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1.
Am J Hum Genet ; 106(1): 112-120, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31883642

RESUMO

Whole-genome sequencing (WGS) can improve assessment of low-frequency and rare variants, particularly in non-European populations that have been underrepresented in existing genomic studies. The genetic determinants of C-reactive protein (CRP), a biomarker of chronic inflammation, have been extensively studied, with existing genome-wide association studies (GWASs) conducted in >200,000 individuals of European ancestry. In order to discover novel loci associated with CRP levels, we examined a multi-ancestry population (n = 23,279) with WGS (∼38× coverage) from the Trans-Omics for Precision Medicine (TOPMed) program. We found evidence for eight distinct associations at the CRP locus, including two variants that have not been identified previously (rs11265259 and rs181704186), both of which are non-coding and more common in individuals of African ancestry (∼10% and ∼1% minor allele frequency, respectively, and rare or monomorphic in 1000 Genomes populations of East Asian, South Asian, and European ancestry). We show that the minor (G) allele of rs181704186 is associated with lower CRP levels and decreased transcriptional activity and protein binding in vitro, providing a plausible molecular mechanism for this African ancestry-specific signal. The individuals homozygous for rs181704186-G have a mean CRP level of 0.23 mg/L, in contrast to individuals heterozygous for rs181704186 with mean CRP of 2.97 mg/L and major allele homozygotes with mean CRP of 4.11 mg/L. This study demonstrates the utility of WGS in multi-ethnic populations to drive discovery of complex trait associations of large effect and to identify functional alleles in noncoding regulatory regions.


Assuntos
Povo Asiático/genética , População Negra/genética , Proteína C-Reativa/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , População Branca/genética , Sequenciamento Completo do Genoma/métodos , Estudos de Coortes , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação
2.
Nature ; 464(7293): 1351-6, 2010 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-20428171

RESUMO

Monozygotic or 'identical' twins have been widely studied to dissect the relative contributions of genetics and environment in human diseases. In multiple sclerosis (MS), an autoimmune demyelinating disease and common cause of neurodegeneration and disability in young adults, disease discordance in monozygotic twins has been interpreted to indicate environmental importance in its pathogenesis. However, genetic and epigenetic differences between monozygotic twins have been described, challenging the accepted experimental model in disambiguating the effects of nature and nurture. Here we report the genome sequences of one MS-discordant monozygotic twin pair, and messenger RNA transcriptome and epigenome sequences of CD4(+) lymphocytes from three MS-discordant, monozygotic twin pairs. No reproducible differences were detected between co-twins among approximately 3.6 million single nucleotide polymorphisms (SNPs) or approximately 0.2 million insertion-deletion polymorphisms. Nor were any reproducible differences observed between siblings of the three twin pairs in HLA haplotypes, confirmed MS-susceptibility SNPs, copy number variations, mRNA and genomic SNP and insertion-deletion genotypes, or the expression of approximately 19,000 genes in CD4(+) T cells. Only 2 to 176 differences in the methylation of approximately 2 million CpG dinucleotides were detected between siblings of the three twin pairs, in contrast to approximately 800 methylation differences between T cells of unrelated individuals and several thousand differences between tissues or between normal and cancerous tissues. In the first systematic effort to estimate sequence variation among monozygotic co-twins, we did not find evidence for genetic, epigenetic or transcriptome differences that explained disease discordance. These are the first, to our knowledge, female, twin and autoimmune disease individual genome sequences reported.


Assuntos
Epigênese Genética/genética , Genoma Humano/genética , Esclerose Múltipla/genética , RNA Mensageiro/genética , Gêmeos Monozigóticos/genética , Adolescente , Adulto , Desequilíbrio Alélico/genética , Mama/metabolismo , Neoplasias da Mama/genética , Linfócitos T CD4-Positivos/metabolismo , Estudos de Casos e Controles , Ilhas de CpG/genética , Variações do Número de Cópias de DNA/genética , Metilação de DNA/genética , Feminino , Predisposição Genética para Doença/genética , Haplótipos/genética , Heterozigoto , Humanos , Mutação INDEL/genética , Pulmão/metabolismo , Neoplasias Pulmonares/genética , Masculino , Polimorfismo Genético/genética , Locos de Características Quantitativas/genética , RNA Mensageiro/análise , RNA Mensageiro/metabolismo
3.
Plant Physiol ; 166(3): 1241-54, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25209985

RESUMO

Horseweed (Conyza canadensis), a member of the Compositae (Asteraceae) family, was the first broadleaf weed to evolve resistance to glyphosate. Horseweed, one of the most problematic weeds in the world, is a true diploid (2n = 2x = 18), with the smallest genome of any known agricultural weed (335 Mb). Thus, it is an appropriate candidate to help us understand the genetic and genomic bases of weediness. We undertook a draft de novo genome assembly of horseweed by combining data from multiple sequencing platforms (454 GS-FLX, Illumina HiSeq 2000, and PacBio RS) using various libraries with different insertion sizes (approximately 350 bp, 600 bp, 3 kb, and 10 kb) of a Tennessee-accessed, glyphosate-resistant horseweed biotype. From 116.3 Gb (approximately 350× coverage) of data, the genome was assembled into 13,966 scaffolds with 50% of the assembly = 33,561 bp. The assembly covered 92.3% of the genome, including the complete chloroplast genome (approximately 153 kb) and a nearly complete mitochondrial genome (approximately 450 kb in 120 scaffolds). The nuclear genome is composed of 44,592 protein-coding genes. Genome resequencing of seven additional horseweed biotypes was performed. These sequence data were assembled and used to analyze genome variation. Simple sequence repeat and single-nucleotide polymorphisms were surveyed. Genomic patterns were detected that associated with glyphosate-resistant or -susceptible biotypes. The draft genome will be useful to better understand weediness and the evolution of herbicide resistance and to devise new management strategies. The genome will also be useful as another reference genome in the Compositae. To our knowledge, this article represents the first published draft genome of an agricultural weed.


Assuntos
Conyza/genética , Genoma de Cloroplastos/genética , Genoma Mitocondrial/genética , Glicina/análogos & derivados , Resistência a Herbicidas , Herbicidas/farmacologia , Evolução Biológica , Conyza/efeitos dos fármacos , Genômica , Glicina/farmacologia , Sequenciamento de Nucleotídeos em Larga Escala , Anotação de Sequência Molecular , Filogenia , Análise de Sequência de DNA , Glifosato
4.
Nature ; 460(7258): 1011-5, 2009 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-19587683

RESUMO

Recent advances in sequencing technologies have initiated an era of personal genome sequences. To date, human genome sequences have been reported for individuals with ancestry in three distinct geographical regions: a Yoruba African, two individuals of northwest European origin, and a person from China. Here we provide a highly annotated, whole-genome sequence for a Korean individual, known as AK1. The genome of AK1 was determined by an exacting, combined approach that included whole-genome shotgun sequencing (27.8x coverage), targeted bacterial artificial chromosome sequencing, and high-resolution comparative genomic hybridization using custom microarrays featuring more than 24 million probes. Alignment to the NCBI reference, a composite of several ethnic clades, disclosed nearly 3.45 million single nucleotide polymorphisms (SNPs), including 10,162 non-synonymous SNPs, and 170,202 deletion or insertion polymorphisms (indels). SNP and indel densities were strongly correlated genome-wide. Applying very conservative criteria yielded highly reliable copy number variants for clinical considerations. Potential medical phenotypes were annotated for non-synonymous SNPs, coding domain indels, and structural variants. The integration of several human whole-genome sequences derived from several ethnic groups will assist in understanding genetic ancestry, migration patterns and population bottlenecks.


Assuntos
Povo Asiático/genética , Genoma Humano/genética , Cromossomos Artificiais Bacterianos/genética , Hibridização Genômica Comparativa , Biologia Computacional , Humanos , Mutação INDEL/genética , Coreia (Geográfico) , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único/genética , Análise de Sequência de DNA
5.
Genes Genomics ; 39(1): 111-119, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28090266

RESUMO

The Fabaceae (legume family) is the third largest and the second of agricultural importance among flowering plant groups. In this study, we report the reconstruction of a composite comparative map composed of ten legume genomes, including seven species from the galegoid clade (Medicago truncatula, Medicago sativa, Lens culinaris, Pisum sativum, Lotus japonicus, Cicer arietinum, Vicia faba) and three species from the phaseoloid clade (Vigna radiata, Phaseolus vulgaris, Glycine max). To accomplish this comparison, a total of 209 cross-species gene-derived markers were employed. The comparative analysis resulted in a single extensive genetic/genomic network composed of 93 chromosomes or linkage groups, from which 110 synteny blocks and other evolutionary events (e.g., 13 inversions) were identified. This comparative map also allowed us to deduce several large scale evolutionary events, such as chromosome fusion/fission, with which might explain differences in chromosome numbers among compared species or between the two clades. As a result, useful properties of cross-species genic markers were re-verified as an efficient tool for cross-species translation of genomic information, and similar approaches, combined with a high throughput bioinformatic marker design program, should be effective for applying the knowledge of trait-associated genes to other important crop species for breeding purposes. Here, we provide a basic comparative framework for the ten legume species, and expect to be usefully applied towards the crop improvement in legume breeding.

6.
DNA Res ; 24(1): 71-80, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-28011721

RESUMO

Hibiscus syriacus (L.) (rose of Sharon) is one of the most widespread garden shrubs in the world. We report a draft of the H. syriacus genome comprised of a 1.75 Gb assembly that covers 92% of the genome with only 1.7% (33 Mb) gap sequences. Predicted gene modeling detected 87,603 genes, mostly supported by deep RNA sequencing data. To define gene family distribution among relatives of H. syriacus, orthologous gene sets containing 164,660 genes in 21,472 clusters were identified by OrthoMCL analysis of five plant species, including H. syriacus, Arabidopsis thaliana, Gossypium raimondii, Theobroma cacao and Amborella trichopoda. We inferred their evolutionary relationships based on divergence times among Malvaceae plant genes and found that gene families involved in flowering regulation and disease resistance were more highly divergent and expanded in H. syriacus than in its close relatives, G. raimondii (DD) and T. cacao. Clustered gene families and gene collinearity analysis revealed that two recent rounds of whole-genome duplication were followed by diploidization of the H. syriacus genome after speciation. Copy number variation and phylogenetic divergence indicates that WGDs and subsequent diploidization led to unequal duplication and deletion of flowering-related genes in H. syriacus and may affect its unique floral morphology.


Assuntos
Flores/crescimento & desenvolvimento , Genoma de Planta , Hibiscus/genética , Poliploidia , Proteínas de Ligação a DNA/genética , Hibiscus/fisiologia , Família Multigênica , Proteínas de Ligação a RNA/genética , Transcriptoma
7.
Genome Biol ; 18(1): 210, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29089032

RESUMO

BACKGROUND: Transposable elements are major evolutionary forces which can cause new genome structure and species diversification. The role of transposable elements in the expansion of nucleotide-binding and leucine-rich-repeat proteins (NLRs), the major disease-resistance gene families, has been unexplored in plants. RESULTS: We report two high-quality de novo genomes (Capsicum baccatum and C. chinense) and an improved reference genome (C. annuum) for peppers. Dynamic genome rearrangements involving translocations among chromosomes 3, 5, and 9 were detected in comparison between C. baccatum and the two other peppers. The amplification of athila LTR-retrotransposons, members of the gypsy superfamily, led to genome expansion in C. baccatum. In-depth genome-wide comparison of genes and repeats unveiled that the copy numbers of NLRs were greatly increased by LTR-retrotransposon-mediated retroduplication. Moreover, retroduplicated NLRs are abundant across the angiosperms and, in most cases, are lineage-specific. CONCLUSIONS: Our study reveals that retroduplication has played key roles for the massive emergence of NLR genes including functional disease-resistance genes in pepper plants.


Assuntos
Capsicum/genética , Resistência à Doença/genética , Evolução Molecular , Duplicação Gênica , Genes de Plantas , Doenças das Plantas/genética , Doenças das Plantas/imunologia , Retroelementos/genética , Cromossomos de Plantas/genética , Especiação Genética , Anotação de Sequência Molecular , Família Multigênica , Proteínas NLR/genética , Fases de Leitura Aberta/genética , Filogenia , Padrões de Referência , Análise de Sequência de RNA , Especificidade da Espécie , Sequências Repetidas Terminais/genética
8.
Sci Transl Med ; 3(65): 65ra4, 2011 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-21228398

RESUMO

Of 7028 disorders with suspected Mendelian inheritance, 1139 are recessive and have an established molecular basis. Although individually uncommon, Mendelian diseases collectively account for ~20% of infant mortality and ~10% of pediatric hospitalizations. Preconception screening, together with genetic counseling of carriers, has resulted in remarkable declines in the incidence of several severe recessive diseases including Tay-Sachs disease and cystic fibrosis. However, extension of preconception screening to most severe disease genes has hitherto been impractical. Here, we report a preconception carrier screen for 448 severe recessive childhood diseases. Rather than costly, complete sequencing of the human genome, 7717 regions from 437 target genes were enriched by hybrid capture or microdroplet polymerase chain reaction, sequenced by next-generation sequencing (NGS) to a depth of up to 2.7 gigabases, and assessed with stringent bioinformatic filters. At a resultant 160x average target coverage, 93% of nucleotides had at least 20x coverage, and mutation detection/genotyping had ~95% sensitivity and ~100% specificity for substitution, insertion/deletion, splicing, and gross deletion mutations and single-nucleotide polymorphisms. In 104 unrelated DNA samples, the average genomic carrier burden for severe pediatric recessive mutations was 2.8 and ranged from 0 to 7. The distribution of mutations among sequenced samples appeared random. Twenty-seven percent of mutations cited in the literature were found to be common polymorphisms or misannotated, underscoring the need for better mutation databases as part of a comprehensive carrier testing strategy. Given the magnitude of carrier burden and the lower cost of testing compared to treating these conditions, carrier screening by NGS made available to the general population may be an economical way to reduce the incidence of and ameliorate suffering associated with severe recessive childhood disorders.


Assuntos
Genes Recessivos/genética , Triagem de Portadores Genéticos/métodos , Testes Genéticos/métodos , Análise de Sequência de DNA/métodos , Sequência de Bases , Criança , Bases de Dados Genéticas , Feminino , Testes Genéticos/economia , Genoma Humano , Heterozigoto , Humanos , Dados de Sequência Molecular , Mutação , Gravidez , Diagnóstico Pré-Natal , Alinhamento de Sequência , Análise de Sequência de DNA/economia
9.
Genome ; 51(10): 779-88, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18923529

RESUMO

Triticeae contains hundreds of species of both annual and perennial types. Although substantial genomic tools are available for annual Triticeae cereals such as wheat and barley, the perennial Triticeae lack sufficient genomic resources for genetic mapping or diversity research. To increase the amount of sequence information available in the perennial Triticeae, three expressed sequence tag (EST) libraries were developed and annotated for Pseudoroegneria spicata, a mixture of both Elymus wawawaiensis and E. lanceolatus, and a Leymus cinereus x L. triticoides interspecific hybrid. The ESTs were combined into unigene sets of 8 780 unigenes for P. spicata, 11 281 unigenes for Leymus, and 7 212 unigenes for Elymus. Unigenes were annotated based on putative orthology to genes from rice, wheat, barley, other Poaceae, Arabidopsis, and the non-redundant database of the NCBI. Simple sequence repeat (SSR) markers were developed, tested for amplification and polymorphism, and aligned to the rice genome. Leymus EST markers homologous to rice chromosome 2 genes were syntenous on Leymus homeologous groups 6a and 6b (previously 1b), demonstrating promise for in silico comparative mapping. All ESTs and SSR markers are available on an EST information management and annotation database (http://titan.biotec.uiuc.edu/triticeae/).


Assuntos
Bases de Dados Genéticas , Grão Comestível/genética , Etiquetas de Sequências Expressas , Repetições Minissatélites/genética , Mapeamento Cromossômico , Clonagem Molecular , Grão Comestível/classificação , Biblioteca Gênica , Genoma de Planta , Poaceae/classificação , Poaceae/genética
10.
PLoS One ; 3(11): e3625, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18985160

RESUMO

Schizophrenia (SCZ) is a common, disabling mental illness with high heritability but complex, poorly understood genetic etiology. As the first phase of a genomic convergence analysis of SCZ, we generated 16.7 billion nucleotides of short read, shotgun sequences of cDNA from post-mortem cerebellar cortices of 14 patients and six, matched controls. A rigorous analysis pipeline was developed for analysis of digital gene expression studies. Sequences aligned to approximately 33,200 transcripts in each sample, with average coverage of 450 reads per gene. Following adjustments for confounding clinical, sample and experimental sources of variation, 215 genes differed significantly in expression between cases and controls. Golgi apparatus, vesicular transport, membrane association, Zinc binding and regulation of transcription were over-represented among differentially expressed genes. Twenty three genes with altered expression and involvement in presynaptic vesicular transport, Golgi function and GABAergic neurotransmission define a unifying molecular hypothesis for dysfunction in cerebellar cortex in SCZ.


Assuntos
Cerebelo/patologia , Esquizofrenia/genética , Análise de Sequência de DNA/métodos , Vesículas Sinápticas/genética , Adulto , Idoso , Autopsia , Estudos de Casos e Controles , Cerebelo/metabolismo , Perfilação da Expressão Gênica , Genoma Humano , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/análise , RNA Mensageiro/metabolismo , Esquizofrenia/patologia , Vesículas Sinápticas/metabolismo
11.
J Gen Virol ; 87(Pt 9): 2699-2707, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16894211

RESUMO

A series of deletion mutants of tobacco mosaic virus movement protein (TMV-MP) was used to identify domains of the protein necessary for membrane association. A membrane fraction was isolated from tobacco BY-2 protoplasts infected with wild-type and mutant TMV that produce MP carrying a 3 aa deletion. Deletions that affected membrane association were clustered around the two major hydrophobic regions of MP that are predicted to be transmembrane. Deletions in other hydrophobic regions also reduced membrane association. In addition, a non-functional mutant of MP, in which one of the known phosphorylation sites was eliminated, was not associated with cellular membranes, while a functional second site revertant restored membrane association. This indicates that MP function requires interaction with membrane; however, membrane association was not sufficient for function. Results are consistent with the hypothesis that TMV-MP is an integral or tightly associated membrane protein that includes two hydrophobic transmembrane domains.


Assuntos
Vírus do Mosaico do Tabaco/fisiologia , Proteínas Virais/química , Proteínas Virais/fisiologia , Sequência de Aminoácidos , Sequência de Bases , Sítios de Ligação/genética , Membrana Celular/virologia , Células Cultivadas , DNA Viral/genética , Retículo Endoplasmático Rugoso/virologia , Interações Hidrofóbicas e Hidrofílicas , Dados de Sequência Molecular , Fosforilação , Proteínas do Movimento Viral em Plantas , Estrutura Terciária de Proteína , Protoplastos/virologia , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Deleção de Sequência , Nicotiana/virologia , Vírus do Mosaico do Tabaco/genética , Proteínas Virais/genética
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