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1.
Genet Sel Evol ; 51(1): 44, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31412777

RESUMO

BACKGROUND: Experimental intercrosses between outbred founder populations are powerful resources for mapping loci that contribute to complex traits i.e. quantitative trait loci (QTL). Here, we present an approach and its accompanying software for high-resolution reconstruction of founder mosaic genotypes in the intercross offspring from such populations using whole-genome high-coverage sequence data on founder individuals (~ 30×) and very low-coverage sequence data on intercross individuals (< 0.5×). Sets of founder-line informative markers were selected for each full-sib family and used to infer the founder mosaic genotypes of the intercross individuals. The application of this approach and the quality of the estimated genome-wide genotypes are illustrated in a large F2 pedigree between two divergently selected lines of chickens. RESULTS: We describe how we obtained whole-genome genotype data for hundreds of individuals in a cost- and time-efficient manner by using a Tn5-based library preparation protocol and an imputation algorithm that was optimized for this application. In total, 7.6 million markers segregated in this pedigree and, within each full-sib family, between 10.0 and 13.7% of these were fully informative, i.e. fixed for alternative alleles in the founders from the divergent lines, and were used for reconstruction of the offspring mosaic genotypes. The genotypes that were estimated based on the low-coverage sequence data were highly consistent (> 95% agreement) with those obtained using individual single nucleotide polymorphism (SNP) genotyping. The estimated resolution of the inferred recombination breakpoints was relatively high, with 50% of them being defined on regions shorter than 10 kb. CONCLUSIONS: A method and software for inferring founder mosaic genotypes in intercross offspring from low-coverage whole-genome sequencing in pedigrees from heterozygous founders are described. They provide high-quality, high-resolution genotypes in a time- and cost-efficient manner. The software is freely available at https://github.com/CarlborgGenomics/Stripes .


Assuntos
Galinhas/genética , Técnicas de Genotipagem , Sequenciamento Completo do Genoma , Animais , Cruzamento , Custos e Análise de Custo , Cruzamentos Genéticos , Conjuntos de Dados como Assunto , Feminino , Efeito Fundador , Técnicas de Genotipagem/economia , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único , Software , Sequenciamento Completo do Genoma/economia
2.
Clin Biochem ; 71: 31-37, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31199903

RESUMO

OBJECTIVE: The 3.7 kb deletion (-α3.7) is the most common form of α+-thalassemia found in multiple populations which can be classified into three subtypes. In order not to mis-identify it, the molecular information within each population is required. We have addressed this in northeast Thai and Laos populations. METHODS: Screening for α+-thalassemia was initially done on 1192 adult Thai subjects. In addition, 77 chromosomes of Thai newborns and 26 chromosomes of Laos with -α3.7 α+-thalassemia were also examined. All subjects were screened for -α3.7 α+-thalassemia and subtyped by PCR-RFLP assay. Exact deletion breakpoint of each -α3.7 subtype was determined by DNA sequencing. α-Globin gene haplotypes were determined. RESULTS: The proportions of -α3.7 subtypes found in 216 Thai -α3.7 chromosomes were 94.9% for -α3.7I, 4.2% for α3.7II and 0.9% for -α3.7III. All 26 Laos -α3.7 chromosomes were of -α3.7I variety. At least six α-globin gene haplotypes were associated with the -α3.7I α+-thalassemia. CONCLUSION: All -α3.7 subtypes were observed among Southeast Asian population. Haplotype analysis indicated a multiple origin of this common disorder in the region. A multiplex PCR assay has been developed for simultaneous detection of all subtypes of -α3.7 α+-thalassemia as well as other α+-thalassemia found in the region including -α4.2 α+-thalassemia, Hb Constant Spring and Hb Paksé.


Assuntos
Efeito Fundador , Haplótipos , Adulto , Ásia Sudeste , Técnicas de Laboratório Clínico , Feminino , Humanos , Masculino , Reação em Cadeia da Polimerase Multiplex , Talassemia alfa/genética
3.
J Genet ; 982019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30945685

RESUMO

Gitelman syndrome is an autosomal recessive salt-wasting tubulopathy caused by mutations in the SLC12A3 gene. A female and a male sibling from two unrelated Greek-Cypriot families presenting with a severe salt-wasting tubulopathy due to compound heterozygous mutations of a novel duplication and a previously reported missense mutation in the SLC12A gene are described. Sanger sequencing was used to identify possible mutations in the SLC12A3 gene. For the detection of duplications/conversions and deletions in the same gene, Multiplex ligation probe amplification (MLPA) analysis was performed. Direct sequencing and MLPA analysis of the SLC12A3 gene identified two compound heterozygous mutations in both unrelated probands. Both probands were identified to carry in compound heterozygosity the known p.Met581Lys and a novelheterozygous duplication of exons 9-14 (E9_E14dup). The diagnosis of Gitelman syndrome was made through clinical assessment, biochemical screening and genetic analysis. The identification of the novel SLC12A3 duplication seems to be characteristic of Greek-Cypriot patients and suggests a possible ancestral mutational event that has spread in Cyprus due to a possible founder effect. Testing for Gitelman syndrome probable variants can be performed before proceeding to a full gene sequencing dropping the diagnostic cost. In addition, this report adds to the mutational spectrum observed.


Assuntos
Efeito Fundador , Duplicação Gênica , Síndrome de Gitelman/genética , Heterozigoto , Criança , Pré-Escolar , Feminino , Testes Genéticos , Síndrome de Gitelman/patologia , Humanos , Masculino , Linhagem , Fenótipo , Prognóstico , Membro 3 da Família 12 de Carreador de Soluto/genética
4.
Bioengineered ; 10(1): 98-107, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31023186

RESUMO

Progranulin has multiple functions in several physiological and pathological processes, including embryonic development, wound repair, tumorigenesis, inflammation and neurodegeneration. To investigate the transcriptional regulation of the PGRN gene, a luciferase knock-in reporter system was established in HEK293 cells by integrating luciferase gene in the genome controlled by the endogenous PGRN promoter using CRISPR/Cas9. PCR results demonstrated the site-specific integration of the exogenous luciferase gene into the genome. To validate the novel luciferase knock-in system, a CRISPR/Cas9 transcription activation/repression system for the PGRN gene was constructed and applied to the knock-in system. In addition, phorbol ester (phorbol 12-myristate, 13-acetate), previously reported as activating the expression of PGRN, was applied to the system. The results indicated that luciferase activity was directly correlated with the activity of the PGRN endogenous promoter. This novel system will be a useful tool for investigating the transcriptional regulation of PGRN, and it has great potential in screening the drugs targeting PGRN.


Assuntos
Proteína 9 Associada à CRISPR/genética , Sistemas CRISPR-Cas , Efeito Fundador , Técnicas de Introdução de Genes/métodos , Luciferases/genética , Progranulinas/genética , Sequência de Bases , Proteína 9 Associada à CRISPR/metabolismo , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Edição de Genes , Regulação da Expressão Gênica/efeitos dos fármacos , Genes Reporter , Genoma Humano , Células HEK293 , Humanos , Luciferases/metabolismo , Progranulinas/agonistas , Progranulinas/metabolismo , Regiões Promotoras Genéticas/efeitos dos fármacos , Transdução de Sinais , Acetato de Tetradecanoilforbol/farmacologia , Transcrição Genética/efeitos dos fármacos
5.
Cell Mol Life Sci ; 76(20): 4155-4164, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31030226

RESUMO

Evolved xCas9(3.7) variant with broad PAM compatibility has been reported in cell lines, while its editing efficiency was site-specific. Here, we show that xCas9(3.7) can recognize a broad PAMs including NGG, NGA, and NGT, in both embryos and Founder (F0) rabbits. Furthermore, the codon-optimized xCas9-derived base editors, exBE4 and exABE, can dramatically improve the base editing efficiencies in rabbit embryos. Our results demonstrated that the optimized xCas9 with expanded PAM compatibility and enhanced base editing efficiency could be used for precise gene modifications in organisms.


Assuntos
Proteína 9 Associada à CRISPR/genética , Sistemas CRISPR-Cas , Efeito Fundador , Edição de Genes/métodos , Marcação de Genes/métodos , RNA Guia/genética , Animais , Animais Geneticamente Modificados , Proteína 9 Associada à CRISPR/metabolismo , Códon , Distrofina/genética , Distrofina/metabolismo , Embrião de Mamíferos , Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Microinjeções , Plasmídeos/química , Plasmídeos/metabolismo , Proteínas de Ligação a Poli(A)/genética , Proteínas de Ligação a Poli(A)/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismo , RNA Guia/metabolismo , Coelhos , Repetições de Trinucleotídeos , Zigoto
6.
PLoS Pathog ; 15(4): e1007701, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30934020

RESUMO

Knowledge of the within-host frequencies of resistance-associated amino acid variants (RAVs) is important to the identification of optimal drug combinations for the treatment of hepatitis C virus (HCV) infection. Multiple RAVs may exist in infected individuals, often below detection limits, at any resistance locus, defining the diversity of accessible resistance pathways. We developed a multiscale mathematical model to estimate the pre-treatment frequencies of the entire spectrum of mutants at chosen loci. Using a codon-level description of amino acids, we performed stochastic simulations of intracellular dynamics with every possible nucleotide variant as the infecting strain and estimated the relative infectivity of each variant and the resulting distribution of variants produced. We employed these quantities in a deterministic multi-strain model of extracellular dynamics and estimated mutant frequencies. Our predictions captured database frequencies of the RAV R155K, resistant to NS3/4A protease inhibitors, presenting a successful test of our formalism. We found that mutational pathway maps, interconnecting all viable mutants, and strong founder effects determined the mutant spectrum. The spectra were vastly different for HCV genotypes 1a and 1b, underlying their differential responses to drugs. Using a fitness landscape determined recently, we estimated that 13 amino acid variants, encoded by 44 codons, exist at the residue 93 of the NS5A protein, illustrating the massive diversity of accessible resistance pathways at specific loci. Accounting for this diversity, which our model enables, would help optimize drug combinations. Our model may be applied to describe the within-host evolution of other flaviviruses and inform vaccine design strategies.


Assuntos
Antivirais/farmacologia , Farmacorresistência Viral/genética , Efeito Fundador , Hepacivirus/genética , Hepatite C Crônica/genética , Mutação , Proteínas não Estruturais Virais/genética , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Humanos , Modelos Teóricos , Inibidores de Proteases/farmacologia
7.
Mol Vis ; 25: 155-164, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30820151

RESUMO

Purpose: To identify the genetic basis for retinitis pigmentosa (RP) in a cohort of Jewish patients from Caucasia. Methods: Patients underwent a detailed ophthalmic evaluation, including funduscopic examination, visual field testing, optical coherence tomography (OCT), and electrophysiological tests, electroretinography (ERG) and visual evoked potentials (VEP). Genetic analysis was performed with a combination of whole exome sequencing (WES) and Sanger sequencing. Bioinformatic analysis of the WES results was performed via a customized pipeline. Pathogenicity of the identified intronic variant was evaluated in silico using the web tool Human Splicing Finder, and in vitro, using a minigene-based splicing assay. Linkage disequilibrium (LD) analysis was used to demonstrate a founder effect, and the decay of LD over generations around the mutation in Caucasus Jewish chromosomes was modeled to estimate the age of the most recent common ancestor. Results: In eight patients with RP from six unrelated families, all of Caucasus Jewish ancestry, we identified a novel homozygous intronic variant, located at position -9 of PDE6B intron 15. The c.1921-9C>G variant was predicted to generate a novel acceptor splice site, nine bases upstream of the original splice site of intron 15. In vitro splicing assay demonstrated that this novel acceptor splice site is used instead of the wild-type site, leading to an 8-bp insertion into exon 16, which is predicted to cause a frameshift. The presence of a common ancestral haplotype in mutation-bearing chromosomes was compatible with a founder effect. Conclusions: The PDE6B c.1921-9C>G intronic mutation is a founder mutation that accounts for at least 40% (6/15 families) of autosomal recessive RP among Caucasus Jews. This result is highly important for molecular diagnosis, carrier screening, and genetic counseling in this population.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/genética , Mutação da Fase de Leitura , Judeus , Sítios de Splice de RNA , Retinite Pigmentosa/genética , Adulto , Idoso , Biologia Computacional , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/deficiência , Eletrorretinografia , Potenciais Evocados Visuais/fisiologia , Éxons , Feminino , Efeito Fundador , Expressão Gênica , Genes Recessivos , Homozigoto , Humanos , Íntrons , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Retina/diagnóstico por imagem , Retina/metabolismo , Retina/patologia , Retinite Pigmentosa/diagnóstico por imagem , Retinite Pigmentosa/etnologia , Retinite Pigmentosa/patologia , Sibéria/etnologia , Tomografia de Coerência Óptica , Sequenciamento Completo do Exoma
8.
Database (Oxford) ; 20192019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30759220

RESUMO

Next generation sequencing multi-gene panels have greatly improved the diagnostic yield and cost effectiveness of genetic testing and are rapidly being integrated into the clinic for hereditary cancer risk. With this technology comes a dramatic increase in the volume, type and complexity of data. This invaluable data though is too often buried or inaccessible to researchers, especially to those without strong analytical or programming skills. To effectively share comprehensive, integrated genotypic-phenotypic data, we built Color Data, a publicly available, cloud-based database that supports broad access and data literacy. The database is composed of 50 000 individuals who were sequenced for 30 genes associated with hereditary cancer risk and provides useful information on allele frequency and variant classification, as well as associated phenotypic information such as demographics and personal and family history. Our user-friendly interface allows researchers to easily execute their own queries with filtering, and the results of queries can be shared and/or downloaded. The rapid and broad dissemination of these research results will help increase the value of, and reduce the waste in, scientific resources and data. Furthermore, the database is able to quickly scale and support integration of additional genes and human hereditary conditions. We hope that this database will help researchers and scientists explore genotype-phenotype correlations in hereditary cancer, identify novel variants for functional analysis and enable data-driven drug discovery and development.


Assuntos
Bases de Dados Genéticas , Variação Genética , Adulto , Alelos , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Feminino , Efeito Fundador , Genótipo , Humanos , Judeus/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Ferramenta de Busca , Interface Usuário-Computador
10.
Genetics ; 211(4): 1155-1177, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30765420

RESUMO

To understand gene function, the cre/loxP conditional system is the most powerful available for temporal and spatial control of expression in mouse. However, the research community requires more cre recombinase expressing transgenic mouse strains (cre-drivers) that restrict expression to specific cell types. To address these problems, a high-throughput method for large-scale production that produces high-quality results is necessary. Further, endogenous promoters need to be chosen that drive cell type specific expression, or we need to further focus the expression by manipulating the promoter. Here we test the suitability of using knock-ins at the docking site 5' of Hprt for rapid development of numerous cre-driver strains focused on expression in adulthood, using an improved cre tamoxifen inducible allele (icre/ERT2), and testing a novel inducible-first, constitutive-ready allele (icre/f3/ERT2/f3). In addition, we test two types of promoters either to capture an endogenous expression pattern (MaxiPromoters), or to restrict expression further using minimal promoter element(s) designed for expression in restricted cell types (MiniPromoters). We provide new cre-driver mouse strains with applicability for brain and eye research. In addition, we demonstrate the feasibility and applicability of using the locus 5' of Hprt for the rapid generation of substantial numbers of cre-driver strains. We also provide a new inducible-first constitutive-ready allele to further speed cre-driver generation. Finally, all these strains are available to the research community through The Jackson Laboratory.


Assuntos
Encéfalo/metabolismo , Olho/metabolismo , Técnicas de Introdução de Genes/métodos , Camundongos Transgênicos/genética , Tamoxifeno/farmacologia , Ativação Transcricional/efeitos dos fármacos , Animais , Efeito Fundador , Hipoxantina Fosforribosiltransferase/genética , Hipoxantina Fosforribosiltransferase/metabolismo , Integrases/genética , Integrases/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Regiões Promotoras Genéticas
11.
G3 (Bethesda) ; 9(3): 889-899, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30718274

RESUMO

Pedigree-derived relationships for individuals from an intercross of several lines cannot easily account for the segregation variance that is mainly caused by loci with alternative alleles fixed in different lines. However, when all founders are genotyped for a large number of markers, such relationships can be derived for descendants as expected genomic relationships conditional on the observed founder allele frequencies. A tabular method was derived in detail for autosomes and the X-chromosome. As a case study, we analyzed litter size and body weights at three different ages in an advanced mouse intercross (29 generations, total pedigree size 19,266) between a line selected for high litter size (FL1) and a highly inbred control line (DUKsi). Approximately 60% of the total genetic variance was due to segregation variance. Estimated heritability values were 0.20 (0.03), 0.34 (0.04), 0.23 (0.03), 0.41 (0.03) and 0.47 (0.02) for litter size, litter weight and body weight at ages of 21, 42 and 63 days, respectively (standard errors in brackets). These values were between 12% and 65% higher than observed in analyses that treated founders as unrelated. Fields of applications include experimental populations (selection experiments or advanced intercross lines) with a limited number of founders, which can be genotyped at a reasonable cost. In principle any number of founder lines can be treated. Additional genotypes from individuals in later generations can be combined into a joint relationship matrix by capitalizing on previously published approaches.


Assuntos
Peso Corporal/genética , Cruzamentos Genéticos , Efeito Fundador , Frequência do Gene , Tamanho da Ninhada de Vivíparos/genética , Animais , Feminino , Genética Populacional , Masculino , Camundongos , Linhagem , Polimorfismo de Nucleotídeo Único
12.
J Assist Reprod Genet ; 36(4): 727-739, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30617673

RESUMO

PURPOSE: Pre-implantation genetic diagnosis (PGD) for molecular disorders requires the construction of parental haplotypes. Classically, haplotype resolution ("phasing") is obtained by genotyping multiple polymorphic markers in both parents and at least one additional relative. However, this process is time-consuming, and immediate family members are not always available. The recent availability of massive genomic data for many populations promises to eliminate the needs for developing family-specific assays and for recruiting additional family members. In this study, we aimed to validate population-assisted haplotype phasing for PGD. METHODS: Targeted sequencing of CFTR gene variants and ~ 1700 flanking polymorphic SNPs (± 2 Mb) was performed on 54 individuals from 12 PGD families of (a) Full Ashkenazi (FA; n = 16), (b) mixed Ashkenazi (MA; n = 23 individuals with at least one Ashkenazi and one non-Ashkenazi grandparents), or (c) non-Ashkenazi (NA; n = 15) descent. Heterozygous genotype calls in each individual were phased using various whole genome reference panels and appropriate computational models. All computationally derived haplotype predictions were benchmarked against trio-based phasing. RESULTS: Using the Ashkenazi reference panel, phasing of FA was highly accurate (99.4% ± 0.2% accuracy); phasing of MA was less accurate (95.4% ± 4.5% accuracy); and phasing of NA was predictably low (83.4% ± 6.6% accuracy). Strikingly, for founder mutation carriers, our haplotyping approach facilitated near perfect phasing accuracy (99.9% ± 0.1% and 98.2% ± 2.8% accuracy for W1282X and delF508 carriers, respectively). CONCLUSIONS: Our results demonstrate the feasibility of replacing classical haplotype phasing with population-based phasing with uncompromised accuracy.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Genótipo , Haplótipos/genética , Diagnóstico Pré-Implantação , Algoritmos , Alelos , Feminino , Efeito Fundador , Heterozigoto , Humanos , Judeus/genética , Polimorfismo de Nucleotídeo Único/genética , Análise de Sequência de DNA
13.
J Immunol ; 202(3): 777-786, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30587532

RESUMO

Variations in the proportion and number of specific immune cell types among healthy individuals are influenced by both heritable and nonheritable factors. Mouse models, subjected to fewer nonheritable factors than humans, allow the identification of genetic factors that shape the immune system. We characterized immunological trait variability in the Collaborative Cross (CC), a powerful genetic resource of recombinant inbred mouse strains derived from eight diverse founder strains. Of the 18 immunological traits studied in more than 60 CC strains, eight showed genome-wide significant linkage, revealing new genetic loci linked to specific immune traits. We also found that these traits were highly subject to heritable influences. As for humans, mouse immunological traits varied as a continuum rather than as discrete immunophenotypes. The CC thus represents a useful resource to identify factors that determine immunological variations, as well as defining other immune traits likely to be heritable in humans.


Assuntos
Ligação Genética , Variação Genética/imunologia , Imunofenotipagem , Camundongos Endogâmicos/genética , Camundongos Endogâmicos/imunologia , Animais , Mapeamento Cromossômico , Análise por Conglomerados , Cruzamentos Genéticos , Feminino , Efeito Fundador , Haplótipos , Masculino , Camundongos , Fenótipo
14.
Clin. biomed. res ; 39(2): 107-115, 2019.
Artigo em Português | LILACS | ID: biblio-1022678

RESUMO

Cândido Godói (CG) é um pequeno município brasileiro localizado no noroeste do Rio Grande do Sul e é conhecido como "Cidade dos Gêmeos" devido à alta taxa de nascimentos gemelares na região. Diante de um fato tão notável, muitas explicações foram sugeridas. Entre estas teorias, a que mais recebeu atenção da mídia, mesmo sem base científica, foi a de que a gemelaridade seria fruto de experimentos de um médico nazista alemão foragido após a Segunda Guerra Mundial. A convite da própria comunidade de CG, nosso grupo de pesquisa trabalha para resolver este mistério desde 1994, analisando diferentes fatores possivelmente relacionados, em especial suas características genéticas. Aqui, nós sumarizamos os principais resultados obtidos em mais de duas décadas de pesquisa, com foco nas particularidades do processo de comunicação dos resultados, aspectos éticos e como os achados científicos naquela comunidade contribuem não apenas com a resolução de um mistério histórico e local, mas também com o estudo de outras questões, como a reprodução humana e as bases biológicas da gemelaridade. (AU)


Cândido Godói (CG) is a small town located in the northwest region of Rio Grande do Sul state which is known as "Town of Twins" because of the high rate of twin births. Many explanations have been suggested for such a noteworthy fact. The theory that has received most attention from the press, despite a lack of scientific evidence, was that twinning would result from experiments conducted by a Nazi German physician who had been a fugitive after World War II. Invited by the local community, our research team has been dedicated to solving this mystery since 1994 by analyzing different possibly related factors, especially genetic characteristics. In this paper, we summarize the main results obtained in more than two decades of research, focusing on the particular communication process of the results, ethical aspects, and how the scientific findings in that community have contributed not only to the resolution of a historical and localized mystery, but also with the study of other issues such as human reproduction and biological basis of the twinning process. (AU)


Assuntos
Humanos , Gêmeos , Isolamento Reprodutivo , Genética Populacional , Efeito Fundador , Fertilidade
15.
Cancer Genet ; 228-229: 93-97, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30553478

RESUMO

Portuguese immigration to Brazil occurred in several waves and greatly contributed to the genetic composition of current Brazilian population. In this study, we evaluated the frequency of a Portuguese founder Alu insertion in BRCA2 exon 3 (c.156_157insAlu) among individuals fulfilling Hereditary Breast and Ovarian Cancer (HBOC) syndrome criteria in 1,380 unrelated families originated from three distinct Brazilian States. We identified the c.156_157insAlu BRCA2 mutation in nine (9/1,380; 0.65%) probands analised. In carrier probands, European ancestry had the highest proportion (80%), followed by the African (10%) and Amerindian and in most families with the rearrangement, haplotype analyses were compatible with the Portuguese ancestral haplotype. In conclusion, the present study reports a low albeit relevant frequency of the Portuguese BRCA2 founder mutation c.156_157insAlu in Brazilian patients at-risk for HBOC Brazilian population.


Assuntos
Genes BRCA2 , Testes Genéticos , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Grupo com Ancestrais do Continente Asiático/genética , Brasil , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Efeito Fundador , Triagem de Portadores Genéticos , Haplótipos , Humanos , Mutação INDEL
16.
Nat Commun ; 9(1): 5433, 2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30575759

RESUMO

Tibetan barley (Hordeum vulgare L., qingke) is the principal cereal cultivated on the Tibetan Plateau for at least 3,500 years, but its origin and domestication remain unclear. Here, based on deep-coverage whole-genome and published exome-capture resequencing data for a total of 437 accessions, we show that contemporary qingke is derived from eastern domesticated barley and it is introduced to southern Tibet most likely via north Pakistan, India, and Nepal between 4,500 and 3,500 years ago. The low genetic diversity of qingke suggests Tibet can be excluded as a center of origin or domestication for barley. The rapid decrease in genetic diversity from eastern domesticated barley to qingke can be explained by a founder effect from 4,500 to 2,000 years ago. The haplotypes of the five key domestication genes of barley support a feral or hybridization origin for Tibetan weedy barley and reject the hypothesis of native Tibetan wild barley.


Assuntos
Domesticação , Efeito Fundador , Genoma de Planta , Hordeum/genética , Filogeografia , Tibet
17.
Proc Natl Acad Sci U S A ; 115(34): E8007-E8016, 2018 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-30072435

RESUMO

Isolated congenital asplenia (ICA) is the only known human developmental defect exclusively affecting a lymphoid organ. In 2013, we showed that private deleterious mutations in the protein-coding region of RPSA, encoding ribosomal protein SA, caused ICA by haploinsufficiency with complete penetrance. We reported seven heterozygous protein-coding mutations in 8 of the 23 kindreds studied, including 6 of the 8 multiplex kindreds. We have since enrolled 33 new kindreds, 5 of which are multiplex. We describe here 11 new heterozygous ICA-causing RPSA protein-coding mutations, and the first two mutations in the 5'-UTR of this gene, which disrupt mRNA splicing. Overall, 40 of the 73 ICA patients (55%) and 23 of the 56 kindreds (41%) carry mutations located in translated or untranslated exons of RPSA. Eleven of the 43 kindreds affected by sporadic disease (26%) carry RPSA mutations, whereas 12 of the 13 multiplex kindreds (92%) carry RPSA mutations. We also report that 6 of 18 (33%) protein-coding mutations and the two (100%) 5'-UTR mutations display incomplete penetrance. Three mutations were identified in two independent kindreds, due to a hotspot or a founder effect. Finally, RPSA ICA-causing mutations were demonstrated to be de novo in 7 of the 23 probands. Mutations in RPSA exons can affect the translated or untranslated regions and can underlie ICA with complete or incomplete penetrance.


Assuntos
Éxons , Síndromes de Imunodeficiência/genética , Mutação , Penetrância , Biossíntese de Proteínas/genética , Processamento de RNA/genética , Receptores de Laminina/genética , Proteínas Ribossômicas/genética , Baço/anormalidades , Regiões 5' não Traduzidas , Feminino , Efeito Fundador , Heterozigoto , Humanos , Síndromes de Imunodeficiência/metabolismo , Masculino , Receptores de Laminina/biossíntese , Proteínas Ribossômicas/biossíntese , Baço/metabolismo
18.
Mol Vis ; 24: 471-477, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30078984

RESUMO

Purpose: To identify disease-causing gene mutations in 21 northern Chinese families with congenital cataracts. Methods: Medical record collection and ophthalmologic examinations were conducted for 21 families with congenital cataracts. A volume of 5 ml of peripheral blood was drawn from each participant for genomic DNA isolation. Thirty-four known candidate genes for congenital cataracts were analyzed in the probands of 21 families with targeted next-generation sequencing (NGS). Bioinformatics analysis of the sequence variants was performed through computational predictive programs. Sanger sequencing was used to perform the cosegregation analysis. Genotyping and haplotype analyses were performed in two patients with a p.V44M mutation in the GJA8 gene. Results: Twelve disease-causing mutations were detected in 13 of the 21 patients, and the mutation detection rate was 61.9%. The 12 gene mutations included one nonsense, one splice site, seven missense, and three insert and deletion (INDELs) mutations. Four mutations were novel. Of the 13 patients with pathogenic gene mutations, five (38.5%) were affected by mutations in lens crystallin genes, three (23%) were affected by mutations in connexin genes, three (23%) were affected by mutations in transcription factor genes, one (7.7%) was affected by a mutation in a transmembrane transporter gene, and one (7.7%) was affected by a mutation in a chromatin-modifying protein gene. Two families carried the p.V44M mutation in the GJA8 gene. Haplotype analysis revealed a chromosome region of 475 kb containing the mutation in the GJA8 gene was harbored by two families. Conclusions: Compared with traditional Sanger sequencing, targeted NGS for genetic testing of congenital cataracts markedly increases the mutation detection rate and is cost-effective. The p.V44M mutation in the GJA8 gene was the most common mutation and was due to a founder effect within the Chinese cohort studied. The results of this study expand the gene mutation spectrum of congenital cataracts.


Assuntos
Aquaporinas/genética , Catarata/genética , Conexinas/genética , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Proteínas do Olho/genética , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição de Choque Térmico/genética , Mutação , Adolescente , Adulto , Grupo com Ancestrais do Continente Asiático , Catarata/congênito , Catarata/etnologia , Catarata/patologia , Criança , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , Família , Feminino , Efeito Fundador , Expressão Gênica , Haplótipos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cristalino/metabolismo , Cristalino/patologia , Masculino , Pessoa de Meia-Idade , Linhagem
19.
Genet Sel Evol ; 50(1): 39, 2018 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-30075705

RESUMO

BACKGROUND: A common measure employed to evaluate the efficacy of livestock improvement schemes is the genetic trend, which is calculated as the means of predicted breeding values for animals born in successive time periods. This implies that different cohorts refer to the same base population. For genetic evaluation schemes integrating genomic information with records for all animals, genotyped or not, this is often not the case: expected means for pedigree founders are zero whereas values for genotyped animals are expected to sum to zero at the (mean) time corresponding to the frequencies that are used to center marker allele counts when calculating genomic relationships. METHODS: The paper examines estimates of genetic trends from single-step genomic evaluations. After a review of methods which propose to align pedigree-based and genomic relationship matrices, simulation is used to illustrate the effects of alignments and choice of assumed gene frequencies on trajectories of genetic trends. RESULTS: The results show that methods available to alleviate differences between the founder populations implied by the two types of relationship matrices perform well; in particular, the meta-founder approach is advantageous. An application to data from routine genetic evaluation of Australian sheep is shown, confirming their effectiveness for practical data. CONCLUSIONS: Aligning pedigree and genomic relationship matrices for single step genetic evaluation for populations under selection is essential. Fitting meta-founders is an effective and simple method to avoid distortion of estimates of genetic trends.


Assuntos
Genômica/métodos , Técnicas de Genotipagem/veterinária , Ovinos/genética , Algoritmos , Animais , Cruzamento , Efeito Fundador , Frequência do Gene , Genética Populacional , Linhagem , Polimorfismo de Nucleotídeo Único , Seleção Genética
20.
PLoS One ; 13(6): e0197784, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29864145

RESUMO

Berardinelli-Seip Congenital Lipodystrophy (BSCL) is a rare autosomal recessive disease characterized by the almost complete absence of adipose tissue. Due to a strong founder effect that resulted in a higher prevalence of BSCL in Rio Grande do Norte (RN), a state in northeastern Brazil, it has been essential that health professionals develop knowledge about this disease. Nurses are often the first point of contact with patients during health care assistance. The purpose of this study was to investigate the knowledge of these professionals about BSCL in two main hospitals in RN state. A questionnaire was applied to 199 nurses working in the Hospital Regional Mariano Coelho-HRMC (Regional Hospital Mariano Coelho), in Currais Novos-RN, and in the Hospital Universitário Onofre Lopes-HUOL (University Hospital Onofre Lopes), in Natal-RN. This study showed that most nursing professionals do not know about the disease, although they have already received patients with BSCL in those hospitals. The nurses from HRMC and HUOL lacked knowledge of BSCL and the healthcare of these patients requires immediate improvement. Significant efforts are required to close the gap between current and needed practice patterns.


Assuntos
Tecido Adiposo/fisiopatologia , Lipodistrofia Generalizada Congênita/epidemiologia , Lipodistrofia Generalizada Congênita/genética , Enfermeiras e Enfermeiros , Adulto , Brasil/epidemiologia , Educação em Enfermagem , Feminino , Efeito Fundador , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Lipodistrofia Generalizada Congênita/fisiopatologia , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários
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