Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 26.365
Filtrar
2.
Gene ; 720: 144081, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31473322

RESUMO

Despite the existing research, the etiology of rheumatoid arthritis (RA), an autoimmune disease remains poorly understood with early and accurate diagnosis difficult to achieve. MicroRNAs (miRNAs) play an important role in biological processes as modulators of transcription and translation. Previous studies have demonstrated a downregulation of several genes in early RA stages and in addition, miRNAs may serve as early biomarkers of subclinical changes in early RA. When comparing the four groups (ANOVA P < 0.01, fold change > 4), we found 253 differentially expressed miRNAs. Of these, 97 miRNAs were identified as overexpressed in early rheumatoid arthritis. The validation of miRNA microarray expression was performed in a set by RT-qPCR and showed strong agreement with microarray expression data. The putative targets of overexpressed microRNAs in early RA were significantly enriched in apoptosis, tolerance loss and Wnt pathways. Moreover, ROC analysis showed values of AUC 0.76 and P < 0.05 for miR 361-5p, identifying this miRNA as a potential biomarker of disease. We identified specific microRNAs associated with early rheumatoid arthritis and proposed them as early biomarkers of disease. Our results provide novel insight into immune disease physiopathology and describe unreported microRNAs in RA with potential for clinical use.


Assuntos
Artrite Reumatoide/genética , Biomarcadores/análise , Genoma Humano , MicroRNAs/genética , Adulto , Artrite Reumatoide/patologia , Estudos de Casos e Controles , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Curva ROC
3.
Lancet ; 394(10198): 604-610, 2019 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-31395443

RESUMO

Human genomic sequencing has potential diagnostic, prognostic, and therapeutic value across a wide breadth of clinical disciplines. One barrier to widespread adoption is the paucity of evidence for improved outcomes in patients who do not already have an indication for more focused testing. In this Series paper, we review clinical outcome studies in genomic medicine and discuss the important features and key challenges to building evidence for next generation sequencing in the context of routine patient care.


Assuntos
Genômica/métodos , Medicina de Precisão/métodos , Testes Diagnósticos de Rotina , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Avaliação de Resultados da Assistência ao Paciente , Padrão de Cuidado
4.
Zhonghua Bing Li Xue Za Zhi ; 48(8): 596-603, 2019 Aug 08.
Artigo em Chinês | MEDLINE | ID: mdl-31422589

RESUMO

Objective: To explore molecular characteristics of endometrial endometrioid cancer according to The Cancer Genome Atlas (TCGA) based molecular classification of endometrial carcinomas and to confirm simple and clinically applicable surrogate methodologies in pathological practice. Methods: Two hundred and twenty-eight cases of endometrial endometroid adenocarcinomas (EnACs) collected from August 2001 to August 2017 from Peking University Health Science Center, Peking University Third Hospital were molecularly categorized by using Sanger sequencing for the exonuclease domain mutations (EDM) of POLE, and by immunohistochemistry for p53 and mismatch repair (MMR) proteins. The cohort was classified into polymerase-E exonuclease domain mutation (POLE EDM), mismatch repair deficiency (MMR-D), p53 abnormal (p53-abn) and p53 wild type (p53-wt) groups. The correlation between molecular subgroups and the clinical-pathological features including prognosis were analyzed. Results: The cohort was distributed as follows: 11(4.8%) POLE EDM, 47(20.6%) MMR-D, 9(4.0%) p53-abn and 161(70.6%) p53-wt. p53-wt subgroup patients demonstrated significantly higher lymph node metastasis (P=0.011) and more advanced stage (P=0.036) than those of somatic hypermutation group cases (POLE EDM and MMR-D). In the FIGO grade 2-3 EnACs cohort, TCGA molecular subtyping was significantly correlated with progression-free survival and overall survival (P=0.043). POLE EDM subgroup had the best survival, while p53-abn subgroup had the worst. Conclusions: Identification of POLE EDM and MMR-D subgroups provides independent and highly valuable prognostic information beyond established histological classification. Based on immunohistochemistry of MMR, p53 and POLE mutational analysis, this pragmatic molecular classification scheme can be served as a reliable surrogate for TCGA molecular classification, which has potential to be used routinely in Chinese pathological practice.


Assuntos
Carcinoma Endometrioide , Neoplasias do Endométrio , Feminino , Genoma Humano , Humanos , Prognóstico
5.
Gene ; 718: 144050, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31425740

RESUMO

Individual specific variable drug response against similar drugs raises a significant challenge for the effective and safe treatment of many human diseases. Pharmacogenomics is the branch which try to deal with these challenge by relating drug response to patient specific genome in order to better customize patient treatments. Pharmacogenomics based research focus on the whole genome, but since last few years after realizing the importance, it mainly centralized towards genes of pharmacological importance called pharmacogenes, and try to explore association between their variants and variable drug response in world's different population. This research was initiated with the resulted data from human genome based research projects and later on assisted by exome sequencing projects. Simultaneously, it was boost-up with the participation of various pharmacogenomics groups lead by PGRN. By realizing the significance of pharmacogenes, and their variant related information, in health science, scientific communities are already started to look for genes of pharmacogenomics importance with different aspect. This article aims to provide an inclusive insight on current state of knowledge of pharmacogenes, recent trends and progress in the understanding of the pharmacogenes and the implications for personalized medicine.


Assuntos
Genoma Humano , Farmacogenética/métodos , Farmacogenética/tendências , Medicina de Precisão/métodos , Medicina de Precisão/tendências , Humanos
6.
Gene ; 720: 144056, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31437466

RESUMO

Repeated implantation failure (RIF) was mainly due to poor endometrium receptivity. Long noncoding RNAs (lncRNAs) could regulate endometrium receptivity and act in competing endogenous RNA (ceRNA) theory. However, the regulatory mechanism of the lncRNA-miRNA-mRNA network in repeated implantation failure (RIF) is unclear. We obtained RIF-related expression profiles of lncRNAs, mRNAs, and miRNAs using mid-secretory endometrial tissue samples from 5 women with RIF and 5 controls by RNA-sequencing. Co-expression analysis revealed that three functional modules were enriched in immune response/inflammation process; two functional modules were enriched in metabolic/ biosynthetic process, and one functional module were enriched in cell cycle pathway. By adding the miRNA data, ceRNA regulatory relationship of each module was reconstructed. The ceRNA network of the whole differentially expressed RNAs revealed 10 hub lncRNAs. Among them, TRG-AS1, SIMM25, and NEAT1 were involved in the module1, module2, and module3, respectively; LNC00511 and SLC26A4-AS1 in the module4; H19 in the module5. The real-time polymerase chain reaction (RT-PCR) results of 15 randomly selected RNAs were consistent with our sequencing data. These can be used as novel potential biomarkers for RIF. Furthermore, they might be involved in endometrium receptivity by acting as ceRNA.


Assuntos
Biomarcadores/metabolismo , Endométrio/metabolismo , Redes Reguladoras de Genes , Genoma Humano , MicroRNAs/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Adulto , Estudos de Casos e Controles , Implantação do Embrião , Endométrio/patologia , Feminino , Fertilização In Vitro , Regulação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos
7.
Am J Orthod Dentofacial Orthop ; 156(1): 104-112.e3, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31256822

RESUMO

INTRODUCTION: Mandibular prognathism (MP) is subject to major polygenic influence and segregates within families in autosomal dominance with variable expressivity and incomplete penetrance. We aimed to identify the inheritance pattern and genes and loci involved in the development of MP in Mediterranean families and to evaluate the dentoskeletal characteristics of affected individuals. METHODS: Fifty-one eastern Mediterranean families with individuals affected by MP were identified. Data and biospecimens were collected from 14 of the families, including clinical examination, lateral cephalography (on subjects with Class III malocclusion), and 5 mL blood drawn from consenting affected and nonaffected relatives. Next-generation sequencing (NGS) was performed on 8 families (7 Lebanese, 1 Lebanese/Syrian), including large numbers of affected individuals over many generations and severe conditions, with the use of whole-exome sequencing. RESULTS: Most pedigrees suggested autosomal-dominant inheritance with an equal number of affected male and female individuals. Affected individuals had macrognathic and prognathic mandibles with dentoalveolar compensation. Genetic screening did not correspond with previously reported MP-linked genes, but yielded 3 novel genes (C1orf167, NBPF8, NBPF9) on chromosome 1 potentially responsible for mandibular development and macrognathism. CONCLUSIONS: In this first genetic study with the use of NGS on the largest reported number of families with MP, novel genes (C1orf167, NBPF8, NBPF9) were associated with familial MP in the eastern Mediterranean population.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença/genética , Má Oclusão de Angle Classe III/genética , Prognatismo/genética , Adulto , Grupo com Ancestrais do Continente Asiático , Cefalometria , Cromossomos Humanos Par 1/genética , Feminino , Genoma Humano , Humanos , Líbano , Masculino , Má Oclusão de Angle Classe III/sangue , Má Oclusão de Angle Classe III/diagnóstico por imagem , Má Oclusão de Angle Classe III/patologia , Pessoa de Meia-Idade , Linhagem , Prognatismo/sangue , Prognatismo/diagnóstico por imagem , Prognatismo/patologia , Análise de Sequência de DNA , Síria , Adulto Jovem
9.
Genome Biol ; 20(1): 128, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31262363

RESUMO

As the scale of genomic and health-related data explodes and our understanding of these data matures, the privacy of the individuals behind the data is increasingly at stake. Traditional approaches to protect privacy have fundamental limitations. Here we discuss emerging privacy-enhancing technologies that can enable broader data sharing and collaboration in genomics research.


Assuntos
Privacidade Genética , Genômica/ética , Disseminação de Informação/ética , Genoma Humano , Humanos
10.
Genome Biol ; 20(1): 141, 2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31315652

RESUMO

BACKGROUND: The long introns of mammals are pools of evolutionary potential due to the multiplicity of sequences that permit the acquisition of novel exons. However, the permissibility of genes to this type of acquisition and its influence on the evolution of cell regulation is poorly understood. RESULTS: Here, we observe that human genes are highly permissive to the inclusion of novel exonic regions permitting the emergence of novel regulatory features. Our analysis reveals the potential for novel exon acquisition to occur in over 30% of evaluated human genes. Regulatory processes including the rate of splicing efficiency and RNA polymerase II (RNAPII) elongation control this process by modulating the "window of opportunity" for spliceosomal recognition. DNA damage alters this window promoting the inclusion of repeat-derived novel exons that reduce the ribosomal engagement of cell cycle genes. Finally, we demonstrate that the inclusion of novel exons is suppressed in hematological cancer samples and can be reversed by drugs modulating the rate of RNAPII elongation. CONCLUSION: Our work demonstrates that the inclusion of repeat-associated novel intronic regions is a tightly controlled process capable of expanding the regulatory capacity of cells.


Assuntos
Éxons , Regulação da Expressão Gênica , Genoma Humano , Transcriptoma , Dano ao DNA , Elementos de DNA Transponíveis , Genes cdc , Neoplasias Hematológicas/metabolismo , Humanos , Íntrons , Spliceossomos
11.
Sheng Wu Gong Cheng Xue Bao ; 35(7): 1295-1306, 2019 Jul 25.
Artigo em Chinês | MEDLINE | ID: mdl-31328486

RESUMO

Tumor-specific gene mutations might generate suitable neoepitopes for cancer immunotherapy that are highly immunogenic and absent in normal tissues. The high heterogeneity of the tumor genome poses a big challenge for precision cancer immunotherapy. Mutations characteristic of each tumor can help to distinguish it from other tumors. Based on these mutations' characteristic, it is possible to develop immunotherapeutic strategies for specific tumors. In this study, a tumor neoantigen prediction scheme was proposed, in which both the intracellular antigen presentation process and the ability to bind with extracellular MHC molecule were taken into consideration. The overall design is meritorious and may help reduce the cost for validation experiments compared with conventional methods. This strategy was tested with several cancer genome datasets in the TCGA database, and a number of potential tumor neoantigens were predicted for each dataset. These predicted neoantigens showed tumor type specificity and were found in 20% to 70% of cancer patients. This scheme might prove useful clinically in future.


Assuntos
Biologia Computacional , Neoplasias , Antígenos de Neoplasias , Genoma Humano , Humanos , Imunoterapia , Mutação
12.
Biochim Biophys Acta Rev Cancer ; 1872(1): 122-137, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31265877

RESUMO

The rapid evolution of next-generation sequencing (NGS)-based tumor genomic profile detection and the emergence of molecularly targeted therapies have enabled precision oncology. In NGS-based analysis, various types of databases have been developed to perform different functions. However, many problems still exist when using these public databases. Therefore, it is important to better understand the characteristics and limitations of each database and have them complement each other to provide useful clinical evidence for NGS testing. In this review, we elaborate on the important role of databases and their concrete applications in NGS-based somatic mutation detection. We introduce the typically used databases for sequence alignment, variant filtration, and variant interpretation, and compare the differences between the databases with similar functions. Subsequently, we determine the limitations of each database and provide the corresponding solutions. Furthermore, we present an overview diagram to clearly illustrate the database used in the entire NGS-based somatic mutation detection pipeline.


Assuntos
Análise Mutacional de DNA , Bases de Dados Genéticas , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias/genética , Genoma Humano/genética , Humanos , Mutação , Medicina de Precisão , Análise de Sequência de DNA/métodos
13.
Nat Commun ; 10(1): 2373, 2019 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-31147538

RESUMO

We aimed to develop an efficient, flexible and scalable approach to diagnostic genome-wide sequence analysis of genetically heterogeneous clinical presentations. Here we present G2P ( www.ebi.ac.uk/gene2phenotype ) as an online system to establish, curate and distribute datasets for diagnostic variant filtering via association of allelic requirement and mutational consequence at a defined locus with phenotypic terms, confidence level and evidence links. An extension to Ensembl Variant Effect Predictor (VEP), VEP-G2P was used to filter both disease-associated and control whole exome sequence (WES) with Developmental Disorders G2P (G2PDD; 2044 entries). VEP-G2PDD shows a sensitivity/precision of 97.3%/33% for de novo and 81.6%/22.7% for inherited pathogenic genotypes respectively. Many of the missing genotypes are likely false-positive pathogenic assignments. The expected number and discriminative features of background genotypes are defined using control WES. Using only human genetic data VEP-G2P performs well compared to other freely-available diagnostic systems and future phenotypic matching capabilities should further enhance performance.


Assuntos
Deficiências do Desenvolvimento/genética , Testes Genéticos , Genoma Humano , Sequenciamento Completo do Exoma , Alelos , Genótipo , Humanos , Técnicas de Diagnóstico Molecular , Mutação , Fenótipo , Análise de Sequência de DNA , Sequenciamento Completo do Genoma
14.
Nat Commun ; 10(1): 2449, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31164644

RESUMO

DNA base modifications, such as C5-methylcytosine (5mC) and N6-methyldeoxyadenosine (6mA), are important types of epigenetic regulations. Short-read bisulfite sequencing and long-read PacBio sequencing have inherent limitations to detect DNA modifications. Here, using raw electric signals of Oxford Nanopore long-read sequencing data, we design DeepMod, a bidirectional recurrent neural network (RNN) with long short-term memory (LSTM) to detect DNA modifications. We sequence a human genome HX1 and a Chlamydomonas reinhardtii genome using Nanopore sequencing, and then evaluate DeepMod on three types of genomes (Escherichia coli, Chlamydomonas reinhardtii and human genomes). For 5mC detection, DeepMod achieves average precision up to 0.99 for both synthetically introduced and naturally occurring modifications. For 6mA detection, DeepMod achieves ~0.9 average precision on Escherichia coli data, and have improved performance than existing methods on Chlamydomonas reinhardtii data. In conclusion, DeepMod performs well for genome-scale detection of DNA modifications and will facilitate epigenetic analysis on diverse species.


Assuntos
Chlamydomonas reinhardtii/genética , Metilação de DNA , Escherichia coli/genética , Genoma Bacteriano/genética , Genoma Humano/genética , Genoma de Planta/genética , Redes Neurais (Computação) , Bases de Dados de Ácidos Nucleicos , Epigênese Genética , Humanos , Nanoporos
15.
Hum Genet ; 138(7): 691-701, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31161416

RESUMO

Most genotype-phenotype studies have historically lacked population diversity, impacting the generalizability of findings and thereby limiting the ability to equitably implement precision medicine. This well-documented problem has generated much interest in the ascertainment of new cohorts with an emphasis on multiple dimensions of diversity, including race/ethnicity, gender, age, socioeconomic status, disability, and geography. The most well known of these new cohort efforts is arguably All of Us, formerly known as the Precision Medicine Cohort Initiative Program. All of Us intends to ascertain at least one million participants in the United States representative of the multiple dimensions of diversity. As an incentive to participate, All of Us is offering the return of research results, including whole genome sequencing data, as well as the opportunity to contribute to the scientific process as non-scientists. The scale and scope of the proposed return of research results are unprecedented. Here, we briefly review possible return of genetic data models, including the likely data file formats and modes of data transfer or access. We also review the resources required to access and interpret the genetic or genomic data once received by the average participant, highlighting the nuanced anticipated barriers that will challenge both the digitally, computationally literate and illiterate participant alike. This inventory of resources required to receive, process, and interpret return of research results exposes the potential for access disparities and warns the scientific community to mind the gap so that all participants have equal access and understanding of the benefits of human genetic research.


Assuntos
Interpretação Estatística de Dados , Mineração de Dados/normas , Pesquisa em Genética , Genoma Humano , Genômica/métodos , Medicina de Precisão , Humanos , Estados Unidos
16.
BMC Bioinformatics ; 20(Suppl 12): 320, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31216985

RESUMO

BACKGROUND: As Genome-Wide Association Studies (GWAS) have been increasingly used with data from various populations, it has been observed that data from different populations reveal different sets of Single Nucleotide Polymorphisms (SNPs) that are associated with the same disease. Using Type II Diabetes (T2D) as a test case, we develop measures and methods to characterize the functional overlap of SNPs associated with the same disease across populations. RESULTS: We introduce the notion of an Overlap Matrix as a general means of characterizing the functional overlap between different SNP sets at different genomic and functional granularities. Using SNP-to-gene mapping, functional annotation databases, and functional association networks, we assess the degree of functional overlap across nine populations from Asian and European ethnic origins. We further assess the generalizability of the method by applying it to a dataset for another complex disease - Prostate Cancer. Our results show that more overlap is captured as more functional data is incorporated as we go through the pipeline, starting from SNPs and ending at network overlap analyses. We hypothesize that these observed differences in the functional mechanisms of T2D across populations can also explain the common use of different prescription drugs in different populations. We show that this hypothesis is concordant with the literature on the functional mechanisms of prescription drugs. CONCLUSION: Our results show that although the etiology of a complex disease can be associated with distinct processes that are affected in different populations, network-based annotations can capture more functional overlap across populations. These results support the notion that it can be useful to take ethnicity into account in making personalized treatment decisions for complex diseases.


Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único/genética , Grupo com Ancestrais do Continente Asiático , Diabetes Mellitus Tipo 2/tratamento farmacológico , Grupos Étnicos , Genoma Humano , Humanos , Masculino , Neoplasias da Próstata/genética , Mapas de Interação de Proteínas/genética
17.
Sci Data ; 6(1): 91, 2019 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-31201313

RESUMO

Single-molecule long-read sequencing datasets were generated for a son-father-mother trio of Han Chinese descent that is part of the Genome in a Bottle (GIAB) consortium portfolio. The dataset was generated using the Pacific Biosciences Sequel System. The son and each parent were sequenced to an average coverage of 60 and 30, respectively, with N50 subread lengths between 16 and 18 kb. Raw reads and reads aligned to both the GRCh37 and GRCh38 are available at the NCBI GIAB ftp site (ftp://ftp-trace.ncbi.nlm.nih.gov/giab/ftp/data/ChineseTrio/). The GRCh38 aligned read data are archived in NCBI SRA (SRX4739017, SRX4739121, and SRX4739122). This dataset is available for anyone to develop and evaluate long-read bioinformatics methods.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Bases de Dados Genéticas , Genoma Humano , Núcleo Familiar , China , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Análise de Sequência de DNA
18.
Genome Biol ; 20(1): 105, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31155008

RESUMO

BACKGROUND: DNA methylation is thought to be an important determinant of human phenotypic variation, but its inherent cell type specificity has impeded progress on this question. At exceptional genomic regions, interindividual variation in DNA methylation occurs systemically. Like genetic variants, systemic interindividual epigenetic variants are stable, can influence phenotype, and can be assessed in any easily biopsiable DNA sample. We describe an unbiased screen for human genomic regions at which interindividual variation in DNA methylation is not tissue-specific. RESULTS: For each of 10 donors from the NIH Genotype-Tissue Expression (GTEx) program, CpG methylation is measured by deep whole-genome bisulfite sequencing of genomic DNA from tissues representing the three germ layer lineages: thyroid (endoderm), heart (mesoderm), and brain (ectoderm). We develop a computational algorithm to identify genomic regions at which interindividual variation in DNA methylation is consistent across all three lineages. This approach identifies 9926 correlated regions of systemic interindividual variation (CoRSIVs). These regions, comprising just 0.1% of the human genome, are inter-correlated over long genomic distances, associated with transposable elements and subtelomeric regions, conserved across diverse human ethnic groups, sensitive to periconceptional environment, and associated with genes implicated in a broad range of human disorders and phenotypes. CoRSIV methylation in one tissue can predict expression of associated genes in other tissues. CONCLUSIONS: In addition to charting a previously unexplored molecular level of human individuality, this atlas of human CoRSIVs provides a resource for future population-based investigations into how interindividual epigenetic variation modulates risk of disease.


Assuntos
Metilação de DNA , Epigênese Genética , Genoma Humano , Idoso , Encéfalo/metabolismo , Estudos de Casos e Controles , Criança , Doença/genética , Feminino , Gâmbia , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Miocárdio/metabolismo , Gravidez , Fenômenos Fisiológicos da Nutrição Pré-Natal , Estações do Ano , Glândula Tireoide/metabolismo
19.
Hum Genet ; 138(7): 739-748, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31154530

RESUMO

Metabolic syndrome is a complex human disorder characterized by a cluster of conditions (increased blood pressure, hyperglycemia, excessive body fat around the waist, and abnormal cholesterol or triglyceride levels). Any of these conditions increases the risk of serious disorders such as diabetes or cardiovascular disease. Currently, the degree of genetic regulation of this syndrome is under debate and partially unknown. The principal aim of this study was to estimate the genetic component and the common environmental effects in different populations using full pedigree and genomic information. We used three large populations (Gubbio, ARIC, and Ogliastra cohorts) to estimate the heritability of metabolic syndrome. Due to both pedigree and genotyped data, different approaches were applied to summarize relatedness conditions. Linear mixed models (LLM) using average information restricted maximum likelihood (AIREML) algorithm were applied to partition the variances and estimate heritability (h2) and common sib-household effect (c2). Globally, results obtained from pedigree information showed a significant heritability (h2: 0.286 and 0.271 in Gubbio and Ogliastra, respectively), whereas a lower, but still significant heritability was found using SNPs data ([Formula: see text]: 0.167 and 0.254 in ARIC and Ogliastra). The remaining heritability between h2 and [Formula: see text] ranged between 0.031 and 0.237. Finally, the common environmental c2 in Gubbio and Ogliastra were also significant accounting for about 11% of the phenotypic variance. Availability of different kinds of populations and data helped us to better understand what happened when heritability of metabolic syndrome is estimated and account for different possible confounding. Furthermore, the opportunity of comparing different results provided more precise and less biased estimation of heritability.


Assuntos
Predisposição Genética para Doença , Genética Populacional/métodos , Genoma Humano , Estudo de Associação Genômica Ampla , Genômica/métodos , Síndrome Metabólica/genética , Polimorfismo de Nucleotídeo Único , Estudos de Coortes , Feminino , Genótipo , Humanos , Masculino , Modelos Genéticos , Linhagem
20.
Hum Genet ; 138(7): 757-769, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31168775

RESUMO

An ethnicity is characterized by genomic fragments, single nucleotide polymorphisms (SNPs), and structural variations specific to it. However, the widely used 'standard human reference genome' GRCh37/38 is based on Caucasians. Therefore, de novo-assembled reference genomes for specific ethnicities would have advantages for genetics and precision medicine applications, especially with the long-read sequencing techniques that facilitate genome assembly. In this study, we assessed the de novo-assembled Chinese Han reference genome HX1 vis-à-vis the standard GRCh38 for improving the quality of assembly and for ethnicity-specific applications. Surprisingly, all genomic sequencing datasets mapped better to GRCh38 than to HX1, even for the datasets of the Chinese Han population. This gap was mainly due to the massive structural misassembly of the HX1 reference genome rather than the SNPs between the ethnicities, and this misassembly could not be corrected by short-read whole-genome sequencing (WGS). For example, HX1 and the other de novo-assembled personal genomes failed to assemble the mitochondrial genome as a contig. We mapped 97.1% of dbSNP, 98.8% of ClinVar, and 97.2% of COSMIC variants to HX1. HX1-absent, non-synonymous ClinVar SNPs were involved in 140 genes and many important functions in various diseases, most of which were due to the assembly failure of essential exons. In contrast, the HX1-specific regions were scantly expressible, as shown in the cell lines and clinical samples of Chinese patients. Our results demonstrated that the de novo-assembled individual genome such as HX1 did not have advantages against the standard GRCh38 genome due to insufficient assembly quality, and that it is, therefore, not recommended for common use.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Grupos Étnicos/genética , Genoma Humano , Genômica/normas , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Padrões de Referência , Análise de Sequência de DNA/normas , Algoritmos , Mapeamento de Sequências Contíguas , Genética Populacional , Humanos , Polimorfismo de Nucleotídeo Único , Transcriptoma
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA