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1.
Cell ; 178(4): 850-866.e26, 2019 08 08.
Artículo en Inglés | MEDLINE | ID: mdl-31398340

RESUMEN

We performed a comprehensive assessment of rare inherited variation in autism spectrum disorder (ASD) by analyzing whole-genome sequences of 2,308 individuals from families with multiple affected children. We implicate 69 genes in ASD risk, including 24 passing genome-wide Bonferroni correction and 16 new ASD risk genes, most supported by rare inherited variants, a substantial extension of previous findings. Biological pathways enriched for genes harboring inherited variants represent cytoskeletal organization and ion transport, which are distinct from pathways implicated in previous studies. Nevertheless, the de novo and inherited genes contribute to a common protein-protein interaction network. We also identified structural variants (SVs) affecting non-coding regions, implicating recurrent deletions in the promoters of DLG2 and NR3C2. Loss of nr3c2 function in zebrafish disrupts sleep and social function, overlapping with human ASD-related phenotypes. These data support the utility of studying multiplex families in ASD and are available through the Hartwell Autism Research and Technology portal.


Asunto(s)
Trastorno del Espectro Autista/genética , Predisposición Genética a la Enfermedad/genética , Linaje , Mapas de Interacción de Proteínas/genética , Animales , Niño , Bases de Datos Genéticas , Modelos Animales de Enfermedad , Femenino , Eliminación de Gen , Guanilato-Quinasas/genética , Humanos , Patrón de Herencia/genética , Aprendizaje Automático , Masculino , Núcleo Familiar , Regiones Promotoras Genéticas/genética , Receptores de Mineralocorticoides/genética , Factores de Riesgo , Proteínas Supresoras de Tumor/genética , Secuenciación Completa del Genoma , Pez Cebra/genética
2.
Epigenetics Chromatin ; 17(1): 21, 2024 Jul 16.
Artículo en Inglés | MEDLINE | ID: mdl-39014503

RESUMEN

BACKGROUND: Cis-regulatory elements (CREs) play a pivotal role in gene expression regulation, allowing cells to serve diverse functions and respond to external stimuli. Understanding CREs is essential for personalized medicine and disease research, as an increasing number of genetic variants associated with phenotypes and diseases overlap with CREs. However, existing databases often focus on subsets of regulatory elements and present each identified instance of element individually, confounding the effort to obtain a comprehensive view. To address this gap, we have created CREdb, a comprehensive database with over 10 million human regulatory elements across 1,058 cell types and 315 tissues harmonized from different data sources. We curated and aligned the cell types and tissues to standard ontologies for efficient data query. RESULTS: Data from 11 sources were curated and mapped to standard ontological terms. 11,223,434 combined elements are present in the final database, and these were merged into 5,666,240 consensus elements representing the combined ranges of the individual elements informed by their overlap. Each consensus element contains curated metadata including the number of elements supporting it and a hash linking to the source databases. The inferred activity of each consensus element in various cell-type and tissue context is also provided. Examples presented here show the potential utility of CREdb in annotating non-coding genetic variants and informing chromatin accessibility profiling analysis. CONCLUSIONS: We developed CREdb, a comprehensive database of CREs, to simplify the analysis of CREs by providing a unified framework for researchers. CREdb compiles consensus ranges for each element by integrating the information from all instances identified across various source databases. This unified database facilitates the functional annotation of non-coding genetic variants and complements chromatin accessibility profiling analysis. CREdb will serve as an important resource in expanding our knowledge of the epigenome and its role in human diseases.


Asunto(s)
Bases de Datos Genéticas , Humanos , Secuencias Reguladoras de Ácidos Nucleicos , Regulación de la Expresión Génica
3.
Nat Commun ; 10(1): 2396, 2019 06 03.
Artículo en Inglés | MEDLINE | ID: mdl-31160561

RESUMEN

Modern genetic studies indicate that human brain evolution is driven primarily by changes in gene regulation, which requires understanding the biological function of largely non-coding gene regulatory elements, many of which act in tissue specific manner. We leverage chromatin interaction profiles in human fetal and adult cortex to assign three classes of human-evolved elements to putative target genes. We find that human-evolved elements involving DNA sequence changes and those involving epigenetic changes are associated with human-specific gene regulation via effects on different classes of genes representing distinct biological pathways. However, both types of human-evolved elements converge on specific cell types and laminae involved in cerebral cortical expansion. Moreover, human evolved elements interact with neurodevelopmental disease risk genes, and genes with a high level of evolutionary constraint, highlighting a relationship between brain evolution and vulnerability to disorders affecting cognition and behavior. These results provide novel insights into gene regulatory mechanisms driving the evolution of human cognition and mechanisms of vulnerability to neuropsychiatric conditions.


Asunto(s)
Corteza Cerebral/embriología , Epigénesis Genética/genética , Evolución Molecular , Regulación del Desarrollo de la Expresión Génica/genética , Células-Madre Neurales/metabolismo , Trastornos del Neurodesarrollo/genética , Encéfalo/embriología , Encéfalo/metabolismo , Corteza Cerebral/metabolismo , Predisposición Genética a la Enfermedad , Humanos , Elementos Reguladores de la Transcripción/genética
4.
Focus (Am Psychiatr Publ) ; 17(1): 66-72, 2019 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32015716

RESUMEN

(Gandal et al., "Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap" Science 09 Feb 2018:Vol. 359, Issue 6376, pp. 693-697 (DOI: 10.1126/science.aad6469). Reprinted with permission from AAAS).

5.
Science ; 359(6376): 693-697, 2018 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-29439242

RESUMEN

The predisposition to neuropsychiatric disease involves a complex, polygenic, and pleiotropic genetic architecture. However, little is known about how genetic variants impart brain dysfunction or pathology. We used transcriptomic profiling as a quantitative readout of molecular brain-based phenotypes across five major psychiatric disorders-autism, schizophrenia, bipolar disorder, depression, and alcoholism-compared with matched controls. We identified patterns of shared and distinct gene-expression perturbations across these conditions. The degree of sharing of transcriptional dysregulation is related to polygenic (single-nucleotide polymorphism-based) overlap across disorders, suggesting a substantial causal genetic component. This comprehensive systems-level view of the neurobiological architecture of major neuropsychiatric illness demonstrates pathways of molecular convergence and specificity.


Asunto(s)
Predisposición Genética a la Enfermedad , Trastornos Mentales/genética , Herencia Multifactorial , Enfermedades del Sistema Nervioso/genética , Corteza Cerebral/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Polimorfismo de Nucleótido Simple , Transcripción Genética
6.
Diabetes ; 66(11): 2903-2914, 2017 11.
Artículo en Inglés | MEDLINE | ID: mdl-28838971

RESUMEN

Type 2 diabetes (T2D) affects more than 415 million people worldwide, and its costs to the health care system continue to rise. To identify common or rare genetic variation with potential therapeutic implications for T2D, we analyzed and replicated genome-wide protein coding variation in a total of 8,227 individuals with T2D and 12,966 individuals without T2D of Latino descent. We identified a novel genetic variant in the IGF2 gene associated with ∼20% reduced risk for T2D. This variant, which has an allele frequency of 17% in the Mexican population but is rare in Europe, prevents splicing between IGF2 exons 1 and 2. We show in vitro and in human liver and adipose tissue that the variant is associated with a specific, allele-dosage-dependent reduction in the expression of IGF2 isoform 2. In individuals who do not carry the protective allele, expression of IGF2 isoform 2 in adipose is positively correlated with both incidence of T2D and increased plasma glycated hemoglobin in individuals without T2D, providing support that the protective effects are mediated by reductions in IGF2 isoform 2. Broad phenotypic examination of carriers of the protective variant revealed no association with other disease states or impaired reproductive health. These findings suggest that reducing IGF2 isoform 2 expression in relevant tissues has potential as a new therapeutic strategy for T2D, even beyond the Latin American population, with no major adverse effects on health or reproduction.


Asunto(s)
Diabetes Mellitus Tipo 2/genética , Factor II del Crecimiento Similar a la Insulina/metabolismo , Sitios de Empalme de ARN/genética , Tejido Adiposo , Línea Celular , Regulación de la Expresión Génica/fisiología , Variación Genética , Genotipo , Humanos , Factor II del Crecimiento Similar a la Insulina/genética , Hígado , Americanos Mexicanos/genética , México , Isoformas de Proteínas , Células Madre , Población Blanca
7.
Nat Genet ; 43(7): 712-4, 2011 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-21666693

RESUMEN

J.B.S. Haldane proposed in 1947 that the male germline may be more mutagenic than the female germline. Diverse studies have supported Haldane's contention of a higher average mutation rate in the male germline in a variety of mammals, including humans. Here we present, to our knowledge, the first direct comparative analysis of male and female germline mutation rates from the complete genome sequences of two parent-offspring trios. Through extensive validation, we identified 49 and 35 germline de novo mutations (DNMs) in two trio offspring, as well as 1,586 non-germline DNMs arising either somatically or in the cell lines from which the DNA was derived. Most strikingly, in one family, we observed that 92% of germline DNMs were from the paternal germline, whereas, in contrast, in the other family, 64% of DNMs were from the maternal germline. These observations suggest considerable variation in mutation rates within and between families.


Asunto(s)
Familia , Variación Genética , Genoma Humano , Mutación de Línea Germinal/genética , Mapeo Cromosómico , Análisis Mutacional de ADN , Femenino , Humanos , Masculino , Reacción en Cadena de la Polimerasa
8.
Genome Biol ; 12(9): R84, 2011 Sep 14.
Artículo en Inglés | MEDLINE | ID: mdl-21917140

RESUMEN

BACKGROUND: Rare coding variants constitute an important class of human genetic variation, but are underrepresented in current databases that are based on small population samples. Recent studies show that variants altering amino acid sequence and protein function are enriched at low variant allele frequency, 2 to 5%, but because of insufficient sample size it is not clear if the same trend holds for rare variants below 1% allele frequency. RESULTS: The 1000 Genomes Exon Pilot Project has collected deep-coverage exon-capture data in roughly 1,000 human genes, for nearly 700 samples. Although medical whole-exome projects are currently afoot, this is still the deepest reported sampling of a large number of human genes with next-generation technologies. According to the goals of the 1000 Genomes Project, we created effective informatics pipelines to process and analyze the data, and discovered 12,758 exonic SNPs, 70% of them novel, and 74% below 1% allele frequency in the seven population samples we examined. Our analysis confirms that coding variants below 1% allele frequency show increased population-specificity and are enriched for functional variants. CONCLUSIONS: This study represents a large step toward detecting and interpreting low frequency coding variation, clearly lays out technical steps for effective analysis of DNA capture data, and articulates functional and population properties of this important class of genetic variation.


Asunto(s)
Exones , Genoma Humano , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN/métodos , Algoritmos , Alelos , Secuencia de Bases , Frecuencia de los Genes , Genética de Población , Genotipo , Humanos , Mutación INDEL , Análisis de Secuencia por Matrices de Oligonucleótidos , Sensibilidad y Especificidad , Alineación de Secuencia/métodos
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