de Interação de Proteínas/genética , Irmãos , Sequenciamento Completo do Genoma
6.
Nat Genet ; 53(8): 1243-1249, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34326547

RESUMO

The genetic effect-size distribution of a disease describes the number of risk variants, the range of their effect sizes and sample sizes that will be required to discover them. Accurate estimation has been a challenge. Here I propose Fourier Mixture Regression (FMR), validating that it accurately estimates real and simulated effect-size distributions. Applied to summary statistics for ten diseases (average [Formula: see text]), FMR estimates that 100,000-1,000,000 cases will be required for genome-wide significant SNPs to explain 50% of SNP heritability. In such large studies, genome-wide significance becomes increasingly conservative, and less stringent thresholds achieve high true positive rates if confounding is controlled. Across traits, polygenicity varies, but the range of their effect sizes is similar. Compared with effect sizes in the top 10% of heritability, including most discovered thus far, those in the bottom 10-50% are orders of magnitude smaller and more numerous, spanning a large fraction of the genome.


Assuntos
Estudo de Associação Genômica Ampla , Modelos Genéticos , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único , Bancos de Espécimes Biológicos , Análise de Fourier , Predisposição Genética para Doença , Humanos , Desequilíbrio de Ligação , Análise de Regressão , Reino Unido
7.
Nat Genet ; 53(8): 1260-1269, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34226706

RESUMO

Exome association studies to date have generally been underpowered to systematically evaluate the phenotypic impact of very rare coding variants. We leveraged extensive haplotype sharing between 49,960 exome-sequenced UK Biobank participants and the remainder of the cohort (total n ≈ 500,000) to impute exome-wide variants with accuracy R2 > 0.5 down to minor allele frequency (MAF) ~0.00005. Association and fine-mapping analyses of 54 quantitative traits identified 1,189 significant associations (P < 5 × 10-8) involving 675 distinct rare protein-altering variants (MAF < 0.01) that passed stringent filters for likely causality. Across all traits, 49% of associations (578/1,189) occurred in genes with two or more hits; follow-up analyses of these genes identified allelic series containing up to 45 distinct 'likely-causal' variants. Our results demonstrate the utility of within-cohort imputation in population-scale genome-wide association studies, provide a catalog of likely-causal, large-effect coding variant associations and foreshadow the insights that will be revealed as genetic biobank studies continue to grow.


Assuntos
Bancos de Espécimes Biológicos , Frequência do Gene , Proteínas/genética , Sequenciamento Completo do Exoma/estatística & dados numéricos , Pressão Sanguínea/genética , Mapeamento Cromossômico/métodos , Mapeamento Cromossômico/estatística & dados numéricos , Marcadores Genéticos , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Desequilíbrio de Ligação , Proteínas de Membrana/genética , Modelos Genéticos , Fenótipo , Polimorfismo de Nucleotídeo Único , Proteínas/metabolismo , Receptores do Fator Natriurético Atrial/genética , Reino Unido , Sequenciamento Completo do Exoma/métodos
8.
Mol Ecol ; 30(16): 3896-3897, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34218481

RESUMO

Several recent publications have stated that epistatic fitness interactions cause the fixation of inversions that suppress recombination among the loci involved. Under this type of selection, however, the suppression of recombination in an inversion heterozygote can create a form of heterozygote advantage, which prevents the inversion from becoming fixed by selection. This process has been explicitly modelled by previous workers.


Assuntos
Epistasia Genética , Recombinação Genética , Inversão Cromossômica/genética , Heterozigoto , Humanos , Desequilíbrio de Ligação , Modelos Genéticos , Seleção Genética
9.
Gene ; 801: 145835, 2021 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-34274475

RESUMO

BACKGROUND: Recurrent pregnancy loss (RPL) is major pregnancy complication, with poorly defined cause.Forkhead Box P3 (FOXP3) is a transcription factor that supports Treg activation and development and attenuates immune responses. As FOXP3 production is genetically determined, we tested the association of FOXP3 gene variants with RPL. METHODS: A retrospective case-control study, performed between April 2019 and February 2020. Study subjects comprised 62 RPL cases and 60 control women. Genotyping of the four FOXP3 variants rs2294021 (T > C), rs2232365 (G > A), rs3761548 (C > A), and rs141704699 (C > T) was done by real-time PCR, with defined clusters. Logistic odds ratios (ORs) of RPL risk were estimated with 95% confidence interval (CI) after adjustment; statistical significance set at P < 0.05. RESULTS: Minor allele frequency (MAF) of rs2294021 was significantly lower [P < 0.001; OR(95% CI) = 0.25(0.11-0.55)], while rs2232365 MAF was significantly higher [P = 0.045; OR(95% CI) = 1.85(1.05-3.28)] in cases, hence assigning RPL-protection and -susceptibility to these variants, respectively. Increased RPL risk was seen in rs2232365 homozygous minor allele carrying genotype [OR(95% CI) = 5.14(1.01-26.15)], while reduced RPL risk was noted in rs2294021 heterozygous [OR(95% CI) = 0.30(0.11-0.80)], and homozygous minor allele [OR(95% CI) = 0.10(0.01-0.83)] genotype carriers. Moderate linkage disequilibrium analysis was seen between the tested variants. Increased frequency of TACC, and reduced frequency of CGAC haplotypes were seen in RPL cases when compared to controls, thereby assigning RPL susceptibility and protection to these haplotypes, respectively. CONCLUSION: These results suggest that FOXP3 variants and haplotypes are associated with idiopathic RPL, suggesting the likely contribution of Treg to RPL.


Assuntos
Aborto Habitual/genética , Fatores de Transcrição Forkhead/genética , Polimorfismo de Nucleotídeo Único , Adulto , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Haplótipos , Humanos , Cazaquistão , Desequilíbrio de Ligação , Gravidez , Estudos Retrospectivos
10.
Cell Mol Life Sci ; 78(15): 5743-5754, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34196733

RESUMO

GWAS involves testing genetic variants across the genomes of many individuals of a population to identify genotype-phenotype association. It was initially developed and has proven highly successful in human disease genetics. In plants genome-wide association studies (GWAS) initially focused on single feature polymorphism and recombination and linkage disequilibrium but has now been embraced by a plethora of different disciplines with several thousand studies being published in model and crop species within the last decade or so. Here we will provide a comprehensive review of these studies providing cases studies on biotic resistance, abiotic tolerance, yield associated traits, and metabolic composition. We also detail current strategies of candidate gene validation as well as the functional study of haplotypes. Furthermore, we provide a critical evaluation of the GWAS strategy and its alternatives as well as future perspectives that are emerging with the emergence of pan-genomic datasets.


Assuntos
Produtos Agrícolas/genética , Genoma de Planta/genética , Estudos de Associação Genética/métodos , Estudo de Associação Genômica Ampla/métodos , Haplótipos/genética , Humanos , Desequilíbrio de Ligação/genética , Polimorfismo de Nucleotídeo Único/genética
11.
Genet Sel Evol ; 53(1): 57, 2021 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-34217202

RESUMO

BACKGROUND: Twin and multiple births are rare in cattle and have a negative impact on the performance and health of cows and calves. Therefore, selection against multiple birth would be desirable in dairy cattle breeds such as Holstein. We applied different methods to decipher the genetic architecture of this trait using de-regressed breeding values for maternal multiple birth of ~ 2500 Holstein individuals to perform genome-wide association analyses using ~ 600 K imputed single nucleotide polymorphisms (SNPs). RESULTS: In the population studied, we found no significant genetic trend over time of the estimated breeding values for multiple birth, which indicates that this trait has not been selected for in the past. In addition to several suggestive non-significant quantitative trait loci (QTL) on different chromosomes, we identified a major QTL on chromosome 11 for maternal multiple birth that explains ~ 16% of the total genetic variance. Using a haplotype-based approach, this QTL was fine-mapped to a 70-kb window on chromosome 11 between 31.00 and 31.07 Mb that harbors two functional candidate genes (LHCGR and FSHR). Analysis of whole-genome sequence data by linkage-disequilibrium estimation revealed a regulatory variant in the 5'-region of LHCGR as a possible candidate causal variant for the identified major QTL. Furthermore, the identified haplotype showed significant effects on stillbirth and days to first service. CONCLUSIONS: QTL detection and subsequent identification of causal variants in livestock species remain challenging in spite of the availability of large-scale genotype and phenotype data. Here, we report for the first time a major QTL for multiple birth in Holstein cattle and provide evidence for a linked variant in the non-coding region of a functional candidate gene. This discovery, which is a first step towards the understanding of the genetic architecture of this polygenic trait, opens the path for future selection against this undesirable trait, and thus contributes to increased animal health and welfare.


Assuntos
Bovinos/genética , Tamanho da Ninhada de Vivíparos/genética , Locos de Características Quantitativas , Receptores do FSH/genética , Receptores do LH/genética , Animais , Bovinos/fisiologia , Feminino , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Natimorto/genética , Natimorto/veterinária
12.
BMC Plant Biol ; 21(1): 305, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193036

RESUMO

BACKGROUND: Natural variations derived from both evolutionary selection and genetic recombination, presume to have important functions to respond to various abiotic stresses, which could be used to improve drought tolerance via genomic selection. RESULTS: In the present study, the NAC-encoding gene of ZmNAC080308 was cloned and sequenced in 199 inbred lines in maize. Phylogenetic analysis showed that ZmNAC080308 is closely clusteredinto the same group with other well-known NAC genes responding to improve drought tolerance. In total, 86 SNPs and 47 InDels were identified in the generic region of ZmNAC080308, 19 of these variations were associated with GY (grain yield) in different environments. Nine variations in the 5'-UTR region of ZmNAC080308 are closely linked, they might regulate the gene expression and respond to improve GY under drought condition via Sp1-mediated transactivation. Two haplotypes (Hap1 and Hap2) identified in the, 5'-UTR region using the nine variations, and Hap2 containing insertion variants, exhibited 15.47 % higher GY under drought stress condition. Further, a functional marker was developed to predict the drought stress tolerance in a US maize inbred line panel. Lines carrying Hap2 exhibited > 10 % higher GY than those carrying Hap1 under drought stress condition. In Arabidopsis, overexpression ZmNAC080308 enhanced drought tolerance. CONCLUSIONS: ZmNAC080308 is an important gene responding to drought tolerance, a functional marker is developed for improving maize drought tolerance by selecting this gene.


Assuntos
Secas , Variação Genética , Proteínas de Plantas/genética , Sementes/crescimento & desenvolvimento , Estresse Fisiológico/genética , Zea mays/genética , Zea mays/fisiologia , Regiões 5' não Traduzidas/genética , Sequência de Aminoácidos , Arabidopsis/genética , Núcleo Celular/metabolismo , Regulação da Expressão Gênica de Plantas , Marcadores Genéticos , Genótipo , Desequilíbrio de Ligação/genética , Filogenia , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas , Polimorfismo de Nucleotídeo Único/genética , Plântula/metabolismo , Frações Subcelulares/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
13.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201603

RESUMO

Melon (Cucumis melo L.) is an economically important horticultural crop with abundant morphological and genetic variability. Complex genetic variations exist even among melon varieties and remain unclear to date. Therefore, unraveling the genetic variability among the three different melon varieties, muskmelon (C. melo subsp. melo), makuwa (C. melo L. var. makuwa), and cantaloupes (C. melo subsp. melo var. cantalupensis), could provide a basis for evolutionary research. In this study, we attempted a systematic approach with genotyping-by-sequencing (GBS)-derived single nucleotide polymorphisms (SNPs) to reveal the genetic structure and diversity, haplotype differences, and marker-based varieties differentiation. A total of 6406 GBS-derived SNPs were selected for the diversity analysis, in which the muskmelon varieties showed higher heterozygote SNPs. Linkage disequilibrium (LD) decay varied significantly among the three melon varieties, in which more rapid LD decay was observed in muskmelon (r2 = 0.25) varieties. The Bayesian phylogenetic tree provided the intraspecific relationships among the three melon varieties that formed, as expected, individual clusters exhibiting the greatest genetic distance based on the posterior probability. The haplotype analysis also supported the phylogeny result by generating three major networks for 48 haplotypes. Further investigation for varieties discrimination allowed us to detect a total of 52 SNP markers that discriminated muskmelon from makuwa varieties, of which two SNPs were converted into cleaved amplified polymorphic sequence markers for practical use. In addition to these markers, the genome-wide association study identified two SNPs located in the genes on chromosome 6, which were significantly associated with the phenotypic traits of melon seed. This study demonstrated that a systematic approach using GBS-derived SNPs could serve to efficiently classify and manage the melon varieties in the genebank.


Assuntos
Cucumis melo/genética , Marcadores Genéticos , Polimorfismo de Nucleotídeo Único , Variação Genética , Genética Populacional , Genoma de Planta , Estudo de Associação Genômica Ampla , Haplótipos/genética , Desequilíbrio de Ligação , Fenótipo , Filogenia , Sementes/genética
14.
Transl Psychiatry ; 11(1): 386, 2021 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-34247186

RESUMO

Executive functions are metacognitive capabilities that control and coordinate mental processes. In the transdiagnostic PsyCourse Study, comprising patients of the affective-to-psychotic spectrum and controls, we investigated the genetic basis of the time course of two core executive subfunctions: set-shifting (Trail Making Test, part B (TMT-B)) and updating (Verbal Digit Span backwards) in 1338 genotyped individuals. Time course was assessed with four measurement points, each 6 months apart. Compared to the initial assessment, executive performance improved across diagnostic groups. We performed a genome-wide association study to identify single nucleotide polymorphisms (SNPs) associated with performance change over time by testing for SNP-by-time interactions using linear mixed models. We identified nine genome-wide significant SNPs for TMT-B in strong linkage disequilibrium with each other on chromosome 5. These were associated with decreased performance on the continuous TMT-B score across time. Variant rs150547358 had the lowest P value = 7.2 × 10-10 with effect estimate beta = 1.16 (95% c.i.: 1.11, 1.22). Implementing data of the FOR2107 consortium (1795 individuals), we replicated these findings for the SNP rs150547358 (P value = 0.015), analyzing the difference of the two available measurement points two years apart. In the replication study, rs150547358 exhibited a similar effect estimate beta = 0.85 (95% c.i.: 0.74, 0.97). Our study demonstrates that longitudinally measured phenotypes have the potential to unmask novel associations, adding time as a dimension to the effects of genomics.


Assuntos
Função Executiva , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único
15.
Gene ; 800: 145832, 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34274476

RESUMO

OBJECTIVE: To investigate the association of FOXO3a polymorphisms and ankylosing spondylitis (AS) susceptibility in Eastern Chinese Han population. METHODS: FOXO3a polymorphisms rs12206094, rs12212067, rs2253310, rs3800232, and rs4946933 were genotyped in 650 AS patients and 646 controls by the improved Multiple Ligase Detection Reaction. RESULTS: The distribution of genotype in rs12212067 polymorphism was significantly different between AS patients and controls (P = 0.020), especially in male population (P = 0.009). There was significant difference of the genotype frequency distribution at rs3800232 between patients and controls in male population. The results of binary regression analysis showed that the rs12212067 GG genotype and rs3800232 TT genotype were obviously correlated with elevated AS risk, and the associations were still significant after being adjusted by age and gender (all P < 0.05). Interestingly, rs12212067 and rs3800232 genotypes were associated with disease activity of patients. Additionally, haplotype block rs12212067G- rs3800232T (OR = 1.403, 95%CI = 1.011-1.949) was further shown to confer promoting effect on developing AS. CONCLUSION: Among Eastern Chinese Han population, FOXO3a polymorphism rs12212067 and rs3800232 may contribute to increased risk of developing AS, but well-designed multicenter studies are needed to further confirm these preliminary findings in the future.


Assuntos
Proteína Forkhead Box O3/genética , Polimorfismo de Nucleotídeo Único , Espondilite Anquilosante/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Espondilite Anquilosante/etiologia
16.
Nat Commun ; 12(1): 4481, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34294692

RESUMO

Eurasians have ~2% Neanderthal ancestry, but we lack a comprehensive understanding of the genome-wide influence of Neanderthal introgression on modern human diseases and traits. Here, we quantify the contribution of introgressed alleles to the heritability of more than 400 diverse traits. We show that genomic regions in which detectable Neanderthal ancestry remains are depleted of heritability for all traits considered, except those related to skin and hair. Introgressed variants themselves are also depleted for contributions to the heritability of most traits. However, introgressed variants shared across multiple Neanderthal populations are enriched for heritability and have consistent directions of effect on several traits with potential relevance to human adaptation to non-African environments, including hair and skin traits, autoimmunity, chronotype, bone density, lung capacity, and menopause age. Integrating our results, we propose a model in which selection against introgressed functional variation was the dominant trend (especially for cognitive traits); however, for a few traits, introgressed variants provided beneficial variation via uni-directional (e.g., lightening skin color) or bi-directional (e.g., modulating immune response) effects.


Assuntos
Introgressão Genética , Modelos Genéticos , Herança Multifatorial , Homem de Neandertal/genética , Adaptação Fisiológica/genética , Alelos , Animais , Cognição , Feminino , Variação Genética , Genoma Humano , Estudo de Associação Genômica Ampla , Cabelo/anatomia & histologia , Humanos , Desequilíbrio de Ligação , Masculino , Homem de Neandertal/anatomia & histologia , Homem de Neandertal/fisiologia , Fenótipo , Seleção Genética
17.
Nat Commun ; 12(1): 4487, 2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34301922

RESUMO

Testicular germ cell tumors (TGCT) are the most common tumor in young white men and have a high heritability. In this study, the international Testicular Cancer Consortium assemble 10,156 and 179,683 men with and without TGCT, respectively, for a genome-wide association study. This meta-analysis identifies 22 TGCT susceptibility loci, bringing the total to 78, which account for 44% of disease heritability. Men with a polygenic risk score (PRS) in the 95th percentile have a 6.8-fold increased risk of TGCT compared to men with median scores. Among men with independent TGCT risk factors such as cryptorchidism, the PRS may guide screening decisions with the goal of reducing treatment-related complications causing long-term morbidity in survivors. These findings emphasize the interconnected nature of two known pathways that promote TGCT susceptibility: male germ cell development within its somatic niche and regulation of chromosomal division and structure, and implicate an additional biological pathway, mRNA translation.


Assuntos
Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Neoplasias Embrionárias de Células Germinativas/genética , Polimorfismo de Nucleotídeo Único , Neoplasias Testiculares/genética , Linhagem Celular Tumoral , Mapeamento Cromossômico , Redes Reguladoras de Genes/genética , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Metanálise como Assunto , Neoplasias Embrionárias de Células Germinativas/metabolismo , Mapas de Interação de Proteínas/genética , Neoplasias Testiculares/metabolismo
18.
Genet Sel Evol ; 53(1): 63, 2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34301193

RESUMO

BACKGROUND: Linkage disequilibrium (LD) is a key parameter to study the history of populations and to identify and fine map quantitative trait loci (QTL) and it has been studied for many years in animal populations. The advent of new genotyping technologies has allowed whole-genome LD studies in most cattle populations. However, to date, long-range LD (LRLD) between distant variants on the genome has not been investigated in detail in cattle. Here, we present the first comprehensive study of LRLD in French beef cattle by analysing data on 672 Charolais (CHA), 462 Limousine (LIM) and 326 Blonde d'Aquitaine (BLA) individuals that were genotyped on the Illumina BovineHD Beadchip. Furthermore, whole-genome LD and haplotype block structure were analysed in these three breeds. RESULTS: We computed linkage disequilibrium (r2) values for 5.9, 5.6 and 6.0 billion pairs of SNPs on the 29 autosomes of CHA, LIM and BLA, respectively. Mean r2 values drop to less than 0.1 for distances between SNPs greater than 120 kb. However, for the first time, we detected the existence of LRLD in the three main French beef breeds. In total, 598, 266, and 795 LRLD events (r2 ≥ 0.6) were detected in CHA, LIM and BLA, respectively. Each breed had predominantly population-specific LRLD interactions, although shared LRLD events occurred in a number of regions (55 LRLD events were shared between two breeds and nine between the three breeds). Examples of possible functional gene interactions and QTL co-location were observed with some of these LRLD events, which suggests epistatic selection. CONCLUSIONS: We identified long-range linkage disequilibrium for the first time in French beef cattle populations. Epistatic selection may be the main source of the observed LRLD events, but other forces may also be involved. LRLD information should be accounted for in genome-wide association studies.


Assuntos
Bovinos/genética , Desequilíbrio de Ligação , Animais , Estudo de Associação Genômica Ampla/métodos , Técnicas de Genotipagem/métodos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Carne Vermelha/normas
19.
Am J Hum Genet ; 108(8): 1488-1501, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34214457

RESUMO

Across species, offspring of related individuals often exhibit significant reduction in fitness-related traits, known as inbreeding depression (ID), yet the genetic and molecular basis for ID remains elusive. Here, we develop a method to quantify enrichment of ID within specific genomic annotations and apply it to human data. We analyzed the phenomes and genomes of ∼350,000 unrelated participants of the UK Biobank and found, on average of over 11 traits, significant enrichment of ID within genomic regions with high recombination rates (>21-fold; p < 10-5), with conserved function across species (>19-fold; p < 10-4), and within regulatory elements such as DNase I hypersensitive sites (∼5-fold; p = 8.9 × 10-7). We also quantified enrichment of ID within trait-associated regions and found suggestive evidence that genomic regions contributing to additive genetic variance in the population are enriched for ID signal. We find strong correlations between functional enrichment of SNP-based heritability and that of ID (r = 0.8, standard error: 0.1). These findings provide empirical evidence that ID is most likely due to many partially recessive deleterious alleles in low linkage disequilibrium regions of the genome. Our study suggests that functional characterization of ID may further elucidate the genetic architectures and biological mechanisms underlying complex traits and diseases.


Assuntos
Estudo de Associação Genômica Ampla , Genômica/métodos , Depressão por Endogamia/genética , Desequilíbrio de Ligação , Herança Multifatorial/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Feminino , Humanos , Masculino
20.
Mol Ecol ; 30(16): 3965-3973, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34145933

RESUMO

Due to its central importance to many aspects of evolutionary biology and population genetics, the long-term effective population size (Ne ) has been estimated for numerous species and populations. However, estimating contemporary Ne is difficult and in practice this parameter is often unknown. In principle, contemporary Ne can be estimated using either analyses of temporal changes in allele frequencies, or the extent of linkage disequilibrium (LD) between unlinked markers. We applied these approaches to estimate contemporary Ne of a relatively recently founded island population of collared flycatchers (Ficedula albicollis). We sequenced the genomes of 85 birds sampled in 1993 and 2015, and applied several temporal methods to estimate Ne at a few thousand (4000-7000). The approach based on LD provided higher estimates of Ne (20,000-32,000) and was associated with high variance, often resulting in infinite Ne . We conclude that whole-genome sequencing data offers new possibilities to estimate high (>1000) contemporary Ne , but also note that such estimates remain challenging, in particular for LD-based methods for contemporary Ne estimation.


Assuntos
Aves Canoras , Animais , Genética Populacional , Genoma , Genômica , Desequilíbrio de Ligação , Densidade Demográfica , Aves Canoras/genética
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