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1.
Anticancer Res ; 39(10): 5353-5359, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570429

RESUMO

BACKGROUND: Identification of genetic prognostic biomarkers, such as germline variants, are urgently needed to choose optimal treatment for metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: The prognostic value of anoctamin 7 (ANO7) rs77559646 on docetaxel response was tested in a prospective PROSTY randomized trial and a retrospective Auria Biobank set. The variant rs77559646 was genotyped and its association with progression-free survival (PFS) and overall survival (OS) was tested. RESULTS: In comparison with the non-carriers, the variant carriers had longer PFS (p=0.005) and OS (p=0.003) in the PROSTY cohort. In the retrospective cohort, there was a borderline association with PFS (p=0.09), but not in OS (p=0.9). In both cohorts, Cox regression multivariate models revealed that rs77559646 was an independent prognostic factor for favourable PFS. CONCLUSION: The rs77559646 was shown to be a prognostic germline biomarker for better response to docetaxel treatments. To our knowledge, this is the first time that a non-coding germline variant has been associated with chemotherapy of mCRPC.


Assuntos
Anoctaminas/genética , Antineoplásicos/uso terapêutico , Docetaxel/uso terapêutico , Variação Genética/genética , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Idoso , Biomarcadores Tumorais/genética , Estudos de Coortes , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Estudos Prospectivos , Neoplasias de Próstata Resistentes à Castração/patologia , Estudos Retrospectivos
2.
Mem Inst Oswaldo Cruz ; 114: e190149, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576902

RESUMO

Human polycystic echinococcosis is a parasitic infection caused by the larval stage of Echinococcus vogeli, which occurs in rural areas of Central and South America. Until now, little information on the genetic variability of E. vogeli is available. Here, 32 samples from human-excised E. vogeli cysts had a 396-bp sequence of the mitochondrial cytochrome oxidase I (COI) gene sequenced and compared to another 17 COI sequences representing nine Echinococcus species. A Bayesian COI tree revealed that all E. vogeli sequences formed a monophyletic and well-supported clade with an E. vogeli reference sequence. The occurrence of geographically restricted E. vogeli COI haplotypes suggests retention of ancestral polymorphisms with little migration in Acre, Brazil.


Assuntos
Echinococcus/genética , Variação Genética/genética , Animais , Teorema de Bayes , Brasil , Equinococose/parasitologia , Echinococcus/isolamento & purificação , Haplótipos , Humanos
3.
Mem Inst Oswaldo Cruz ; 114: e190184, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576903

RESUMO

American visceral leishmaniasis (AVL) has two main scenarios of transmission as follows: scattered cases in rural areas and urban outbreaks. Urban AVL is in active dispersion from the northeastern border of Argentina-Paraguay-Brazil to the South. The presence of Lutzomyia longipalpis was initially reported in urban environments in the northwestern border of the country. The presence of Lu. longipalpis, environmental variables associated with its distribution, and its genetic diversity were assessed in Salvador Mazza, Argentina, on the border with Bolivia. The genetic analysis showed high haplotype diversity, low nucleotide diversity, and low nucleotide polymorphism index. We discuss the hypothesis of an expanding urban population with introgressive hybridisation of older haplogroups found in their path in natural forest or rural environments, acquiring a new adaptability to urban environments, and the possibility of changes in vector capacity.


Assuntos
Distribuição Animal , Variação Genética/genética , Insetos Vetores/genética , Psychodidae/genética , Animais , Argentina , Bolívia , Brasil , DNA Mitocondrial/genética , Genes de Insetos/genética , Haplótipos , Insetos Vetores/classificação , Leishmaniose Cutânea/transmissão , Masculino , Filogeografia , Psychodidae/classificação
4.
Br J Anaesth ; 123(6): 853-864, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31558312

RESUMO

Chronic post-surgical pain (CPSP) is a debilitating condition affecting 10-50% of surgical patients. The current treatment strategy for CPSP is not optimal, and the identification of genetic variation in surgical patients might help to improve prediction and treatment of CPSP. The neurotransmitter dopamine (DA) has been associated with several chronic pain disorders. This narrative review focuses on DA neurotransmission as a potential target in the treatment of CPSP. The current knowledge on genetic variation within DA neurotransmission and its role in CPSP susceptibility are reviewed. Three genes involved in DA neurotransmission (COMT, GCH1, and DRD2) have been associated with variability in pain sensitivity, development of CPSP, and analgesic requirement. The direction of the effect of the association is sometimes inconclusive because of contradictory results, but ample evidence suggests a modulatory role of DA. Because of this modulatory role, DA is an excellent pharmacological target in the treatment of pain. Pharmacotherapy focused on DA neurotransmission has potential in both prevention (via D1-like receptors) and treatment (via D2-like receptors and DA reuptake inhibitors) of CPSP. The development of prediction models including genetic risk factors is necessary to better identify patients at risk.


Assuntos
Dopamina/metabolismo , Variação Genética/genética , Dor Pós-Operatória/genética , Dor Pós-Operatória/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Dor Crônica/genética , Dor Crônica/metabolismo , Dopamina/genética , Humanos , Transmissão Sináptica/genética
5.
Nat Med ; 25(9): 1442-1452, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31477907

RESUMO

Our understanding of how the gut microbiome interacts with its human host has been restrained by limited access to longitudinal datasets to examine stability and dynamics, and by having only a few isolates to test mechanistic hypotheses. Here, we present the Broad Institute-OpenBiome Microbiome Library (BIO-ML), a comprehensive collection of 7,758 gut bacterial isolates paired with 3,632 genome sequences and longitudinal multi-omics data. We show that microbial species maintain stable population sizes within and across humans and that commonly used 'omics' survey methods are more reliable when using averages over multiple days of sampling. Variation of gut metabolites within people over time is associated with amino acid levels, and differences across people are associated with differences in bile acids. Finally, we show that genomic diversification can be used to infer eco-evolutionary dynamics and in vivo selection pressures for strains within individuals. The BIO-ML is a unique resource designed to enable hypothesis-driven microbiome research.


Assuntos
Bactérias/genética , Microbioma Gastrointestinal/genética , Filogenia , Seleção Genética/genética , Bactérias/classificação , Bactérias/isolamento & purificação , Ácidos e Sais Biliares/genética , Ácidos e Sais Biliares/metabolismo , Bancos de Espécimes Biológicos , Fezes/microbiologia , Variação Genética/genética , Genoma Bacteriano/genética , Humanos , Metaboloma/genética
6.
Zhonghua Er Ke Za Zhi ; 57(9): 674-679, 2019 Sep 02.
Artigo em Chinês | MEDLINE | ID: mdl-31530352

RESUMO

Objective: To examine genetic variants of familial hematuria (FH) associated genes in 3 families with hematuria with probands initially diagnosed with IgA nephropathy (IgAN). Methods: A retrospective analysis was performed on the clinical data, laboratory tests and genetic test results of three children with hematuria and the probands in three families with hematuria. The families were ascertained at the Department of Pediatrics, Fuzhou General Hospital of Nanjing Military Command from August 2014 to May 2018. Results: The proband of Family One, an 8-year-old boy, manifested gross hematuria. His renal biopsy pathology revealed IgAN. His father also manifested hematuria. Genetic testing showed that the proband and his father carried a heterozygous variant of the CFHR5 gene,533A>G (Asn178Ser). The child of Family Two, a 4-year-old girl, manifested hematuria. Her father, the proband of the family, was 36 years old, and manifested hematuria, proteinuria, high-frequency sensorineural deafness and renal insufficiency. He was diagnosed as IgAN according to clinical manifestations, renal pathology and routine immunohistochemistry without renal biopsy electron microscopy, renal tissue type Ⅳ collagen α3, α4, α5 chains immunofluorescence and skin type Ⅳ collagen α5 chain immunofluorescence. Genetic testing showed that the girl carried a heterozygous variant of the COL4A5 gene,566G>T (Gly189Val), and her father carried the hemizygous variant. The child of Family Three, a 7-year-old girl, manifested hematuria and proteinuria. Her mother, the proband of the family, was 34 years old, and manifested hematuria and proteinuria as well. The proband was diagnosed as IgAN by the same method used for Family Two. The girl's grandfather died of uremia at the age of 44. Genetic testing showed that the girl and her mother carried a heterozygous variant 539G>A (Gly180Glu)in COL4A5 gene. Conclusions: The variant of the CFHR5 gene identified in Family One is of uncertain signifance, and the two variants of the COL4A5 gene identified in Families Two and Three are pathogenic. The probands of Families Two and Three are diagnosed as Alport syndrome. The study suggests that clinicians should examine genetic variants of FH associated genes in families with hematuria when the probands were diagnosed as IgAN by their clinical manifestations, renal pathology and routine immunohistochemistry.


Assuntos
Variação Genética/genética , Hematúria/diagnóstico , Nefrite Hereditária/diagnóstico , Adulto , Criança , Pré-Escolar , Feminino , Testes Genéticos/métodos , Glomerulonefrite por IGA/diagnóstico , Glomerulonefrite por IGA/patologia , Hematúria/genética , Humanos , Rim , Masculino , Nefrite Hereditária/genética , Estudos Retrospectivos , Sequenciamento Completo do Exoma
7.
Cytogenet Genome Res ; 159(1): 32-38, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31542782

RESUMO

Despite the variation observed in the diploid chromosome number of storks (Ciconiiformes, Ciconiidae), from 2n = 52 to 2n = 78, most reports have relied solely on analyses by conventional staining. As most species have similar macrochromosomes, some authors propose that karyotype evolution involves mainly fusions between microchromosomes, which are highly variable in species with different diploid numbers. In order to verify this hypothesis, in this study, the karyotypes of 2 species of storks from South America with different diploid numbers, the jabiru (Jabiru mycteria, 2n = 56) and the maguary stork (Ciconia maguary, 2n = 72), were analyzed by chromosome painting using whole chromosome probes from the macrochromosomes of Gallus gallus (GGA) and Leucopternis albicollis (LAL). The results revealed that J. mycteria and C. maguary share synteny within chromosome pairs 1-9 and Z. The syntenies to the macrochromosomes of G. gallus are conserved, except for GGA4, which is homologous to 2 different pairs, as in most species of birds. A fusion of GGA8 and GGA9 was observed in both species. Additionally, chromosomes corresponding to GGA4p and GGA6 are fused to other segments that did not hybridize to any of the macrochromosome probes used, suggesting that these segments correspond to microchromosomes. Hence, our data corroborate the proposed hypothesis that karyotype evolution is based on fusions involving microchromosomes. In view of the morphological constancy of the macrochromosome pairs in most Ciconiidae, we propose a putative ancestral karyotype for the family, including the GGA8/GGA9 fusion, and a diploid number of 2n = 78. The use of probes for microchromosome pairs should be the next step in identifying other synapomorphies that may help to clarify the phylogeny of this family.


Assuntos
Aves/genética , Coloração Cromossômica/veterinária , Cromossomos/genética , Variação Genética/genética , Cariótipo , Animais , Brasil , Diploide , Evolução Molecular , Feminino , Filogenia
8.
Arch Virol ; 164(11): 2715-2724, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31456086

RESUMO

Bovine coronavirus (BCoV) is a recognized cause of severe neonatal calf diarrhea, with a negative impact on animal welfare, leading to economic losses to the livestock industry. Cattle production is one of the most important economic sectors in Uruguay. The aim of this study was to determine the frequency of BCoV infections and their genetic diversity in Uruguayan calves and to describe the evolutionary history of the virus in South America. The overall detection rate of BCoV in Uruguay was 7.8% (64/824): 7.7% (60/782) in dairy cattle and 9.5% (4/42) in beef cattle. The detection rate of BCoV in samples from deceased and live calves was 10.0% (6/60) and 7.6% (58/763), respectively. Interestingly, there was a lower frequency of BCoV detection in calves born to vaccinated dams (3.3%, 8/240) than in calves born to unvaccinated dams (12.2%, 32/263) (OR: 4.02, 95%CI: 1.81-8.90; p = 0.00026). The frequency of BCoV detection was higher in colder months (11.8%, 44/373) than in warmer months (1.5%, 3/206) (OR: 9.05, 95%CI: 2.77-29.53, p = 0.000013). Uruguayan strains grouped together in two different lineages: one with Argentinean strains and the other with Brazilian strains. Both BCoV lineages were estimated to have entered Uruguay in 2013: one of them from Brazil (95%HPD interval: 2011-2014) and the other from Argentina (95%HPD interval: 2010-2014). The lineages differed by four amino acid changes, and both were divergent from the Mebus reference strain. Surveillance should be maintained to detect possible emerging strains that can clearly diverge at the antigenic level from vaccine strains.


Assuntos
Antígenos Virais/genética , Doenças dos Bovinos/epidemiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/veterinária , Coronavirus Bovino/isolamento & purificação , Animais , Antígenos Virais/imunologia , Argentina/epidemiologia , Brasil/epidemiologia , Bovinos , Doenças dos Bovinos/prevenção & controle , Doenças dos Bovinos/virologia , Infecções por Coronavirus/prevenção & controle , Coronavirus Bovino/genética , DNA Viral/genética , Disenteria/epidemiologia , Disenteria/veterinária , Disenteria/virologia , Variação Genética/genética , Uruguai/epidemiologia , Vacinação
9.
An Acad Bras Cienc ; 91(suppl 3): e20190325, 2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31460594

RESUMO

The West Indian (Trichechus manatus) and Amazonian (T. inunguis) manatees have a sympatric occurrence at the mouth of the Amazon River. A result of this interspecific encounter is the occurrence of hybrids, which are frequently found along the coasts of Amapá state in Brazil, French Guiana and Guyana. Here we present new genetic evidence indicating the occurrence of a hybrid swarm along the Guianas Shield coastline, which is an interspecific hybrid zone that also separates T. manatus populations located east (Brazil) and west (Caribbean, Gulf of Mexico, Florida and Antilles). In addition, we suggest that this hybrid population occupies a peculiar mangrove-rich environment under strong influence of the Amazon River plume, which requires an independent management and should be considered a special conservation area.


Assuntos
Variação Genética/genética , Hibridização Genética , Especificidade da Espécie , Trichechus inunguis/genética , Trichechus manatus/genética , Animais , Teorema de Bayes , Brasil , Região do Caribe , Guiana , Filogenia , Dinâmica Populacional , Rios , Trichechus inunguis/fisiologia , Trichechus manatus/fisiologia
10.
An Acad Bras Cienc ; 91(3): e20180387, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31432899

RESUMO

This study aimed to estimate genetic parameters and correlations between morphological, agronomic and root quality traits of cassava plants, as well as to study cause and effect relationships through path analysis. A total of 814 genotypes were evaluated from 2011 to 2015. The joint analysis of the data was performed by the mixed models approach. The predicted genetic values of the genotypes were used to estimate the genetic correlations among as well the path analysis. The estimates of heritability of the genotype means ranged from 0.31 (commercial fresh root yield - CRY) to 0.62 (plant height - PLH). The highest genetic correlation coefficient estimates were observed for starch yield (STY) × total fresh root yield (FRY) (0.97). The results of the path analysis showed that FRY had the highest direct effect on STY, but the indirect selection based on FRY was not efficient to improve the gain of STY.


Assuntos
Variação Genética/genética , Manihot/genética , Característica Quantitativa Herdável , Seleção Genética/genética , Genótipo
11.
Nature ; 571(7766): 489-499, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31341302

RESUMO

Epigenetic research has accelerated rapidly in the twenty-first century, generating justified excitement and hope, but also a degree of hype. Here we review how the field has evolved over the last few decades and reflect on some of the recent advances that are changing our understanding of biology. We discuss the interplay between epigenetics and DNA sequence variation as well as the implications of epigenetics for cellular memory and plasticity. We consider the effects of the environment and both intergenerational and transgenerational epigenetic inheritance on biology, disease and evolution. Finally, we present some new frontiers in epigenetics with implications for human health.


Assuntos
Doença/genética , Epigênese Genética/genética , Epigenômica/tendências , Interação Gene-Ambiente , Envelhecimento/genética , Animais , Cromatina/genética , Cromatina/metabolismo , Metilação de DNA/genética , Variação Genética/genética , Humanos , Neoplasias/genética
12.
BMC Plant Biol ; 19(1): 328, 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31337341

RESUMO

BACKGROUND: To efficiently protect and exploit germplasm resources for marker development and breeding purposes, we must accurately depict the features of the tea populations. This study focuses on the Camellia sinensis (C. sinensis) population and aims to (i) identify single nucleotide polymorphisms (SNPs) on the genome level, (ii) investigate the genetic diversity and population structure, and (iii) characterize the linkage disequilibrium (LD) pattern to facilitate next genome-wide association mapping and marker-assisted selection. RESULTS: We collected 415 tea accessions from the Origin Center and analyzed the genetic diversity, population structure and LD pattern using the genotyping-by-sequencing (GBS) approach. A total of 79,016 high-quality SNPs were identified; the polymorphism information content (PIC) and genetic diversity (GD) based on these SNPs showed a higher level of genetic diversity in cultivated type than in wild type. The 415 accessions were clustered into three groups by STRUCTURE software and confirmed using principal component analyses (PCA)-wild type, cultivated type, and admixed wild type. However, unweighted pair group method with arithmetic mean (UPGMA) trees indicated the accessions should be grouped into more clusters. Further analyses identified four groups, the Pure Wild Type, Admixed Wild Type, ancient landraces and modern landraces using STRUCTURE, and the results were confirmed by PCA and UPGMA tree method. A higher level of genetic diversity was detected in ancient landraces and Admixed Wild Type than that in the Pure Wild Type and modern landraces. The highest differentiation was between the Pure Wild Type and modern landraces. A relatively fast LD decay with a short range (kb) was observed, and the LD decays of four inferred populations were different. CONCLUSIONS: This study is, to our knowledge, the first population genetic analysis of tea germplasm from the Origin Center, Guizhou Plateau, using GBS. The LD pattern, population structure and genetic differentiation of the tea population revealed by our study will benefit further genetic studies, germplasm protection, and breeding.


Assuntos
Camellia sinensis/genética , China , Variação Genética/genética , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Desequilíbrio de Ligação/genética , Polimorfismo de Nucleotídeo Único/genética , Dinâmica Populacional
13.
Parasitol Res ; 118(9): 2475-2484, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31270681

RESUMO

The Asian bush mosquito Aedes japonicus, endemic to East Asia, is one of the most expansive mosquito species in the world and has as yet established in 15 countries of Europe. Within Germany, the species has been spreading tremendously during the last years, and its four once geographically isolated populations were on the verge of merging in 2017. To reveal relationships and carry-over ways between the various populations, and thus, migration and displacement routes, the genetic make-up of Ae. japonicus from ten different locations throughout its German distribution area was investigated. For this purpose, a part of the mitochondrial DNA (nad4 gene) of collected specimens was sequenced and seven loci of short tandem repeats (microsatellites) were genotyped. When related to similar genetic studies carried out between 2012 and 2015, the results suggest that admixtures had since occurred, but no complete genetic mixture of populations had taken place. At the time of sampling for the present study, the western collection sites were still uniform in their genetic make-up; however, a carry-over of individuals from the southeastern to the northern and southwestern German populations was determined. Further introductions from abroad are possible. In summary, the genetic diversity of Ae. japonicus in Germany had grown considerably, thus increasing ecological variability and adaptability of the species. At this point (10 years after the first detection), it is not possible anymore to draw conclusions on the origins of the populations.


Assuntos
Aedes/genética , DNA Mitocondrial/genética , Variação Genética/genética , Espécies Introduzidas/estatística & dados numéricos , Repetições de Microssatélites/genética , Animais , Genética Populacional , Genótipo , Alemanha
14.
BMC Med Genet ; 20(1): 126, 2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31311520

RESUMO

BACKGROUND: Osteodysplasia of the oral and maxillofacial bone is generally accompanied by systemic bone abnormalities (such as short stature, joint contracture) or other systemic abnormalities (such as renal, dermatological, cardiovascular, optic, or hearing disorders). However, it does not always present this way. Recent reports have suggested that genome-wide sequencing is an effective method for identifying rare or new disorders. Here, we performed whole-exome sequencing (WES) in a patient with a unique form of acquired, local osteodysplasia of the oral and maxillofacial region. CASE PRESENTATION: A 46-year-old woman presented to our hospital with the complaint of gradually moving mandibular teeth (for 6 months), changing facial appearance, and acquired osteolysis of the oral and maxillofacial bones, showing mandibular hypoplasia without family history. Upon skeletal examination, there were no abnormal findings outside of the oral and maxillofacial area; the patient had a height of 157 cm and bone mineral density (according to dual energy x-ray absorptiometry) of 90%. Results of blood and urine tests, including evaluation of bone metabolism markers and neurological and cardiovascular examinations, were normal. We performed WES of genomic DNA extracted from the blood of this patient and her mother, who did not have the disease, as a negative control. We identified 83 new missense variants in the patient, not detected in her mother, including a candidate single nucleotide variant in exon 14 of PCNT (pericentrin). Critical homozygous or compound heterozygous variants in PCNT are a known cause of microcephalic osteodysplastic primordial dwarfism type II accompanied by mandibular hypoplasia, which is similar to the maxillofacial phenotype in this patient. CONCLUSIONS: Protein simulations performed using Polymorphism Phenotyping v2 and Combined Annotation Dependent Depletion software indicated that this missense variant is likely to disrupt the PCNT protein structure. These results suggest that this is a new form of osteolysis related to this PCNT variant.


Assuntos
Antígenos/genética , Nanismo/genética , Retardo do Crescimento Fetal/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Microcefalia/genética , Osteocondrodisplasias/genética , Antígenos/química , Sequência de Bases , Densidade Óssea , Nanismo/diagnóstico por imagem , Nanismo/fisiopatologia , Éxons , Feminino , Retardo do Crescimento Fetal/diagnóstico por imagem , Retardo do Crescimento Fetal/fisiopatologia , Heterozigoto , Homozigoto , Humanos , Mandíbula/patologia , Microcefalia/diagnóstico por imagem , Microcefalia/fisiopatologia , Pessoa de Meia-Idade , Osteocondrodisplasias/diagnóstico por imagem , Osteocondrodisplasias/fisiopatologia , Osteólise , Fenótipo , Tomógrafos Computadorizados , Odontopatias/congênito , Odontopatias/diagnóstico por imagem , Odontopatias/genética , Raiz Dentária/anormalidades , Raiz Dentária/diagnóstico por imagem , Sequenciamento Completo do Exoma
15.
Nat Commun ; 10(1): 3009, 2019 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-31285442

RESUMO

Quantitative genetics theory predicts that X-chromosome dosage compensation (DC) will have a detectable effect on the amount of genetic and therefore phenotypic trait variances at associated loci in males and females. Here, we systematically examine the role of DC in humans in 20 complex traits in a sample of more than 450,000 individuals from the UK Biobank and 1600 gene expression traits from a sample of 2000 individuals as well as across-tissue gene expression from the GTEx resource. We find approximately twice as much X-linked genetic variation across the UK Biobank traits in males (mean h2SNP = 0.63%) compared to females (mean h2SNP = 0.30%), confirming the predicted DC effect. Our DC estimates for complex traits and gene expression are consistent with a small proportion of genes escaping X-inactivation in a trait- and tissue-dependent manner. Finally, we highlight examples of biologically relevant X-linked heterogeneity between the sexes that bias DC estimates if unaccounted for.


Assuntos
Genes Ligados ao Cromossomo X/genética , Loci Gênicos/genética , Variação Genética/genética , Herança Multifatorial/genética , Inativação do Cromossomo X/genética , Conjuntos de Dados como Assunto , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Modelos Genéticos , Fenótipo , Fatores Sexuais
16.
PLoS Med ; 16(6): e1002828, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31211782

RESUMO

BACKGROUND: Systematic reviews of randomised controlled trials (RCTs) have suggested that maternal vitamin D (25[OH]D) and calcium supplementation increase birth weight. However, limitations of many trials were highlighted in the reviews. Our aim was to combine genetic and RCT data to estimate causal effects of these two maternal traits on offspring birth weight. METHODS AND FINDINGS: We performed two-sample mendelian randomisation (MR) using genetic instrumental variables associated with 25(OH)D and calcium that had been identified in genome-wide association studies (GWAS; sample 1; N = 122,123 for 25[OH]D and N = 61,275 for calcium). Associations between these maternal genetic variants and offspring birth weight were calculated in the UK Biobank (UKB) (sample 2; N = 190,406). We used data on mother-child pairs from two United Kingdom birth cohorts (combined N = 5,223) in sensitivity analyses to check whether results were influenced by fetal genotype, which is correlated with the maternal genotype (r ≈ 0.5). Further sensitivity analyses to test the reliability of the results included MR-Egger, weighted-median estimator, 'leave-one-out', and multivariable MR analyses. We triangulated MR results with those from RCTs, in which we used randomisation to supplementation with vitamin D (24 RCTs, combined N = 5,276) and calcium (6 RCTs, combined N = 543) as an instrumental variable to determine the effects of 25(OH)D and calcium on birth weight. In the main MR analysis, there was no strong evidence of an effect of maternal 25(OH)D on birth weight (difference in mean birth weight -0.03 g [95% CI -2.48 to 2.42 g, p = 0.981] per 10% higher maternal 25[OH]D). The effect estimate was consistent across our MR sensitivity analyses. Instrumental variable analyses applied to RCTs suggested a weak positive causal effect (5.94 g [95% CI 2.15-9.73, p = 0.002] per 10% higher maternal 25[OH]D), but this result may be exaggerated because of risk of bias in the included RCTs. The main MR analysis for maternal calcium also suggested no strong evidence of an effect on birth weight (-20 g [95% CI -44 to 5 g, p = 0.116] per 1 SD higher maternal calcium level). Some sensitivity analyses suggested that the genetic instrument for calcium was associated with birth weight via exposures that are independent of calcium levels (horizontal pleiotropy). Application of instrumental variable analyses to RCTs suggested that calcium has a substantial effect on birth weight (178 g [95% CI 121-236 g, p = 1.43 × 10-9] per 1 SD higher maternal calcium level) that was not consistent with any of the MR results. However, the RCT instrumental variable estimate may have been exaggerated because of risk of bias in the included RCTs. Other study limitations include the low response rate of UK Biobank, which may bias MR estimates, and the lack of suitable data to test whether the effects of genetic instruments on maternal calcium levels during pregnancy were the same as those outside of pregnancy. CONCLUSIONS: Our results suggest that maternal circulating 25(OH)D does not influence birth weight in otherwise healthy newborns. However, the effect of maternal circulating calcium on birth weight is unclear and requires further exploration with more research including RCT and/or MR analyses with more valid instruments.


Assuntos
Peso ao Nascer/fisiologia , Cálcio/sangue , Estudo de Associação Genômica Ampla/métodos , Análise da Randomização Mendeliana/métodos , Vitamina D/análogos & derivados , Adulto , Biomarcadores/sangue , Feminino , Variação Genética/genética , Humanos , Recém-Nascido , Estudos Longitudinais , Masculino , Saúde Materna , Gravidez , Vitamina D/sangue , Vitamina D/genética
17.
PLoS Genet ; 15(6): e1008205, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31188830

RESUMO

The relationship between population size, inbreeding, loss of genetic variation and evolutionary potential of fitness traits is still unresolved, and large-scale empirical studies testing theoretical expectations are surprisingly scarce. Here we present a highly replicated experimental evolution setup with 120 lines of Drosophila melanogaster having experienced inbreeding caused by low population size for a variable number of generations. Genetic variation in inbred lines and in outbred control lines was assessed by genotyping-by-sequencing (GBS) of pooled samples consisting of 15 males per line. All lines were reared on a novel stressful medium for 10 generations during which body mass, productivity, and extinctions were scored in each generation. In addition, we investigated egg-to-adult viability in the benign and the stressful environments before and after rearing at the stressful conditions for 10 generations. We found strong positive correlations between levels of genetic variation and evolutionary response in all investigated traits, and showed that genomic variation was more informative in predicting evolutionary responses than population history reflected by expected inbreeding levels. We also found that lines with lower genetic diversity were at greater risk of extinction. For viability, the results suggested a trade-off in the costs of adapting to the stressful environments when tested in a benign environment. This work presents convincing support for long-standing evolutionary theory, and it provides novel insights into the association between genetic variation and evolutionary capacity in a gradient of diversity rather than dichotomous inbred/outbred groups.


Assuntos
Variação Genética/genética , Genética Populacional , Genótipo , Endogamia , Animais , Drosophila melanogaster/genética , Feminino , Genômica , Masculino , Fenótipo , Densidade Demográfica , Análise de Sequência de DNA
18.
Phytopathology ; 109(10): 1793-1800, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31179857

RESUMO

The western Himalayan region in Pakistan has been shown to be the center of diversity of Puccinia striiformis; however, little is known about its genetic relations with the eastern part of the Himalayas. We studied the genetic structure of P. striiformis from Nepal (35 isolates) and Bhutan (31 isolates) in comparison with 81 Pakistani samples collected during 2015 and 2016, through microsatellite genotyping. Genetic analyses revealed a recombinant and highly diverse population structure in Pakistan, Bhutan, and Nepal. A high level of genotypic diversity (>0.90) was observed for the three countries of Pakistan (0.96), Bhutan (0.96), and Nepal (0.91) with the detection of 108 distinct multilocus genotypes (MLGs) in the overall population; 59 for Pakistan, 27 for Bhutan, and 26 for Nepal. Mean number of alleles per locus and gene diversity were higher in Nepal (3.19 and 0.458, respectively) than Bhutan (3.12 and 0.458, respectively). A nonsignificant difference between the observed and the expected heterozygosity in all populations further confirmed the recombinant structure. A clear population subdivision between the Himalayan region of Nepal, Bhutan, and Pakistan was evident, as revealed by FST values (ranging between 0.111 to 0.198), discriminant analysis of principal components, and resampling of MLGs. Limited gene flow could be present between Nepal and Bhutan, while the population from Pakistan was clearly distinct, and no divergence was present between two populations from Pakistan (Bajaur and Malakand). The overall high diversity and recombination signature suggested the potential role of recombination in the eastern Himalayan region (Nepal and Bhutan), which needs to be considered during host resistance deployment and in the context of aerial dispersal of the pathogen. Further surveillance should be made in the Himalayan region for disease management in the region and in the context of worldwide invasions.


Assuntos
Basidiomycota , Basidiomycota/genética , Butão , Fluxo Gênico , Variação Genética/genética , Genótipo , Nepal , Paquistão , Recombinação Genética
19.
Mol Immunol ; 112: 40-50, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31078115

RESUMO

The classical HLA class I genes (HLA Ia) were extensively studied because of their implication in clinical fields and anthropology. Less is known about worldwide genetic diversity and linkage disequilibrium for non-classical HLA class I genes (HLA Ib) and HLA pseudogenes. Notably, HLA-H, which is deleted in a fraction of the population, remains scarcely explored. The aims of this study were 1/ to get further insight into HLA-H genetic diversity and into how this variability potentially affects its expression and 2/ to define HLA Ib worldwide allelic diversity and linkage. Exome sequence data from the 1000 Genomes Project were used to define second field HLA-A, -E, -F, -G and -H typing using PolyPheMe software. Allelic and two-loci haplotype frequencies were estimated using Gene[Rate] software both at worldwide and continental levels. Eleven novel HLA-H alleles identified in exome data were validated by NGS performed on 25 genomic DNA samples from the same cohort. Phylogenetic analysis and frequency distribution of HLA-H alleles revealed three clades, each predominantly represented in Admixed American, European and East Asian populations, African populations and South Asian populations. Among these eleven novel alleles, two potentially encode complete transmembrane HLA proteins. We confirm the high LD between HLA-H and -A, and between HLA-H and -G, and show the three genes have distinct worldwide allelic distribution. Conversely, HLA-E and HLA-F both showed little LD, displayed restricted allelic diversity and practically no difference in their distribution across the planet. Our work thus reveals an unexpectedly high HLA-H genetic diversity, with alleles highly represented in Asia possibly encoding a functional HLA protein. Functional implication of these results remains to be explored, both in physiological and pathological contexts.


Assuntos
Variação Genética/genética , Antígenos HLA-DQ/genética , Haplótipos/genética , Proteína da Hemocromatose/genética , Alelos , Ásia , Grupo com Ancestrais do Continente Asiático/genética , Frequência do Gene/genética , Genes MHC Classe I/genética , Humanos , Desequilíbrio de Ligação/genética , Filogenia
20.
Arch Virol ; 164(8): 2179-2182, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31111258

RESUMO

We identified two novel circoviruses, HK02976 and HK00220, in oral swabs from bats. The size of their full genome was 2,010 nucleotides (nt). The full-genome sequence of our strains shared 96.1% nucleotide sequence identity with each other, and 39.9%-69.5% identity with bat-associated circoviruses (BatACVs)1-9. Based on the species demarcation threshold for viruses of the family Circoviridae, which is 80% genome-wide nucleotide sequence identity, we have tentatively named this group of viruses "bat-associated circovirus 10" (BatACV10).


Assuntos
Quirópteros/virologia , Circovirus/genética , Animais , Sequência de Bases/genética , Infecções por Circoviridae/virologia , Variação Genética/genética , Genoma Viral/genética , Japão , Fases de Leitura Aberta/genética , Filogenia
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