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1.
Ideggyogy Sz ; 74(3-4): 139-144, 2021 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-33938663

RESUMEN

Background and purpose: Niemann-Pick type C is a rare lysosomal storage disease caused by impaired intracellular cholesterol transport. The autosomal recessive disease is caused by mutations in NPC1 or NPC2 genes. Methods: Clinical-laboratory features, genotype-phenotype correlation and miglustat treatment response of our patients diagnosed with early infantile Niemann-Pick type C were evaluated. Results: In this article, four Niemann-Pick type C patients diagnosed in the early infantile period are presented. Common features of our patients were hepatomegaly, splenomegaly, cholestasis and retardation in motor development. Patients 1 and 2 are twins, with homozygous mutation c.2776G>A p.(Ala926Thr) in NPC1 gene and severe lung involvement. Lung involvement, which is mostly associated with NPC2 gene mutation in the literature, was severe in our patients and they died early. In patients 3 and 4, there were respectively c.2972del p.(Gln991Argfs*6) mutation in NPC1 gene and c.133C>T p.(Gln45*) homozygous mutation in NPC2 gene. In these two patients, improvement in neurological findings were observed with treatment of miglustat. Conclusion: In our twin patients, severe lung involvement was observed. Two of our four early infantile Niemann-Pick type C patients exhibited neurological gains with miglustat treatment.


Asunto(s)
Enfermedad de Niemann-Pick Tipo C , 1-Desoxinojirimicina/análogos & derivados , 1-Desoxinojirimicina/uso terapéutico , Estudios de Asociación Genética , Humanos , Mutación , Enfermedad de Niemann-Pick Tipo C/tratamiento farmacológico , Enfermedad de Niemann-Pick Tipo C/genética
2.
Int J Mol Sci ; 22(6)2021 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-33801843

RESUMEN

Recessive variants of the SLC26A4 gene are globally a common cause of hearing impairment. In the past, cell lines and transgenic mice were widely used to investigate the pathogenicity associated with SLC26A4 variants. However, discrepancies in pathogenicity between humans and cell lines or transgenic mice were documented for some SLC26A4 variants. For instance, the p.C565Y variant, which was reported to be pathogenic in humans, did not exhibit functional pathogenic consequences in cell lines. To address the pathogenicity of p.C565Y, we used a genotype-based approach in which we generated knock-in mice that were heterozygous (Slc26a4+/C565Y), homozygous (Slc26a4C565Y/C565Y), and compound heterozygous (Slc26a4919-2A>G/C565Y) for this variant. Subsequent phenotypic characterization revealed that mice with these genotypes demonstrated normal auditory and vestibular functions, and normal inner-ear morphology and pendrin expression. These findings indicate that the p.C565Y variant is nonpathogenic for mice, and that a single p.C565Y allele is sufficient to maintain normal inner-ear physiology in mice. Our results highlight the differences in pathogenicity associated with certain SLC26A4 variants between transgenic mice and humans, which should be considered when interpreting the results of animal studies for SLC26A4-related deafness.


Asunto(s)
Modelos Animales de Enfermedad , Estudios de Asociación Genética/métodos , Predisposición Genética a la Enfermedad/genética , Pérdida Auditiva Sensorineural/genética , Mutación , Transportadores de Sulfato/genética , Animales , Genotipo , Pérdida Auditiva Sensorineural/metabolismo , Humanos , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Fenotipo , Transportadores de Sulfato/fisiología , Acueducto Vestibular/metabolismo , Acueducto Vestibular/patología
3.
Nat Commun ; 12(1): 2337, 2021 04 20.
Artículo en Inglés | MEDLINE | ID: mdl-33879782

RESUMEN

While recent advancements in computation and modelling have improved the analysis of complex traits, our understanding of the genetic basis of the time at symptom onset remains limited. Here, we develop a Bayesian approach (BayesW) that provides probabilistic inference of the genetic architecture of age-at-onset phenotypes in a sampling scheme that facilitates biobank-scale time-to-event analyses. We show in extensive simulation work the benefits BayesW provides in terms of number of discoveries, model performance and genomic prediction. In the UK Biobank, we find many thousands of common genomic regions underlying the age-at-onset of high blood pressure (HBP), cardiac disease (CAD), and type-2 diabetes (T2D), and for the genetic basis of onset reflecting the underlying genetic liability to disease. Age-at-menopause and age-at-menarche are also highly polygenic, but with higher variance contributed by low frequency variants. Genomic prediction into the Estonian Biobank data shows that BayesW gives higher prediction accuracy than other approaches.


Asunto(s)
Edad de Inicio , Genoma Humano , Modelos Genéticos , Herencia Multifactorial , Factores de Edad , Algoritmos , Teorema de Bayes , Enfermedades Cardiovasculares/genética , Simulación por Computador , Bases de Datos Genéticas , Diabetes Mellitus Tipo 2/genética , Estonia , Femenino , Estudios de Asociación Genética , Estudio de Asociación del Genoma Completo , Genómica , Humanos , Hipertensión/genética , Menarquia/genética , Menopausia/genética , Fenotipo , Polimorfismo de Nucleótido Simple , Reino Unido
4.
Nat Commun ; 12(1): 2182, 2021 04 12.
Artículo en Inglés | MEDLINE | ID: mdl-33846329

RESUMEN

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10-72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10-4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10-5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.


Asunto(s)
Cromosomas Humanos X/genética , Lípidos/sangre , Proteínas del Ojo/metabolismo , Femenino , Regulación de la Expresión Génica , Estudios de Asociación Genética , Sitios Genéticos , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Proteínas del Tejido Nervioso/metabolismo , Fenómica , Polimorfismo de Nucleótido Simple/genética , Tejido Subcutáneo/metabolismo , Secuenciación Completa del Genoma
5.
Nat Commun ; 12(1): 2224, 2021 04 13.
Artículo en Inglés | MEDLINE | ID: mdl-33850126

RESUMEN

Prioritizing genes for translation to therapeutics for common diseases has been challenging. Here, we propose an approach to identify drug targets with high probability of success by focusing on genes with both gain of function (GoF) and loss of function (LoF) mutations associated with opposing effects on phenotype (Bidirectional Effect Selected Targets, BEST). We find 98 BEST genes for a variety of indications. Drugs targeting those genes are 3.8-fold more likely to be approved than non-BEST genes. We focus on five genes (IGF1R, NPPC, NPR2, FGFR3, and SHOX) with evidence for bidirectional effects on stature. Rare protein-altering variants in those genes result in significantly increased risk for idiopathic short stature (ISS) (OR = 2.75, p = 3.99 × 10-8). Finally, using functional experiments, we demonstrate that adding an exogenous CNP analog (encoded by NPPC) rescues the phenotype, thus validating its potential as a therapeutic treatment for ISS. Our results show the value of looking for bidirectional effects to identify and validate drug targets.


Asunto(s)
Genes , Preparaciones Farmacéuticas , Descubrimiento de Drogas , Enanismo/genética , Estudios de Asociación Genética , Humanos , Péptido Natriurético Tipo-C/genética , Fenotipo , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Receptor IGF Tipo 1/genética , Receptores del Factor Natriurético Atrial/genética , Proteína de la Caja Homeótica de Baja Estatura/genética
6.
Int J Mol Sci ; 22(6)2021 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-33809601

RESUMEN

Recurrent implantation failure (RIF) refers to the occurrence of more than two failed in vitro fertilization-embryo transfers (IVF-ETs) in the same individual. RIF can occur for many reasons, including embryo characteristics, immunological factors, and coagulation factors. Genetics can also contribute to RIF, with some single-nucleotide variants (SNVs) reported to be associated with RIF occurrence. We examined SNVs in a long non-coding RNA, homeobox (HOX) transcript antisense RNA (HOTAIR), which is known to affect cancer development. HOTAIR regulates epigenetic outcomes through histone modifications and chromatin remodeling. We recruited 155 female RIF patients and 330 healthy controls, and genotyped HOTAIR SNVs, including rs4759314, rs920778, rs7958904, and rs1899663, in all participants. Differences in these SNVs were compared between the patient and control groups. We identified significant differences in the occurrence of heterozygous genotypes and the dominant expression model for the rs1899663 and rs7958904 SNVs between RIF patients and control subjects. These HOTAIR variants were associated with serum hemoglobin (Hgb), luteinizing hormone (LH), total cholesterol (T. chol), and blood urea nitrogen (BUN) levels, as assessed by analysis of variance (ANOVA). We analyzed the four HOTAIR SNVs and found significant differences in haplotype patterns between RIF patients and healthy controls. The results of this study showed that HOTAIR is not only associated with the development of cancer but also with pregnancy-associated diseases. This study represents the first report showing that HOTAIR is correlated with RIF.


Asunto(s)
Fertilización In Vitro , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple/genética , ARN Largo no Codificante/genética , Adulto , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes/genética , Humanos , Desequilibrio de Ligamiento/genética , Recurrencia , Insuficiencia del Tratamiento
8.
Int J Mol Sci ; 22(6)2021 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-33809404

RESUMEN

Dynamic remodeling of the actin cytoskeleton plays a central role in the elongation of cotton fibers, which are the most important natural fibers in the global textile industry. Here, a high-resolution mapping approach combined with comparative sequencing and a transgenic method revealed that a G65V substitution in the cotton actin Gh_D04G0865 (GhACT17D in the wild-type) is responsible for the Gossypium hirsutum Ligon lintless-1 (Li1) mutant (GhACT17DM). In the mutant GhACT17DM from Li1 plant, Gly65 is substituted with valine on the lip of the nucleotide-binding domain of GhACT17D, which probably affects the polymerization of F-actin. Over-expression of GhACT17DM, but not GhACT17D, driven by either a CaMV35 promoter or a fiber-specific promoter in cotton produced a Li1-like phenotype. Compared with the wild-type control, actin filaments in Li1 fibers showed higher growth and shrinkage rates, decreased filament skewness and parallelness, and increased filament density. Taken together, our results indicate that the incorporation of GhACT17DM during actin polymerization disrupts the establishment and dynamics of the actin cytoskeleton, resulting in defective fiber elongation and the overall dwarf and twisted phenotype of the Li1 mutant.


Asunto(s)
Citoesqueleto de Actina/metabolismo , Actinas/genética , Fibra de Algodón , Gossypium/genética , Mutación/genética , Actinas/química , Secuencia de Aminoácidos , Secuencia Conservada , Estudios de Asociación Genética , Gossypium/crecimiento & desarrollo , Fenotipo , Mapeo Físico de Cromosoma , Proteínas de Plantas/química , Proteínas de Plantas/genética , Plantas Modificadas Genéticamente , Homología Estructural de Proteína
9.
Int J Mol Sci ; 22(6)2021 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-33808655

RESUMEN

Chronic stress is encountered in our everyday life and is thought to contribute to a number of diseases. Many of these stress-related disorders display a sex bias. Because glucocorticoid hormones are the main biological mediator of chronic stress, researchers have been interested in understanding the sexual dimorphism in glucocorticoid stress response to better explain the sex bias in stress-related diseases. Although not yet demonstrated for glucocorticoid regulation, sex chromosomes do influence sex-specific biology as soon as conception. Then a transient rise in testosterone start to shape the male brain during the prenatal period differently to the female brain. These organizational effects are completed just before puberty. The cerebral regions implicated in glucocorticoid regulation at rest and after stress are thereby impacted in a sex-specific manner. After puberty, the high levels of all gonadal hormones will interact with glucocorticoid hormones in specific crosstalk through their respective nuclear receptors. In addition, stress occurring early in life, in particular during the prenatal period and in adolescence will prime in the long-term glucocorticoid stress response through epigenetic mechanisms, again in a sex-specific manner. Altogether, various molecular mechanisms explain sex-specific glucocorticoid stress responses that do not exclude important gender effects in humans.


Asunto(s)
Glucocorticoides/metabolismo , Caracteres Sexuales , Estrés Fisiológico , Estrés Psicológico , Adolescente , Animales , Niño , Desarrollo Infantil , Desarrollo Embrionario/genética , Estudios de Asociación Genética , Hormonas Gonadales/metabolismo , Humanos , Hidrocortisona/metabolismo , Pubertad/genética , Pubertad/metabolismo , Factores Sexuales , Esteroides/metabolismo , Estrés Fisiológico/genética , Estrés Psicológico/genética
10.
Int J Mol Sci ; 22(6)2021 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-33804065

RESUMEN

Seed coat color is an important agronomic trait of edible seed pumpkin in Cucurbita maxima. In this study, the development pattern of seed coat was detected in yellow and white seed coat accessions Wuminglv and Agol. Genetic analysis suggested that a single recessive gene white seed coat (wsc) is involved in seed coat color regulation in Cucurbita maxima. An F2 segregating population including 2798 plants was used for fine mapping and a candidate region containing nine genes was identified. Analysis of 54 inbred accessions revealed four main Insertion/Deletion sites in the promoter of CmaCh15G005270 encoding an MYB transcription factor were co-segregated with the phenotype of seed coat color. RNA-seq analysis and qRT-PCR revealed that some genes involved in phenylpropanoid/flavonoid metabolism pathway displayed remarkable distinction in Wuminglv and Agol during the seed coat development. The flanking InDel marker S1548 was developed to predict the seed coat color in the MAS breeding with an accuracy of 100%. The results may provide valuable information for further studies in seed coat color formation and structure development in Cucurbitaceae crops and help the molecular breeding of Cucurbita maxima.


Asunto(s)
Cucurbita/genética , Pigmentación/genética , Sitios de Carácter Cuantitativo/genética , Semillas/genética , Mapeo Cromosómico , Cucurbita/anatomía & histología , Estudios de Asociación Genética , Genotipo , Fenotipo , Fitomejoramiento , Semillas/anatomía & histología
11.
Int J Mol Sci ; 22(6)2021 Mar 23.
Artículo en Inglés | MEDLINE | ID: mdl-33806855

RESUMEN

Azoospermia affects 1% of men, and it can be due to: (i) hypothalamic-pituitary dysfunction, (ii) primary quantitative spermatogenic disturbances, (iii) urogenital duct obstruction. Known genetic factors contribute to all these categories, and genetic testing is part of the routine diagnostic workup of azoospermic men. The diagnostic yield of genetic tests in azoospermia is different in the different etiological categories, with the highest in Congenital Bilateral Absence of Vas Deferens (90%) and the lowest in Non-Obstructive Azoospermia (NOA) due to primary testicular failure (~30%). Whole-Exome Sequencing allowed the discovery of an increasing number of monogenic defects of NOA with a current list of 38 candidate genes. These genes are of potential clinical relevance for future gene panel-based screening. We classified these genes according to the associated-testicular histology underlying the NOA phenotype. The validation and the discovery of novel NOA genes will radically improve patient management. Interestingly, approximately 37% of candidate genes are shared in human male and female gonadal failure, implying that genetic counselling should be extended also to female family members of NOA patients.


Asunto(s)
Azoospermia/diagnóstico , Azoospermia/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Alelos , Animales , Biomarcadores , Deleción Cromosómica , Cromosomas Humanos Y , Femenino , Pruebas Genéticas , Humanos , Masculino , Fenotipo , Espermatogénesis/genética , Secuenciación del Exoma Completo
12.
Int J Mol Sci ; 22(6)2021 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-33810044

RESUMEN

Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated protein (Cas9)-mediated genome editing has become an important way for molecular breeding in crop plants. To promote rice breeding, we edited the Grain Size 3 (GS3) gene for obtaining valuable and stable long-grain rice mutants. Furthermore, isobaric tags for the relative and absolute quantitation (iTRAQ)-based proteomic method were applied to determine the proteome-wide changes in the GS3 mutants compared with wild type (WT). Two target sites were designed to construct the vector, and the Agrobacterium-mediated method was used for rice transformation. Specific mutations were successfully introduced, and the grain length (GL) and 1000-grain weight (GWT) of the mutants were increased by 31.39% and 27.15%, respectively, compared with WT. The iTRAQ-based proteomic analysis revealed that a total of 31 proteins were differentially expressed in the GS3 mutants, including 20 up-regulated and 11 down-regulated proteins. Results showed that differentially expressed proteins (DEPs) were mainly related to cysteine synthase, cysteine proteinase inhibitor, vacuolar protein sorting-associated, ubiquitin, and DNA ligase. Furthermore, functional analysis revealed that DEPs were mostly enriched in cellular process, metabolic process, binding, transmembrane, structural, and catalytic activities. Pathway enrichment analysis revealed that DEPs were mainly involved in lipid metabolism and oxylipin biosynthesis. The protein-to-protein interaction (PPI) network found that proteins related to DNA damage-binding, ubiquitin-40S ribosomal, and cysteine proteinase inhibitor showed a higher degree of interaction. The homozygous mutant lines featured by stable inheritance and long-grain phenotype were obtained using the CRISPR/Cas9 system. This study provides a convenient and effective way of improving grain yield, which could significantly accelerate the breeding process of long-grain japonica parents and promote the development of high-yielding rice.


Asunto(s)
Sistemas CRISPR-Cas , Edición Génica , Genes de Plantas , Mutagénesis , Oryza/genética , Proteínas de Plantas/genética , Carácter Cuantitativo Heredable , Secuencia de Bases , Inhibidores de Cisteína Proteinasa , ADN Bacteriano/genética , Grano Comestible/genética , Grano Comestible/metabolismo , Regulación de la Expresión Génica de las Plantas , Orden Génico , Redes Reguladoras de Genes , Estudios de Asociación Genética , Vectores Genéticos/genética , Genoma de Planta , Técnicas de Genotipaje , Mutación , Oryza/clasificación , Oryza/metabolismo , Fitomejoramiento , Proteínas de Plantas/metabolismo , Proteómica , Transducción de Señal
13.
Methods Mol Biol ; 2212: 55-67, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33733350

RESUMEN

Epistasis, or gene-gene interaction, contributes substantially to trait variation in organisms ranging from yeast to humans, and modeling epistasis directly is critical to understanding the genotype-phenotype map. However, inference of genetic interactions is challenging compared to inference of individual allele effects due to low statistical power. Furthermore, genetic interactions can appear inconsistent across different quantitative traits, presenting a challenge for the interpretation of detected interactions. Here we present a method called the Combined Analysis of Pleiotropy and Epistasis (CAPE) that combines information across multiple quantitative traits to infer directed epistatic interactions. By combining information across multiple traits, CAPE not only increases power to detect genetic interactions but also interprets these interactions across traits to identify a single interaction that is consistent across all observed data. This method generates informative, interpretable interaction networks that explain how variants interact with each other to influence groups of related traits. This method could potentially be used to link genetic variants to gene expression, physiological endophenotypes, and higher-level disease traits.


Asunto(s)
Epistasis Genética , Pleiotropía Genética , Modelos Genéticos , Carácter Cuantitativo Heredable , Programas Informáticos , Redes Reguladoras de Genes , Estudios de Asociación Genética , Genotipo , Humanos , Fenotipo , Sitios de Carácter Cuantitativo
14.
Methods Mol Biol ; 2212: 69-92, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33733351

RESUMEN

Undiscovered gene-to-gene interaction (epistasis) is a possible explanation for the "missing heritability" of complex traits and diseases. On a genome-wide scale, screening for epistatic effects among all possible pairs of genetic markers faces two main complications. Firstly, the classical statistical methods for modeling epistasis are computationally very expensive, which makes them impractical on such large scale. Secondly, straightforward corrections for multiple testing using the classical methods tend to be too coarse and inefficient at discovering the epistatic effects in such a large scale application. In this chapter, we describe both the underlying framework and practical examples of two-stage statistical testing methods that alleviate both of the aforementioned complications.


Asunto(s)
Epistasis Genética , Pruebas Genéticas/métodos , Modelos Genéticos , Polimorfismo de Nucleótido Simple , Carácter Cuantitativo Heredable , Programas Informáticos , Estudios de Asociación Genética , Genoma Humano , Genotipo , Humanos , Patrón de Herencia , Fenotipo , Sitios de Carácter Cuantitativo
15.
Methods Mol Biol ; 2212: 105-120, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33733353

RESUMEN

Reliable methods of phenotype prediction from genomic data play an increasingly important role in many areas of plant and animal breeding. Thus, developing methods that enhance prediction accuracy is of major interest. Here, we provide three methods for this purpose: (1) Genomic Best Linear Unbiased Prediction (GBLUP) as a model just accounting for additive SNP effects; (2) Epistatic Random Regression BLUP (ERRBLUP) as a full epistatic model which incorporates all pairwise SNP interactions, and (3) selective Epistatic Random Regression BLUP (sERRBLUP) as an epistatic model which incorporates a subset of pairwise SNP interactions selected based on their absolute effect sizes or the effect variances, which is computed based on solutions from the ERRBLUP model. We compared the predictive ability obtained from GBLUP, ERRBLUP, and sERRBLUP with genotypes from a publicly available wheat dataset and respective simulated phenotypes. Results showed that sERRBLUP provides a substantial increase in prediction accuracy compared to the other methods when the optimal proportion of SNP interactions is kept in the model, especially when an optimal proportion of SNP interactions is selected based on the SNP interaction effect sizes. All methods described here are implemented in the R-package EpiGP, which is able to process large-scale genomic data in a computationally efficient way.


Asunto(s)
Epistasis Genética , Modelos Genéticos , Modelos Estadísticos , Fenotipo , Carácter Cuantitativo Heredable , Triticum/genética , Conjuntos de Datos como Asunto , Estudios de Asociación Genética , Genotipo , Heterocigoto , Fitomejoramiento/métodos , Tumores de Planta/genética , Tumores de Planta/microbiología , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Triticum/anatomía & histología , Triticum/metabolismo
16.
Methods Mol Biol ; 2212: 155-168, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33733355

RESUMEN

Epistasis is the interaction between genes or genetic variants (such as Single Nucleotide Polymorphisms or SNPs) that influences a phenotype or a disease outcome. Statistically and biologically, significant evidence of epistatic loci for several traits and diseases is well known in human, animals, and plants. However, there is no straightforward way to compute a large number of pairwise epistasis among millions of variants along the whole genome, relate them to phenotypes or diseases, and visualize them. The WISH-R package (WISH-R) was developed to address this technology gap to calculate epistatic interactions using a linear or generalized linear model on a genome-wide level using genomic data and phenotype/disease data in a fully parallelized environment, and visualize genome-wide epistasis in many ways. This method protocol chapter provides an easy-to-follow systematic guide to install this R software in computers on Win OS, Mac OS, and Linux platforms and can be downloaded from https://github.com/QSG-Group/WISH with a user guide. The WISH-R package has several inbuilt functions to reduce genotype data dimensionality and hence computational demand. WISH-R software can be used to build scale-free weighted SNP interaction networks and relate them to quantitative traits or phenotypes and case-control diseases outcomes. The software leads to integrating biological knowledge to identify disease- or trait-relevant SNP or gene modules, hub genes, potential biomarkers, and pathways related to complex traits and diseases.


Asunto(s)
Epistasis Genética , Redes Reguladoras de Genes , Modelos Genéticos , Polimorfismo de Nucleótido Simple , Carácter Cuantitativo Heredable , Programas Informáticos , Animales , Mapeo Cromosómico , Femenino , Estudios de Asociación Genética , Genoma , Genotipo , Humanos , Masculino , Fenotipo , Plantas/genética , Sitios de Carácter Cuantitativo
17.
Methods Mol Biol ; 2212: 181-190, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33733357

RESUMEN

If one uses data to identify the most likely epistatic interaction between two genetic units, and then tests if the identified interaction is associated with a phenotype, the nominal statistical evidence will be inflated. Corrections are available but computationally expensive for genome-wide studies. We provide a first-order correction that can be applied in practice with essentially no additional computational cost.


Asunto(s)
Algoritmos , Epistasis Genética , Estudios de Asociación Genética , Modelos Genéticos , Polimorfismo de Nucleótido Simple , Simulación por Computador , Genotipo , Humanos , Reducción de Dimensionalidad Multifactorial , Fenotipo , Estadística como Asunto
18.
Methods Mol Biol ; 2212: 265-275, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33733361

RESUMEN

Epistasis is the phenomenon about the interactions between genes, leading to complex phenotypic effects. The interactions between three or more mutations called "high-order epistasis" aroused significant interests in recent studies. However, there are still debates for analysis of high-order epistasis due to the non-linear model complexity and statistical artifacts. A recent "epistasis" Python package was therefore developed to characterize high-order epistasis by estimating non-linear scaling for mutation effects to extract high-order epistasis using linear models. This method successfully discovered statistically significant high-order epistasis on several real genotype-phenotype maps. We provided a concise and step-by-step guide to apply the "epistasis" by reproducing the high-order epistasis discoveries on real genotype-phenotype data using the latest API of the package.


Asunto(s)
Algoritmos , Aspergillus niger/genética , Epistasis Genética , Escherichia coli/genética , Estudios de Asociación Genética , Conjuntos de Datos como Asunto , Genotipo , Humanos , Mutación , Dinámicas no Lineales , Fenotipo , Programas Informáticos
19.
Methods Mol Biol ; 2212: 291-305, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33733363

RESUMEN

To develop medical treatments and prevention, the association between disease and genetic variants needs to be identified. The main goal of genome-wide association study (GWAS) is to discover the underlying reason for vulnerability to disease and utilize this knowledge for the development of prevention and treatment against these diseases. Given the methods available to address the scientific problems involved in the search for epistasis, there is not any standard for detecting epistasis, and this remains a problem due to limited statistical power. The GenEpi package is a Python package that uses a two-level workflow machine learning model to detect within-gene and cross-gene epistasis. This protocol chapter shows the usage of GenEpi with example data. The package uses a three-step procedure to reduce dimensionality, select the within-gene epistasis, and select the cross-gene epistasis. The package also provides a medium to build prediction models with the combination of genetic features and environmental influences.


Asunto(s)
Biología Computacional/métodos , Epistasis Genética , Estudios de Asociación Genética , Aprendizaje Automático , Programas Informáticos , Bases de Datos Genéticas , Genoma Humano , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Fenotipo , Polimorfismo de Nucleótido Simple
20.
Nat Commun ; 12(1): 1515, 2021 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-33750777

RESUMEN

Ribosome-profiling has uncovered pervasive translation in non-canonical open reading frames, however the biological significance of this phenomenon remains unclear. Using genetic variation from 71,702 human genomes, we assess patterns of selection in translated upstream open reading frames (uORFs) in 5'UTRs. We show that uORF variants introducing new stop codons, or strengthening existing stop codons, are under strong negative selection comparable to protein-coding missense variants. Using these variants, we map and validate gene-disease associations in two independent biobanks containing exome sequencing from 10,900 and 32,268 individuals, respectively, and elucidate their impact on protein expression in human cells. Our results suggest translation disrupting mechanisms relating uORF variation to reduced protein expression, and demonstrate that translation at uORFs is genetically constrained in 50% of human genes.


Asunto(s)
Enfermedad/genética , Sistemas de Lectura Abierta , ARN Mensajero/genética , ARN Mensajero/metabolismo , Regiones no Traducidas 5' , Regulación de la Expresión Génica , Redes Reguladoras de Genes , Estudios de Asociación Genética , Genoma Humano , Humanos , Fenotipo , Fosfotransferasas (Aceptor del Grupo Fosfato)/genética , Fosfotransferasas (Aceptor del Grupo Fosfato)/metabolismo , Biosíntesis de Proteínas , Procesamiento Proteico-Postraduccional , Proteínas/genética , Receptor EphB2
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