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1.
Nat Commun ; 10(1): 5508, 2019 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-31796735

RESUMO

Typically, estimating genetic parameters, such as disease heritability and between-disease genetic correlations, demands large datasets containing all relevant phenotypic measures and detailed knowledge of family relationships or, alternatively, genotypic and phenotypic data for numerous unrelated individuals. Here, we suggest an alternative, efficient estimation approach through the construction of two disease metrics from large health datasets: temporal disease prevalence curves and low-dimensional disease embeddings. We present eleven thousand heritability estimates corresponding to five study types: twins, traditional family studies, health records-based family studies, single nucleotide polymorphisms, and polygenic risk scores. We also compute over six hundred thousand estimates of genetic, environmental and phenotypic correlations. Furthermore, we find that: (1) disease curve shapes cluster into five general patterns; (2) early-onset diseases tend to have lower prevalence than late-onset diseases (Spearman's ρ = 0.32, p < 10-16); and (3) the disease onset age and heritability are negatively correlated (ρ = -0.46, p < 10-16).


Assuntos
Bases de Dados Genéticas , Predisposição Genética para Doença , Adolescente , Adulto , Idoso , Algoritmos , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Padrões de Herança/genética , Pessoa de Meia-Idade , Fenótipo , Prevalência , Adulto Jovem
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.
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
4.
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
5.
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
7.
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
8.
BMC Res Notes ; 12(1): 346, 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31215455

RESUMO

OBJECTIVE: According to oral traditions of horse caretakers and trainers, the differences in the position and number of facial hair whorls may be associated with temperamental traits. Elucidating genetic background of facial hair whorls and its relationship to temperamental traits may promote more efficient breeding and maintenance of racehorses. In this study, we estimated heritabilities of the position and number of facial hair whorls in Japanese Thoroughbred horses. RESULTS: The number of facial hair whorls varied from one to four and heritability estimate in 4024 Thoroughbred horses was low (h2= 0.160). The positions of facial hair whorls were categorized into high, medium, and low, based on their locations. This trait was estimated to have high heritability (h2= 0.643) in 3782 Thoroughbred horses. These results indicated that a larger proportion of the variation in the studied population was due to genetic factors for facial hair whorls position. Because a similar result was also observed in another horse breed, Polish Konik horses, high heritability of facial hair whorl position may be characteristic of multiple horse breeds. We expect that these results will stimulate future studies to elucidate the relationship among temperamental traits and facial hair whorls in all horse breeds.


Assuntos
Cabelo/anatomia & histologia , Cavalos/genética , Padrões de Herança/genética , Animais , Face , Fenótipo
9.
Einstein (Sao Paulo) ; 17(3): eRC4577, 2019 Jun 13.
Artigo em Inglês, Português | MEDLINE | ID: mdl-31215591

RESUMO

Epidermolysis bullosa describes a group of skin conditions caused by mutations in genes encoding proteins related to dermal-epidermal adhesion. In the United States, 50 cases of epidermolysis bullosa per 1 million live births are estimated, 92% of which classified as simplex, 5% dystrophic, 1% junctional and 2% non-classified. Dystrophic epidermolysis bullosa is associated with autosomal, dominant and recessive inheritance. Epidermolysis bullosa causes severe psychological, economic and social impacts, and there is currently no curative therapy, only symptom control. Embryonic selection is available for epidermolysis bullosa patients in order to prevent perpetuation of the condition in their offspring.


Assuntos
Epidermólise Bolhosa Distrófica/genética , Aconselhamento Genético/métodos , Mutação , Adulto , Colágeno Tipo VII/genética , Feminino , Humanos , Padrões de Herança/genética , Reação em Cadeia da Polimerase
10.
Genet Epidemiol ; 43(7): 776-785, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31218750

RESUMO

Nontraditional glycemic biomarkers, including fructosamine, glycated albumin, and 1,5-anhydroglucitol (1,5-AG) are potential alternatives or complement to traditional measures of hyperglycemia. Genetic variants are associated with these biomarkers, but the heritability, or extent to which genetics control their variation, is not known. We estimated pedigree-based, SNP-based, and bivariate heritabilities for traditional glycemic biomarkers (fasting glucose, HbA1c), and nontraditional biomarkers (fructosamine, glycated albumin, 1,5-AG) among white participants in the Atherosclerosis Risk in Communities (ARIC) Study (N = 400 first-degree relatives from sibships, N = 5,575 unrelated individuals). Pedigree-based heritabilities (representing heritability from the entire genome) for nontraditional biomarkers were substantial (0.44-0.55) and comparable to HbA1c (0.34); the fasting glucose estimate was nonsignificant. SNP-based heritabilities (representing heritability from common variants) were lower than pedigree-based heritabilities for all biomarkers. Bivariate heritabilities showed shared genetics between fructosamine and glycated albumin (0.46 pedigree-based, 1.00 SNP-based) and glycated albumin and 1,5-AG (0.50 pedigree-based, 0.47 SNP-based). Genetic factors contribute to a considerable proportion of the variance of fructosamine, glycated albumin, and 1,5-AG and a portion of this heritability likely comes from common variants.


Assuntos
Aterosclerose/genética , Biomarcadores/metabolismo , Hiperglicemia/genética , Padrões de Herança/genética , Glicemia/metabolismo , Feminino , Frutosamina/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Albumina Sérica/metabolismo
11.
Horm Behav ; 114: 104540, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31202819

RESUMO

Parenting qualities are known to transmit across generations, but less is known about genetic processes that may modify how strongly parenting quality carries across generations. We examined in prospective data whether oxytocinergic genes of offspring moderate the intergenerational transmission of warm and accepting parent-child relationship qualities. The sample comprised 1167 Finnish parents (G2, 62% female) and their mothers (G1). At the study baseline, G1 mothers (Mage = 38) reported parent-child relationship qualities towards G2 children (age range 3-18). After 28-34 years, G2 offspring reported parent-child relationship qualities towards their own children using the same questionnaire. A cumulative genetic score was computed for G2 by summing up previously identified four alleles associated with non-optimal parenting or social impairments across OXTR (rs1042778, rs2254298, rs53576) and CD38 (rs3796863) genes. Results indicated no interaction effects of G2 cumulative genetic score on the transmission of parent-child relationship qualities. Among single polymorphisms in OXTR, the interaction effects of rs53576 and rs1042778 were found. G1 maternal emotional warmth was associated with higher G2 emotional warmth among G2 participants with the OXTR rs53576 AA/AG genotype, but not among those with the GG genotype. G1 maternal acceptance was associated with higher G2 acceptance among those G2 participants with the OXTR rs1042778 GG/GT genotype, but not among those with the TT genotype. Oxytocinergic genes may influence sensitivity to quality of parent-child relationship, although this needs replication in future studies.


Assuntos
Padrões de Herança/genética , Ocitocina/genética , Relações Pais-Filho , Poder Familiar , Receptores de Ocitocina/genética , ADP-Ribosil Ciclase 1/genética , Adolescente , Adulto , Alelos , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Interação Gene-Ambiente , Genótipo , Humanos , Masculino , Glicoproteínas de Membrana/genética , Pessoa de Meia-Idade , Mães , Poder Familiar/psicologia , Pais , Polimorfismo Genético , Estudos Prospectivos
12.
Genet Epidemiol ; 43(5): 577-591, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31045279

RESUMO

It is 100 years since R. A. Fisher proposed that a Mendelian model of genetic variant effects, additive over loci, could explain the patterns of observed phenotypic correlations between relatives. His loci were hypothetical and his model theoretical. It is only about 50 years since the first genetic markers allowed the detection of even variants with major effects on phenotype, and only 20 years since the development of single-nucleotide polymorphism technology provided dense markers over the genome. Then both mappings in defined pedigrees and population-based genome-wide association studies samples allowed the detection of multiple contributing variants of smaller effect. Finally, with methods based on genotypic correlations between individuals, or on allelic associations between loci, the additive heritability contributions of the genome can be estimated from large population samples. In this review we trace, from 1918 to 2018, the analysis of observed phenotypic correlations between relatives to estimate underlying genetic components of traits in human populations. As with studies from 1918 onward, we use height as the example trait where not only data are readily available, but where Fisher's model of large numbers of variants of infinitesimal effect appears to provide a good approximation to reality. However, we also trace the use of phenotypic and genotypic correlations between relatives in mapping causal variants and resolving genetic contributions to more complex human traits. With the availability of DNA sequence data, we can hope to not only estimate the total genetic contribution to a trait, but to resolve effects of individual genetic variants on biological function.


Assuntos
Família , Genoma Humano , Modelos Genéticos , Sequência de Bases , Mapeamento Cromossômico , Marcadores Genéticos , Genética Populacional , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Padrões de Herança/genética , Desequilíbrio de Ligação/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Característica Quantitativa Herdável
13.
Int J Mol Sci ; 20(9)2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31075877

RESUMO

We investigated whether likely pathogenic variants co-segregating with gastroschisis through a family-based approach using bioinformatic analyses were implicated in body wall closure. Gene Ontology (GO)/Panther functional enrichment and protein-protein interaction analysis by String identified several biological networks of highly connected genes in UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, AOX1, NOTCH1, HIST1H2BB, RPS3, THBS1, ADCY9, and FGFR4. SVS-PhoRank identified a dominant model in OR10G4 (also as heterozygous de novo), ITIH3, PLEKHG4B, SLC9A3, ITGA2, AOX1, and ALPP, including a recessive model in UGT1A7, UGT1A6, PER2, PTPRD, and UGT1A3. A heterozygous compound model was observed in CDYL, KDM5A, RASGRP1, MYBPC2, PDE4DIP, F5, OBSCN, and UGT1A. These genes were implicated in pathogenetic pathways involving the following GO related categories: xenobiotic, regulation of metabolic process, regulation of cell adhesion, regulation of gene expression, inflammatory response, regulation of vascular development, keratinization, left-right symmetry, epigenetic, ubiquitination, and regulation of protein synthesis. Multiple background modifiers interacting with disease-relevant pathways may regulate gastroschisis susceptibility. Based in our findings and considering the plausibility of the biological pattern of mechanisms and gene network modeling, we suggest that the gastroschisis developmental process may be the consequence of several well-orchestrated biological and molecular mechanisms which could be interacting with gastroschisis predispositions within the first ten weeks of development.


Assuntos
Parede Abdominal/patologia , Biologia Computacional/métodos , Gastrosquise/genética , Variação Genética , Ontologia Genética , Humanos , Padrões de Herança/genética , Mapas de Interação de Proteínas/genética , Recidiva
15.
PLoS One ; 14(4): e0215994, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31017969

RESUMO

Prenatal hypoxia can induce cardiovascular diseases in the offspring. This study determined whether and how prenatal hypoxia may cause malignant hypertension and impaired vascular functions in spontaneous hypertension rat (SHR) offspring at adolescent stage. Pregnant SHR were placed in a hypoxic chamber (11% O2) or normal environment (21% O2) from gestational day 6 until birth. Body weight and blood pressure (BP) of SHR offspring were measured every week from 5 weeks old. Mesenteric arteries were tested. Gestational hypoxia resulted in growth restriction during 6-12 weeks and a significant elevation in systolic pressure in adolescent offspring at 12 weeks old. Notably, endothelial vasodilatation of mesenteric arteries was impaired in SHR adolescent offspring exposed to prenatal hypoxia, vascular responses to acetylcholine (ACh) and sodium nitroprusside (SNP) were reduced, as well as plasma nitric oxide levels and expression of endothelial nitric oxide synthase (eNOS) in vessels were decreased. Moreover, mesenteric arteries in SHR offspring following prenatal hypoxia showed enhanced constriction responses to phenylephrine (PE), associated with up-regulated activities of L-type calcium channel (Ca2+-dependent), RhoA/Rock pathway signaling (Ca2+-sensitization), and intracellular Ca2+ flow. Pressurized myograph demonstrated altered mechanical properties with aggravated stiffness in vessels, while histological analysis revealed vascular structural disorganization in prenatal hypoxia offspring. The results demonstrated that blood pressure and vascular function in young SHR offspring were affected by prenatal hypoxia, providing new information on development of hypertension in adolescent offspring with inherited hypertensive backgrounds.


Assuntos
Padrões de Herança/genética , Artérias Mesentéricas/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Animais , Pressão Sanguínea , Peso Corporal , Feminino , Artérias Mesentéricas/ultraestrutura , Tamanho do Órgão , Gravidez , Ratos Endogâmicos SHR , Fatores de Risco , Transdução de Sinais , Vasodilatação
16.
Int J Mol Sci ; 20(7)2019 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-30934785

RESUMO

In skeletal muscle, adiponectin has varied and pleiotropic functions, ranging from metabolic, anti-inflammatory, insulin-sensitizing to regenerative roles. Despite the important functions exerted by adiponectin, the study of the hormone in myopathies is still marginal. Myopathies include inherited and non-inherited/acquired neuromuscular pathologies characterized by muscular degeneration and weakness. This review reports current knowledge about adiponectin in myopathies, regarding in particular the role of adiponectin in some hereditary myopathies (as Duchenne muscular dystrophy) and non-inherited/acquired myopathies (such as idiopathic inflammatory myopathies and fibromyalgia). These studies show that some myopathies are characterized by decreased concentration of plasma adiponectin and that hormone replenishment induces beneficial effects in the diseased muscles. Overall, these findings suggest that adiponectin could constitute a future new therapeutic approach for the improvement of the abnormalities caused by myopathies.


Assuntos
Adiponectina/metabolismo , Doenças Musculares/metabolismo , Animais , Humanos , Padrões de Herança/genética , Músculo Esquelético/metabolismo
17.
Psychiatr Genet ; 29(4): 103-110, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30933048

RESUMO

BACKGROUND: Anorexia nervosa is a complex neuropsychiatric disorder presenting with life-threatening low body weight, and a persistent fear of gaining weight. To date, no whole exome sequencing was performed in male individuals with anorexia nervosa. AIM AND METHODS: Here, we performed an exome analysis in two independent families with male individuals with anorexia nervosa and found variants in the Neuronatin (NNAT) gene in both probands. To confirm our data, we carried out the screening of the NNAT gene in a cohort of 8 male and 144 female individuals with anorexia nervosa. RESULTS: Exome sequencing revealed a nonsense variant p.Trp33* in NNAT in one patient and a rare variant in the 5'UTR region of NNAT in the other patient. Screening of the NNAT gene in a cohort of 8 male and 144 female individuals with anorexia nervosa allowed to identify 11 other NNAT variants showing that 40.00% and 6.25% of male and female anorexia nervosa individuals carried a NNAT variant, respectively. Moreover, two novel missense variants were identified in female anorexia nervosa patients. CONCLUSION: Our data suggest that NNAT variants and NNAT expression changes may be associated with susceptibility to eating disorders such as anorexia nervosa.


Assuntos
Anorexia Nervosa/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Proteínas de Membrana/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Exoma/genética , Feminino , Humanos , Padrões de Herança/genética , Masculino , Mutação de Sentido Incorreto/genética , Linhagem , Sequenciamento Completo do Exoma
18.
Nat Commun ; 10(1): 1640, 2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30967548

RESUMO

Gene-drive systems developed in several organisms result in super-Mendelian inheritance of transgenic insertions. Here, we generalize this "active genetic" approach to preferentially transmit allelic variants (allelic-drive) resulting from only a single or a few nucleotide alterations. We test two configurations for allelic-drive: one, copy-cutting, in which a non-preferred allele is selectively targeted for Cas9/guide RNA (gRNA) cleavage, and a more general approach, copy-grafting, that permits selective inheritance of a desired allele located in close proximity to the gRNA cut site. We also characterize a phenomenon we refer to as lethal-mosaicism that dominantly eliminates NHEJ-induced mutations and favors inheritance of functional cleavage-resistant alleles. These two efficient allelic-drive methods, enhanced by lethal mosaicism and a trans-generational drive process we refer to as "shadow-drive", have broad practical applications in improving health and agriculture and greatly extend the active genetics toolbox.


Assuntos
Alelos , Reparo do DNA por Junção de Extremidades/genética , Drosophila/genética , Tecnologia de Impulso Genético/métodos , Agricultura/métodos , Animais , Animais Geneticamente Modificados/genética , Sistemas CRISPR-Cas/genética , Análise Mutacional de DNA , Feminino , Edição de Genes/métodos , Padrões de Herança/genética , Masculino , Mosaicismo , RNA Guia/genética
20.
Nat Biomed Eng ; 3(2): 147-157, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30923642

RESUMO

Dilated cardiomyopathy (DCM) is a leading cause of morbidity and mortality worldwide; yet how genetic variation and environmental factors impact DCM heritability remains unclear. Here, we report that compound genetic interactions between DNA sequence variants contribute to the complex heritability of DCM. By using genetic data from a large family with a history of DCM, we discovered that heterozygous sequence variants in the TROPOMYOSIN 1 (TPM1) and VINCULIN (VCL) genes cose-gregate in individuals affected by DCM. In vitro studies of patient-derived and isogenic human-pluripotent-stem-cell-derived cardio-myocytes that were genome-edited via CRISPR to create an allelic series of TPM1 and VCL variants revealed that cardiomyocytes with both TPM1 and VCL variants display reduced contractility and sarcomeres that are less organized. Analyses of mice genetically engineered to harbour these human TPM1 and VCL variants show that stress on the heart may also influence the variable penetrance and expressivity of DCM-associated genetic variants in vivo. We conclude that compound genetic variants can interact combinatorially to induce DCM, particularly when influenced by other disease-provoking stressors.


Assuntos
Cardiomiopatia Dilatada/genética , Predisposição Genética para Doença , Variação Genética , Animais , Cardiomiopatia Dilatada/fisiopatologia , Matriz Extracelular/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Padrões de Herança/genética , Masculino , Camundongos , Modelos Biológicos , Contração Muscular/genética , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Linhagem , Células-Tronco Pluripotentes/metabolismo , Regulação para Cima/genética
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