Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 59
Filtrar
Mais filtros

Base de dados
Tipo de documento
Intervalo de ano de publicação
1.
Bioinformatics ; 39(3)2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36752514

RESUMO

MOTIVATION: With the rapidly growing volume of knowledge and data in biomedical databases, improved methods for knowledge-graph-based computational reasoning are needed in order to answer translational questions. Previous efforts to solve such challenging computational reasoning problems have contributed tools and approaches, but progress has been hindered by the lack of an expressive analysis workflow language for translational reasoning and by the lack of a reasoning engine-supporting that language-that federates semantically integrated knowledge-bases. RESULTS: We introduce ARAX, a new reasoning system for translational biomedicine that provides a web browser user interface and an application programming interface (API). ARAX enables users to encode translational biomedical questions and to integrate knowledge across sources to answer the user's query and facilitate exploration of results. For ARAX, we developed new approaches to query planning, knowledge-gathering, reasoning and result ranking and dynamically integrate knowledge providers for answering biomedical questions. To illustrate ARAX's application and utility in specific disease contexts, we present several use-case examples. AVAILABILITY AND IMPLEMENTATION: The source code and technical documentation for building the ARAX server-side software and its built-in knowledge database are freely available online (https://github.com/RTXteam/RTX). We provide a hosted ARAX service with a web browser interface at arax.rtx.ai and a web API endpoint at arax.rtx.ai/api/arax/v1.3/ui/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Bases de Conhecimento , Software , Bases de Dados Factuais , Idioma , Navegador
2.
Mol Psychiatry ; 27(9): 3842-3856, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35546635

RESUMO

Bipolar disorder is an often-severe mental health condition characterized by alternation between extreme mood states of mania and depression. Despite strong heritability and the recent identification of 64 common variant risk loci of small effect, pathophysiological mechanisms remain unknown. Here, we analyzed genome sequences from 41 multiply-affected pedigrees and identified variants in 741 genes with nominally significant linkage or association with bipolar disorder. These 741 genes overlapped known risk genes for neurodevelopmental disorders and clustered within gene networks enriched for synaptic and nuclear functions. The top variant in this analysis - prioritized by statistical association, predicted deleteriousness, and network centrality - was a missense variant in the gene encoding D-amino acid oxidase (DAOG131V). Heterologous expression of DAOG131V in human cells resulted in decreased DAO protein abundance and enzymatic activity. In a knock-in mouse model of DAOG131, DaoG130V/+, we similarly found decreased DAO protein abundance in hindbrain regions, as well as enhanced stress susceptibility and blunted behavioral responses to pharmacological inhibition of N-methyl-D-aspartate receptors (NMDARs). RNA sequencing of cerebellar tissue revealed that DaoG130V resulted in decreased expression of two gene networks that are enriched for synaptic functions and for genes expressed, respectively, in Purkinje neurons or granule neurons. These gene networks were also down-regulated in the cerebellum of patients with bipolar disorder compared to healthy controls and were enriched for additional rare variants associated with bipolar disorder risk. These findings implicate dysregulation of NMDAR signaling and of gene expression in cerebellar neurons in bipolar disorder pathophysiology and provide insight into its genetic architecture.


Assuntos
Transtorno Bipolar , Receptores de N-Metil-D-Aspartato , Camundongos , Animais , Humanos , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Transtorno Bipolar/genética , Transtorno Bipolar/metabolismo , D-Aminoácido Oxidase/genética , D-Aminoácido Oxidase/metabolismo , Redes Reguladoras de Genes/genética , Cerebelo/metabolismo
3.
BMC Bioinformatics ; 23(1): 400, 2022 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-36175836

RESUMO

BACKGROUND: Biomedical translational science is increasingly using computational reasoning on repositories of structured knowledge (such as UMLS, SemMedDB, ChEMBL, Reactome, DrugBank, and SMPDB in order to facilitate discovery of new therapeutic targets and modalities. The NCATS Biomedical Data Translator project is working to federate autonomous reasoning agents and knowledge providers within a distributed system for answering translational questions. Within that project and the broader field, there is a need for a framework that can efficiently and reproducibly build an integrated, standards-compliant, and comprehensive biomedical knowledge graph that can be downloaded in standard serialized form or queried via a public application programming interface (API). RESULTS: To create a knowledge provider system within the Translator project, we have developed RTX-KG2, an open-source software system for building-and hosting a web API for querying-a biomedical knowledge graph that uses an Extract-Transform-Load approach to integrate 70 knowledge sources (including the aforementioned core six sources) into a knowledge graph with provenance information including (where available) citations. The semantic layer and schema for RTX-KG2 follow the standard Biolink model to maximize interoperability. RTX-KG2 is currently being used by multiple Translator reasoning agents, both in its downloadable form and via its SmartAPI-registered interface. Serializations of RTX-KG2 are available for download in both the pre-canonicalized form and in canonicalized form (in which synonyms are merged). The current canonicalized version (KG2.7.3) of RTX-KG2 contains 6.4M nodes and 39.3M edges with a hierarchy of 77 relationship types from Biolink. CONCLUSION: RTX-KG2 is the first knowledge graph that integrates UMLS, SemMedDB, ChEMBL, DrugBank, Reactome, SMPDB, and 64 additional knowledge sources within a knowledge graph that conforms to the Biolink standard for its semantic layer and schema. RTX-KG2 is publicly available for querying via its API at arax.rtx.ai/api/rtxkg2/v1.2/openapi.json . The code to build RTX-KG2 is publicly available at github:RTXteam/RTX-KG2 .


Assuntos
Conhecimento , Reconhecimento Automatizado de Padrão , Semântica , Software , Ciência Translacional Biomédica
4.
Proc Natl Acad Sci U S A ; 116(12): 5819-5827, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30833390

RESUMO

Preterm birth (PTB) complications are the leading cause of long-term morbidity and mortality in children. By using whole blood samples, we integrated whole-genome sequencing (WGS), RNA sequencing (RNA-seq), and DNA methylation data for 270 PTB and 521 control families. We analyzed this combined dataset to identify genomic variants associated with PTB and secondary analyses to identify variants associated with very early PTB (VEPTB) as well as other subcategories of disease that may contribute to PTB. We identified differentially expressed genes (DEGs) and methylated genomic loci and performed expression and methylation quantitative trait loci analyses to link genomic variants to these expression and methylation changes. We performed enrichment tests to identify overlaps between new and known PTB candidate gene systems. We identified 160 significant genomic variants associated with PTB-related phenotypes. The most significant variants, DEGs, and differentially methylated loci were associated with VEPTB. Integration of all data types identified a set of 72 candidate biomarker genes for VEPTB, encompassing genes and those previously associated with PTB. Notably, PTB-associated genes RAB31 and RBPJ were identified by all three data types (WGS, RNA-seq, and methylation). Pathways associated with VEPTB include EGFR and prolactin signaling pathways, inflammation- and immunity-related pathways, chemokine signaling, IFN-γ signaling, and Notch1 signaling. Progress in identifying molecular components of a complex disease is aided by integrated analyses of multiple molecular data types and clinical data. With these data, and by stratifying PTB by subphenotype, we have identified associations between VEPTB and the underlying biology.


Assuntos
Predisposição Genética para Doença/genética , Nascimento Prematuro/genética , Metilação de DNA/genética , Feminino , Genômica/métodos , Humanos , Recém-Nascido , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Transdução de Sinais/genética , Sequenciamento Completo do Genoma/métodos
5.
PLoS Genet ; 14(5): e1007274, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29750799

RESUMO

Modifiers of Mendelian disorders can provide insights into disease mechanisms and guide therapeutic strategies. A recent genome-wide association (GWA) study discovered genetic modifiers of Huntington's disease (HD) onset in Europeans. Here, we performed whole genome sequencing and GWA analysis of a Venezuelan HD cluster whose families were crucial for the original mapping of the HD gene defect. The Venezuelan HD subjects develop motor symptoms earlier than their European counterparts, implying the potential for population-specific modifiers. The main Venezuelan HD family inherits HTT haplotype hap.03, which differs subtly at the sequence level from European HD hap.03, suggesting a different ancestral origin but not explaining the earlier age at onset in these Venezuelans. GWA analysis of the Venezuelan HD cluster suggests both population-specific and population-shared genetic modifiers. Genome-wide significant signals at 7p21.2-21.1 and suggestive association signals at 4p14 and 17q21.2 are evident only in Venezuelan HD, but genome-wide significant association signals at the established European chromosome 15 modifier locus are improved when Venezuelan HD data are included in the meta-analysis. Venezuelan-specific association signals on chromosome 7 center on SOSTDC1, which encodes a bone morphogenetic protein antagonist. The corresponding SNPs are associated with reduced expression of SOSTDC1 in non-Venezuelan tissue samples, suggesting that interaction of reduced SOSTDC1 expression with a population-specific genetic or environmental factor may be responsible for modification of HD onset in Venezuela. Detection of population-specific modification in Venezuelan HD supports the value of distinct disease populations in revealing novel aspects of a disease and population-relevant therapeutic strategies.


Assuntos
Genes Modificadores/genética , Estudo de Associação Genômica Ampla/métodos , Doença de Huntington/genética , Sequenciamento Completo do Genoma/métodos , Proteínas Adaptadoras de Transdução de Sinal , Idade de Início , Saúde da Família , Feminino , Interação Gene-Ambiente , Genética Populacional , Haplótipos , Humanos , Proteína Huntingtina/genética , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Polimorfismo de Nucleotídeo Único , Proteínas/genética , Venezuela
6.
PLoS Genet ; 13(4): e1006675, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28448578

RESUMO

The indigenous people of the Tibetan Plateau have been the subject of much recent interest because of their unique genetic adaptations to high altitude. Recent studies have demonstrated that the Tibetan EPAS1 haplotype is involved in high altitude-adaptation and originated in an archaic Denisovan-related population. We sequenced the whole-genomes of 27 Tibetans and conducted analyses to infer a detailed history of demography and natural selection of this population. We detected evidence of population structure between the ancestral Han and Tibetan subpopulations as early as 44 to 58 thousand years ago, but with high rates of gene flow until approximately 9 thousand years ago. The CMS test ranked EPAS1 and EGLN1 as the top two positive selection candidates, and in addition identified PTGIS, VDR, and KCTD12 as new candidate genes. The advantageous Tibetan EPAS1 haplotype shared many variants with the Denisovan genome, with an ancient gene tree divergence between the Tibetan and Denisovan haplotypes of about 1 million years ago. With the exception of EPAS1, we observed no evidence of positive selection on Denisovan-like haplotypes.


Assuntos
Adaptação Fisiológica/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Genoma Humano , Seleção Genética/genética , Altitude , Sistema Enzimático do Citocromo P-450/genética , Feminino , Haplótipos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Masculino , Anotação de Sequência Molecular , Proteínas/genética , Receptores de Calcitriol/genética , Tibet
7.
Am J Hum Genet ; 97(3): 435-44, 2015 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-26320893

RESUMO

Huntington disease (HD) reflects the dominant consequences of a CAG-repeat expansion in HTT. Analysis of common SNP-based haplotypes has revealed that most European HD subjects have distinguishable HTT haplotypes on their normal and disease chromosomes and that ∼50% of the latter share the same major HD haplotype. We reasoned that sequence-level investigation of this founder haplotype could provide significant insights into the history of HD and valuable information for gene-targeting approaches. Consequently, we performed whole-genome sequencing of HD and control subjects from four independent families in whom the major European HD haplotype segregates with the disease. Analysis of the full-sequence-based HTT haplotype indicated that these four families share a common ancestor sufficiently distant to have permitted the accumulation of family-specific variants. Confirmation of new CAG-expansion mutations on this haplotype suggests that unlike most founders of human disease, the common ancestor of HD-affected families with the major haplotype most likely did not have HD. Further, availability of the full sequence data validated the use of SNP imputation to predict the optimal variants for capturing heterozygosity in personalized allele-specific gene-silencing approaches. As few as ten SNPs are capable of revealing heterozygosity in more than 97% of European HD subjects. Extension of allele-specific silencing strategies to the few remaining homozygous individuals is likely to be achievable through additional known SNPs and discovery of private variants by complete sequencing of HTT. These data suggest that the current development of gene-based targeting for HD could be extended to personalized allele-specific approaches in essentially all HD individuals of European ancestry.


Assuntos
Evolução Molecular , Haplótipos/genética , Doença de Huntington/genética , Proteínas do Tecido Nervoso/genética , Expansão das Repetições de Trinucleotídeos/genética , População Branca/genética , Sequência de Bases , Efeito Fundador , Heterozigoto , Humanos , Proteína Huntingtina , Dados de Sequência Molecular , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Análise de Sequência de DNA
8.
Am J Hum Genet ; 97(3): 475-82, 2015 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-26299364

RESUMO

Adams-Oliver syndrome (AOS) is a rare developmental disorder characterized by the presence of aplasia cutis congenita (ACC) of the scalp vertex and terminal limb-reduction defects. Cardiovascular anomalies are also frequently observed. Mutations in five genes have been identified as a cause for AOS prior to this report. Mutations in EOGT and DOCK6 cause autosomal-recessive AOS, whereas mutations in ARHGAP31, RBPJ, and NOTCH1 lead to autosomal-dominant AOS. Because RBPJ, NOTCH1, and EOGT are involved in NOTCH signaling, we hypothesized that mutations in other genes involved in this pathway might also be implicated in AOS pathogenesis. Using a candidate-gene-based approach, we prioritized DLL4, a critical NOTCH ligand, due to its essential role in vascular development in the context of cardiovascular features in AOS-affected individuals. Targeted resequencing of the DLL4 gene with a custom enrichment panel in 89 independent families resulted in the identification of seven mutations. A defect in DLL4 was also detected in two families via whole-exome or genome sequencing. In total, nine heterozygous mutations in DLL4 were identified, including two nonsense and seven missense variants, the latter encompassing four mutations that replace or create cysteine residues, which are most likely critical for maintaining structural integrity of the protein. Affected individuals with DLL4 mutations present with variable clinical expression with no emerging genotype-phenotype correlations. Our findings demonstrate that DLL4 mutations are an additional cause of autosomal-dominant AOS or isolated ACC and provide further evidence for a key role of NOTCH signaling in the etiology of this disorder.


Assuntos
Displasia Ectodérmica/genética , Displasia Ectodérmica/patologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Deformidades Congênitas dos Membros/genética , Deformidades Congênitas dos Membros/patologia , Mutação/genética , Dermatoses do Couro Cabeludo/congênito , Transdução de Sinais/genética , Proteínas Adaptadoras de Transdução de Sinal , Sequência de Aminoácidos , Sequência de Bases , Proteínas de Ligação ao Cálcio , Heterozigoto , Humanos , Dados de Sequência Molecular , Linhagem , Receptores Notch/genética , Dermatoses do Couro Cabeludo/genética , Dermatoses do Couro Cabeludo/patologia , Análise de Sequência de DNA
9.
Proc Natl Acad Sci U S A ; 112(11): 3576-81, 2015 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-25730879

RESUMO

We sequenced the genomes of 200 individuals from 41 families multiply affected with bipolar disorder (BD) to identify contributions of rare variants to genetic risk. We initially focused on 3,087 candidate genes with known synaptic functions or prior evidence from genome-wide association studies. BD pedigrees had an increased burden of rare variants in genes encoding neuronal ion channels, including subunits of GABAA receptors and voltage-gated calcium channels. Four uncommon coding and regulatory variants also showed significant association, including a missense variant in GABRA6. Targeted sequencing of 26 of these candidate genes in an additional 3,014 cases and 1,717 controls confirmed rare variant associations in ANK3, CACNA1B, CACNA1C, CACNA1D, CACNG2, CAMK2A, and NGF. Variants in promoters and 5' and 3' UTRs contributed more strongly than coding variants to risk for BD, both in pedigrees and in the case-control cohort. The genes and pathways identified in this study regulate diverse aspects of neuronal excitability. We conclude that rare variants in neuronal excitability genes contribute to risk for BD.


Assuntos
Transtorno Bipolar/genética , Transtorno Bipolar/fisiopatologia , Predisposição Genética para Doença , Variação Genética , Neurônios/fisiologia , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Humanos , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Transdução de Sinais/genética , População Branca/genética
10.
Am J Hum Genet ; 95(3): 275-84, 2014 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-25132448

RESUMO

Notch signaling determines and reinforces cell fate in bilaterally symmetric multicellular eukaryotes. Despite the involvement of Notch in many key developmental systems, human mutations in Notch signaling components have mainly been described in disorders with vascular and bone effects. Here, we report five heterozygous NOTCH1 variants in unrelated individuals with Adams-Oliver syndrome (AOS), a rare disease with major features of aplasia cutis of the scalp and terminal transverse limb defects. Using whole-genome sequencing in a cohort of 11 families lacking mutations in the four genes with known roles in AOS pathology (ARHGAP31, RBPJ, DOCK6, and EOGT), we found a heterozygous de novo 85 kb deletion spanning the NOTCH1 5' region and three coding variants (c.1285T>C [p.Cys429Arg], c.4487G>A [p.Cys1496Tyr], and c.5965G>A [p.Asp1989Asn]), two of which are de novo, in four unrelated probands. In a fifth family, we identified a heterozygous canonical splice-site variant (c.743-1 G>T) in an affected father and daughter. These variants were not present in 5,077 in-house control genomes or in public databases. In keeping with the prominent developmental role described for Notch1 in mouse vasculature, we observed cardiac and multiple vascular defects in four of the five families. We propose that the limb and scalp defects might also be due to a vasculopathy in NOTCH1-related AOS. Our results suggest that mutations in NOTCH1 are the most common cause of AOS and add to a growing list of human diseases that have a vascular and/or bony component and are caused by alterations in the Notch signaling pathway.


Assuntos
Anormalidades Múltiplas/genética , Displasia Ectodérmica/genética , Displasia Ectodérmica/patologia , Deformidades Congênitas dos Membros/genética , Deformidades Congênitas dos Membros/patologia , Mutação/genética , Receptor Notch1/genética , Dermatoses do Couro Cabeludo/congênito , Adolescente , Adulto , Animais , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Camundongos , Linhagem , Dermatoses do Couro Cabeludo/genética , Dermatoses do Couro Cabeludo/patologia , Adulto Jovem
11.
PLoS Genet ; 10(1): e1004144, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24497848

RESUMO

The determination of the relationship between a pair of individuals is a fundamental application of genetics. Previously, we and others have demonstrated that identity-by-descent (IBD) information generated from high-density single-nucleotide polymorphism (SNP) data can greatly improve the power and accuracy of genetic relationship detection. Whole-genome sequencing (WGS) marks the final step in increasing genetic marker density by assaying all single-nucleotide variants (SNVs), and thus has the potential to further improve relationship detection by enabling more accurate detection of IBD segments and more precise resolution of IBD segment boundaries. However, WGS introduces new complexities that must be addressed in order to achieve these improvements in relationship detection. To evaluate these complexities, we estimated genetic relationships from WGS data for 1490 known pairwise relationships among 258 individuals in 30 families along with 46 population samples as controls. We identified several genomic regions with excess pairwise IBD in both the pedigree and control datasets using three established IBD methods: GERMLINE, fastIBD, and ISCA. These spurious IBD segments produced a 10-fold increase in the rate of detected false-positive relationships among controls compared to high-density microarray datasets. To address this issue, we developed a new method to identify and mask genomic regions with excess IBD. This method, implemented in ERSA 2.0, fully resolved the inflated cryptic relationship detection rates while improving relationship estimation accuracy. ERSA 2.0 detected all 1(st) through 6(th) degree relationships, and 55% of 9(th) through 11(th) degree relationships in the 30 families. We estimate that WGS data provides a 5% to 15% increase in relationship detection power relative to high-density microarray data for distant relationships. Our results identify regions of the genome that are highly problematic for IBD mapping and introduce new software to accurately detect 1(st) through 9(th) degree relationships from whole-genome sequence data.


Assuntos
Mapeamento Cromossômico/métodos , Genética Populacional , Polimorfismo de Nucleotídeo Único/genética , Software , Algoritmos , Ligação Genética , Genoma Humano , Genômica , Mutação em Linhagem Germinativa/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Linhagem
12.
Am J Hum Genet ; 89(3): 382-97, 2011 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-21855840

RESUMO

Assignment of alleles to haplotypes for nearly all the variants on all chromosomes can be performed by genetic analysis of a nuclear family with three or more children. Whole-genome sequence data enable deterministic phasing of nearly all sequenced alleles by permitting assignment of recombinations to precise chromosomal positions and specific meioses. We demonstrate this process of genetic phasing on two families each with four children. We generate haplotypes for all of the children and their parents; these haplotypes span all genotyped positions, including rare variants. Misassignments of phase between variants (switch errors) are nearly absent. Our algorithm can also produce multimegabase haplotypes for nuclear families with just two children and can handle families with missing individuals. We implement our algorithm in a suite of software scripts (Haploscribe). Haplotypes and family genome sequences will become increasingly important for personalized medicine and for fundamental biology.


Assuntos
Algoritmos , Cromossomos Humanos/genética , Variação Genética , Haplótipos/genética , Padrões de Herança/genética , Modelos Genéticos , Software , Humanos , Mutação/genética , Linhagem , Análise de Sequência de DNA/métodos
13.
Am J Med Genet A ; 164A(10): 2656-62, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25091416

RESUMO

Adams-Oliver syndrome (AOS) is a rare malformation syndrome characterized by the presence of two anomalies: aplasia cutis congenita of the scalp and transverse terminal limb defects. Many affected individuals also have additional malformations, including a variety of intracranial anomalies such as periventricular calcification in keeping with cerebrovascular microbleeds, impaired neuronal migration, epilepsy, and microcephaly. Cardiac malformations can be present, as can vascular dysfunction in the forms of cutis marmorata telangiectasia congenita, pulmonary vein stenoses, and abnormal hepatic microvasculature. Elucidated genetic causes include four genes in different pathways, leading to a model of AOS as a multi-pathway disorder. We identified an infant with mild aplasia cutis congenita and terminal transverse limb defects, developmental delay and a severe, diffuse angiopathy with incomplete microvascularization. Whole-genome sequencing documented two rare truncating variants in DOCK6, a gene associated with a type of autosomal recessive AOS that recurrently features periventricular calcification and impaired neurodevelopment. We highlight an unexpectedly high frequency of likely deleterious mutations in this gene in the general population, relative to the rarity of the disease, and discuss possible explanations for this discrepancy.


Assuntos
Displasia Ectodérmica/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Deformidades Congênitas dos Membros/genética , Mutação/genética , Dermatoses do Couro Cabeludo/congênito , Anormalidades Múltiplas/genética , Feminino , Genes Recessivos/genética , Humanos , Recém-Nascido , Dermatoses do Couro Cabeludo/genética
14.
Alzheimers Dement ; 10(5 Suppl): S277-S283.e10, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24239249

RESUMO

BACKGROUND: A mutation in presenilin 1 (E280A) causes early-onset Alzheimer's disease. Understanding the origin of this mutation will inform medical genetics. METHODS: We sequenced the genomes of 102 individuals from Antioquia, Colombia. We applied identity-by-descent analysis to identify regions of common ancestry. We estimated the age of the E280A mutation and the local ancestry of the haplotype harboring this mutation. RESULTS: All affected individuals share a minimal haplotype of 1.8 Mb containing E280A. We estimate a time to most recent common ancestor of E280A of 10 (95% credible interval, 7.2-12.6) generations. We date the de novo mutation event to 15 (95% credible interval, 11-25) generations ago. We infer a western European geographic origin of the shared haplotype. CONCLUSIONS: The age and geographic origin of E280A are consistent with a single founder dating from the time of the Spanish Conquistadors who began colonizing Colombia during the early 16th century.


Assuntos
Doença de Alzheimer/genética , Predisposição Genética para Doença , Mutação , Presenilina-1/genética , Idade de Início , Colômbia , Efeito Fundador , Haplótipos , Humanos , Padrões de Herança , População Branca/genética
15.
J Virol ; 86(16): 8821-34, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22696644

RESUMO

The 331-kbp chlorovirus Paramecium bursaria chlorella virus 1 (PBCV-1) genome was resequenced and annotated to correct errors in the original 15-year-old sequence; 40 codons was considered the minimum protein size of an open reading frame. PBCV-1 has 416 predicted protein-encoding sequences and 11 tRNAs. A proteome analysis was also conducted on highly purified PBCV-1 virions using two mass spectrometry-based protocols. The mass spectrometry-derived data were compared to PBCV-1 and its host Chlorella variabilis NC64A predicted proteomes. Combined, these analyses revealed 148 unique virus-encoded proteins associated with the virion (about 35% of the coding capacity of the virus) and 1 host protein. Some of these proteins appear to be structural/architectural, whereas others have enzymatic, chromatin modification, and signal transduction functions. Most (106) of the proteins have no known function or homologs in the existing gene databases except as orthologs with proteins of other chloroviruses, phycodnaviruses, and nuclear-cytoplasmic large DNA viruses. The genes encoding these proteins are dispersed throughout the virus genome, and most are transcribed late or early-late in the infection cycle, which is consistent with virion morphogenesis.


Assuntos
Paramecium/virologia , Phycodnaviridae/química , Phycodnaviridae/genética , Proteoma/análise , Proteínas Virais/análise , Genoma Viral , Espectrometria de Massas , Dados de Sequência Molecular , Fases de Leitura Aberta , Análise de Sequência de DNA
16.
J Alzheimers Dis ; 96(2): 591-607, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37840487

RESUMO

BACKGROUND: Comprehensive treatment of Alzheimer's disease and related dementias (ADRD) requires not only pharmacologic treatment but also management of existing medical conditions and lifestyle modifications including diet, cognitive training, and exercise. Personalized, multimodal therapies are needed to best prevent and treat Alzheimer's disease (AD). OBJECTIVE: The Coaching for Cognition in Alzheimer's (COCOA) trial was a prospective randomized controlled trial to test the hypothesis that a remotely coached multimodal lifestyle intervention would improve early-stage AD. METHODS: Participants with early-stage AD were randomized into two arms. Arm 1 (N = 24) received standard of care. Arm 2 (N = 31) additionally received telephonic personalized coaching for multiple lifestyle interventions. The primary outcome was a test of the hypothesis that the Memory Performance Index (MPI) change over time would be better in the intervention arm than in the control arm. The Functional Assessment Staging Test was assessed for a secondary outcome. COCOA collected psychometric, clinical, lifestyle, genomic, proteomic, metabolomic, and microbiome data at multiple timepoints (dynamic dense data) across two years for each participant. RESULTS: The intervention arm ameliorated 2.1 [1.0] MPI points (mean [SD], p = 0.016) compared to the control over the two-year intervention. No important adverse events or side effects were observed. CONCLUSION: Multimodal lifestyle interventions are effective for ameliorating cognitive decline and have a larger effect size than pharmacological interventions. Dietary changes and exercise are likely to be beneficial components of multimodal interventions in many individuals. Remote coaching is an effective intervention for early stage ADRD. Remote interventions were effective during the COVID pandemic.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Doença de Alzheimer/terapia , Estudos Prospectivos , Proteômica , Estilo de Vida , Disfunção Cognitiva/terapia , Cognição
17.
J Alzheimers Dis ; 96(1): 329-342, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37742646

RESUMO

BACKGROUND: A carbohydrate-restricted diet aimed at lowering insulin levels has the potential to slow Alzheimer's disease (AD). Restricting carbohydrate consumption reduces insulin resistance, which could improve glucose uptake and neural health. A hallmark feature of AD is widespread cortical thinning; however, no study has demonstrated that lower net carbohydrate (nCHO) intake is linked to attenuated cortical atrophy in patients with AD and confirmed amyloidosis. OBJECTIVE: We tested the hypothesis that individuals with AD and confirmed amyloid burden eating a carbohydrate-restricted diet have thicker cortex than those eating a moderate-to-high carbohydrate diet. METHODS: A total of 31 patients (mean age 71.4±7.0 years) with AD and confirmed amyloid burden were divided into two groups based on a 130 g/day nCHO cutoff. Cortical thickness was estimated from T1-weighted MRI using FreeSurfer. Cortical surface analyses were corrected for multiple comparisons using cluster-wise probability. We assessed group differences using a two-tailed two-independent sample t-test. Linear regression analyses using nCHO as a continuous variable, accounting for confounders, were also conducted. RESULTS: The lower nCHO group had significantly thicker cortex within somatomotor and visual networks. Linear regression analysis revealed that lower nCHO intake levels had a significant association with cortical thickness within the frontoparietal, cingulo-opercular, and visual networks. CONCLUSIONS: Restricting carbohydrates may be associated with reduced atrophy in patients with AD. Lowering nCHO to under 130 g/day would allow patients to follow the well-validated MIND diet while benefiting from lower insulin levels.


Assuntos
Doença de Alzheimer , Insulinas , Humanos , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/complicações , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Amiloide , Proteínas Amiloidogênicas , Dieta com Restrição de Carboidratos , Carboidratos , Atrofia/complicações
18.
Commun Biol ; 6(1): 768, 2023 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-37481675

RESUMO

Aging manifests as progressive deteriorations in homeostasis, requiring systems-level perspectives to investigate the gradual molecular dysregulation of underlying biological processes. Here, we report systemic changes in the molecular regulation of biological processes under multiple lifespan-extending interventions. Differential Rank Conservation (DIRAC) analyses of mouse liver proteomics and transcriptomics data show that mechanistically distinct lifespan-extending interventions (acarbose, 17α-estradiol, rapamycin, and calorie restriction) generally tighten the regulation of biological modules. These tightening patterns are similar across the interventions, particularly in processes such as fatty acid oxidation, immune response, and stress response. Differences in DIRAC patterns between proteins and transcripts highlight specific modules which may be tightened via augmented cap-independent translation. Moreover, the systemic shifts in fatty acid metabolism are supported through integrated analysis of liver transcriptomics data with a mouse genome-scale metabolic model. Our findings highlight the power of systems-level approaches for identifying and characterizing the biological processes involved in aging and longevity.


Assuntos
Metabolismo dos Lipídeos , Longevidade , Animais , Camundongos , Envelhecimento , Modelos Animais de Doenças , Fígado , Ácidos Graxos
19.
Bioinformatics ; 27(22): 3216-7, 2011 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-21965822

RESUMO

SUMMARY: With the rapidly expanding availability of data from personal genomes, exomes and transcriptomes, medical researchers will frequently need to test whether observed genomic variants are novel or known. This task requires downloading and handling large and diverse datasets from a variety of sources, and processing them with bioinformatics tools and pipelines. Alternatively, researchers can upload data to online tools, which may conflict with privacy requirements. We present here Kaviar, a tool that greatly simplifies the assessment of novel variants. Kaviar includes: (i) an integrated and growing database of genomic variation from diverse sources, including over 55 million variants from personal genomes, family genomes, transcriptomes, SNV databases and population surveys; and (ii) software for querying the database efficiently.


Assuntos
Variação Genética , Software , Bases de Dados de Ácidos Nucleicos , Genômica , Humanos , Transcriptoma
20.
Nature ; 441(7090): 173-8, 2006 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-16688168

RESUMO

The innate immune system is absolutely required for host defence, but, uncontrolled, it leads to inflammatory disease. This control is mediated, in part, by cytokines that are secreted by macrophages. Immune regulation is extraordinarily complex, and can be best investigated with systems approaches (that is, using computational tools to predict regulatory networks arising from global, high-throughput data sets). Here we use cluster analysis of a comprehensive set of transcriptomic data derived from Toll-like receptor (TLR)-activated macrophages to identify a prominent group of genes that appear to be regulated by activating transcription factor 3 (ATF3), a member of the CREB/ATF family of transcription factors. Network analysis predicted that ATF3 is part of a transcriptional complex that also contains members of the nuclear factor (NF)-kappaB family of transcription factors. Promoter analysis of the putative ATF3-regulated gene cluster demonstrated an over-representation of closely apposed ATF3 and NF-kappaB binding sites, which was verified by chromatin immunoprecipitation and hybridization to a DNA microarray. This cluster included important cytokines such as interleukin (IL)-6 and IL-12b. ATF3 and Rel (a component of NF-kappaB) were shown to bind to the regulatory regions of these genes upon macrophage activation. A kinetic model of Il6 and Il12b messenger RNA expression as a function of ATF3 and NF-kappaB promoter binding predicted that ATF3 is a negative regulator of Il6 and Il12b transcription, and this hypothesis was validated using Atf3-null mice. ATF3 seems to inhibit Il6 and Il12b transcription by altering chromatin structure, thereby restricting access to transcription factors. Because ATF3 is itself induced by lipopolysaccharide, it seems to regulate TLR-stimulated inflammatory responses as part of a negative-feedback loop.


Assuntos
Fator 3 Ativador da Transcrição/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Biologia de Sistemas , Receptor 4 Toll-Like/antagonistas & inibidores , Fator 3 Ativador da Transcrição/deficiência , Fator 3 Ativador da Transcrição/genética , Animais , Sequência de Bases , Sítios de Ligação , Análise por Conglomerados , Regulação da Expressão Gênica/efeitos dos fármacos , Cinética , Lipopolissacarídeos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Elementos de Resposta/genética , Receptor 4 Toll-Like/metabolismo , Transcrição Gênica/efeitos dos fármacos , Transcrição Gênica/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA