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1.
Nat Commun ; 11(1): 4930, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004804

RESUMO

Inference of causality between gene expression and complex traits using Mendelian randomization (MR) is confounded by pleiotropy and linkage disequilibrium (LD) of gene-expression quantitative trait loci (eQTL). Here, we propose an MR method, MR-link, that accounts for unobserved pleiotropy and LD by leveraging information from individual-level data, even when only one eQTL variant is present. In simulations, MR-link shows false-positive rates close to expectation (median 0.05) and high power (up to 0.89), outperforming all other tested MR methods and coloc. Application of MR-link to low-density lipoprotein cholesterol (LDL-C) measurements in 12,449 individuals with expression and protein QTL summary statistics from blood and liver identifies 25 genes causally linked to LDL-C. These include the known SORT1 and ApoE genes as well as PVRL2, located in the APOE locus, for which a causal role in liver was not known. Our results showcase the strength of MR-link for transcriptome-wide causal inferences.


Assuntos
LDL-Colesterol/sangue , Regulação da Expressão Gênica , Predisposição Genética para Doença , Modelos Genéticos , Locos de Características Quantitativas , Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , LDL-Colesterol/metabolismo , Simulação por Computador , Conjuntos de Dados como Assunto , Pleiotropia Genética , Humanos , Desequilíbrio de Ligação , Metabolismo dos Lipídeos/genética , Análise da Randomização Mendeliana , Redes e Vias Metabólicas/genética , Herança Multifatorial , Nectinas/genética , Nectinas/metabolismo , Países Baixos , Proteômica , RNA-Seq
2.
Nat Commun ; 11(1): 4912, 2020 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-32999275

RESUMO

Most signals detected by genome-wide association studies map to non-coding sequence and their tissue-specific effects influence transcriptional regulation. However, key tissues and cell-types required for functional inference are absent from large-scale resources. Here we explore the relationship between genetic variants influencing predisposition to type 2 diabetes (T2D) and related glycemic traits, and human pancreatic islet transcription using data from 420 donors. We find: (a) 7741 cis-eQTLs in islets with a replication rate across 44 GTEx tissues between 40% and 73%; (b) marked overlap between islet cis-eQTL signals and active regulatory sequences in islets, with reduced eQTL effect size observed in the stretch enhancers most strongly implicated in GWAS signal location; (c) enrichment of islet cis-eQTL signals with T2D risk variants identified in genome-wide association studies; and (d) colocalization between 47 islet cis-eQTLs and variants influencing T2D or glycemic traits, including DGKB and TCF7L2. Our findings illustrate the advantages of performing functional and regulatory studies in disease relevant tissues.


Assuntos
Glicemia/genética , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Ilhotas Pancreáticas/metabolismo , Locos de Características Quantitativas , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Glicemia/metabolismo , Linhagem Celular Tumoral , Estudos de Coortes , Diabetes Mellitus Tipo 2/sangue , Diacilglicerol Quinase/genética , Diacilglicerol Quinase/metabolismo , Elementos Facilitadores Genéticos , Feminino , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , RNA-Seq , Análise de Sequência de DNA , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Proteína 2 Semelhante ao Fator 7 de Transcrição/metabolismo , Adulto Jovem
3.
Plant Genome ; 13(1): e20007, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-33016637

RESUMO

Crown rust, caused by Puccinia coronata f. sp. avenae Erikss., is the most important disease impacting cultivated oat (Avena sativa L.). Genetic resistance is the most desirable management strategy. The genetic architecture of crown rust resistance is not fully understood, and previous mapping investigations have mostly ignored temporal variation. A collection of elite oat lines sourced from oat breeding programs in the American Upper Midwest and Canada was genotyped using a high-density genotyping-by-sequencing system and evaluated for crown rust disease severity at multiple time points throughout the growing season in three disease nursery environments. Genome-wide association mapping was conducted for disease severity on each observation date of each trial, area under the disease progress curve for each trial, heading date for each trial, and area under the disease progress curve in a multi-environment model. Crown rust resistance quantitative trait loci (QTL) were detected on linkage groups Mrg05, Mrg12, Mrg15, Mrg18, Mrg20, and Mrg33. None of these QTL were coincident with a days-to-heading QTL detected on Mrg02. Only the QTL detected on Mrg15 was detected in multiple mapping models. The QTL on Mrg05, Mrg12, Mrg18, Mrg20, and Mrg33 were detected on only a single observation date and were not detected on observations just days before and after. This result uncovers the importance of temporal variation in mapping experiments which is usually ignored. It is possible that high density temporal data could be used to more precisely characterize the nature of plant resistance in other systems.


Assuntos
Avena , Basidiomycota , Avena/genética , Estudo de Associação Genômica Ampla , Doenças das Plantas/genética , Locos de Características Quantitativas
4.
Plant Genome ; 13(1): e20013, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-33016639

RESUMO

Vitamin A deficiency is one of the most prevalent nutritional deficiencies worldwide. Sorghum [Sorghum bicolor L. (Moench)] is a major cereal crop consumed by millions of people in regions with high vitamin A deficiency. We quantified carotenoid concentrations in a diverse sorghum panel using high-performance liquid chromatography and conducted a genome-wide association study (GWAS) of grain carotenoids to identify genes underlying carotenoid variation. There was moderate variation for ß-carotene (00.8 µg g-1 ), lutein (0.3-9.4 µg g-1 ), and zeaxanthin (0.2-9.1 µg g-1 ), but ß-cryptoxanthin and α-carotene were nearly undetectable. Genotype had the largest effect size, at 81% for zeaxanthin, 62% for ß-carotene, and 53% for lutein. Using multiple models, GWAS identified several significant associations between carotenoids and single nucleotide polymorphisms (SNPs), some of which colocalized with known carotenoid genes that have not been previously implicated in carotenoid variation. Several of the candidate genes identified have also been identified in maize (Zea mays L.) and Arabidopsis (Arabidopsis thaliana) carotenoid GWAS studies. Notably, an SNP inside the putative ortholog of maize zeaxanthin epoxidase (ZEP) had the most significant association with zeaxanthin and with the ratio between lutein and zeaxanthin, suggesting that ZEP is a major gene controlling sorghum carotenoid variation. Overall findings suggest there is oligogenic inheritance for sorghum carotenoids and suitable variation for marker-assisted selection. The high carotenoid germplasm and significant associations identified in this study can be used in biofortification efforts to improve the nutritional quality of sorghum.


Assuntos
Sorghum , Biofortificação , Carotenoides , Grão Comestível , Estudo de Associação Genômica Ampla , Provitaminas , Locos de Características Quantitativas , Sorghum/genética
5.
Yi Chuan ; 42(9): 889-897, 2020 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-32952123

RESUMO

Osteoporosis is a typical polygenic disease, and its heritability is as high as 85%. The incidence of osteoporosis has jumped to the fifth among the common diseases. Although a large number of osteoporosis-susceptible SNPs have been identified, most of them are in the non-coding regions of the genome and the functional mechanisms are unknown. The purpose of this study was to explore the function of non-coding osteoporosis-susceptible SNP rs4325274 and dissect the molecular regulatory mechanisms through integrating bioinformatics analysis and functional experiments. Firstly, we found the SNP rs4325274 resided in a putative enhancer element through functional annotation. eQTL and Hi-C analysis found that the SOX6 gene might be a potential distal target of rs4325274. We conducted the motif prediction using multiple databases and verified the result using ChIP-seq data from GEO database. The result showed that the transcription factor HNF1A could preferentially bind to SNP rs4325274-G allele. We further demonstrated that SNP rs4325274 acted as an enhancer regulating SOX6 gene expression by using dual-luciferase reporter assays. Knockdown of HNF1A decreased the SOX6 gene expression. Taken together, our results uncovered a new mechanism of a non-coding functional SNP rs4325274 as a distal enhancer to modulate SOX6 expression, which provides new insights into deciphering molecular regulatory mechanisms underlying non-coding susceptibility SNPs on complex diseases.


Assuntos
Osteoporose , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição SOXD/genética , Alelos , Predisposição Genética para Doença , Humanos , Osteoporose/genética , Locos de Características Quantitativas
6.
Nat Commun ; 11(1): 4763, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32958765

RESUMO

Many animal species remain separate not because their individuals fail to produce viable hybrids but because they "choose" not to mate. However, we still know very little of the genetic mechanisms underlying changes in these mate preference behaviours. Heliconius butterflies display bright warning patterns, which they also use to recognize conspecifics. Here, we couple QTL for divergence in visual preference behaviours with population genomic and gene expression analyses of neural tissue (central brain, optic lobes and ommatidia) across development in two sympatric Heliconius species. Within a region containing 200 genes, we identify five genes that are strongly associated with divergent visual preferences. Three of these have previously been implicated in key components of neural signalling (specifically an ionotropic glutamate receptor and two regucalcins), and overall our candidates suggest shifts in behaviour involve changes in visual integration or processing. This would allow preference evolution without altering perception of the wider environment.


Assuntos
Borboletas/fisiologia , Genes de Insetos , Especiação Genética , Preferência de Acasalamento Animal , Percepção Visual/genética , Animais , Borboletas/genética , Feminino , Regulação da Expressão Gênica , Fluxo Gênico , Genes de Insetos/genética , Genoma de Inseto/genética , Masculino , Mutação , Locos de Características Quantitativas , Especificidade da Espécie , Simpatria , Asas de Animais
7.
Nat Commun ; 11(1): 4402, 2020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32879318

RESUMO

Genome-wide association studies have identified genetic variation contributing to complex disease risk. However, assigning causal genes and mechanisms has been more challenging because disease-associated variants are often found in distal regulatory regions with cell-type specific behaviours. Here, we collect ATAC-seq, Hi-C, Capture Hi-C and nuclear RNA-seq data in stimulated CD4+ T cells over 24 h, to identify functional enhancers regulating gene expression. We characterise changes in DNA interaction and activity dynamics that correlate with changes in gene expression, and find that the strongest correlations are observed within 200 kb of promoters. Using rheumatoid arthritis as an example of T cell mediated disease, we demonstrate interactions of expression quantitative trait loci with target genes, and confirm assigned genes or show complex interactions for 20% of disease associated loci, including FOXO1, which we confirm using CRISPR/Cas9.


Assuntos
Artrite Reumatoide/genética , Linfócitos T CD4-Positivos/metabolismo , Cromatina , Proteína Forkhead Box O1/genética , Doenças Autoimunes/genética , Linfócitos T CD4-Positivos/citologia , Cromatina/química , Cromatina/genética , Elementos Facilitadores Genéticos , Proteína Forkhead Box O1/metabolismo , Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Células HEK293 , Humanos , Cultura Primária de Células , Regiões Promotoras Genéticas , Locos de Características Quantitativas
8.
Nat Commun ; 11(1): 4904, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32994391

RESUMO

Mammalian frugivores are critical seed dispersers, but many are under threat of extinction. Futhermore, the impact of past and future defaunation on plant assemblages has yet to be quantified at the global scale. Here, we integrate palm and mammalian frugivore trait and occurrence data and reveal a global positive relationship between fruit size and frugivore body size. Global variation in fruit size is better explained by present-day frugivore assemblages than by Late Pleistocene assemblages, suggesting ecological and evolutionary reorganization after end-Pleistocene extinctions, except in the Neotropics, where some large-fruited palm species may have outlived their main seed dispersers by thousands of years. Our simulations of frugivore extinction over the next 100 years suggest that the impact of defaunation will be highest in the Old World tropics, and an up to 4% assemblage-level decrease in fruit size would be required to maintain the global body size-fruit size relationship. Overall, our results suggest that while some palm species may be able to keep pace with future defaunation through evolutionary changes in fruit size, large-fruited species may be especially vulnerable to continued defaunation.


Assuntos
Arecaceae/fisiologia , Coevolução Biológica , Conservação dos Recursos Naturais , Frutas/anatomia & histologia , Mamíferos/fisiologia , Animais , Arecaceae/anatomia & histologia , Tamanho Corporal/genética , Conjuntos de Dados como Assunto , Extinção Biológica , Frutas/genética , Herbivoria/fisiologia , Mamíferos/anatomia & histologia , Tamanho do Órgão/genética , Locos de Características Quantitativas , Dispersão de Sementes/fisiologia
9.
Science ; 369(6503): 561-565, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32732423

RESUMO

Most neuropsychiatric disease risk variants are in noncoding sequences and lack functional interpretation. Because regulatory sequences often reside in open chromatin, we reasoned that neuropsychiatric disease risk variants may affect chromatin accessibility during neurodevelopment. Using human induced pluripotent stem cell (iPSC)-derived neurons that model developing brains, we identified thousands of genetic variants exhibiting allele-specific open chromatin (ASoC). These neuronal ASoCs were partially driven by altered transcription factor binding, overrepresented in brain gene enhancers and expression quantitative trait loci, and frequently associated with distal genes through chromatin contacts. ASoCs were enriched for genetic variants associated with brain disorders, enabling identification of functional schizophrenia risk variants and their cis-target genes. This study highlights ASoC as a functional mechanism of noncoding neuropsychiatric risk variants, providing a powerful framework for identifying disease causal variants and genes.


Assuntos
Alelos , Encéfalo/metabolismo , Cromatina/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Esquizofrenia/genética , Elementos Facilitadores Genéticos , Humanos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Risco
10.
PLoS Genet ; 16(8): e1008995, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32833967

RESUMO

Pan-genomic open reading frames (ORFs) potentially carry protein-coding gene or coding variant information in a population. In this study, we suggest that pan-genomic ORFs are promising to be utilized in estimation of heritability and genomic prediction. A Saccharomyces cerevisiae dataset with whole-genome SNPs, pan-genomic ORFs, and the copy numbers of those ORFs is used to test the effectiveness of ORF data as a predictor in three prediction models for 35 traits. Our results show that the ORF-based heritability can capture more genetic effects than SNP-based heritability for all traits. Compared to SNP-based genomic prediction (GBLUP), pan-genomic ORF-based genomic prediction (OBLUP) is distinctly more accurate for all traits, and the predictive abilities on average are more than doubled across all traits. For four traits, the copy number of ORF-based prediction(CBLUP) is more accurate than OBLUP. When using different numbers of isolates in training sets in ORF-based prediction, the predictive abilities for all traits increased as more isolates are added in the training sets, suggesting that with very large training sets the prediction accuracy will be in the range of the square root of the heritability. We conclude that pan-genomic ORFs have the potential to be a supplement of single nucleotide polymorphisms in estimation of heritability and genomic prediction.


Assuntos
Genoma/genética , Genômica , Fases de Leitura Aberta/genética , Locos de Características Quantitativas/genética , Animais , Cruzamento , Estudo de Associação Genômica Ampla , Genótipo , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
11.
PLoS Genet ; 16(8): e1008947, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32833970

RESUMO

Genome-wide association studies (GWAS) have successfully identified tens of thousands of genetic variants associated with various phenotypes, but together they explain only a fraction of heritability, suggesting many variants have yet to be discovered. Recently it has been recognized that incorporating functional information of genetic variants can improve power for identifying novel loci. For example, S-PrediXcan and TWAS tested the association of predicted gene expression with phenotypes based on GWAS summary statistics by leveraging the information on genetic regulation of gene expression and found many novel loci. However, as genetic variants may have effects on more than one gene and through different mechanisms, these methods likely only capture part of the total effects of these variants. In this paper, we propose a summary statistics-based mixed effects score test (sMiST) that tests for the total effect of both the effect of the mediator by imputing genetically predicted gene expression, like S-PrediXcan and TWAS, and the direct effects of individual variants. It allows for multiple functional annotations and multiple genetically predicted mediators. It can also perform conditional association analysis while adjusting for other genetic variants (e.g., known loci for the phenotype). Extensive simulation and real data analyses demonstrate that sMiST yields p-values that agree well with those obtained from individual level data but with substantively improved computational speed. Importantly, a broad application of sMiST to GWAS is possible, as only summary statistics of genetic variant associations are required. We apply sMiST to a large-scale GWAS of colorectal cancer using summary statistics from ∼120, 000 study participants and gene expression data from the Genotype-Tissue Expression (GTEx) project. We identify several novel and secondary independent genetic loci.


Assuntos
Neoplasias Colorretais/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas/genética , Neoplasias Colorretais/patologia , Biologia Computacional , Regulação Neoplásica da Expressão Gênica/genética , Variação Genética/genética , Genótipo , Humanos , Modelos Estatísticos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
12.
Plant Mol Biol ; 104(1-2): 173-185, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32734417

RESUMO

KEY MESSAGE: A novel and major QTL for the effective tiller number was identified on chromosomal arm 1BL and validated in two genetic backgrounds The effective tiller number (ETN) substantially influences plant architecture and the wheat yield improvement. In this study, we constructed a genetic map of the 2SY (20828/SY95-71) recombinant inbred line population based on the Wheat 55K array as well as the simple sequence repeat (SSR) and Kompetitive Allele Specific PCR (KASP) markers. A comparison between the genetic and physical maps indicated the marker positions were consistent in the two maps. Additionally, we identified seven tillering-related quantitative trait locus (QTLs), including Qetn-sau-1B.1, which is a major QTL localized to a 6.17-cM interval flanked by markers AX-89635557 and AX-111544678 on chromosome 1BL. The Qetn-sau-1B.1 QTL was detected in eight environments and explained 12.12-55.71% of the phenotypic variance. Three genes associated with the ETN were detected in the physical interval of Qetn-sau-1B.1. We used a tightly linked KASP marker, KASP-AX-110129912, to further validate this QTL in two other populations with different genetic backgrounds. The results indicated that Qetn-sau-1B.1 significantly increased the ETN by up to 23.5%. The results of this study will be useful for the precise mapping and cloning of Qetn-sau-1B.1.


Assuntos
Cromossomos de Plantas , Locos de Características Quantitativas/genética , Triticum/genética , Bangladesh , Mapeamento Cromossômico , Marcadores Genéticos/genética , Genótipo , Repetições de Microssatélites , Anotação de Sequência Molecular , Fenótipo
13.
Medicine (Baltimore) ; 99(31): e21326, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32756117

RESUMO

Northern corn leaf blight (NCLB), a corn disease infected by Exserohilum turcicum, can cause loss of harvest and economy. Identification or evaluation of NCLB-resistant quantitative trait loci (QTL) and genes could improve maize breeds. This study aimed to identify novel QTLs for NCLB-resistance.Two maize strains (BB and BC) were utilized to generate B73 × B97 and B73 × CML322 and constructed the genetic linkage using high-throughput single nucleotide polymorphism (SNP) linkage map analysis of 170 (BB) and 163(BC) recombinant inbred line (RIL) genomic DNA samples. NCLB-resistant QTL was associated with phenotypic data from the field trial of 170 BB and 163 BC strains over two years using these 1100 SNPs to identify high-density NCLB-resistant QTLs.In BB, QTL of the NCLB resistance was on chromosome 1 and 3 (LOD scores between 2.74 and 5.44); in BC, QTL of NCLB resistance was on chromosome 1, 2, 4, 8, and 9 (LOD scores between 2.52 and 8.53). A number of genes or genetic information related to NCLB resistance in both BB and BC were identified with the maximum number of genes/NCLB resistance-related QTL on chromosome 3 for BB and on chromosome 1 for BC.This study successfully mapped and identified NCLB-resistant QTL and genes for these 2 different maize strains, which provides insightful information for future study of NCLB-resistance and selection of NCLB-resistant maize variants.


Assuntos
Doenças das Plantas/genética , Zea mays/genética , Marcadores Genéticos , Imunidade Inata , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas
14.
PLoS Comput Biol ; 16(8): e1008120, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32804935

RESUMO

Complexity of cell-type composition has created much skepticism surrounding the interpretation of bulk tissue transcriptomic studies. Recent studies have shown that deconvolution algorithms can be applied to computationally estimate cell-type proportions from gene expression data of bulk blood samples, but their performance when applied to brain tissue is unclear. Here, we have generated an immunohistochemistry (IHC) dataset for five major cell-types from brain tissue of 70 individuals, who also have bulk cortical gene expression data. With the IHC data as the benchmark, this resource enables quantitative assessment of deconvolution algorithms for brain tissue. We apply existing deconvolution algorithms to brain tissue by using marker sets derived from human brain single cell and cell-sorted RNA-seq data. We show that these algorithms can indeed produce informative estimates of constituent cell-type proportions. In fact, neuronal subpopulations can also be estimated from bulk brain tissue samples. Further, we show that including the cell-type proportion estimates as confounding factors is important for reducing false associations between Alzheimer's disease phenotypes and gene expression. Lastly, we demonstrate that using more accurate marker sets can substantially improve statistical power in detecting cell-type specific expression quantitative trait loci (eQTLs).


Assuntos
Algoritmos , Encéfalo , Perfilação da Expressão Gênica/métodos , Análise de Sequência de RNA/métodos , Transcriptoma/genética , Encéfalo/citologia , Encéfalo/metabolismo , Biologia Computacional , Humanos , Imuno-Histoquímica , Especificidade de Órgãos/genética , Fenótipo , Locos de Características Quantitativas/genética , Análise de Célula Única
15.
PLoS Biol ; 18(8): e3000836, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32804946

RESUMO

Pleiotropy-when a single mutation affects multiple traits-is a controversial topic with far-reaching implications. Pleiotropy plays a central role in debates about how complex traits evolve and whether biological systems are modular or are organized such that every gene has the potential to affect many traits. Pleiotropy is also critical to initiatives in evolutionary medicine that seek to trap infectious microbes or tumors by selecting for mutations that encourage growth in some conditions at the expense of others. Research in these fields, and others, would benefit from understanding the extent to which pleiotropy reflects inherent relationships among phenotypes that correlate no matter the perturbation (vertical pleiotropy). Alternatively, pleiotropy may result from genetic changes that impose correlations between otherwise independent traits (horizontal pleiotropy). We distinguish these possibilities by using clonal populations of yeast cells to quantify the inherent relationships between single-cell morphological features. Then, we demonstrate how often these relationships underlie vertical pleiotropy and how often these relationships are modified by genetic variants (quantitative trait loci [QTL]) acting via horizontal pleiotropy. Our comprehensive screen measures thousands of pairwise trait correlations across hundreds of thousands of yeast cells and reveals ample evidence of both vertical and horizontal pleiotropy. Additionally, we observe that the correlations between traits can change with the environment, genetic background, and cell-cycle position. These changing dependencies suggest a nuanced view of pleiotropy: biological systems demonstrate limited pleiotropy in any given context, but across contexts (e.g., across diverse environments and genetic backgrounds) each genetic change has the potential to influence a larger number of traits. Our method suggests that exploiting pleiotropy for applications in evolutionary medicine would benefit from focusing on traits with correlations that are less dependent on context.


Assuntos
Pleiotropia Genética , Modelos Genéticos , Herança Multifatorial , Locos de Características Quantitativas , Proteínas de Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/genética , Evolução Biológica , Ciclo Celular/genética , Células Clonais , Variação Genética , Ensaios de Triagem em Larga Escala , Mutação , Fenótipo , Saccharomyces cerevisiae/crescimento & desenvolvimento , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Análise de Célula Única
16.
Nat Commun ; 11(1): 4140, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32811829

RESUMO

Investigating the evolution of complex phenotypes and the underlying molecular bases of their variation is critical to understand how organisms adapt to their environment. Applying classical quantitative genetics on a segregating population derived from a Can-0xCol-0 cross, we identify the MADS-box transcription factor FLOWERING LOCUS M (FLM) as a player of the phenotypic variation in plant growth and color. We show that allelic variation at FLM modulates plant growth strategy along the leaf economics spectrum, a trade-off between resource acquisition and resource conservation, observable across thousands of plant species. Functional differences at FLM rely on a single intronic substitution, disturbing transcript splicing and leading to the accumulation of non-functional FLM transcripts. Associations between this substitution and phenotypic and climatic data across Arabidopsis natural populations, show how noncoding genetic variation at a single gene might be adaptive through pleiotropic effects.


Assuntos
Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Arabidopsis/genética , Regulação da Expressão Gênica de Plantas/genética , Proteínas de Domínio MADS/genética , Proteínas de Domínio MADS/metabolismo , Processamento de RNA/genética , Alelos , Arabidopsis/metabolismo , Evolução Molecular , Pleiotropia Genética , Variação Genética , Íntrons , Fenótipo , Folhas de Planta/genética , Folhas de Planta/fisiologia , Locos de Características Quantitativas/genética , Temperatura
17.
PLoS Genet ; 16(8): e1008927, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32797036

RESUMO

The genetic control of gene expression is a core component of human physiology. For the past several years, transcriptome-wide association studies have leveraged large datasets of linked genotype and RNA sequencing information to create a powerful gene-based test of association that has been used in dozens of studies. While numerous discoveries have been made, the populations in the training data are overwhelmingly of European descent, and little is known about the generalizability of these models to other populations. Here, we test for cross-population generalizability of gene expression prediction models using a dataset of African American individuals with RNA-Seq data in whole blood. We find that the default models trained in large datasets such as GTEx and DGN fare poorly in African Americans, with a notable reduction in prediction accuracy when compared to European Americans. We replicate these limitations in cross-population generalizability using the five populations in the GEUVADIS dataset. Via realistic simulations of both populations and gene expression, we show that accurate cross-population generalizability of transcriptome prediction only arises when eQTL architecture is substantially shared across populations. In contrast, models with non-identical eQTLs showed patterns similar to real-world data. Therefore, generating RNA-Seq data in diverse populations is a critical step towards multi-ethnic utility of gene expression prediction.


Assuntos
Afro-Americanos/genética , Estudo de Associação Genômica Ampla/métodos , Modelos Genéticos , Transcriptoma , Perfilação da Expressão Gênica/métodos , Perfilação da Expressão Gênica/normas , Estudo de Associação Genômica Ampla/normas , Humanos , Locos de Características Quantitativas , RNA-Seq/métodos , RNA-Seq/normas , Padrões de Referência
18.
PLoS One ; 15(8): e0237657, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32817676

RESUMO

The majority of genome-wide association studies (GWAS) loci are not annotated to known genes in the human genome, which renders biological interpretations difficult. Transcriptome-wide association studies (TWAS) associate complex traits with genotype-based prediction of gene expression deriving from expression quantitative loci(eQTL) studies, thus improving the interpretability of GWAS findings. However, these results can sometimes suffer from a high false positive rate, because predicted expression of different genes may be highly correlated due to linkage disequilibrium between eQTL. We propose a novel statistical method, Gene Score Regression (GSR), to detect causal gene sets for complex traits while accounting for gene-to-gene correlations. We consider non-causal genes that are highly correlated with the causal genes will also exhibit a high marginal association with the complex trait. Consequently, by regressing on the marginal associations of complex traits with the sum of the gene-to-gene correlations in each gene set, we can assess the amount of variance of the complex traits explained by the predicted expression of the genes in each gene set and identify plausible causal gene sets. GSR can operate either on GWAS summary statistics or observed gene expression. Therefore, it may be widely applied to annotate GWAS results and identify the underlying biological pathways. We demonstrate the high accuracy and computational efficiency of GSR compared to state-of-the-art methods through simulations and real data applications. GSR is openly available at https://github.com/li-lab-mcgill/GSR.


Assuntos
Estudo de Associação Genômica Ampla/estatística & dados numéricos , Anotação de Sequência Molecular , Herança Multifatorial/genética , Transcriptoma/genética , Regulação da Expressão Gênica/genética , Predisposição Genética para Doença , Genoma Humano/genética , Genótipo , Humanos , Desequilíbrio de Ligação , Modelos Genéticos , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas
19.
PLoS One ; 15(8): e0237774, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32797075

RESUMO

The source-sink relationship determines the ultimate grain yield of rice. In this study, we used a set of reciprocal introgression lines (ILs) derived from Xuishui09 × IR2061 to map quantitative trait loci (QTLs) that were associated with sink-, source-, and grain yield-related traits. A total of 95 QTLs influencing eight measured traits were identified using 6181 high-quality single nucleotide polymorphism markers. Nine background-independent QTLs were consistently detected in seven chromosomal regions in different genetic backgrounds. Seven QTLs clusters simultaneously affected sink-, source-, and grain yield-related traits, probably due to the genetic basis of significant correlations of grain yield with source and sink traits. We selected 15 candidate genes in the four QTLs consistently identified in the two populations by performing gene-based association and haplotype analyses using 2288 accessions from the 3K project. Among these, LOC_Os03g48970 for qTSN3b, LOC_Os06g04710 for qFLL6a, and LOC_Os07g32510 for qTGW7 were considered as the most likely candidate genes based on functional annotations. These results provide a basis for further study of candidate genes and for the development of high-yield rice varieties by balancing source-sink relationships using marker-assisted selection.


Assuntos
Grão Comestível/genética , Oryza/genética , Locos de Características Quantitativas , Cromossomos de Plantas/genética , Grão Comestível/crescimento & desenvolvimento , Genes de Plantas , Oryza/crescimento & desenvolvimento , Polimorfismo de Nucleotídeo Único
20.
PLoS One ; 15(8): e0237818, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32853245

RESUMO

Functional and enduring mammary structure is pivotal for producer profitability, and animal health and welfare in beef production. Genetic evaluations for teat and udder score in Canadian Angus cattle have previously been developed. The aim of this study was to identify genomic regions associated with teat and udder structure in Canadian Angus cows thereby enhancing knowledge of the biological architecture of these traits. Thus, we performed a weighted single-step genome wide association study (WssGWAS) to identify candidate genes for teat and udder score in 1,582 Canadian Angus cows typed with the GeneSeek® Genomic Profiler Bovine 130K SNP array. Genomically enhanced estimated breeding values (GEBVs) were converted to SNP marker effects using unequal variances for markers to calculate weights for each SNP over three iterations. At the genome wide level, we detected windows of 20 consecutive SNPs that explained more than 0.5% of the variance observed in these traits. A total of 35 and 28 windows were identified for teat and udder score, respectively, with two SNP windows in common for both traits. Using Ensembl, the SNP windows were used to search for candidate genes and quantitative trait loci (QTL). A total of 94 and 71 characterized genes were identified in the regions for teat and udder score, respectively. Of these, 7 genes were common for both traits. Gene network and enrichment analysis, using Ingenuity Pathway Analysis (IPA), signified key pathways unique to each trait. Genes of interest were associated with immune response and wound healing, adipose tissue development and morphology, and epithelial and vascular development and morphology. Genetic architecture from this GWAS confirms that teat and udder score are distinct, polygenic traits involving varying and complex biological pathways, and that genetic selection for improved teat and udder score is possible.


Assuntos
Bovinos/anatomia & histologia , Bovinos/genética , Estudo de Associação Genômica Ampla , Glândulas Mamárias Animais/anatomia & histologia , Animais , Feminino , Redes Reguladoras de Genes , Anotação de Sequência Molecular , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Software , Estatística como Assunto
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