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1.
Zool Res ; 41(6): 605-620, 2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-32935498

RESUMO

Spain has been one of the main global pandemic epicenters for coronavirus disease 2019 (COVID-19). Here, we analyzed >41 000 genomes (including >26 000 high-quality (HQ) genomes) downloaded from the GISAID repository, including 1 245 (922 HQ) sampled in Spain. The aim of this study was to investigate genome variation of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and reconstruct phylogeographic and transmission patterns in Spain. Phylogeographic analysis suggested at least 34 independent introductions of SARS-CoV-2 to Spain at the beginning of the outbreak. Six lineages spread very successfully in the country, probably favored by super-spreaders, namely, A2a4 (7.8%), A2a5 (38.4%), A2a10 (2.8%), B3a (30.1%), and B9 (8.7%), which accounted for 87.9% of all genomes in the Spanish database. One distinct feature of the Spanish SARS-CoV-2 genomes was the higher frequency of B lineages (39.3%, mainly B3a+B9) than found in any other European country. While B3a, B9, (and an important sub-lineage of A2a5, namely, A2a5c) most likely originated in Spain, the other three haplogroups were imported from other European locations. The B3a strain may have originated in the Basque Country from a B3 ancestor of uncertain geographic origin, whereas B9 likely emerged in Madrid. The time of the most recent common ancestor (TMRCA) of SARS-CoV-2 suggested that the first coronavirus entered the country around 11 February 2020, as estimated from the TMRCA of B3a, the first lineage detected in the country. Moreover, earlier claims that the D614G mutation is associated to higher transmissibility is not consistent with the very high prevalence of COVID-19 in Spain when compared to other countries with lower disease incidence but much higher frequency of this mutation (56.4% in Spain vs. 82.4% in rest of Europe). Instead, the data support a major role of genetic drift in modeling the micro-geographic stratification of virus strains across the country as well as the role of SARS-CoV-2 super-spreaders.


Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/transmissão , Variação Genética , Genoma Viral/genética , Pneumonia Viral/transmissão , Animais , Betacoronavirus/classificação , Betacoronavirus/fisiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Evolução Molecular , Efeito Fundador , Geografia , Haplótipos , Humanos , Mutação , Pandemias , Filogenia , Filogeografia , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Espanha/epidemiologia
2.
PLoS Pathog ; 16(9): e1008853, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32886726

RESUMO

HIV-1 transmission is associated with a severe bottleneck in which a limited number of variants from a pool of genetically diverse quasispecies establishes infection. The IAVI protocol C cohort of discordant couples, female sex workers, other heterosexuals and men who have sex with men (MSM) present varying risks of HIV infection, diverse HIV-1 subtypes and represent a unique opportunity to characterize transmitted/founder viruses (TF) where disease outcome is known. To identify the TF, the HIV-1 repertoire of 38 MSM participants' samples was sequenced close to transmission (median 21 days post infection, IQR 18-41) and assessment of multivariant infection done. Patient derived gag genes were cloned into an NL4.3 provirus to generate chimeric viruses which were characterized for replicative capacity (RC). Finally, an evaluation of how the TF virus predicted disease progression and modified the immune response at both acute and chronic HIV-1 infection was done. There was higher prevalence of multivariant infection compared with previously described heterosexual cohorts. A link was identified between multivariant infection and replicative capacity conferred by gag, whereby TF gag tended to be of lower replicative capacity in multivariant infection (p = 0.02) suggesting an overall lowering of fitness requirements during infection with multiple variants. Notwithstanding, multivariant infection was associated with rapid CD4+ T cell decline and perturbances in the CD4+ T cell and B cell compartments compared to single variant infection, which were reversible upon control of viremia. Strategies aimed at identifying and mitigating multivariant infection could contribute toward improving HIV-1 prognosis and this may involve strategies that tighten the stringency of the transmission bottleneck such as treatment of STI. Furthermore, the sequences and chimeric viruses help with TF based experimental vaccine immunogen design and can be used in functional assays to probe effective immune responses against TF.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Efeito Fundador , Infecções por HIV , HIV-1/fisiologia , Replicação Viral , Produtos do Gene gag do Vírus da Imunodeficiência Humana , Doença Aguda , Adolescente , Adulto , Linfócitos B/imunologia , Linfócitos B/patologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD4-Positivos/virologia , Feminino , Infecções por HIV/genética , Infecções por HIV/imunologia , Infecções por HIV/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Viremia/genética , Viremia/imunologia , Viremia/patologia , Replicação Viral/genética , Replicação Viral/imunologia , Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética , Produtos do Gene gag do Vírus da Imunodeficiência Humana/imunologia
5.
Science ; 369(6499): 103-108, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32631894

RESUMO

During sexual transmission, the high genetic diversity of HIV-1 within an individual is frequently reduced to one founder variant that initiates infection. Understanding the drivers of this bottleneck is crucial to developing effective infection control strategies. Little is known about the importance of the source partner during this bottleneck. To test the hypothesis that the source partner affects the number of HIV founder variants, we developed a phylodynamic model calibrated using genetic and epidemiological data on all existing transmission pairs for whom the direction of transmission and the infection stage of the source partner are known. Our results suggest that acquiring infection from someone in the acute (early) stage of infection increases the risk of multiple-founder variant transmission compared with acquiring infection from someone in the chronic (later) stage of infection. This study provides the first direct test of source partner characteristics to explain the low frequency of multiple-founder strain infections.


Assuntos
Efeito Fundador , Infecções por HIV/transmissão , Infecções por HIV/virologia , HIV-1/genética , Variação Genética , HIV-1/classificação , Humanos , Filogenia , Parceiros Sexuais , Carga Viral
6.
J Dairy Sci ; 103(7): 6346-6353, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32359986

RESUMO

The availability of genomic marker panels has made possible more precise estimates of breeding values. Sheep breeding programs are implementing genomic selection. In Latxa dairy sheep breed, a previous study using pre-corrected data and a small number of genotyped animals did not show a clear advantage of genomic selection. The objective of the present study was to ascertain the possible benefits of GS for the Latxa breed based on more data than before and using better tools, in particular single-step genomic BLUP using metafounders to model missing pedigree. Goodness of prediction of pedigree and genomic evaluations was analyzed by cross-validation comparing predictions of young rams using whole and partial (truncated) data sets. The results showed that with the current available data, genetic and genomic evaluations have the same accuracy. Contrary to the previous study, predictions were nearly unbiased, which shows the advantage of using single-step genomic BLUP. However, genomic information did not yield more precise evaluations. This could be explained by the small number of sibs in the young rams.


Assuntos
Genômica , Seleção Artificial , Carneiro Doméstico/genética , Animais , Feminino , Efeito Fundador , Genoma , Genômica/métodos , Genótipo , Masculino , Linhagem
7.
Nat Rev Genet ; 21(8): 449-460, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32265525

RESUMO

The domestication of animals led to a major shift in human subsistence patterns, from a hunter-gatherer to a sedentary agricultural lifestyle, which ultimately resulted in the development of complex societies. Over the past 15,000 years, the phenotype and genotype of multiple animal species, such as dogs, pigs, sheep, goats, cattle and horses, have been substantially altered during their adaptation to the human niche. Recent methodological innovations, such as improved ancient DNA extraction methods and next-generation sequencing, have enabled the sequencing of whole ancient genomes. These genomes have helped reconstruct the process by which animals entered into domestic relationships with humans and were subjected to novel selection pressures. Here, we discuss and update key concepts in animal domestication in light of recent contributions from ancient genomics.


Assuntos
Animais Selvagens , Domesticação , Genômica , Criação de Animais Domésticos , Animais , DNA Antigo , DNA Mitocondrial , Efeito Fundador , Genômica/história , Genômica/métodos , História Antiga , Modelos Teóricos , Seleção Genética , Análise Espaço-Temporal
8.
Open Heart ; 7(1): e001220, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32341788

RESUMO

Objective: The myosin-binding protein C (MYBPC3) c.927-2A>G founder mutation accounts for >90% of sarcomeric hypertrophic cardiomyopathy (HCM) in Iceland. This cross-sectional observational study explored the penetrance and phenotypic burden among carriers of this single, prevalent founder mutation. Methods: We studied 60 probands with HCM caused by MYBPC3 c.927-2A>G and 225 first-degree relatives. All participants underwent comprehensive clinical evaluation and relatives were genotyped. Results: Genetic and clinical evaluation of relatives identified 49 genotype-positive (G+) relatives with left ventricular hypertrophy (G+/LVH+), 59 G+without LVH (G+/LVH-) and 117 genotype-negative relatives (unaffected). Compared with HCM probands, G+/LVH+ relatives were older at HCM diagnosis, had less LVH, a less prevalent diastolic dysfunction, fewer ECG abnormalities, lower serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I levels, and fewer symptoms. The penetrance of HCM was influenced by age and sex; specifically, LVH was present in 39% of G+males but only 9% of G+females under age 40 years (p=0.015), versus 86% and 83%, respectively, after age 60 (p=0.89). G+/LVH- subjects had normal wall thicknesses, diastolic function and NT-proBNP levels, but subtle changes in LV geometry and more ECG abnormalities than their unaffected relatives. Conclusions: Phenotypic expression of the Icelandic MYBPC3 founder mutation varies by age, sex and proband status. Men are more likely to have LVH at a younger age, and disease manifestations were more prominent in probands than in relatives identified via family screening. G+/LVH- individuals had subtle clinical differences from unaffected relatives well into adulthood, indicating subclinical phenotypic expression of the pathogenic mutation.


Assuntos
Cardiomiopatia Hipertrófica/genética , Proteínas de Transporte/genética , Efeito Fundador , Heterozigoto , Mutação , Sarcômeros/genética , Função Ventricular Esquerda/genética , Remodelação Ventricular/genética , Adulto , Idade de Início , Idoso , Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/fisiopatologia , Estudos Transversais , Feminino , Predisposição Genética para Doença , Hemodinâmica/genética , Hereditariedade , Humanos , Islândia , Masculino , Pessoa de Meia-Idade , Linhagem , Penetrância , Fenótipo , Fatores de Risco
9.
PLoS One ; 15(2): e0229025, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32069299

RESUMO

Mutations in CYP4F22 cause autosomal recessive congenital ichthyosis (ARCI). However, less than 10% of all ARCI patients carry a mutation in CYP4F22. In order to identify the molecular basis of ARCI among our patients (a cohort of ninety-two Spanish individuals) we performed a mutational analysis using direct Sanger sequencing in combination with a multigene targeted NGS panel. From these, eight ARCI families (three of them with Moroccan origin) were found to carry five different CYP4F22 mutations, of which two were novel. Computational analysis showed that the mutations found were present in highly conserved residues of the protein and may affect its structure and function. Seven of the eight families were carriers of a highly recurrent CYP4F22 variant, c.1303C>T; p.(His435Tyr). A 12Mb haplotype was reconstructed in all c.1303C>T carriers by genotyping ten microsatellite markers flanking the CYP4F22 gene. A prevalent 2.52Mb haplotype was observed among Spanish carrier patients suggesting a recent common ancestor. A smaller core haplotype of 1.2Mb was shared by Spanish and Moroccan families. Different approaches were applied to estimate the time to the most recent common ancestor (TMRCA) of carrier patients with Spanish origin. The age of the mutation was calculated by using DMLE and BDMC2. The algorithms estimated that the c.1303C>T variant arose approximately 2925 to 4925 years ago, while Spanish carrier families derived from a common ancestor who lived in the XIII century. The present study reports five CYP4F22 mutations, two of them novel, increasing the number of CYP4F22 mutations currently listed. Additionally, our results suggest that the recurrent c.1303C>T change has a founder effect in Spanish population and c.1303C>T carrier families originated from a single ancestor with probable African ancestry.


Assuntos
Sistema Enzimático do Citocromo P-450/genética , Efeito Fundador , Genes Recessivos , Ictiose Lamelar/genética , Mutação , Alelos , Substituição de Aminoácidos , Criança , Pré-Escolar , Sistema Enzimático do Citocromo P-450/química , Feminino , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Linhagem , Fenótipo , Conformação Proteica , Espanha , Relação Estrutura-Atividade
10.
J Leukoc Biol ; 107(6): 993-1007, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32068302

RESUMO

Cutting-edge questions in αß T cell biology were addressed by investigating a range of different genetically modified mouse models. In comparison, the γδ T cell field lacks behind on the availability of such models. Nevertheless, transgenic mouse models proved useful for the investigation of γδ T cell biology and their stepwise development in the thymus. In general, animal models and especially mouse models give access to a wide range of opportunities of modulating γδ T cells, which is unachievable in human beings. Because of their complex biology and specific tissue tropism, it is especially challenging to investigate γδ T cells in in vitro experiments since they might not reliably reflect their behavior and phenotype under physiologic conditions. This review aims to provide a comprehensive historical overview about how different transgenic mouse models contributed in regards of the understanding of γδ T cell biology, whereby a special focus is set on studies including the elusive role of the γδTCR. Furthermore, evolutionary and translational remarks are discussed under the aspect of future implications for the field. The ultimate full understanding of γδ T cells will pave the way for their usage as a powerful new tool in immunotherapy.


Assuntos
Linhagem da Célula/imunologia , Efeito Fundador , Camundongos Transgênicos/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/genética , Linfócitos T/imunologia , Animais , Diferenciação Celular , Linhagem da Célula/genética , Movimento Celular , Expressão Gênica , Humanos , Imunoterapia/métodos , Camundongos , Camundongos Transgênicos/genética , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Transdução de Sinais , Especificidade da Espécie , Linfócitos T/classificação , Linfócitos T/citologia , Timo/citologia , Timo/imunologia
11.
PLoS One ; 15(1): e0227260, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31978118

RESUMO

Sarcomas represent less than 1% of all solid neoplasms in adults and over 20% in children. Their etiology is unclear, but genetic susceptibility plays an important role in this scenario. Sarcoma is central in Li-Fraumeni Syndrome (LFS), a familial predisposition cancer syndrome. In Brazil, the high prevalence of p.Arg337His mutations in the TP53 gene brings about a unique condition: a cluster of LFS. In the present work, we studied 502 sarcoma patients not selected by age or family history in an attempt to assess the impact of the so-called "Brazilian germline TP53 mutation" (p.Arg337His) on this tumor type. We found that 8% of patients are carriers, with leiomyosarcoma being the main histologic type of sarcoma, corresponding to 52.5% of the patients with the mutated TP53 gene. These findings emphasize the importance of genetic counseling and can better guide the management of sarcoma patients.


Assuntos
Predisposição Genética para Doença , Síndrome de Li-Fraumeni/genética , Sarcoma/genética , Proteína Supressora de Tumor p53/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil/epidemiologia , Feminino , Efeito Fundador , Aconselhamento Genético , Mutação em Linhagem Germinativa , Humanos , Síndrome de Li-Fraumeni/diagnóstico , Síndrome de Li-Fraumeni/epidemiologia , Síndrome de Li-Fraumeni/patologia , Masculino , Pessoa de Meia-Idade , Prevalência , Sarcoma/diagnóstico , Sarcoma/epidemiologia , Sarcoma/patologia , Adulto Jovem
12.
PLoS One ; 15(1): e0227127, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31923263

RESUMO

If viruses or other pathogens infect a single host, the outcome of infection may depend on the initial basic reproduction number R0, the expected number of host cells infected by a single infected cell. This article shows that sometimes, phylogenetic models can estimate the initial R0, using only sequences sampled from the pathogenic population during its exponential growth or shortly thereafter. When evaluated by simulations mimicking the bursting viral reproduction of HIV and simultaneous sampling of HIV gp120 sequences during early viremia, the estimated R0 displayed useful accuracies in achievable experimental designs. Estimates of R0 have several potential applications to investigators interested in the progress of infection in single hosts, including: (1) timing a pathogen's movement through different microenvironments; (2) timing the change points in a pathogen's mode of spread (e.g., timing the change from cell-free spread to cell-to-cell spread, or vice versa, in an HIV infection); (3) quantifying the impact different initial microenvironments have on pathogens (e.g., in mucosal challenge with HIV, quantifying the impact that the presence or absence of mucosal infection has on R0); (4) quantifying subtle changes in infectability in therapeutic trials (either human or animal), even when therapies do not produce total sterilizing immunity; and (5) providing a variable predictive of the clinical efficacy of prophylactic therapies.


Assuntos
Número Básico de Reprodução , Efeito Fundador , Estatística como Assunto/métodos , Viroses/epidemiologia , Vírus/patogenicidade , Sequência de Aminoácidos , Animais , Proteína gp120 do Envelope de HIV/genética , Infecções por HIV/epidemiologia , Humanos , Modelos Genéticos , Filogenia
13.
Theor Appl Genet ; 133(3): 785-808, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31996971

RESUMO

KEY MESSAGE: A locus on wheat chromosome 2A was found to control field resistance to both leaf and glume blotch caused by the necrotrophic fungal pathogen Parastagonospora nodorum. The necrotrophic fungal pathogen Parastagonospora nodorum is the causal agent of Septoria nodorum leaf blotch and glume blotch, which are common wheat (Triticum aestivum L.) diseases in humid and temperate areas. Susceptibility to Septoria nodorum leaf blotch can partly be explained by sensitivity to corresponding P. nodorum necrotrophic effectors (NEs). Susceptibility to glume blotch is also quantitative; however, the underlying genetics have not been studied in detail. Here, we genetically map resistance/susceptibility loci to leaf and glume blotch using an eight-founder wheat multiparent advanced generation intercross population. The population was assessed in six field trials across two sites and 4 years. Seedling infiltration and inoculation assays using three P. nodorum isolates were also carried out, in order to compare quantitative trait loci (QTL) identified under controlled conditions with those identified in the field. Three significant field resistance QTL were identified on chromosomes 2A and 6A, while four significant seedling resistance QTL were detected on chromosomes 2D, 5B and 7D. Among these, QSnb.niab-2A.3 for field resistance to both leaf blotch and glume blotch was detected in Norway and the UK. Colocation with a QTL for seedling reactions against culture filtrate from a Norwegian P. nodorum isolate indicated the QTL could be caused by a novel NE sensitivity. The consistency of this QTL for leaf blotch at the seedling and adult plant stages and culture filtrate infiltration was confirmed by haplotype analysis. However, opposite effects for the leaf blotch and glume blotch reactions suggest that different genetic mechanisms may be involved.


Assuntos
Ascomicetos/patogenicidade , Resistência à Doença/genética , Doenças das Plantas/genética , Triticum/genética , Mapeamento Cromossômico , Cromossomos de Plantas , Efeito Fundador , Noruega , Fenótipo , Doenças das Plantas/microbiologia , Folhas de Planta/microbiologia , Locos de Características Quantitativas , Triticum/microbiologia , Reino Unido
14.
Oecologia ; 192(1): 105-118, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31792607

RESUMO

Multiple mechanisms may act synergistically to promote success of invasive plants. Here, we tested the roles of three non-mutually exclusive mechanisms-founder effects, post-introduction evolution and phenotypic plasticity-in promoting invasion of Chromolaena odorata. We performed a common garden experiment to investigate phenotypic diversification and phenotypic plasticity of the genetically impoverished invader in response to two rainfall treatments (ambient and 50% rainfall). We used ancestor-descendant comparisons to determine post-introduction evolution and the QST-FST approach to estimate past selection on phenotypic traits. We found that eight traits differed significantly between plants from the invasive versus native ranges, for two of which founder effects can be inferred and for six of which post-introduction evolution can be inferred. The invader experienced strong diversifying selection in the invasive range and showed clinal variations in six traits along water and/or temperature gradients. These clinal variations are likely attributed to post-introduction evolution rather than multiple introductions of pre-adapted genotypes, as most of the clinal variations were absent or in opposite directions from those for native populations. Compared with populations, rainfall treatments explained only small proportions of total variations in all studied traits for plants from both ranges, highlighting the importance of heritable phenotypic differentiation. In addition, phenotypic plasticity was similar for plants from both ranges although neutral genetic diversity was much lower for plants from the invasive range. Our results showed that founder effects, post-introduction evolution and phenotypic plasticity may function synergistically in promoting invasion success of C. odorata.


Assuntos
Evolução Biológica , Efeito Fundador , Adaptação Fisiológica , Espécies Introduzidas , Fenótipo
15.
Genes Chromosomes Cancer ; 59(2): 111-118, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31433521

RESUMO

Interpretation of missense variants remains a major challenge for genetic diagnosis, even in well-known genes such as the DNA-mismatch repair (MMR) genes involved in Lynch syndrome. We report the characterization of a variant in MSH2: c.1022T>C, which was identified in 20 apparently unrelated families living in the North of France. A total of 150 patients from 20 families were included in this study. Family segregation studies, tumor analyses and functional analyses at both the RNA and protein levels were performed. Founder effect was evaluated by haplotype analysis.We show that MSH2 c.1022T>C is a missense variant (p.Leu341Pro) that affects protein stability. This variant is frequent in the North of France (7.7% of pathogenic variations identified in MMR genes), and is located on an ancestral haplotype. It is associated with a high risk of a broad tumor spectrum including brain and cutaneous cancers. The MSH2 c.1022T>C variant is a pathogenic founder variation associated with a high risk of cancer. These findings have important implications for genetic counseling and management of variant carriers.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Proteína 2 Homóloga a MutS/genética , Adulto , Idoso , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Reparo de Erro de Pareamento de DNA , Éxons , Feminino , Efeito Fundador , França/epidemiologia , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Haplótipos , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Proteína 2 Homóloga a MutS/metabolismo , Mutação de Sentido Incorreto , Linhagem , Polimorfismo de Nucleotídeo Único
16.
Cancer Genet ; 240: 54-58, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31778928

RESUMO

Li-Fraumeni and Li-Fraumeni-like (LFS/LFL) Syndrome are cancer predisposition syndromes caused by germline pathogenic variants in TP53 and are associated with an increased risk of multiple early-onset cancers. In Southern and Southeastern Brazil, a germline founder variant with partial penetrance located in the oligomerization domain of TP53, c.1010G>A p.(Arg337His, commonly known as R337H), has been detected in 0.3% of the general population. Recently, the functional MIR605 variant rs2043556 (A>G) has been identified as a novel LFS phenotype modifier in families with germline TP53 DNA binding variants. In this study, our goal was to verify MIR605 rs2043556 allele frequencies and further explore its possible effects on the phenotype of 238 Brazilian individuals carrying TP53 p.(Arg337His). The MIR605 rs2043556 G allele was detected in 136 (57.1%) individuals, including 25 homozygotes (10.5%), and although it had been previously associated with an earlier mean age of tumor onset, this effect was not observed in this study (p = 0.8). However, in p.(Arg337His) mutation carriers, the GG genotype was significantly associated with the occurrence of multiple primary tumors (p = 0.005). We provide further evidence of MIR605 rs2043556 G allele's effect as a phenotype modulator in carriers of germline TP53 pathogenic variants.


Assuntos
Predisposição Genética para Doença , Síndrome de Li-Fraumeni/genética , MicroRNAs/genética , Neoplasias Primárias Múltiplas/genética , Proteína Supressora de Tumor p53/genética , Adulto , Idade de Início , Brasil/epidemiologia , Feminino , Efeito Fundador , Mutação em Linhagem Germinativa , Humanos , Síndrome de Li-Fraumeni/epidemiologia , Masculino , Neoplasias Primárias Múltiplas/epidemiologia , Polimorfismo de Nucleotídeo Único
17.
Commun Biol ; 2: 473, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31886413

RESUMO

The mosquito Anopheles gambiae s.s. is distributed across most of sub-Saharan Africa and is of major scientific and public health interest for being an African malaria vector. Here we present population genomic analyses of 111 specimens sampled from west to east Africa, including the first whole genome sequences from oceanic islands, the Comoros. Genetic distances between populations of A. gambiae are discordant with geographic distances but are consistent with a stepwise migration scenario in which the species increases its range from west to east Africa through consecutive founder events over the last ~200,000 years. Geological barriers like the Congo River basin and the East African rift seem to play an important role in shaping this process. Moreover, we find a high degree of genetic isolation of populations on the Comoros, confirming the potential of these islands as candidate sites for potential field trials of genetically engineered mosquitoes for malaria control.


Assuntos
Anopheles/genética , Efeito Fundador , Genética Populacional , Mosquitos Vetores/genética , África Oriental , África Ocidental , Animais , Geografia , Malária/epidemiologia , Malária/parasitologia , Malária/transmissão , Densidade Demográfica , Dinâmica Populacional
18.
Genes (Basel) ; 11(1)2019 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-31877759

RESUMO

Variants in more than 271 different genes have been linked to hereditary retinal diseases, making comprehensive genomic approaches mandatory for accurate diagnosis. We explored the genetic landscape of retinal disorders in consanguineous families from North-Western Pakistan, harboring a population of approximately 35 million inhabitants that remains relatively isolated and highly inbred (~50% consanguinity). We leveraged on the high degree of consanguinity by applying genome-wide high-density single-nucleotide polymorphism (SNP) genotyping followed by targeted Sanger sequencing of candidate gene(s) lying inside autozygous intervals. In addition, we performed whole-exome sequencing (WES) on at least one proband per family. We identified 7 known and 4 novel variants in a total of 10 genes (ABCA4, BBS2, CNGA1, CNGA3, CNGB3, MKKS, NMNAT1, PDE6B, RPE65, and TULP1) previously known to cause inherited retinal diseases. In spite of all families being consanguineous, compound heterozygosity was detected in one family. All homozygous pathogenic variants resided in autozygous intervals ≥2.0 Mb in size. Putative founder variants were observed in the ABCA4 (NM_000350.2:c.214G>A; p.Gly72Arg; ten families) and NMNAT1 genes (NM_022787.3:c.25G>A; p.Val9Met; two families). We conclude that geographic isolation and sociocultural tradition of intrafamilial mating in North-Western Pakistan favor both the clinical manifestation of rare "generic" variants and the prevalence of founder mutations.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Mutação , Doenças Retinianas/genética , Sequenciamento Completo do Exoma/métodos , Consanguinidade , Análise Mutacional de DNA , Feminino , Efeito Fundador , Humanos , Masculino , Nicotinamida-Nucleotídeo Adenililtransferase/genética , Paquistão/epidemiologia , Linhagem , Prevalência , Doenças Retinianas/epidemiologia , Análise de Sequência de DNA
19.
PLoS Genet ; 15(11): e1008480, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31765389

RESUMO

Human population isolates provide a snapshot of the impact of historical demographic processes on population genetics. Such data facilitate studies of the functional impact of rare sequence variants on biomedical phenotypes, as strong genetic drift can result in higher frequencies of variants that are otherwise rare. We present the first whole genome sequencing (WGS) study of the VIKING cohort, a representative collection of samples from the isolated Shetland population in northern Scotland, and explore how its genetic characteristics compare to a mainland Scottish population. Our analyses reveal the strong contributions played by the founder effect and genetic drift in shaping genomic variation in the VIKING cohort. About one tenth of all high-quality variants discovered are unique to the VIKING cohort or are seen at frequencies at least ten fold higher than in more cosmopolitan control populations. Multiple lines of evidence also suggest relaxation of purifying selection during the evolutionary history of the Shetland isolate. We demonstrate enrichment of ultra-rare VIKING variants in exonic regions and for the first time we also show that ultra-rare variants are enriched within regulatory regions, particularly promoters, suggesting that gene expression patterns may diverge relatively rapidly in human isolates.


Assuntos
Demografia , Variação Genética/genética , Genética Populacional , Sequências Reguladoras de Ácido Nucleico/genética , Regiões 5' não Traduzidas/genética , Alelos , Cromatina/genética , Europa (Continente) , Éxons/genética , Efeito Fundador , Deriva Genética , Estudo de Associação Genômica Ampla , Genômica , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Escócia , Sequenciamento Completo do Genoma
20.
G3 (Bethesda) ; 9(12): 4159-4168, 2019 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-31636085

RESUMO

Evolve-and-resequence (E+R) experiments leverage next-generation sequencing technology to track the allele frequency dynamics of populations as they evolve. While previous work has shown that adaptive alleles can be detected by comparing frequency trajectories from many replicate populations, this power comes at the expense of high-coverage (>100x) sequencing of many pooled samples, which can be cost-prohibitive. Here, we show that accurate estimates of allele frequencies can be achieved with very shallow sequencing depths (<5x) via inference of known founder haplotypes in small genomic windows. This technique can be used to efficiently estimate frequencies for any number of bi-allelic SNPs in populations of any model organism founded with sequenced homozygous strains. Using both experimentally-pooled and simulated samples of Drosophila melanogaster, we show that haplotype inference can improve allele frequency accuracy by orders of magnitude for up to 50 generations of recombination, and is robust to moderate levels of missing data, as well as different selection regimes. Finally, we show that a simple linear model generated from these simulations can predict the accuracy of haplotype-derived allele frequencies in other model organisms and experimental designs. To make these results broadly accessible for use in E+R experiments, we introduce HAF-pipe, an open-source software tool for calculating haplotype-derived allele frequencies from raw sequencing data. Ultimately, by reducing sequencing costs without sacrificing accuracy, our method facilitates E+R designs with higher replication and resolution, and thereby, increased power to detect adaptive alleles.


Assuntos
Frequência do Gene/genética , Análise de Sequência de DNA/métodos , Animais , Simulação por Computador , Drosophila melanogaster , Feminino , Efeito Fundador , Haplótipos , Modelos Lineares , Recombinação Genética/genética , Seleção Genética , Software , Fatores de Tempo
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