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1.
Nat Commun ; 12(1): 1050, 2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33594080

RESUMO

Attributing the similarity between individuals to genetic and non-genetic factors is central to genetic analyses. In this paper we use the genomic relationship ([Formula: see text]) among 417,060 individuals to investigate the phenotypic covariance between pairs of individuals for 32 traits across the spectrum of relatedness, from unrelated pairs through to identical twins. We find linear relationships between phenotypic covariance and [Formula: see text] that agree with the SNP-based heritability ([Formula: see text]) in unrelated pairs ([Formula: see text]), and with pedigree-estimated heritability in close relatives ([Formula: see text]). The covariance increases faster than [Formula: see text] in distant relatives ([Formula: see text]), and we attribute this to imperfect linkage disequilibrium between causal variants and the common variants used to construct [Formula: see text]. We also examine the effect of assortative mating on heritability estimates from different experimental designs. We find that full-sib identity-by-descent regression estimates for height (0.66 s.e. 0.07) are consistent with estimates from close relatives (0.82 s.e. 0.04) after accounting for the effect of assortative mating.


Assuntos
Genoma Humano , Filogenia , Adulto , Idoso , Bancos de Espécimes Biológicos , Índice de Massa Corporal , Escolaridade , Humanos , Padrões de Herança/genética , Desequilíbrio de Ligação , Pessoa de Meia-Idade , Modelos Genéticos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Característica Quantitativa Herdável , Análise de Regressão , Reino Unido
2.
Nat Commun ; 12(1): 730, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33526789

RESUMO

Thousands of genomic structural variants (SVs) segregate in the human population and can impact phenotypic traits and diseases. Their identification in whole-genome sequence data of large cohorts is a major computational challenge. Most current approaches identify SVs in single genomes and afterwards merge the identified variants into a joint call set across many genomes. We describe the approach PopDel, which directly identifies deletions of about 500 to at least 10,000 bp in length in data of many genomes jointly, eliminating the need for subsequent variant merging. PopDel scales to tens of thousands of genomes as we demonstrate in evaluations on up to 49,962 genomes. We show that PopDel reliably reports common, rare and de novo deletions. On genomes with available high-confidence reference call sets PopDel shows excellent recall and precision. Genotype inheritance patterns in up to 6794 trios indicate that genotypes predicted by PopDel are more reliable than those of previous SV callers. Furthermore, PopDel's running time is competitive with the fastest tested previous tools. The demonstrated scalability and accuracy of PopDel enables routine scans for deletions in large-scale sequencing studies.


Assuntos
Genoma Humano/genética , Variação Estrutural do Genoma , Metagenômica/métodos , Deleção de Sequência , Estudos de Viabilidade , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Padrões de Herança , Masculino , Reprodutibilidade dos Testes , Análise de Sequência de DNA
3.
Nat Commun ; 12(1): 627, 2021 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-33504798

RESUMO

Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders.


Assuntos
Deficiências do Desenvolvimento/genética , Genes Ligados ao Cromossomo X , Doenças Genéticas Ligadas ao Cromossomo X/genética , Variação Genética , Cromossomos Humanos X/genética , Feminino , Genes Recessivos , Humanos , Padrões de Herança/genética , Masculino , Herança Multifatorial/genética , Mutação/genética , Fenótipo , Caracteres Sexuais
4.
Mol Genet Genomics ; 296(2): 331-339, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33404883

RESUMO

Allelic transmission ratio distortion (TRD) is the significant deviation from the expected ratio under Mendelian inheritance theory, which may be resulted from multiple disrupted biological processes, including germline selection, meiotic drive, gametic competition, imprint error, and embryo lethality. However, it is less known that whether or what extent the allelic TRD is present in farm animals. In this study, whole-genome resequencing technology was applied to reveal TRD loci in chicken by constructing a full-sib F1 hybrid population. Through the whole-genome resequencing data of two parents (30 ×) and 38 offspring (5 ×), we detected a total of 2850 TRD SNPs (p-adj < 0.05) located within 400 genes showing TRD, and all of them were unevenly distributed on macrochromosomes and microchromosomes. Our findings suggested that TRD in the chicken chromosome 16 might play an important role in chicken immunity and disease resistance and the MYH1F with significant TRD and allele-specific expression could play a key role in the fast muscle development. In addition, functional enrichment analyses revealed that many genes (e.g., TGFBR2, TGFBR3, NOTCH1, and NCOA1) with TRD were found in the significantly enriched biological process and InterPro terms in relation to embryonic lethality and germline selection. Our results suggested that TRD is considerably prevalent in the chicken genome and has functional implications.


Assuntos
Galinhas/genética , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Genoma/veterinária , Animais , Galinhas/imunologia , Mapeamento Cromossômico , Resistência à Doença , Feminino , Genética Populacional , Genótipo , Padrões de Herança , Masculino
5.
Nat Commun ; 11(1): 5562, 2020 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-33144568

RESUMO

Cigarette smoking is the leading cause of preventable morbidity and mortality. Genetic variation contributes to initiation, regular smoking, nicotine dependence, and cessation. We present a Fagerström Test for Nicotine Dependence (FTND)-based genome-wide association study in 58,000 European or African ancestry smokers. We observe five genome-wide significant loci, including previously unreported loci MAGI2/GNAI1 (rs2714700) and TENM2 (rs1862416), and extend loci reported for other smoking traits to nicotine dependence. Using the heaviness of smoking index from UK Biobank (N = 33,791), rs2714700 is consistently associated; rs1862416 is not associated, likely reflecting nicotine dependence features not captured by the heaviness of smoking index. Both variants influence nearby gene expression (rs2714700/MAGI2-AS3 in hippocampus; rs1862416/TENM2 in lung), and expression of genes spanning nicotine dependence-associated variants is enriched in cerebellum. Nicotine dependence (SNP-based heritability = 8.6%) is genetically correlated with 18 other smoking traits (rg = 0.40-1.09) and co-morbidities. Our results highlight nicotine dependence-specific loci, emphasizing the FTND as a composite phenotype that expands genetic knowledge of smoking.


Assuntos
Predisposição Genética para Doença , Característica Quantitativa Herdável , Tabagismo/genética , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Padrões de Herança/genética , Desequilíbrio de Ligação/genética , Metanálise como Assunto , Anotação de Sequência Molecular , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
6.
Nat Commun ; 11(1): 5553, 2020 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-33144570

RESUMO

Cas9/gRNA-mediated gene-drive systems have advanced development of genetic technologies for controlling vector-borne pathogen transmission. These technologies include population suppression approaches, genetic analogs of insecticidal techniques that reduce the number of insect vectors, and population modification (replacement/alteration) approaches, which interfere with competence to transmit pathogens. Here, we develop a recoded gene-drive rescue system for population modification of the malaria vector, Anopheles stephensi, that relieves the load in females caused by integration of the drive into the kynurenine hydroxylase gene by rescuing its function. Non-functional resistant alleles are eliminated via a dominantly-acting maternal effect combined with slower-acting standard negative selection, and rare functional resistant alleles do not prevent drive invasion. Small cage trials show that single releases of gene-drive males robustly result in efficient population modification with ≥95% of mosquitoes carrying the drive within 5-11 generations over a range of initial release ratios.


Assuntos
Anopheles/genética , Malária/parasitologia , Alelos , Animais , Proteína 9 Associada à CRISPR/metabolismo , Feminino , Genética Populacional , Proteínas de Fluorescência Verde/metabolismo , Heterozigoto , Padrões de Herança/genética , Quinurenina 3-Mono-Oxigenase/genética , Masculino , Modelos Genéticos , Mosaicismo , Fenótipo , Filogenia , RNA Guia/metabolismo
7.
Med Sci (Paris) ; 36(10): 945-948, 2020 Oct.
Artigo em Francês | MEDLINE | ID: mdl-33026341

RESUMO

More than 10 million enslaved Africans were transported to the Americas between 1500 and 1900. Recent genetic studies investigate regional African ancestry components in present-day Africa-Americans, and allow comparison with the extensive records documenting these deportations. The genetic evidence generally agrees with the historical records but brings additional insights in this dark episode of human history.


Assuntos
Afro-Americanos/genética , Pessoas Escravizadas , Escravização/história , Genética Populacional , África , Oceano Atlântico , Comércio/história , DNA Mitocondrial/análise , DNA Mitocondrial/genética , Pessoas Escravizadas/história , Fluxo Gênico/fisiologia , Variação Genética , História do Século XVI , História do Século XVII , História do Século XVIII , História do Século XIX , Humanos , Padrões de Herança/genética , Estados Unidos
8.
Am J Hum Genet ; 107(4): 622-635, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32946763

RESUMO

Quantifying the functional effects of complex disease risk variants can provide insights into mechanisms underlying disease biology. Genome-wide association studies have identified 39 regions associated with risk of epithelial ovarian cancer (EOC). The vast majority of these variants lie in the non-coding genome, where they likely function through interaction with gene regulatory elements. In this study we first estimated the heritability explained by known common low penetrance risk alleles for EOC. The narrow sense heritability (hg2) of EOC overall and high-grade serous ovarian cancer (HGSOCs) were estimated to be 5%-6%. Partitioned SNP heritability across broad functional categories indicated a significant contribution of regulatory elements to EOC heritability. We collated epigenomic profiling data for 77 cell and tissue types from Roadmap Epigenomics and ENCODE, and from H3K27Ac ChIP-seq data generated in 26 ovarian cancer and precursor-related cell and tissue types. We identified significant enrichment of risk single-nucleotide polymorphisms (SNPs) in active regulatory elements marked by H3K27Ac in HGSOCs. To further investigate how risk SNPs in active regulatory elements influence predisposition to ovarian cancer, we used motifbreakR to predict the disruption of transcription factor binding sites. We identified 469 candidate causal risk variants in H3K27Ac peaks that are predicted to significantly break transcription factor (TF) motifs. The most frequently broken motif was REST (p value = 0.0028), which has been reported as both a tumor suppressor and an oncogene. Overall, these systematic functional annotations with epigenomic data improve interpretation of EOC risk variants and shed light on likely cells of origin.


Assuntos
Carcinoma Epitelial do Ovário/genética , Proteínas Correpressoras/genética , Cistadenocarcinoma Seroso/genética , Elementos Facilitadores Genéticos , Histonas/genética , Proteínas do Tecido Nervoso/genética , Neoplasias Ovarianas/genética , Alelos , Sítios de Ligação , Carcinoma Epitelial do Ovário/diagnóstico , Carcinoma Epitelial do Ovário/patologia , Mapeamento Cromossômico , Proteínas Correpressoras/metabolismo , Cistadenocarcinoma Seroso/diagnóstico , Cistadenocarcinoma Seroso/patologia , Feminino , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Histonas/metabolismo , Humanos , Padrões de Herança , Proteínas do Tecido Nervoso/metabolismo , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/patologia , Penetrância , Polimorfismo de Nucleotídeo Único , Risco
9.
Mol Cell ; 80(2): 246-262.e4, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32949493

RESUMO

CRISPR-Cas9-based gene drive systems possess the inherent capacity to spread progressively throughout target populations. Here we describe two self-copying (or active) guide RNA-only genetic elements, called e-CHACRs and ERACRs. These elements use Cas9 produced in trans by a gene drive either to inactivate the cas9 transgene (e-CHACRs) or to delete and replace the gene drive (ERACRs). e-CHACRs can be inserted at various genomic locations and carry two or more gRNAs, the first copying the e-CHACR and the second mutating and inactivating the cas9 transgene. Alternatively, ERACRs are inserted at the same genomic location as a gene drive, carrying two gRNAs that cut on either side of the gene drive to excise it. e-CHACRs efficiently inactivate Cas9 and can drive to completion in cage experiments. Similarly, ERACRs, particularly those carrying a recoded cDNA-restoring endogenous gene activity, can drive reliably to fully replace a gene drive. We compare the strengths of these two systems.


Assuntos
Deleção de Genes , Tecnologia de Impulso Genético , Animais , Proteína 9 Associada à CRISPR/metabolismo , Cromossomos/genética , Drosophila melanogaster/genética , Feminino , Proteínas de Fluorescência Verde/metabolismo , Padrões de Herança/genética , Mutagênese/genética , RNA Guia/genética , Transgenes
10.
PLoS Biol ; 18(8): e3000792, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32745129

RESUMO

A ubiquitous feature of the circadian clock across life forms is its organization as a network of cellular oscillators, with individual cellular oscillators within the network often exhibiting considerable heterogeneity in their intrinsic periods. The interaction of coupling and heterogeneity in circadian clock networks is hypothesized to influence clock's entrainability, but our knowledge of mechanisms governing period heterogeneity within circadian clock networks remains largely elusive. In this study, we aimed to explore the principles that underlie intercellular period variation in circadian clock networks (clonal period heterogeneity). To this end, we employed a laboratory selection approach and derived a panel of 25 clonal cell populations exhibiting circadian periods ranging from 22 to 28 h. We report that a single parent clone can produce progeny clones with a wide distribution of circadian periods, and this heterogeneity, in addition to being stochastically driven, has a heritable component. By quantifying the expression of 20 circadian clock and clock-associated genes across our clone panel, we found that inheritance of expression patterns in at least three clock genes might govern clonal period heterogeneity in circadian clock networks. Furthermore, we provide evidence suggesting that heritable epigenetic variation in gene expression regulation might underlie period heterogeneity.


Assuntos
Proteínas CLOCK/genética , Relógios Circadianos/genética , Ritmo Circadiano/genética , Epigênese Genética , Redes Reguladoras de Genes , Animais , Proteínas CLOCK/metabolismo , Linhagem Celular Tumoral , Células Clonais , Perfilação da Expressão Gênica , Genes Reporter , Heterogeneidade Genética , Humanos , Padrões de Herança , Luciferases/genética , Luciferases/metabolismo , Camundongos , Células NIH 3T3 , Osteoblastos/citologia , Osteoblastos/metabolismo , Processos Estocásticos
11.
PLoS One ; 15(8): e0237834, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32853269

RESUMO

Water deficit is one of the major limitations to food production worldwide and most climate change scenarios predict an aggravation of the situation. To face the expected increase in drought stress in the coming years, breeders are working to elucidate the genetic control of barley growth and productivity traits under water deficit. Barley is known as a relatively drought tolerant crop and genetic variability was observed for drought tolerance traits. The objectives of the present study were the quantification of morphological and physiological responses in a collection of 209 spring barley genotypes to drought stress, and the genetic analysis by genome-wide association study to find quantitative trait loci (QTL) and the allele contributions for each of the investigated traits. In six pot experiments, 209 spring barley genotypes were grown under a well-watered and water-limited regime. Stress phases were initiated individually for each genotype at the beginning of tillering and spiking for the vegetative- and the generative stage experiments, respectively, and terminated when the transpiration rates of stress treatments reached 10% of the well-watered control. After the stress phase, a total of 42 productivity related traits such as the dry matter of plant organs, tiller number, leaf length, leaf area, amount of water soluble carbohydrates in the stems, proline content in leaves and osmotic adjustment of corresponding well-watered and stressed plants were analysed, and QTL analyses were performed to find marker-trait associations. Significant water deficit effects were observed for almost all traits and significant genotype x treatment interactions (GxT) were observed for 37 phenotypic traits. Genome-wide association studies (GWAS) revealed 77 significant loci associated with 16 phenotypic traits during the vegetative stage experiment and a total of 85 significant loci associated with 13 phenotypic traits during the generative stage experiment for traits such as leaf area, number of green leaves, grain yield, harvest index and stem length. For traits with significant GxT interactions, genotypic differences for relative values were analysed using one way ANOVA. More than 110 loci for GxT interaction were found for 17 phenotypic traits explaining in many cases more than 50% of the genetic variance.


Assuntos
Hordeum/genética , Hordeum/fisiologia , Locos de Características Quantitativas/genética , Estações do Ano , Água , Adaptação Fisiológica , Análise de Variância , Biomassa , Desidratação , Secas , Variação Genética , Genótipo , Hordeum/anatomia & histologia , Padrões de Herança/genética , Fenótipo , Análise de Regressão
13.
Med Sci (Paris) ; 36(8-9): 813-816, 2020.
Artigo em Francês | MEDLINE | ID: mdl-32821057

RESUMO

The prediction of a person's aspect from analysis of an anonymous DNA sample has made significant progress in the last decade. Pigmentation (eyes, hair and, more recently, skin colour) can now be determined with good accuracy; face shape is still not amenable to prediction (except, in general lines, from ancestry). Age can apparently also be determined from methylation profiles. Police forces are, understandably, very interested in this technology, with a tendency to over-estimate its accuracy. Legislation varies greatly, with some nations opting for complete prohibition (Germany) and others allowing wide application of the approach (United Kingdom).


Assuntos
Genética Forense/tendências , Fenótipo , Adulto , Grupos Étnicos/genética , Genética Forense/métodos , Estudos de Associação Genética , Humanos , Recém-Nascido , Padrões de Herança/genética , Masculino , Polimorfismo de Nucleotídeo Único , Retratos como Assunto , Pigmentação da Pele/genética , Gêmeos/genética
14.
Gac. méd. espirit ; 22(2): 42-50, mayo.-ago. 2020.
Artigo em Espanhol | LILACS | ID: biblio-1124834

RESUMO

RESUMEN Fundamento: La retinosis pigmentaria constituye una causa de discapacidad visual que provoca alteraciones psicológicas y sociales al paciente. Objetivo: Describir las características clínicas y epidemiológicas en pacientes discapacitados visuales por retinosis pigmentaria de la provincia Sancti Spíritus. Metodología: Se realizó un estudio descriptivo, que incluyó 140 pacientes discapacitados visuales afectados por retinosis pigmentaria. Resultados: El grupo etario entre los 29 y 56 años fue el más afectado (78.1 %), el 65 % era del sexo masculino, predominó el color blanco de la piel (87.1 %), sobresalió la catarata como la afección ocular (13.6 %), el 16.4 % presentó hipertensión arterial; la mayoría de los discapacitados no presentó hábitos tóxicos (55 %), prevaleció el debut precoz en el 70 % de los casos. La forma típica de la enfermedad se observó en el 98.5 % de los enfermos, el 67 % manifestó un estadio clínico de la enfermedad grado IV, así como la herencia autosómica recesiva en el 36.4 %. Conclusiones: Predominio de los enfermos en los grupos etario entre 29 y 56 años, masculino, color blanco de la piel; la catarata como patología ocular más frecuente junto a la hipertensión arterial dentro las enfermedades sistémicas; la mayoría de los discapacitados no presentó hábitos tóxicos. El debut precoz, la forma típica, el estadio IV de la enfermedad, así como la herencia autosómica dominante prevalecieron en el estudio.


ABSTRACT Background: Retinitis pigmentosa is a cause of visual impairment that causes psychological and social alterations to the patient. Objective: To describe the clinical and epidemiological characteristics in visual impaired patients due to retinitis pigmentosa in Sancti Spíritus province. Methodology: A descriptive study was carried out, which included 140 visual impaired patients affected by retinitis pigmentosa. Results: The age group between 29 and 56 years old was the most affected (78.1 %), 65 % were male, white skin predominated (87.1 %), cataract stood out as an eye condition (13.6 %), 16.4 % presented arterial hypertension; most of the disabled did not present toxic habits (55 %), early debut prevailed in 70 % of cases. The typical form of the disease was observed in 98.5 % of patients, 67 % showed a clinical stage of grade IV disease, as well as autosomal recessive inheritance in 36.4 %. Conclusions: Prevalence of patients in the age groups between 29 and 56 years, male, white skin color; cataract as the most frequent ocular pathology together with arterial hypertension within systemic diseases; the majority of the disabled patients did not show toxic habits. Early debut, typical form, stage IV disease, and autosomal dominant inheritance prevailed in the study.


Assuntos
Retinite Pigmentosa , Padrões de Herança , Pessoas com Deficiência Visual
15.
Proc Natl Acad Sci U S A ; 117(30): 17702-17709, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32661163

RESUMO

A dominant male-determining locus (M-locus) establishes the male sex (M/m) in the yellow fever mosquito, Aedes aegypti Nix, a gene in the M-locus, was shown to be a male-determining factor (M factor) as somatic knockout of Nix led to feminized males (M/m) while transient expression of Nix resulted in partially masculinized females (m/m), with male reproductive organs but retained female antennae. It was not clear whether any of the other 29 genes in the 1.3-Mb M-locus are also needed for complete sex-conversion. Here, we report the generation of multiple transgenic lines that express Nix under the control of its own promoter. Genetic and molecular analyses of these lines provided insights unattainable from previous transient experiments. We show that the Nix transgene alone, in the absence of the M-locus, was sufficient to convert females into males with all male-specific sexually dimorphic features and male-like gene expression. The converted m/m males are flightless, unable to perform the nuptial flight required for mating. However, they were able to father sex-converted progeny when presented with cold-anesthetized wild-type females. We show that myo-sex, a myosin heavy-chain gene also in the M-locus, was required for male flight as knockout of myo-sex rendered wild-type males flightless. We also show that Nix-mediated female-to-male conversion was 100% penetrant and stable over many generations. Therefore, Nix has great potential for developing mosquito control strategies to reduce vector populations by female-to-male sex conversion, or to aid in a sterile insect technique that requires releasing only non-biting males.


Assuntos
Aedes/genética , Voo Animal , Genes de Insetos , Estudos de Associação Genética , Proteínas de Membrana/genética , Processos de Determinação Sexual/genética , Animais , Animais Geneticamente Modificados , Sistemas CRISPR-Cas , Feminino , Loci Gênicos , Genótipo , Padrões de Herança , Masculino , Penetrância , Fenótipo , Regiões Promotoras Genéticas
16.
Nucleic Acids Res ; 48(14): 7883-7898, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32609810

RESUMO

Circular DNA can arise from all parts of eukaryotic chromosomes. In yeast, circular ribosomal DNA (rDNA) accumulates dramatically as cells age, however little is known about the accumulation of other chromosome-derived circles or the contribution of such circles to genetic variation in aged cells. We profiled circular DNA in Saccharomyces cerevisiae populations sampled when young and after extensive aging. Young cells possessed highly diverse circular DNA populations but 94% of the circular DNA were lost after ∼15 divisions, whereas rDNA circles underwent massive accumulation to >95% of circular DNA. Circles present in both young and old cells were characterized by replication origins including circles from unique regions of the genome and repetitive regions: rDNA and telomeric Y' regions. We further observed that circles can have flexible inheritance patterns: [HXT6/7circle] normally segregates to mother cells but in low glucose is present in up to 50% of cells, the majority of which must have inherited this circle from their mother. Interestingly, [HXT6/7circle] cells are eventually replaced by cells carrying stable chromosomal HXT6 HXT6/7 HXT7 amplifications, suggesting circular DNAs are intermediates in chromosomal amplifications. In conclusion, the heterogeneity of circular DNA offers flexibility in adaptation, but this heterogeneity is remarkably diminished with age.


Assuntos
Senescência Celular/genética , Replicação do DNA , DNA Circular/química , Saccharomyces cerevisiae/genética , DNA Circular/análise , Variação Genética , Padrões de Herança , Proteínas de Transporte de Monossacarídeos/genética , Sequências Repetitivas de Ácido Nucleico , Origem de Replicação , Proteínas de Saccharomyces cerevisiae/genética
17.
PLoS Biol ; 18(7): e3000745, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32667908

RESUMO

Mutations create genetic variation for other evolutionary forces to operate on and cause numerous genetic diseases. Nevertheless, how de novo mutations arise remains poorly understood. Progress in the area is hindered by the fact that error rates of conventional sequencing technologies (1 in 100 or 1,000 base pairs) are several orders of magnitude higher than de novo mutation rates (1 in 10,000,000 or 100,000,000 base pairs per generation). Moreover, previous analyses of germline de novo mutations examined pedigrees (and not germ cells) and thus were likely affected by selection. Here, we applied highly accurate duplex sequencing to detect low-frequency, de novo mutations in mitochondrial DNA (mtDNA) directly from oocytes and from somatic tissues (brain and muscle) of 36 mice from two independent pedigrees. We found mtDNA mutation frequencies 2- to 3-fold higher in 10-month-old than in 1-month-old mice, demonstrating mutation accumulation during the period of only 9 mo. Mutation frequencies and patterns differed between germline and somatic tissues and among mtDNA regions, suggestive of distinct mutagenesis mechanisms. Additionally, we discovered a more pronounced genetic drift of mitochondrial genetic variants in the germline of older versus younger mice, arguing for mtDNA turnover during oocyte meiotic arrest. Our study deciphered for the first time the intricacies of germline de novo mutagenesis using duplex sequencing directly in oocytes, which provided unprecedented resolution and minimized selection effects present in pedigree studies. Moreover, our work provides important information about the origins and accumulation of mutations with aging/maturation and has implications for delayed reproduction in modern human societies. Furthermore, the duplex sequencing method we optimized for single cells opens avenues for investigating low-frequency mutations in other studies.


Assuntos
Envelhecimento/genética , Mamíferos/genética , Mitocôndrias/genética , Mutação/genética , Oócitos/metabolismo , Especificidade de Órgãos/genética , Animais , Análise Mutacional de DNA , DNA Mitocondrial/genética , Feminino , Frequência do Gene/genética , Deriva Genética , Células Germinativas/metabolismo , Padrões de Herança/genética , Modelos Logísticos , Masculino , Camundongos , Modelos Genéticos , Taxa de Mutação , Nucleotídeos/genética , Linhagem
18.
CuidArte, Enferm ; 14(2): 247-250, jul.-dez.2020.
Artigo em Português | BDENF - Enfermagem | ID: biblio-1148121

RESUMO

Introdução: A síndrome de Marfan é um distúrbio genético raro, com padrão de herança autossômico dominante, caracterizado por alterações no tecido conjuntivo com comprometimento, principalmente, dos sistemas esqueléticos, ocular e cardiovascular. O diagnóstico da SMF pode ser realizado clinicamente através dos critérios da nosologia Ghent ou por exame de biologia molecular para identificação de mutações no gene da Fibrilina-1 (FBN1). A nosologia Ghent é caracterizada pela presença de um conjunto de manifestações consideradas "maiores" e "menores" em vários tecidos diferentes, incluindo esquelético, ocular, cardiovascular, pulmonar, nervoso e pele. Objetivo: Aplicar os critérios da nosologia Ghent em pacientes com fenótipo clínico compatível com a síndrome de Marfan para definição do diagnóstico, tratamento e aconselhamento genético. Material e Método: Os dados foram obtidos a partir da consulta dos prontuários médicos e aplicados ao protocolo proposto pela nosologia e os escores analisados como concordantes ou não para o diagnóstico da SMF. Resultados: A amostra estudada foi composta por oito indivíduos, com idade média de 13 anos, três do gênero masculino e cinco do feminino. Destes, cinco apresentaram os critérios definidos por Ghent. Após confirmação do diagnóstico, os pacientes foram encaminhados para tratamentos médicos apropriados considerando a sintomatologia presente. Conclusão: Os resultados evidenciaram a importância da utilização da nosologia Ghent para definição diagnóstica da SMF nos casos em que o alto custo dos testes de biologia molecular inviabilizam a sua realização.(AU)


Introduction: Marfan's syndrome is a rare genetic disorder, with a dominant autosomal inheritance pattern, characterized by alterations in the connective tissue, which mainly affect the skeletal, ocular and cardiovascular systems. The diagnosis of FMS can be performed clinically through the criteria of Ghent nosology or by molecular biology examination to identify mutations in the Fibrillin-1 gene (FBN1). Ghent nosology is characterized by the presence of a set of manifestations considered "larger" and "smaller" in several different tissues, including skeletal, ocular, cardiovascular, pulmonary, nervous and skin. Objective: To apply the criteria of Ghent nosology in patients with clinical phenotype compatible with Marfan syndrome to define the diagnosis, treatment and genetic counseling. Material and Method: The data were obtained from the medical records consultation and applied to the protocol proposed by nosology and the scores analyzed as concordant or not for the diagnosis of SMF. Results: The sample studied was composed of eight individuals, with mean age of 13 years, three male and five female. Of these, five presented the criteria defined by Ghent. After confirmation of the diagnosis, the patients were referred for appropriate medical treatment considering the symptomatology present. Conclusion: The results showed the importance of the use of Ghent nosology for the diagnostic definition of FMS in cases where the high cost of molecular biology tests makes its performance impossible.(AU)


Introducción: El síndrome de Marfan es un trastorno genético poco común, con un patrón de herencia autosómico dominante, caracterizado por cambios en el tejido conectivo con afectación, principalmente del sistema esquelético, ocular y cardiovascular. El diagnóstico de SMF se puede hacer clínicamente a través de los criterios de nosología Ghent o examinando la biología molecular para identificar mutaciones en el gen de la fibrilina-1 (FBN1). La nosología Ghent se caracteriza por la presencia de un conjunto de manifestaciones consideradas "mayores" y "menores" en diversos tejidos, entre los que se encuentran el esquelético, ocular, cardiovascular, pulmonar, nervioso y cutáneo. Objetivo: Aplicar los criterios de la nosología Ghent en pacientes con un fenotipo clínico compatible con el síndrome de Marfan para definir el diagnóstico, tratamiento y consejo genético. Material y Método: Los datos se obtuvieron de la consulta de historias clínicas y se aplicaron al protocolo propuesto por nosología y se analizaron las puntuaciones como concordantes o no para el diagnóstico de SFM. Resultados: La muestra estudiada estuvo compuesta por ocho individuos, con una edad promedio de 13 años, tres hombres y cinco mujeres. De estos, cinco cumplieron los criterios definidos por Ghent. Una vez confirmado el diagnóstico, los pacientes fueron derivados a los tratamientos médicos adecuados teniendo en cuenta los síntomas presentes. Conclusión: Los resultados mostraron la importancia de utilizar la nosología Ghent para diagnosticar la SMF en los casos en que el alto costo de las pruebas de biología molecular imposibilita su realización.(AU)


Assuntos
Humanos , Adolescente , Técnicas e Procedimentos Diagnósticos , Fibrilina-1 , Doenças Genéticas Inatas , Síndrome de Marfan , Tecido Conjuntivo/anormalidades , Padrões de Herança , Aconselhamento Genético , Processo de Enfermagem
19.
Ann Hematol ; 99(7): 1475-1483, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32524201

RESUMO

Large deletions in the ß-globin gene cluster lead to increased HbF levels by delaying the γ- to ß-globin switch process. However, these deletions when inherited as a homozygous condition or when co-inherited with ß-thalassemia result in variable clinical phenotypes. Individuals or families with a clinically presenting child, where the parents had HbF levels ≥ 10%, were further screened for the presence of large ß-globin cluster deletions. Six deletions in the ß-globin gene cluster were screened by GAP-PCR, and the uncharacterized deletions were further analyzed by gene dosage or by multiplex ligation-dependent probe amplification (MLPA). Among 192 individuals suspected for the inheritance of large deletions, 138 were heterozygous for large deletions, 45 were compound heterozygous of a large ß-globin cluster deletion and ß-thalassemia, and 9 were found to be homozygous for deletions. Among the heterozygotes, the Asian Indian inversion-deletion was found to be the most common deletion (39.9%), followed by the HPFH-3 deletion (30.0%). Other deletions 49.3 kb, δß-thalassemia (21.2%), and 32.6 kb deletion (4.4%) were also found to be prevalent in our population. Patients compound heterozygous or homozygous for HPFH-3 and 32.6 kb deletions showed a milder clinical presentation, as compared with the patients compound heterozygous or homozygous for the Asian Indian inversion-deletion and 49.3 kb δß-thalassemia. This comprehensive study highlights the mutation spectrum of large ß-globin cluster deletions and the clinical heterogeneity in the patients homozygous or compound heterozygous with ß-thalassemia, thus asserting the need for molecular characterization of these deletions.


Assuntos
Hemoglobina Fetal/genética , Estudos de Associação Genética , Heterogeneidade Genética , Talassemia beta/epidemiologia , Talassemia beta/genética , Talassemia delta/epidemiologia , Talassemia delta/genética , Idade de Início , Criança , Mortalidade da Criança , Pré-Escolar , Feminino , Hemoglobina Fetal/análise , Estudos de Associação Genética/estatística & dados numéricos , Humanos , Índia/epidemiologia , Lactente , Padrões de Herança/genética , Masculino , Talassemia beta/sangue , Talassemia beta/mortalidade , Talassemia delta/sangue , Talassemia delta/mortalidade
20.
Nat Genet ; 52(7): 669-679, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32514122

RESUMO

The overwhelming majority of participants in current genetic studies are of European ancestry. To elucidate disease biology in the East Asian population, we conducted a genome-wide association study (GWAS) with 212,453 Japanese individuals across 42 diseases. We detected 320 independent signals in 276 loci for 27 diseases, with 25 novel loci (P < 9.58 × 10-9). East Asian-specific missense variants were identified as candidate causal variants for three novel loci, and we successfully replicated two of them by analyzing independent Japanese cohorts; p.R220W of ATG16L2 (associated with coronary artery disease) and p.V326A of POT1 (associated with lung cancer). We further investigated enrichment of heritability within 2,868 annotations of genome-wide transcription factor occupancy, and identified 378 significant enrichments across nine diseases (false discovery rate < 0.05) (for example, NKX3-1 for prostate cancer). This large-scale GWAS in a Japanese population provides insights into the etiology of complex diseases and highlights the importance of performing GWAS in non-European populations.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Estudos de Coortes , Feminino , Predisposição Genética para Doença/etnologia , Variação Genética , Humanos , Padrões de Herança , Japão , Masculino , Fatores Sexuais , Fatores de Transcrição/genética
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