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1.
Am J Hum Genet ; 107(3): 379-380, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32888506

RESUMO

It is imperative for participation in genetics and genomics research to reflect humanity's diversity so that all people can enjoy its benefits. This will take a concerted effort by the research community and must include greater engagement with individuals and communities underrepresented in research. In engaging with vulnerable populations, it is essential that researchers guard against harm resulting from their participation.


Assuntos
Pesquisa Biomédica , Variação Genética/genética , Populações Vulneráveis , Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Europeu/genética , Genoma Humano , Genômica , Genética Humana , Humanos
2.
PLoS One ; 15(8): e0238295, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32866190

RESUMO

African American breast cancer genetics is less understood compared to European American breast cancer susceptibility. Despite the many advantages of gene panel screening, studies investigating African American inherited breast cancer risk and comparing variant contributions between ethnicities are infrequent. Thus, 97 breast cancer-affected individuals of African and European descent from the Alabama Hereditary Cancer Cohort were screened using the research-based gene-panel, B.O.P. (Breast, Ovarian, and Prostate cancer). Upon sequencing and bioinformatic processing, rare coding variants in 14 cancer susceptibility genes were categorized according to the American College of Medical Genetics guidelines and compared between ethnicities. Overall, 107 different variants were identified, the majority of which were benign/likely benign. A pathogenic/likely pathogenic variant was detected in 8.6% and 6.5% of African American and European American cases, respectively, which was not statistically significant. However, African Americans were more likely to have at least one variant of uncertain significance (VUS; p-value 0.006); they also had significantly more VUSs in BRCA1/2 compared to European Americans (p-value 0.015). Additionally, 51.4% of African Americans and 32.3% of European Americans harbored multiple rare variants, and African Americans were more likely to have at least one VUS and one benign/likely benign variant (p-value 0.032), as well as multiple benign/likely benign variants (p-value 0.089). Moreover, of the 15 variants detected in multiple breast cancer cases, ATM c.2289T>C (p.F763L), a VUS, along with two likely benign variants, BRCA2 c.2926_2927delinsAT (p.S976I) and RAD51D c.251T>A (p.L84H), were determined to be associated with African American breast cancer risk when compared to ethnic-specific controls. Ultimately, B.O.P. screening provides essential insight towards the variant contributions in clinically relevant cancer susceptibility genes and differences between ethnicities, stressing the need for future research to elucidate inherited breast cancer risk.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Grupos Populacionais/genética , Detecção Precoce de Câncer/métodos , Feminino , Testes Genéticos/métodos , Humanos
3.
Hum Genomics ; 14(1): 30, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917282

RESUMO

The COVID-19 pandemic has strengthened the interest in the biological mechanisms underlying the complex interplay between infectious agents and the human host. The spectrum of phenotypes associated with the SARS-CoV-2 infection, ranging from the absence of symptoms to severe systemic complications, raised the question as to what extent the variable response to coronaviruses (CoVs) is influenced by the variability of the hosts' genetic background.To explore the current knowledge about this question, we designed a systematic review encompassing the scientific literature published from Jan. 2003 to June 2020, to include studies on the contemporary outbreaks caused by SARS-CoV-1, MERS-CoV and SARS-CoV-2 (namely SARS, MERS and COVID-19 diseases). Studies were eligible if human genetic variants were tested as predictors of clinical phenotypes.An ad hoc protocol for the rapid review process was designed according to the PRISMA paradigm and registered at the PROSPERO database (ID: CRD42020180860). The systematic workflow provided 32 articles eligible for data abstraction (28 on SARS, 1 on MERS, 3 on COVID-19) reporting data on 26 discovery cohorts. Most studies considered the definite clinical diagnosis as the primary outcome, variably coupled with other outcomes (severity was the most frequently analysed). Ten studies analysed HLA haplotypes (1 in patients with COVID-19) and did not provide consistent signals of association with disease-associated phenotypes. Out of 22 eligible articles that investigated candidate genes (2 as associated with COVID-19), the top-ranked genes in the number of studies were ACE2, CLEC4M (L-SIGN), MBL, MxA (n = 3), ACE, CD209, FCER2, OAS-1, TLR4, TNF-α (n = 2). Only variants in MBL and MxA were found as possibly implicated in CoV-associated phenotypes in at least two studies. The number of studies for each predictor was insufficient to conduct meta-analyses.Studies collecting large cohorts from different ancestries are needed to further elucidate the role of host genetic variants in determining the response to CoVs infection. Rigorous design and robust statistical methods are warranted.


Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/genética , Interações Hospedeiro-Patógeno/genética , Pneumonia Viral/genética , Betacoronavirus/patogenicidade , Infecções por Coronavirus/epidemiologia , Variação Genética/genética , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Pandemias , Fenótipo , Pneumonia Viral/epidemiologia , Vírus da SARS/genética , Vírus da SARS/patogenicidade , Síndrome Respiratória Aguda Grave/epidemiologia , Síndrome Respiratória Aguda Grave/genética
4.
Nat Commun ; 11(1): 4556, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917883

RESUMO

Previous genetic studies have identified local population structure within the Netherlands; however their resolution is limited by use of unlinked markers and absence of external reference data. Here we apply advanced haplotype sharing methods (ChromoPainter/fineSTRUCTURE) to study fine-grained population genetic structure and demographic change across the Netherlands using genome-wide single nucleotide polymorphism data (1,626 individuals) with associated geography (1,422 individuals). We identify 40 haplotypic clusters exhibiting strong north/south variation and fine-scale differentiation within provinces. Clustering is tied to country-wide ancestry gradients from neighbouring lands and to locally restricted gene flow across major Dutch rivers. North-south structure is temporally stable, with west-east differentiation more transient, potentially influenced by migrations during the middle ages. Despite superexponential population growth, regional demographic estimates reveal population crashes contemporaneous with the Black Death. Within Dutch and international data, GWAS incorporating fine-grained haplotypic covariates are less confounded than standard methods.


Assuntos
Grupos Étnicos/genética , Genética Populacional , Estudo de Associação Genômica Ampla , Estudos de Casos e Controles , Análise por Conglomerados , Emigração e Imigração , Grupo com Ancestrais do Continente Europeu/genética , Fluxo Gênico , Variação Genética/genética , Genoma , Geografia , Haplótipos , Humanos , Pessoa de Meia-Idade , Modelos Genéticos , Países Baixos , Polimorfismo de Nucleotídeo Único
5.
Genome Res ; 30(10): 1434-1448, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32878977

RESUMO

The human pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the major pandemic of the twenty-first century. We analyzed more than 4700 SARS-CoV-2 genomes and associated metadata retrieved from public repositories. SARS-CoV-2 sequences have a high sequence identity (>99.9%), which drops to >96% when compared to bat coronavirus genome. We built a mutation-annotated reference SARS-CoV-2 phylogeny with two main macro-haplogroups, A and B, both of Asian origin, and more than 160 sub-branches representing virus strains of variable geographical origins worldwide, revealing a rather uniform mutation occurrence along branches that could have implications for diagnostics and the design of future vaccines. Identification of the root of SARS-CoV-2 genomes is not without problems, owing to conflicting interpretations derived from either using the bat coronavirus genomes as an outgroup or relying on the sampling chronology of the SARS-CoV-2 genomes and TMRCA estimates; however, the overall scenario favors haplogroup A as the ancestral node. Phylogenetic analysis indicates a TMRCA for SARS-CoV-2 genomes dating to November 12, 2019, thus matching epidemiological records. Sub-haplogroup A2 most likely originated in Europe from an Asian ancestor and gave rise to subclade A2a, which represents the major non-Asian outbreak, especially in Africa and Europe. Multiple founder effect episodes, most likely associated with super-spreader hosts, might explain COVID-19 pandemic to a large extent.


Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/epidemiologia , Genoma Viral/genética , Pneumonia Viral/epidemiologia , Animais , Ásia/epidemiologia , Sequência de Bases/genética , Quirópteros/virologia , Mapeamento Cromossômico , Europa (Continente)/epidemiologia , Evolução Molecular , Variação Genética/genética , Humanos , Pandemias , Filogenia , Filogeografia , Homologia de Sequência do Ácido Nucleico
7.
Nat Commun ; 11(1): 3795, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32732942

RESUMO

Angiosperms have become the dominant terrestrial plant group by diversifying for ~145 million years into a broad range of environments. During the course of evolution, numerous morphological innovations arose, often preceded by whole genome duplications (WGD). The mustard family (Brassicaceae), a successful angiosperm clade with ~4000 species, has been diversifying into many evolutionary lineages for more than 30 million years. Here we develop a species inventory, analyze morphological variation, and present a maternal, plastome-based genus-level phylogeny. We show that increased morphological disparity, despite an apparent absence of clade-specific morphological innovations, is found in tribes with WGDs or diversification rate shifts. Both are important processes in Brassicaceae, resulting in an overall high net diversification rate. Character states show frequent and independent gain and loss, and form varying combinations. Therefore, Brassicaceae pave the way to concepts of phylogenetic genome-wide association studies to analyze the evolution of morphological form and function.


Assuntos
Evolução Biológica , Brassicaceae/classificação , Brassicaceae/genética , Evolução Molecular , Genoma de Planta/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla , Filogenia
8.
PLoS Genet ; 16(8): e1008947, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32833970

RESUMO

Genome-wide association studies (GWAS) have successfully identified tens of thousands of genetic variants associated with various phenotypes, but together they explain only a fraction of heritability, suggesting many variants have yet to be discovered. Recently it has been recognized that incorporating functional information of genetic variants can improve power for identifying novel loci. For example, S-PrediXcan and TWAS tested the association of predicted gene expression with phenotypes based on GWAS summary statistics by leveraging the information on genetic regulation of gene expression and found many novel loci. However, as genetic variants may have effects on more than one gene and through different mechanisms, these methods likely only capture part of the total effects of these variants. In this paper, we propose a summary statistics-based mixed effects score test (sMiST) that tests for the total effect of both the effect of the mediator by imputing genetically predicted gene expression, like S-PrediXcan and TWAS, and the direct effects of individual variants. It allows for multiple functional annotations and multiple genetically predicted mediators. It can also perform conditional association analysis while adjusting for other genetic variants (e.g., known loci for the phenotype). Extensive simulation and real data analyses demonstrate that sMiST yields p-values that agree well with those obtained from individual level data but with substantively improved computational speed. Importantly, a broad application of sMiST to GWAS is possible, as only summary statistics of genetic variant associations are required. We apply sMiST to a large-scale GWAS of colorectal cancer using summary statistics from ∼120, 000 study participants and gene expression data from the Genotype-Tissue Expression (GTEx) project. We identify several novel and secondary independent genetic loci.


Assuntos
Neoplasias Colorretais/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas/genética , Neoplasias Colorretais/patologia , Biologia Computacional , Regulação Neoplásica da Expressão Gênica/genética , Variação Genética/genética , Genótipo , Humanos , Modelos Estatísticos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
9.
PLoS One ; 15(8): e0238108, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32853264

RESUMO

Somatic structural variants are an important contributor to cancer development and evolution. Accurate detection of these complex variants from whole genome sequencing data is influenced by a multitude of parameters. However, there are currently no tools for guiding study design nor are there applications that could predict the performance of somatic structural variant detection. To address this gap, we developed Shiny-SoSV, a user-friendly web-based calculator for determining the impact of common variables on the sensitivity, precision and F1 score of somatic structural variant detection, including choice of variant detection tool, sequencing depth of coverage, variant allele fraction, and variant breakpoint resolution. Using simulation studies, we determined singular and combinatoric effects of these variables, modelled the results using a generalised additive model, allowing structural variant detection performance to be predicted for any combination of predictors. Shiny-SoSV provides an interactive and visual platform for users to easily compare individual and combined impact of different parameters. It predicts the performance of a proposed study design, on somatic structural variant detection, prior to the commencement of benchwork. Shiny-SoSV is freely available at https://hcpcg.shinyapps.io/Shiny-SoSV with accompanying user's guide and example use-cases.


Assuntos
Biologia Computacional/métodos , Variação Genética/genética , Algoritmos , Carcinogênese/genética , Genoma/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Internet , Neoplasias/genética , Software
10.
Nat Commun ; 11(1): 4020, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32782262

RESUMO

While variance components analysis has emerged as a powerful tool in complex trait genetics, existing methods for fitting variance components do not scale well to large-scale datasets of genetic variation. Here, we present a method for variance components analysis that is accurate and efficient: capable of estimating one hundred variance components on a million individuals genotyped at a million SNPs in a few hours. We illustrate the utility of our method in estimating and partitioning variation in a trait explained by genotyped SNPs (SNP-heritability). Analyzing 22 traits with genotypes from 300,000 individuals across about 8 million common and low frequency SNPs, we observe that per-allele squared effect size increases with decreasing minor allele frequency (MAF) and linkage disequilibrium (LD) consistent with the action of negative selection. Partitioning heritability across 28 functional annotations, we observe enrichment of heritability in FANTOM5 enhancers in asthma, eczema, thyroid and autoimmune disorders.


Assuntos
Variação Genética/genética , Genoma Humano/genética , Modelos Genéticos , Alelos , Frequência do Gene , Genótipo , Humanos , Desequilíbrio de Ligação , Herança Multifatorial/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Característica Quantitativa Herdável
11.
Am J Hum Genet ; 107(2): 175-182, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32763188

RESUMO

Expanded carrier screening (ECS) for recessive monogenic diseases requires prior knowledge of genomic variation, including DNA variants that cause disease. The composition of pathogenic variants differs greatly among human populations, but historically, research about monogenic diseases has focused mainly on people with European ancestry. By comparison, less is known about pathogenic DNA variants in people from other parts of the world. Consequently, inclusion of currently underrepresented Indigenous and other minority population groups in genomic research is essential to enable equitable outcomes in ECS and other areas of genomic medicine. Here, we discuss this issue in relation to the implementation of ECS in Australia, which is currently being evaluated as part of the national Government's Genomics Health Futures Mission. We argue that significant effort is required to build an evidence base and genomic reference data so that ECS can bring significant clinical benefit for many Aboriginal and/or Torres Strait Islander Australians. These efforts are essential steps to achieving the Australian Government's objectives and its commitment "to leveraging the benefits of genomics in the health system for all Australians." They require culturally safe, community-led research and community involvement embedded within national health and medical genomics programs to ensure that new knowledge is integrated into medicine and health services in ways that address the specific and articulated cultural and health needs of Indigenous people. Until this occurs, people who do not have European ancestry are at risk of being, in relative terms, further disadvantaged.


Assuntos
Metagenômica/métodos , Grupos Populacionais/genética , Austrália , Variação Genética/genética , Humanos
12.
Am J Hum Genet ; 107(3): 473-486, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32781046

RESUMO

Africa contains more human genetic variation than any other continent, but the majority of the population-scale analyses of the African peoples have focused on just two of the four major linguistic groups, the Niger-Congo and Afro-Asiatic, leaving the Nilo-Saharan and Khoisan populations under-represented. In order to assess genetic variation and signatures of selection within a Nilo-Saharan population and between the Nilo-Saharan and Niger-Congo and Afro-Asiatic, we sequenced 50 genomes from the Nilo-Saharan Lugbara population of North-West Uganda and 250 genomes from 6 previously unsequenced Niger-Congo populations. We compared these data to data from a further 16 Eurasian and African populations including the Gumuz, another putative Nilo-Saharan population from Ethiopia. Of the 21 million variants identified in the Nilo-Saharan population, 3.57 million (17%) were not represented in dbSNP and included predicted non-synonymous mutations with possible phenotypic effects. We found greater genetic differentiation between the Nilo-Saharan Lugbara and Gumuz populations than between any two Afro-Asiatic or Niger-Congo populations. F3 tests showed that Gumuz contributed a genetic component to most Niger-Congo B populations whereas Lugabara did not. We scanned the genomes of the Lugbara for evidence of selective sweeps. We found selective sweeps at four loci (SLC24A5, SNX13, TYRP1, and UVRAG) associated with skin pigmentation, three of which already have been reported to be under selection. These selective sweeps point toward adaptations to the intense UV radiation of the Sahel.


Assuntos
Adaptação Fisiológica/genética , Variação Genética/genética , Seleção Genética/genética , Pigmentação da Pele/genética , Grupo com Ancestrais do Continente Africano/genética , Antiporters/genética , Gerenciamento de Dados , Etiópia/epidemiologia , Feminino , Genética Populacional , Genoma Humano/genética , Haplótipos/genética , Humanos , Masculino , Glicoproteínas de Membrana/genética , Oxirredutases/genética , Polimorfismo de Nucleotídeo Único/genética , Nexinas de Classificação/genética , Proteínas Supressoras de Tumor/genética , Uganda/epidemiologia
13.
Genome Med ; 12(1): 57, 2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32605661

RESUMO

BACKGROUND: COVID-19 (coronavirus disease 2019) has caused a major epidemic worldwide; however, much is yet to be known about the epidemiology and evolution of the virus partly due to the scarcity of full-length SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) genomes reported. One reason is that the challenges underneath sequencing SARS-CoV-2 directly from clinical samples have not been completely tackled, i.e., sequencing samples with low viral load often results in insufficient viral reads for analyses. METHODS: We applied a novel multiplex PCR amplicon (amplicon)-based and hybrid capture (capture)-based sequencing, as well as ultra-high-throughput metatranscriptomic (meta) sequencing in retrieving complete genomes, inter-individual and intra-individual variations of SARS-CoV-2 from serials dilutions of a cultured isolate, and eight clinical samples covering a range of sample types and viral loads. We also examined and compared the sensitivity, accuracy, and other characteristics of these approaches in a comprehensive manner. RESULTS: We demonstrated that both amplicon and capture methods efficiently enriched SARS-CoV-2 content from clinical samples, while the enrichment efficiency of amplicon outran that of capture in more challenging samples. We found that capture was not as accurate as meta and amplicon in identifying between-sample variations, whereas amplicon method was not as accurate as the other two in investigating within-sample variations, suggesting amplicon sequencing was not suitable for studying virus-host interactions and viral transmission that heavily rely on intra-host dynamics. We illustrated that meta uncovered rich genetic information in the clinical samples besides SARS-CoV-2, providing references for clinical diagnostics and therapeutics. Taken all factors above and cost-effectiveness into consideration, we proposed guidance for how to choose sequencing strategy for SARS-CoV-2 under different situations. CONCLUSIONS: This is, to the best of our knowledge, the first work systematically investigating inter- and intra-individual variations of SARS-CoV-2 using amplicon- and capture-based whole-genome sequencing, as well as the first comparative study among multiple approaches. Our work offers practical solutions for genome sequencing and analyses of SARS-CoV-2 and other emerging viruses.


Assuntos
Betacoronavirus/genética , Genoma Viral/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento Completo do Genoma/métodos , Infecções por Coronavirus , Variação Genética/genética , Interações Hospedeiro-Patógeno/genética , Humanos , Reação em Cadeia da Polimerase Multiplex/métodos , Pandemias , Pneumonia Viral , RNA Viral/genética
14.
PLoS One ; 15(7): e0235434, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32649700

RESUMO

The genetic diversity of North American soybean cultivars has been largely influenced by a small number of ancestors. High yielding breeding lines that possess exotic pedigrees have been developed, but identifying beneficial exotic alleles has been difficult as a result of complex interactions of yield alleles with genetic backgrounds and environments as well as the highly quantitative nature of yield. PI 416937 has been utilized in the development of many high yielding lines that have been entered into the USDA Southern States Uniform Tests over the past ~20 years. The primary goal of this research was to identify genomic regions under breeding selection from PI 416937 and introduce a methodology for identifying and potentially utilizing beneficial diversity from lines prevalent in the ancestry of elite cultivars. Utilizing SoySNP50K Infinium BeadChips, 52 high yielding PI 416937-derived lines as well as their parents were genotyped to identify PI 416937 alleles under breeding selection. Nine genomic regions across three chromosomes and 17 genomic regions across seven chromosomes were identified where PI 416937 alleles were under positive or negative selection. Minimal significant associations between PI 416937 alleles and yield were observed in replicated yield trials of five RIL populations, highlighting the difficulty of consistently detecting yield associations.


Assuntos
Cruzamento , Variação Genética/genética , Soja/genética , Alelos , Mapeamento Cromossômico , Cromossomos de Plantas , Genoma de Planta/genética , Genômica , Genótipo , Humanos , Locos de Características Quantitativas/genética , Sementes/genética , Sementes/crescimento & desenvolvimento , Soja/crescimento & desenvolvimento , Estados Unidos
15.
PLoS Comput Biol ; 16(7): e1007504, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32692749

RESUMO

NGS studies have uncovered an ever-growing catalog of human variation while leaving an enormous gap between observed variation and experimental characterization of variant function. High-throughput screens powered by NGS have greatly increased the rate of variant functionalization, but the development of comprehensive statistical methods to analyze screen data has lagged. In the massively parallel reporter assay (MPRA), short barcodes are counted by sequencing DNA libraries transfected into cells and the cell's output RNA in order to simultaneously measure the shifts in transcription induced by thousands of genetic variants. These counts present many statistical challenges, including overdispersion, depth dependence, and uncertain DNA concentrations. So far, the statistical methods used have been rudimentary, employing transformations on count level data and disregarding experimental and technical structure while failing to quantify uncertainty in the statistical model. We have developed an extensive framework for the analysis of NGS functionalization screens available as an R package called malacoda (available from github.com/andrewGhazi/malacoda). Our software implements a probabilistic, fully Bayesian model of screen data. The model uses the negative binomial distribution with gamma priors to model sequencing counts while accounting for effects from input library preparation and sequencing depth. The method leverages the high-throughput nature of the assay to estimate the priors empirically. External annotations such as ENCODE data or DeepSea predictions can also be incorporated to obtain more informative priors-a transformative capability for data integration. The package also includes quality control and utility functions, including automated barcode counting and visualization methods. To validate our method, we analyzed several datasets using malacoda and alternative MPRA analysis methods. These data include experiments from the literature, simulated assays, and primary MPRA data. We also used luciferase assays to experimentally validate several hits from our primary data, as well as variants for which the various methods disagree and variants detectable only with the aid of external annotations.


Assuntos
Biologia Computacional/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Modelos Estatísticos , Análise de Sequência de DNA/métodos , Software , Teorema de Bayes , Variação Genética/genética , Humanos
16.
Am J Hum Genet ; 107(3): 544-554, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32730804

RESUMO

RNA polymerase II interacts with various other complexes and factors to ensure correct initiation, elongation, and termination of mRNA transcription. One of these proteins is SR-related CTD-associated factor 4 (SCAF4), which is important for correct usage of polyA sites for mRNA termination. Using exome sequencing and international matchmaking, we identified nine likely pathogenic germline variants in SCAF4 including two splice-site and seven truncating variants, all residing in the N-terminal two thirds of the protein. Eight of these variants occurred de novo, and one was inherited. Affected individuals demonstrated a variable neurodevelopmental disorder characterized by mild intellectual disability, seizures, behavioral abnormalities, and various skeletal and structural anomalies. Paired-end RNA sequencing on blood lymphocytes of SCAF4-deficient individuals revealed a broad deregulation of more than 9,000 genes and significant differential splicing of more than 2,900 genes, indicating an important role of SCAF4 in mRNA processing. Knockdown of the SCAF4 ortholog CG4266 in the model organism Drosophila melanogaster resulted in impaired locomotor function, learning, and short-term memory. Furthermore, we observed an increased number of active zones in larval neuromuscular junctions, representing large glutamatergic synapses. These observations indicate a role of CG4266 in nervous system development and function and support the implication of SCAF4 in neurodevelopmental phenotypes. In summary, our data show that heterozygous, likely gene-disrupting variants in SCAF4 are causative for a variable neurodevelopmental disorder associated with impaired mRNA processing.


Assuntos
Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Convulsões/genética , Fatores de Processamento de Serina-Arginina/genética , Animais , Criança , Drosophila melanogaster/genética , Feminino , Técnicas de Silenciamento de Genes , Variação Genética/genética , Heterozigoto , Humanos , Deficiência Intelectual/fisiopatologia , Locomoção/genética , Masculino , Mutação/genética , Transtornos do Neurodesenvolvimento/fisiopatologia , RNA Polimerase II/genética , Processamento Pós-Transcricional do RNA/genética , RNA Mensageiro/genética , Convulsões/fisiopatologia , Sequenciamento Completo do Exoma
17.
Am J Hum Genet ; 107(2): 330-341, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32619401

RESUMO

Sperm malformation is a direct factor for male infertility. Multiple morphological abnormalities of the flagella (MMAF), a severe form of asthenoteratozoospermia, are characterized by immotile spermatozoa with malformed and/or absent flagella in the ejaculate. Previous studies indicated genetic heterogeneity in MMAF. To further define genetic factors underlying MMAF, we performed whole-exome sequencing in a cohort of 90 Chinese MMAF-affected men. Two cases (2.2%) were identified as carrying bi-allelic missense DNAH8 variants, variants which were either absent or rare in the control human population and were predicted to be deleterious by multiple bioinformatic tools. Re-analysis of exome data from a second cohort of 167 MMAF-affected men from France, Iran, and North Africa permitted the identification of an additional male carrying a DNAH8 homozygous frameshift variant. DNAH8 encodes a dynein axonemal heavy-chain component that is expressed preferentially in the testis. Hematoxylin-eosin staining and electron microscopy analyses of the spermatozoa from men harboring bi-allelic DNAH8 variants showed a highly aberrant morphology and ultrastructure of the sperm flagella. Immunofluorescence assays performed on the spermatozoa from men harboring bi-allelic DNAH8 variants revealed the absent or markedly reduced staining of DNAH8 and its associated protein DNAH17. Dnah8-knockout male mice also presented typical MMAF phenotypes and sterility. Interestingly, intracytoplasmic sperm injections using the spermatozoa from Dnah8-knockout male mice resulted in good pregnancy outcomes. Collectively, our experimental observations from humans and mice demonstrate that DNAH8 is essential for sperm flagellar formation and that bi-allelic deleterious DNAH8 variants lead to male infertility with MMAF.


Assuntos
Anormalidades Múltiplas/genética , Dineínas do Axonema/genética , Flagelos/genética , Variação Genética/genética , Infertilidade Masculina/genética , Cauda do Espermatozoide/patologia , Alelos , Animais , Estudos de Coortes , Exoma/genética , Feminino , Homozigoto , Humanos , Masculino , Camundongos , Camundongos Knockout , Espermatozoides/anormalidades , Testículo/anormalidades , Sequenciamento Completo do Exoma/métodos
18.
Nutr. hosp ; 37(3): 524-533, mayo-jun. 2020. tab, graf
Artigo em Inglês | IBECS | ID: ibc-193860

RESUMO

BACKGROUND: food is a powerful reinforcer that motivates people to eat. The TaqI A1 polymorphism (rs1800497; T>C) downstream of the dopamine D2 receptor (DRD2) gene has been associated with diminished DRD2 receptor density, higher food reinforcement, and impaired eating behavior in adults. OBJECTIVE: to evaluate the association between the rs1800497 polymorphism and the reinforcing value of food and eating in the absence of hunger in Chilean children. MATERIAL AND METHOD: nineteen Chilean children (aged 8-12 years) who were carriers of the A1-allele and 19 age- and gender-matched non-carriers (A2-allele) were evaluated on the reinforcing value of food and eating in the absence of hunger. Anthropometric measures were performed by standard procedures. Briefly, children received a standard pre-load lunch followed by an ad-libitum exposure to palatable foods. RESULTS: no differences were found between A1-allele carriers and non-carriers, whether obese or non-obese, in ad libitum energy intake, macronutrient consumption, or the relative reinforcing value of food (p > 0.05). In obese children, A1 carriers reported significantly lower satiety and fullness before lunch (p < 0.05). However, in children with normal weight A1 carriers were found to exhibit trends for greater satiety and fullness before lunch when compared to non-carriers, but this trend reversed after lunch such that carriers exhibited lower satiety and fullness (p = 0.06). CONCLUSIONS: although TaqI A1 may play an important role in some eating behavior-related traits such as satiety and fullness, especially in obese children, our findings indicate that this polymorphism does not appear to affect eating in the absence of hunger or food reinforcement in children


ANTECEDENTES: los alimentos son un poderoso reforzador de la alimentación. El polimorfismo TaqI A1 (rs1800497; T> C) del gen del receptor 2 de dopamina (DRD2) se ha asociado con una menor densidad de DRD2, un mayor refuerzo alimentario y un comportamiento alimentario alterado en adultos. OBJETIVO: evaluar la asociación entre el polimorfismo rs1800497, el valor reforzador del alimento y la conducta de comer en ausencia de hambre en niños chilenos. MATERIAL Y MÉTODO: treinta y ocho niños chilenos, 19 portadores del alelo A1 y 19 no portadores (alelo A2), pareados por género y edad, fueron evaluados en condiciones de laboratorio para determinar el valor reforzador del alimento y la conducta de comer en ausencia de hambre. Las mediciones antropométricas se realizaron por procedimientos estándar. Brevemente, los niños recibieron un almuerzo estándar seguido de una exposición ad-libitum a alimentos sabrosos. RESULTADOS: no hubo diferencias en la ingesta ad libitum de energía, ni en el consumo de macronutrientes, ni en el valor reforzador del alimento entre los portadores del alelo A1 frente a los no portadores (p > 0,05). Entre los niños obesos, los portadores del alelo A1 reportaron un menor nivel de saciedad y plenitud pre-almuerzo (p < 0,05). Sin embargo, entre los niños con normopeso se observó que los portadores de A1 tenían tendencia a presentar un mayor grado de saciedad y plenitud (pre-almuerzo) frente a los no portadores. Esta tendencia se invirtió post-almuerzo, de modo que los portadores exhibieron menor saciedad y plenitud (p = 0,06). CONCLUSIONES: la variante TaqI A1 podría desempeñar un papel importante en algunos rasgos relacionados con la conducta alimentaria, como la saciedad y la plenitud


Assuntos
Humanos , Masculino , Feminino , Criança , Fome/fisiologia , Variação Genética/genética , Comportamento Alimentar/fisiologia , Ingestão de Energia/genética , Obesidade/genética , Receptores de Dopamina D2/genética , Chile , Variação Genética/efeitos dos fármacos , Polimorfismo Genético/genética , Antropometria , Peso Corporal/genética , Ingestão de Energia/fisiologia , Receptores de Dopamina D2/fisiologia
19.
Medicine (Baltimore) ; 99(26): e20716, 2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32590746

RESUMO

Genome-wide association studies (GWAS) have identified multiple independent cancer susceptibility loci at chromosome 8q24. We aimed to evaluate the associations between variants in the 8q24 region and cancer susceptibility. A comprehensive research synopsis and meta-analysis was performed to evaluate associations between 28 variants in 8q24 and risk of 7 cancers using data from 103 eligible articles totaling 146,932 cancer cases and 219,724 controls. Results: 20 variants were significantly associated with risk of prostate cancer, colorectal cancer, thyroid cancer, breast cancer, bladder cancer, stomach cancer, and glioma, including 1 variant associated with prostate cancer, colorectal cancer, and thyroid cancer. Cumulative epidemiological evidence of an association was graded as strong for DG8S737 -8 allele, rs10090154, rs7000448 in prostate cancer, rs10808556 in colorectal cancer, rs55705857 in gliomas, rs9642880 in bladder cancer, moderate for rs16901979, rs1447295, rs6983267, rs7017300, rs7837688, rs1016343, rs620861, rs10086908 associated in prostate cancer, rs10505477, rs6983267 in colorectal cancer, rs6983267 in thyroid cancer, rs13281615 in breast cancer, and rs1447295 in stomach cancer, weak for rs6983561, rs13254738, rs7008482, rs4242384 in prostate cancer. Data from ENCODE suggested that these variants with strong evidence and other correlated variants might fall within putative functional regions. Our study provides summary evidence that common variants in the 8q24 are associated with risk of multiple cancers in this large-scale research synopsis and meta-analysis. Further studies are needed to explore the mechanisms underlying variants in the 8q24 involved in various human cancers.


Assuntos
Predisposição Genética para Doença/epidemiologia , Variação Genética/genética , Neoplasias/genética , Estudo de Associação Genômica Ampla , Humanos , Neoplasias/classificação , Neoplasias/epidemiologia
20.
PLoS One ; 15(6): e0233377, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32502155

RESUMO

The biology of how faces are built and come to differ from one another is complex. Discovering normal variants that contribute to differences in facial morphology is one key to untangling this complexity, with important implications for medicine and evolutionary biology. This study maps quantitative trait loci (QTL) for skeletal facial shape using Diversity Outbred (DO) mice. The DO is a randomly outcrossed population with high heterozygosity that captures the allelic diversity of eight inbred mouse lines from three subspecies. The study uses a sample of 1147 DO animals (the largest sample yet employed for a shape QTL study in mouse), each characterized by 22 three-dimensional landmarks, 56,885 autosomal and X-chromosome markers, and sex and age classifiers. We identified 37 facial shape QTL across 20 shape principal components (PCs) using a mixed effects regression that accounts for kinship among observations. The QTL include some previously identified intervals as well as new regions that expand the list of potential targets for future experimental study. Three QTL characterized shape associations with size (allometry). Median support interval size was 3.5 Mb. Narrowing additional analysis to QTL for the five largest magnitude shape PCs, we found significant overrepresentation of genes with known roles in growth, skeletal and facial development, and sensory organ development. For most intervals, one or more of these genes lies within 0.25 Mb of the QTL's peak. QTL effect sizes were small, with none explaining more than 0.5% of facial shape variation. Thus, our results are consistent with a model of facial diversity that is influenced by key genes in skeletal and facial development and, simultaneously, is highly polygenic.


Assuntos
Desenvolvimento Ósseo/genética , Ossos Faciais/anatomia & histologia , Desenvolvimento Maxilofacial/genética , Alelos , Animais , Osso e Ossos/anatomia & histologia , Mapeamento Cromossômico/métodos , Camundongos de Cruzamento Colaborativo/genética , Face/anatomia & histologia , Feminino , Variação Genética/genética , Genótipo , Masculino , Camundongos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética
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