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1.
Hum Genet ; 139(1): 103-113, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31165258

RESUMO

About 10 years ago, after the first large-scale genome-wide association studies (GWAS) were conducted to find genes associated with common complex diseases, investigators were surprised to find that the amount of heritability explained by the significant hits was very low for almost all the studied traits. Indeed, when compared to heritability estimates expected from the observed trait concordance within families, the heritability explained by the associated variants was always much smaller, more than ten times smaller for some traits. There was thus a problem of "missing heritability" and different hypotheses were proposed to help find this "missing heritability". These hypotheses involved novel research strategies in which different groups engaged including among others increasing sample sizes of GWAS or looking for rare variants and structural variations that were not captured by the SNP-chips used in GWAS. How successful have these efforts been in finding the "missing heritability"? Could it be that the problem of "missing heritability" was ill-defined? These are the questions that will be addressed in this paper by taking some different examples of complex traits.


Assuntos
Doença/genética , Estudo de Associação Genômica Ampla , Padrões de Herança , Modelos Genéticos , Humanos , Fenótipo
2.
Int Heart J ; 60(6): 1415-1420, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31735781

RESUMO

Hypertrophic cardiomyopathy (HCM) is one of the most common inherited cardiovascular diseases and possesses a high risk for sudden cardiac death. Although mutations in more than 20 genes have been reported to be associated with HCM thus far, the genetic backgrounds of most HCM patients are not fully understood. We performed a genetic analysis in a Chinese family that presented with HCM using next-generation sequencing (NGS). Clinical data, family histories, and blood samples were collected from the proband and family members. Five patients showed typical clinical symptoms of HCM. One subject was the victim of sudden cardiac death. By NGS, we determined that these subjects with HCM symptoms carried a missense heterozygous genetic mutation c.2632C>A (p.V878L) in the myosin heavy chain 7 (MYH7) gene with an autosomal dominant pattern of inheritance. Individuals without this mutation showed no symptoms or cardiac structural abnormalities related to HCM. Bioinformatics evaluation predicted this mutant as "damaging" and "disease causing". Additionally, sequence alignment showed that this mutant is located in an evolutionarily conserved region of MYH7 in multiple species. Our results describe a potentially pathogenic mutation associated with HCM, which may extend the spectrum of HCM phenotypes related to MYH7 gene mutations.


Assuntos
Miosinas Cardíacas/genética , Cardiomiopatia Hipertrófica Familiar/genética , Morte Súbita Cardíaca/etiologia , Mutação de Sentido Incorreto/genética , Cadeias Pesadas de Miosina/genética , Adolescente , Adulto , Idoso , Cardiomiopatia Hipertrófica Familiar/diagnóstico , Feminino , Testes Genéticos , Humanos , Padrões de Herança/genética , Masculino , Pessoa de Meia-Idade , Linhagem , Adulto Jovem
3.
Exp Suppl ; 111: 21-27, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588525

RESUMO

Increasing data about the human genome and associations between certain genetic regions with various conditions and diseases positioned human genetics at the top of the most emerging fields in medicine. Many diagnostics algorithms and therapeutical approaches used in everyday practice are based on genetic data. Molecular genetic diagnostics covered by this book uses genetic data obtained using germline DNA. In this book, the role of somatic mutation testing will be not covered; however, in many chapters, i.e., on hereditary tumor syndromes, the role of somatic mutations as the second hit for tumorigenesis will be mentioned. Genetic variants (genotypes) identified in germline DNA are responsible for transmission of diseases (phenotypes). This chapter will briefly summarize classical inheritance patterns. Most of the heritable human diseases are transmitted in an autosomal recessive way, but others, i.e., inherited tumor syndromes, follow the autosomal dominant pattern. Nomenclature used for pedigree analysis as well as the main features of inheritance patterns are also briefly reviewed.


Assuntos
Carcinogênese/genética , DNA , Padrões de Herança , Neoplasias/genética , Genótipo , Humanos , Linhagem
4.
Genet Sel Evol ; 51(1): 55, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31558151

RESUMO

BACKGROUND: Mate allocation strategies that account for non-additive genetic effects can be used to maximize the overall genetic merit of future offspring. Accounting for dominance effects in genetic evaluations is easier in a genomic context, than in a classical pedigree-based context because the combinations of alleles at loci are known. The objective of our study was two-fold. First, dominance variance components were estimated for age at 100 kg (AGE), backfat depth (BD) at 140 days, and for average piglet weight at birth within litter (APWL). Second, the efficiency of mate allocation strategies that account for dominance and inbreeding depression to maximize the overall genetic merit of future offspring was explored. RESULTS: Genetic variance components were estimated using genomic models that included inbreeding depression with and without non-additive genetic effects (dominance). Models that included dominance effects did not fit the data better than the genomic additive model. Estimates of dominance variances, expressed as a percentage of additive genetic variance, were 20, 11, and 12% for AGE, BD, and APWL, respectively. Estimates of additive and dominance single nucleotide polymorphism effects were retrieved from the genetic variance component estimates and used to predict the outcome of matings in terms of total genetic and breeding values. Maximizing total genetic values instead of breeding values in matings gave the progeny an average advantage of - 0.79 days, - 0.04 mm, and 11.3 g for AGE, BD and APWL, respectively, but slightly reduced the expected additive genetic gain, e.g. by 1.8% for AGE. CONCLUSIONS: Genomic mate allocation accounting for non-additive genetic effects is a feasible and potential strategy to improve the performance of the offspring without dramatically compromising additive genetic gain.


Assuntos
Cruzamento , Polimorfismo de Nucleotídeo Único , Suínos/genética , Animais , Peso Corporal/genética , Cruzamento/métodos , Feminino , Genes Dominantes , Padrões de Herança , Masculino , Seleção Genética
5.
Int J Mol Sci ; 20(17)2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31480315

RESUMO

The CRISPR/Cas9 system has been successfully used in hexaploid wheat. Although it has been reported that the induced mutations can be passed to the next generation, gene editing and transmission patterns in later generations still need to be studied. In this study, we demonstrated that the CRISPR/Cas9 system could achieve efficient mutagenesis in five wheat genes via Agrobacterium-mediated transformation of an sgRNA targeting the D genome, an sgRNA targeting both the A and B homologues and three tri-genome guides targeting the editing of all three homologues. High mutation rates and putative homozygous or biallelic mutations were observed in the T0 plants. The targeted mutations could be stably inherited by the next generation, and the editing efficiency of each mutant line increased significantly across generations. The editing types and inheritance of targeted mutagenesis were similar, which were not related to the targeted subgenome number. The presence of Cas9/sgRNA could cause new mutations in subsequent generations, while mutated lines without Cas9/sgRNA could retain the mutation type. Additionally, off-target mutations were not found in sequences that were highly homologous to the selected sgRNA sequences. Overall, the results suggested that CRISPR/Cas9-induced gene editing via Agrobacterium-mediated transformation plays important roles in wheat genome engineering.


Assuntos
Agrobacterium/metabolismo , Proteína 9 Associada à CRISPR/metabolismo , Sistemas CRISPR-Cas/genética , Padrões de Herança/genética , Mutagênese/genética , Triticum/genética , Sequência de Bases , Edição de Genes , Genes de Plantas , Vetores Genéticos/metabolismo , Genótipo , Taxa de Mutação , RNA Guia/genética
6.
Nat Commun ; 10(1): 4054, 2019 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492842

RESUMO

Transposable elements (TE) comprise roughly half of the human genome. Though initially derided as junk DNA, they have been widely hypothesized to contribute to the evolution of gene regulation. However, the contribution of TE to the genetic architecture of diseases remains unknown. Here, we analyze data from 41 independent diseases and complex traits to draw three conclusions. First, TE are uniquely informative for disease heritability. Despite overall depletion for heritability (54% of SNPs, 39 ± 2% of heritability), TE explain substantially more heritability than expected based on their depletion for known functional annotations. This implies that TE acquire function in ways that differ from known functional annotations. Second, older TE contribute more to disease heritability, consistent with acquiring biological function. Third, Short Interspersed Nuclear Elements (SINE) are far more enriched for blood traits than for other traits. Our results can help elucidate the biological roles that TE play in the genetic architecture of diseases.


Assuntos
Elementos de DNA Transponíveis/genética , Doença/genética , Regulação da Expressão Gênica , Genoma Humano/genética , Padrões de Herança/genética , Retroelementos/genética , Algoritmos , Doenças Autoimunes/sangue , Doenças Autoimunes/genética , Encefalopatias/sangue , Encefalopatias/genética , Evolução Molecular , Humanos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Elementos Nucleotídeos Curtos e Dispersos/genética
7.
Genet Sel Evol ; 51(1): 42, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31387519

RESUMO

BACKGROUND: Columnaris disease (CD) is an emerging problem for the rainbow trout aquaculture industry in the US. The objectives of this study were to: (1) identify common genomic regions that explain a large proportion of the additive genetic variance for resistance to CD in two rainbow trout (Oncorhynchus mykiss) populations; and (2) estimate the gains in prediction accuracy when genomic information is used to evaluate the genetic potential of survival to columnaris infection in each population. METHODS: Two aquaculture populations were investigated: the National Center for Cool and Cold Water Aquaculture (NCCCWA) odd-year line and the Troutlodge, Inc., May odd-year (TLUM) nucleus breeding population. Fish that survived to 21 days post-immersion challenge were recorded as resistant. Single nucleotide polymorphism (SNP) genotypes were available for 1185 and 1137 fish from NCCCWA and TLUM, respectively. SNP effects and variances were estimated using the weighted single-step genomic best linear unbiased prediction (BLUP) for genome-wide association. Genomic regions that explained more than 1% of the additive genetic variance were considered to be associated with resistance to CD. Predictive ability was calculated in a fivefold cross-validation scheme and using a linear regression method. RESULTS: Validation on adjusted phenotypes provided a prediction accuracy close to zero, due to the binary nature of the trait. Using breeding values computed from the complete data as benchmark improved prediction accuracy of genomic models by about 40% compared to the pedigree-based BLUP. Fourteen windows located on six chromosomes were associated with resistance to CD in the NCCCWA population, of which two windows on chromosome Omy 17 jointly explained more than 10% of the additive genetic variance. Twenty-six windows located on 13 chromosomes were associated with resistance to CD in the TLUM population. Only four associated genomic regions overlapped with quantitative trait loci (QTL) between both populations. CONCLUSIONS: Our results suggest that genome-wide selection for resistance to CD in rainbow trout has greater potential than selection for a few target genomic regions that were found to be associated to resistance to CD due to the polygenic architecture of this trait, and because the QTL associated with resistance to CD are not sufficiently informative for selection decisions across populations.


Assuntos
Cruzamento , Mapeamento Cromossômico , Doenças dos Peixes/genética , Infecções por Flavobacteriaceae/veterinária , Flavobacterium , Oncorhynchus mykiss/genética , Animais , Resistência à Doença/genética , Feminino , Pesqueiros , Infecções por Flavobacteriaceae/genética , Padrões de Herança , Masculino , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Seleção Genética
8.
J Biosci ; 44(3)2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31389363

RESUMO

Due to its unique geographical position, juxtaposed in the middle of south-central Asia, east Asia and Southeast Asia, the South Asian Region (SAS) has repeatedly come into contact with people from adjacent regions throughout history and prehistory. The antiquity of the populations and the intricate history of admixture have shaped SAS as one of the most genetically diverse regions in the world. In this article we review our current understanding of the peopling and populations structure of SAS. We do not attempt to be exhaustive but summarize the salient conclusions that have been reached using genetic data and evaluate their robustness. We also identify the unanswered questions and suggest possible approaches that may lead to their answers.


Assuntos
Grupo com Ancestrais do Continente Asiático/história , DNA Antigo/análise , Grupos Étnicos , Genética Populacional , Migração Humana/tendências , Linguagem/história , Antropologia/métodos , Arqueologia/métodos , Ásia/etnologia , Feminino , Marcadores Genéticos , Variação Genética , Genoma Mitocondrial , História Antiga , Humanos , Padrões de Herança , Masculino , Mitocôndrias/genética
9.
Genet Epidemiol ; 43(7): 761-775, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31298783

RESUMO

Numerous methods for estimating heritability have been proposed; however, unlike quantitative phenotypes, heritability estimation for dichotomous phenotypes is computationally and statistically complex, and the use of heritability is infrequent. In this study, we developed a statistical method to estimate heritability of dichotomous phenotypes using a liability threshold model in the context of ascertained family-based samples. This model assumes that dichotomous phenotypes are determined by unobserved latent variables that are normally distributed and can be applied to general pedigree data. The proposed methods were applied to simulated data and Korean type-2 diabetes family-based samples, and the accuracy of the estimates provided by the experimental methods was compared with that of the established methods.


Assuntos
Padrões de Herança/genética , Modelos Genéticos , Adulto , Algoritmos , Simulação por Computador , Diabetes Mellitus Tipo 2/genética , Família , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Fatores de Risco
10.
Hum Genet ; 138(10): 1155-1169, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31342140

RESUMO

Vitamin D inadequacy, assessed by 25-hydroxyvitamin D [25(OH)D], affects around 50% of adults in the United States and is associated with numerous adverse health outcomes. Blood 25(OH)D concentrations are influenced by genetic factors that may determine how much vitamin D intake is required to reach optimal 25(OH)D. Despite large genome-wide association studies (GWASs), only a small portion of the genetic factors contributing to differences in 25(OH)D has been discovered. Therefore, knowledge of a fuller set of genetic factors could be useful for risk prediction of 25(OH)D inadequacy, personalized vitamin D supplementation, and prevention of downstream morbidity and mortality. Using PRSice and weights from published African- and European-ancestry GWAS summary statistics, ancestry-specific polygenic scores (PGSs) were created to capture a more complete set of genetic factors in those of European (n = 9569) or African ancestry (n = 2761) from three cohort studies. The PGS for African ancestry was derived using all input SNPs (a p value cutoff of 1.0) and had an R2 of 0.3%; for European ancestry, the optimal PGS used a p value cutoff of 3.5 × 10-4 in the target/tuning dataset and had an R2 of 1.0% in the validation cohort. Those with highest genetic risk had 25(OH)D that was 2.8-3.0 ng/mL lower than those with lowest genetic risk (p = 0.0463-3.2 × 10-13), requiring an additional 467-500 IU of vitamin D intake to maintain equivalent 25(OH)D. PGSs are a powerful predictive tool that could be leveraged for personalized vitamin D supplementation to prevent the negative downstream effects of 25(OH)D inadequacy.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Europeu/genética , Genética Populacional , Padrões de Herança , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Vitamina D/análogos & derivados , Estudos de Coortes , Bases de Dados Genéticas , Suplementos Nutricionais , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Raios Ultravioleta , Vitamina D/sangue
11.
Adv Exp Med Biol ; 1166: 57-74, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31301046

RESUMO

Epigenetic information refers to heritable changes in gene expression that occur without modifications at the DNA sequence level. These changes are orchestrated by different epigenetic mechanisms such as DNA methylation, posttranslational modifications of histones, and the presence of noncoding RNAs. Epigenetic information regulates chromatin structure to confer cell-specific gene expression.The sperm epigenome is the result of three periods of global resetting during men's life. Germ cell epigenome reprogramming is designed to allow cell totipotency and to prevent the transmission of epimutations via spermatozoa. At the end of these reprogramming events, the sperm epigenome has a very specific epigenetic pattern that is a footprint of past reprogramming events and has an influence on embryo development.Several data demonstrate that not all regions of the epigenome are erased during the reprogramming periods, suggesting the transmission of epigenetic information from fathers to offspring via spermatozoa. Moreover, it is becoming increasingly clear that the sperm epigenome is sensitive to environmental factors during the process of gamete differentiation, suggesting the plasticity of the sperm epigenetic signature according to the circumstances of the individual's life.In this chapter, we provided strong evidences about the association between variations of the sperm epigenome and the exposure to environmental factors. Moreover, we will present data about how epigenetic mechanisms are candidates for transferring paternal environmental information to offspring.


Assuntos
Exposição Ambiental , Epigênese Genética , Padrões de Herança , Metilação de DNA , Bases de Dados Genéticas , Epigenômica , Variação Genética , Células Germinativas , Humanos , Padrões de Herança/genética , Masculino
12.
BMC Plant Biol ; 19(1): 311, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31307375

RESUMO

BACKGROUND: CRISPR/Cas9 gene editing is now revolutionizing the ability to effectively modify plant genomes in the absence of efficient homologous recombination mechanisms that exist in other organisms. However, soybean is allotetraploid and is commonly viewed as difficult and inefficient to transform. In this study, we demonstrate the utility of CRISPR/Cas9 gene editing in soybean at relatively high efficiency. This was shown by specifically targeting the Fatty Acid Desaturase 2 (GmFAD2) that converts the monounsaturated oleic acid (C18:1) to the polyunsaturated linoleic acid (C18:2), therefore, regulating the content of monounsaturated fats in soybean seeds. RESULTS: We designed two gRNAs to guide Cas9 to simultaneously cleave two sites, spaced 1Kb apart, within the second exons of GmFAD2-1A and GmFAD2-1B. In order to test whether the Cas9 and gRNAs would perform properly in transgenic soybean plants, we first tested the CRISPR construct we developed by transient hairy root transformation using Agrobacterium rhizogenesis strain K599. Once confirmed, we performed stable soybean transformation and characterized ten, randomly selected T0 events. Genotyping of CRISPR/Cas9 T0 transgenic lines detected a variety of mutations including large and small DNA deletions, insertions and inversions in the GmFAD2 genes. We detected CRISPR- edited DNA in all the tested T0 plants and 77.8% of the events transmitted the GmFAD2 mutant alleles to T1 progenies. More importantly, null mutants for both GmFAD2 genes were obtained in 40% of the T0 plants we genotyped. The fatty acid profile analysis of T1 seeds derived from CRISPR-edited plants homozygous for both GmFAD2 genes showed dramatic increases in oleic acid content to over 80%, whereas linoleic acid decreased to 1.3-1.7%. In addition, transgene-free high oleic soybean homozygous genotypes were created as early as the T1 generation. CONCLUSIONS: Overall, our data showed that dual gRNA CRISPR/Cas9 system offers a rapid and highly efficient method to simultaneously edit homeologous soybean genes, which can greatly facilitate breeding and gene discovery in this important crop plant.


Assuntos
Ácidos Graxos Dessaturases/genética , Edição de Genes/métodos , Genes de Plantas , RNA Guia , Soja/genética , Ácido alfa-Linoleico/genética , Agrobacterium/genética , Sistemas CRISPR-Cas , Marcadores Genéticos , Vetores Genéticos , Técnicas de Genotipagem , Padrões de Herança , Plantas Geneticamente Modificadas
13.
BMC Plant Biol ; 19(1): 319, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31311507

RESUMO

BACKGROUND: Non-host resistance (NHR) presents a compelling long-term plant protection strategy for global food security, yet the genetic basis of NHR remains poorly understood. For many diseases, including stem rust of wheat [causal organism Puccinia graminis (Pg)], NHR is largely unexplored due to the inherent challenge of developing a genetically tractable system within which the resistance segregates. The present study turns to the pathogen's alternate host, barberry (Berberis spp.), to overcome this challenge. RESULTS: In this study, an interspecific mapping population derived from a cross between Pg-resistant Berberis thunbergii (Bt) and Pg-susceptible B. vulgaris was developed to investigate the Pg-NHR exhibited by Bt. To facilitate QTL analysis and subsequent trait dissection, the first genetic linkage maps for the two parental species were constructed and a chromosome-scale reference genome for Bt was assembled (PacBio + Hi-C). QTL analysis resulted in the identification of a single 13 cM region (~ 5.1 Mbp spanning 13 physical contigs) on the short arm of Bt chromosome 3. Differential gene expression analysis, combined with sequence variation analysis between the two parental species, led to the prioritization of several candidate genes within the QTL region, some of which belong to gene families previously implicated in disease resistance. CONCLUSIONS: Foundational genetic and genomic resources developed for Berberis spp. enabled the identification and annotation of a QTL associated with Pg-NHR. Although subsequent validation and fine mapping studies are needed, this study demonstrates the feasibility of and lays the groundwork for dissecting Pg-NHR in the alternate host of one of agriculture's most devastating pathogens.


Assuntos
Basidiomycota/fisiologia , Berberis/genética , Berberis/microbiologia , Doenças das Plantas/genética , Mapeamento Cromossômico , Cromossomos de Plantas , Resistência à Doença/genética , Perfilação da Expressão Gênica , Genoma de Planta , Hibridização Genética , Padrões de Herança , Fenótipo , Doenças das Plantas/microbiologia , Caules de Planta/microbiologia , Locos de Características Quantitativas
14.
Methods Mol Biol ; 1910: 3-31, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31278660

RESUMO

Organisms display astonishing levels of cell and molecular diversity, including genome size, shape, and architecture. In this chapter, we review how the genome can be viewed as both a structural and an informational unit of biological diversity and explicitly define our intended meaning of genetic information. A brief overview of the characteristic features of bacterial, archaeal, and eukaryotic cell types and viruses sets the stage for a review of the differences in organization, size, and packaging strategies of their genomes. We include a detailed review of genetic elements found outside the primary chromosomal structures, as these provide insights into how genomes are sometimes viewed as incomplete informational entities. Lastly, we reassess the definition of the genome in light of recent advancements in our understanding of the diversity of genomic structures and the mechanisms by which genetic information is expressed within the cell. Collectively, these topics comprise a good introduction to genome biology for the newcomer to the field and provide a valuable reference for those developing new statistical or computation methods in genomics. This review also prepares the reader for anticipated transformations in thinking as the field of genome biology progresses.


Assuntos
Biodiversidade , Eucariotos/genética , Genoma , Genômica , Archaea/genética , Bactérias/genética , Biologia Computacional/métodos , Regulação da Expressão Gênica , Estruturas Genéticas , Genômica/métodos , Padrões de Herança , Vírus/genética
15.
Genes Cells ; 24(8): 524-533, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31273901

RESUMO

The outcome of epigenetic responses to stress depends strictly on genetic background, suggesting that altered phenotypes, when induced, are created by a combination of induced epigenetic factors and pre-existing allelic ones. When individuals with altered phenotypes are selected and subjected to successive breeding, alleles that potentiate epigenetic responses could accumulate in offspring populations. It is reasonable to suppose that many, if not all, of these allelic genes could also be involved in creating new phenotypes under nonstressful conditions. In this review, I discuss the possibility that the accumulation of such alleles in selected individuals with an epigenetic phenotype could give rise to individuals that exhibit the same phenotype even in the absence of stress.


Assuntos
Adaptação Biológica/genética , Evolução Biológica , Epigênese Genética , Alelos , Animais , Cromatina/genética , Cromatina/metabolismo , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Padrões de Herança , Modelos Genéticos , Mutação , Fenótipo , Seleção Genética , Estresse Fisiológico
16.
Plant Genome ; 12(2)2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31290920

RESUMO

Genomic prediction has become an increasingly popular tool for hybrid performance evaluation in plant breeding mainly because that it can reduce cost and accelerate a breeding program. In this study, we propose a systematic procedure to predict hybrid performance using a genomic selection (GS) model that takes both additive and dominance marker effects into account. We first demonstrate the advantage of the additive-dominance effects model over the only additive effects model through a simulation study. Based on the additive-dominance model, we predict genomic estimated breeding values (GEBVs) for individual hybrid combinations and their parental lines. The GEBV-based specific combining ability (SCA) for each hybrid and general combining ability (GCA) for its parental lines are then derived to quantify the degree of midparent heterosis (MPH) or better-parent heterosis (BPH) of the hybrid. Finally, we estimate the variance components resulting from additive and dominance gene action effects and heritability using a genomic best linear unbiased predictor (g-BLUP) model. These estimates are used to justify the results of the genomic prediction study. A pumpkin ( spp.) data set is given to illustrate the provided procedure. The data set consists of 320 parental lines with 61,179 collected single nucleotide polymorphism (SNP) markers; 119, 120, and 120 phenotypic values of hybrids on three quantitative traits within maxima Duchesne; and 89, 111, and 90 phenotypic values of hybrids on the same three quantitative traits within Dechesne.


Assuntos
Cucurbita/fisiologia , Hibridização Genética , Melhoramento Vegetal , Teorema de Bayes , Simulação por Computador , Cucurbita/genética , Conjuntos de Dados como Assunto , Variação Genética , Padrões de Herança , Modelos Genéticos , Modelos Estatísticos , Seleção Genética
18.
Nat Genet ; 51(6): 957-972, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31152163

RESUMO

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.


Assuntos
Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Locos de Características Quantitativas , Característica Quantitativa Herdável , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/fisiopatologia , Mapeamento Cromossômico , Grupo com Ancestrais do Continente Europeu , Estudo de Associação Genômica Ampla , Taxa de Filtração Glomerular , Humanos , Padrões de Herança , Testes de Função Renal , Fenótipo , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica/urina , Uromodulina/urina
19.
G3 (Bethesda) ; 9(8): 2597-2607, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31171566

RESUMO

Fillet yield (FY) and harvest weight (HW) are economically important traits in Nile tilapia production. Genetic improvement of these traits, especially for FY, are lacking, due to the absence of efficient methods to measure the traits without sacrificing fish and the use of information from relatives to selection. However, genomic information could be used by genomic selection to improve traits that are difficult to measure directly in selection candidates, as in the case of FY. The objectives of this study were: (i) to perform genome-wide association studies (GWAS) to dissect the genetic architecture of FY and HW, (ii) to evaluate the accuracy of genotype imputation and (iii) to assess the accuracy of genomic selection using true and imputed low-density (LD) single nucleotide polymorphism (SNP) panels to determine a cost-effective strategy for practical implementation of genomic information in tilapia breeding programs. The data set consisted of 5,866 phenotyped animals and 1,238 genotyped animals (108 parents and 1,130 offspring) using a 50K SNP panel. The GWAS were performed using all genotyped and phenotyped animals. The genotyped imputation was performed from LD panels (LD0.5K, LD1K and LD3K) to high-density panel (HD), using information from parents and 20% of offspring in the reference set and the remaining 80% in the validation set. In addition, we tested the accuracy of genomic selection using true and imputed genotypes comparing the accuracy obtained from pedigree-based best linear unbiased prediction (PBLUP) and genomic predictions. The results from GWAS supports evidence of the polygenic nature of FY and HW. The accuracy of imputation ranged from 0.90 to 0.98 for LD0.5K and LD3K, respectively. The accuracy of genomic prediction outperformed the estimated breeding value from PBLUP. The use of imputation for genomic selection resulted in an increased relative accuracy independent of the trait and LD panel analyzed. The present results suggest that genotype imputation could be a cost-effective strategy for genomic selection in Nile tilapia breeding programs.


Assuntos
Ciclídeos/genética , Estudo de Associação Genômica Ampla , Genoma , Genômica , Modelos Biológicos , Fenótipo , Animais , Estudo de Associação Genômica Ampla/métodos , Genômica/métodos , Genótipo , Padrões de Herança , Polimorfismo de Nucleotídeo Único
20.
Genetics ; 212(4): 991-1008, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31248886

RESUMO

In plant breeding, heritability is often calculated (i) as a measure of precision of trials and/or (ii) to compute the response to selection. It is usually estimated on an entry-mean basis, since the phenotype is usually an aggregated value, as genotypes are replicated in trials, which stands in contrast with animal breeding and human genetics. When this was first proposed, assumptions such as balanced data and independent genotypic effects were made that are often violated in modern plant breeding trials/analyses. Due to this, multiple alternative methods have been proposed, aiming to generalize heritability on an entry-mean basis. In this study, we propose an extension of the concept for heritability on an entry-mean to an entry-difference basis, which allows for more detailed insight and is more meaningful in the context of selection in plant breeding, because the correlation among entry means can be accounted for. We show that under certain circumstances our method reduces to other popular generalized methods for heritability estimation on an entry-mean basis. The approach is exemplified via four examples that show different levels of complexity, where we compare six methods for heritability estimation on an entry-mean basis to our approach (example codes: https://github.com/PaulSchmidtGit/Heritability). Results suggest that heritability on an entry-difference basis is a well-suited alternative for obtaining an overall heritability estimate, and in addition provides one heritability per genotype as well as one per difference between genotypes.


Assuntos
Genes de Plantas , Padrões de Herança , Melhoramento Vegetal , Genótipo , Plantas/genética
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