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1.
Mem Inst Oswaldo Cruz ; 116: e200584, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34076074

RESUMEN

In the present study, we investigated the genetic diversity of Plasmodium vivax metacaspase 1 (PvMCA1) catalytic domain in two municipalities of the main malaria hotspot in Brazil, i.e., the Juruá Valley, and observed complete sequence identity among all P. vivax field isolates and the Sal-1 reference strain. Analysis of PvMCA1 catalytic domain in different P. vivax genomic sequences publicly available also revealed a high degree of conservation worldwide, with very few amino acid substitutions that were not related to putative histidine and cysteine catalytic residues, whose involvement with the active site of protease was herein predicted by molecular modeling. The genetic conservation presented by PvMCA1 may contribute to its eligibility as a druggable target candidate in vivax malaria.


Asunto(s)
Malaria Vivax , Plasmodium vivax , Brasil , Dominio Catalítico , Variación Genética/genética , Humanos , Plasmodium vivax/genética , Proteínas Protozoarias/genética
2.
Cell Rep ; 35(6): 109109, 2021 05 11.
Artículo en Inglés | MEDLINE | ID: mdl-33932326

RESUMEN

It is unclear whether individuals with enormous diversity in B cell receptor repertoires are consistently able to mount effective antibody responses against SARS-CoV-2. We analyzed antibody responses in a cohort of 55 convalescent patients and isolated 54 potent neutralizing monoclonal antibodies (mAbs). While most of the mAbs target the angiotensin-converting enzyme 2 (ACE2) binding surface on the receptor binding domain (RBD) of SARS-CoV-2 spike protein, mAb 47D1 binds only to one side of the receptor binding surface on the RBD. Neutralization by 47D1 is achieved independent of interfering RBD-ACE2 binding. A crystal structure of the mAb-RBD complex shows that the IF motif at the tip of 47D1 CDR H2 interacts with a hydrophobic pocket in the RBD. Diverse immunoglobulin gene usage and convergent epitope targeting characterize neutralizing antibody responses to SARS-CoV-2, suggesting that vaccines that effectively present the receptor binding site on the RBD will likely elicit neutralizing antibody responses in a large fraction of the population.


Asunto(s)
Anticuerpos Neutralizantes/genética , Inmunoglobulinas/genética , Adulto , Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Sitios de Unión/inmunología , /terapia , Epítopos/genética , Epítopos/inmunología , Femenino , Genes de Inmunoglobulinas/genética , Variación Genética/genética , Humanos , Inmunización Pasiva/métodos , Inmunoglobulinas/inmunología , Masculino , Persona de Mediana Edad , Peptidil-Dipeptidasa A/metabolismo , Unión Proteica/inmunología , Dominios Proteicos/genética , Receptores Virales/inmunología , Receptores Virales/metabolismo , /inmunología , /patogenicidad
4.
Nat Commun ; 12(1): 2493, 2021 05 03.
Artículo en Inglés | MEDLINE | ID: mdl-33941778

RESUMEN

The need for precision medicine approaches to monitor health and disease makes it important to develop sensitive and accurate assays for proteome profiles in blood. Here, we describe an approach for plasma profiling based on proximity extension assay combined with next generation sequencing. First, we analyze the variability of plasma profiles between and within healthy individuals in a longitudinal wellness study, including the influence of genetic variations on plasma levels. Second, we follow patients newly diagnosed with type 2 diabetes before and during therapeutic intervention using plasma proteome profiling. The studies show that healthy individuals have a unique and stable proteome profile and indicate that a panel of proteins could potentially be used for early diagnosis of diabetes, including stratification of patients with regards to response to metformin treatment. Although validation in larger cohorts is needed, the analysis demonstrates the usefulness of comprehensive plasma profiling for precision medicine efforts.


Asunto(s)
Proteínas Sanguíneas/análisis , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/diagnóstico , Plasma/química , Proteoma/análisis , Anciano , Diabetes Mellitus Tipo 2/genética , Diagnóstico Precoz , Femenino , Variación Genética/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hipoglucemiantes/uso terapéutico , Estudios Longitudinales , Masculino , Metformina/uso terapéutico , Persona de Mediana Edad , Medicina de Precisión/métodos , Proteómica/métodos
5.
Nat Commun ; 12(1): 2491, 2021 05 03.
Artículo en Inglés | MEDLINE | ID: mdl-33941780

RESUMEN

Mycobacterium kansasii can cause serious pulmonary disease. It belongs to a group of closely-related species of non-tuberculous mycobacteria known as the M. kansasii complex (MKC). Here, we report a population genomics analysis of 358 MKC isolates from worldwide water and clinical sources. We find that recombination, likely mediated by distributive conjugative transfer, has contributed to speciation and on-going diversification of the MKC. Our analyses support municipal water as a main source of MKC infections. Furthermore, nearly 80% of the MKC infections are due to closely-related M. kansasii strains, forming a main cluster that apparently originated in the 1900s and subsequently expanded globally. Bioinformatic analyses indicate that several genes involved in metabolism (e.g., maintenance of the methylcitrate cycle), ESX-I secretion, metal ion homeostasis and cell surface remodelling may have contributed to M. kansasii's success and its ongoing adaptation to the human host.


Asunto(s)
Agua Potable/microbiología , Genoma Bacteriano/genética , Enfermedades Pulmonares/epidemiología , Infecciones por Mycobacterium no Tuberculosas/epidemiología , Mycobacterium kansasii/genética , Metabolismo Energético/genética , Variación Genética/genética , Genética de Población/métodos , Genómica , Humanos , Enfermedades Pulmonares/microbiología , Infecciones por Mycobacterium no Tuberculosas/microbiología , Mycobacterium kansasii/aislamiento & purificación , Virulencia/genética , Microbiología del Agua
6.
mSphere ; 6(3)2021 05 05.
Artículo en Inglés | MEDLINE | ID: mdl-33952657

RESUMEN

Genome-wide variation in SARS-CoV-2 reveals evolution and transmission dynamics which are critical considerations for disease control and prevention decisions. Here, we review estimates of the genome-wide viral mutation rates, summarize current COVID-19 case load in the province of Ontario, Canada (5 January 2021), and analyze published SARS-CoV-2 genomes from Ontario (collected prior to 24 November 2020) to test for more infectious genetic variants or lineages. The reported mutation rate (∼10-6 nucleotide [nt]-1 cycle-1) for SARS-CoV-2 is typical for coronaviruses. Analysis of published SARS-CoV-2 genomes revealed that the G614 spike protein mutation has dominated infections in Ontario and that SARS-CoV-2 lineages present in Ontario have not differed significantly in their rate of spread. These results suggest that the SARS-CoV-2 population circulating in Ontario has not changed significantly to date. However, ongoing genome monitoring is essential for identification of new variants and lineages that may contribute to increased viral transmission.


Asunto(s)
Variación Genética/genética , Genoma Viral/genética , Tasa de Mutación , Glicoproteína de la Espiga del Coronavirus/genética , Secuencia de Bases , Humanos , Ontario , Filogenia , Análisis de Secuencia de ARN
7.
Nat Commun ; 12(1): 3126, 2021 05 25.
Artículo en Inglés | MEDLINE | ID: mdl-34035259

RESUMEN

Hybridization and polyploidization are powerful mechanisms of speciation. Hybrid speciation often coincides with whole-genome duplication (WGD) in eukaryotes. This suggests that WGD may allow hybrids to thrive by increasing fitness, restoring fertility and/or increasing access to adaptive mutations. Alternatively, it has been suggested that hybridization itself may trigger WGD. Testing these models requires quantifying the rate of WGD in hybrids without the confounding effect of natural selection. Here we show, by measuring the spontaneous rate of WGD of more than 1300 yeast crosses evolved under relaxed selection, that some genotypes or combinations of genotypes are more prone to WGD, including some hybrids between closely related species. We also find that higher WGD rate correlates with higher genomic instability and that WGD increases fertility and genetic variability. These results provide evidence that hybridization itself can promote WGD, which in turn facilitates the evolution of hybrids.


Asunto(s)
Duplicación de Gen , Genoma Fúngico/genética , Hibridación Genética , Saccharomyces/genética , Adaptación Fisiológica/genética , Diploidia , Evolución Molecular , Variación Genética/genética , Inestabilidad Genómica/genética , Tasa de Mutación , Filogenia , Poliploidía , Saccharomyces/clasificación , Saccharomyces cerevisiae/genética , Especificidad de la Especie
8.
Neurology ; 96(18): e2251-e2260, 2021 05 04.
Artículo en Inglés | MEDLINE | ID: mdl-34038384

RESUMEN

OBJECTIVE: To identify the causative gene in a large unsolved family with genetic epilepsy with febrile seizures plus (GEFS+), we sequenced the genomes of family members, and then determined the contribution of the identified gene to the pathogenicity of epilepsies by examining sequencing data from 2,772 additional patients. METHODS: We performed whole genome sequencing of 3 members of a GEFS+ family. Subsequently, whole exome sequencing data from 1,165 patients with epilepsy from the Epi4K dataset and 1,329 Australian patients with epilepsy from the Epi25 dataset were interrogated. Targeted resequencing was performed on 278 patients with febrile seizures or GEFS+ phenotypes. Variants were validated and familial segregation examined by Sanger sequencing. RESULTS: Eight previously unreported missense variants were identified in SLC32A1, coding for the vesicular inhibitory amino acid cotransporter VGAT. Two variants cosegregated with the phenotype in 2 large GEFS+ families containing 8 and 10 affected individuals, respectively. Six further variants were identified in smaller families with GEFS+ or idiopathic generalized epilepsy (IGE). CONCLUSION: Missense variants in SLC32A1 cause GEFS+ and IGE. These variants are predicted to alter γ-aminobutyric acid (GABA) transport into synaptic vesicles, leading to altered neuronal inhibition. Examination of further epilepsy cohorts will determine the full genotype-phenotype spectrum associated with SLC32A1 variants.


Asunto(s)
Epilepsia Generalizada/diagnóstico , Epilepsia Generalizada/genética , Variación Genética/genética , Mutación Missense/genética , Convulsiones Febriles/diagnóstico , Convulsiones Febriles/genética , Proteínas del Transporte Vesicular de Aminoácidos Inhibidores/genética , Femenino , Estudios de Asociación Genética/métodos , Humanos , Masculino , Linaje
9.
Am J Hum Genet ; 108(4): 535-548, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33798442

RESUMEN

Genome sequencing is enabling precision medicine-tailoring treatment to the unique constellation of variants in an individual's genome. The impact of recurrent pathogenic variants is often understood, however there is a long tail of rare genetic variants that are uncharacterized. The problem of uncharacterized rare variation is especially acute when it occurs in genes of known clinical importance with functionally consequential variants and associated mechanisms. Variants of uncertain significance (VUSs) in these genes are discovered at a rate that outpaces current ability to classify them with databases of previous cases, experimental evaluation, and computational predictors. Clinicians are thus left without guidance about the significance of variants that may have actionable consequences. Computational prediction of the impact of rare genetic variation is increasingly becoming an important capability. In this paper, we review the technical and ethical challenges of interpreting the function of rare variants in two settings: inborn errors of metabolism in newborns and pharmacogenomics. We propose a framework for a genomic learning healthcare system with an initial focus on early-onset treatable disease in newborns and actionable pharmacogenomics. We argue that (1) a genomic learning healthcare system must allow for continuous collection and assessment of rare variants, (2) emerging machine learning methods will enable algorithms to predict the clinical impact of rare variants on protein function, and (3) ethical considerations must inform the construction and deployment of all rare-variation triage strategies, particularly with respect to health disparities arising from unbalanced ancestry representation.


Asunto(s)
Variación Genética/genética , Genética Médica , Genómica , Aprendizaje Automático , Errores Innatos del Metabolismo/genética , Farmacogenética , Medicina de Precisión , Genoma Humano/genética , Humanos , Recién Nacido
10.
Nat Commun ; 12(1): 2458, 2021 04 28.
Artículo en Inglés | MEDLINE | ID: mdl-33911077

RESUMEN

Miscanthus, a rhizomatous perennial plant, has great potential for bioenergy production for its high biomass and stress tolerance. We report a chromosome-scale assembly of Miscanthus lutarioriparius genome by combining Oxford Nanopore sequencing and Hi-C technologies. The 2.07-Gb assembly covers 96.64% of the genome, with contig N50 of 1.71 Mb. The centromere and telomere sequences are assembled for all 19 chromosomes and chromosome 10, respectively. Allotetraploid origin of the M. lutarioriparius is confirmed using centromeric satellite repeats. The tetraploid genome structure and several chromosomal rearrangements relative to sorghum are clearly demonstrated. Tandem duplicate genes of M. lutarioriparius are functional enriched not only in terms related to stress response, but cell wall biosynthesis. Gene families related to disease resistance, cell wall biosynthesis and metal ion transport are greatly expanded and evolved. The expansion of these families may be an important genomic basis for the enhancement of remarkable traits of M. lutarioriparius.


Asunto(s)
Cromosomas de las Plantas/genética , Genoma de Planta/genética , Poaceae/genética , Composición de Base/genética , Biomasa , Pared Celular/metabolismo , Centrómero/genética , Cloroplastos/genética , Biología Computacional , Variación Genética/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Transporte Iónico/genética , Fotosíntesis/genética , Filogenia , Poaceae/clasificación , Análisis de Secuencia de ADN , Homología de Secuencia , Sorghum/genética , Telómero/genética
11.
Int J Mol Sci ; 22(7)2021 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-33807278

RESUMEN

Pompe disease is an autosomal recessive disorder caused by a deficiency in the enzyme acid alpha-glucosidase. The late-onset form of Pompe disease (LOPD) is characterized by a slowly progressing proximal muscle weakness, often involving respiratory muscles. In LOPD, the levels of GAA enzyme activity and the severity of the clinical pictures may be highly variable among individuals, even in those who harbour the same combination of GAA mutations. The result is an unpredictable genotype-phenotype correlation. The purpose of this study was to identify the genetic factors responsible for the progression, severity and drug response in LOPD. We report here on a detailed clinical, morphological and genetic study, including a whole exome sequencing (WES) analysis of 11 adult LOPD siblings belonging to two Italian families carrying compound heterozygous GAA mutations. We disclosed a heterogeneous pattern of myopathic impairment, associated, among others, with cardiac defects, intracranial vessels abnormality, osteoporosis, vitamin D deficiency, obesity and adverse response to enzyme replacement therapy (ERT). We identified deleterious variants in the genes involved in autophagy, immunity and bone metabolism, which contributed to the severity of the clinical symptoms observed in the LOPD patients. This study emphasizes the multisystem nature of LOPD and highlights the polygenic nature of the complex phenotype disclosed in these patients.


Asunto(s)
Autofagia/genética , Enfermedad del Almacenamiento de Glucógeno Tipo II/genética , alfa-Glucosidasas/genética , Adulto , Anciano , Autofagia/fisiología , Terapia de Reemplazo Enzimático/métodos , Familia , Femenino , Variación Genética/genética , Humanos , Italia , Masculino , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Mutación , Linaje , Músculos Respiratorios , Hermanos , alfa-Glucosidasas/metabolismo
12.
Medicine (Baltimore) ; 100(17): e25689, 2021 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-33907143

RESUMEN

BACKGROUND: An increasing body of studies has investigated that genetic polymorphisms in microRNA (miRNA) may be related to susceptibility to rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, some results remain controversial. Thus, a meta-analysis was embarked on assessing whether some miRNA polymorphisms are associated with the risk of RA and SLE. METHODS: Relevant studies were acquired on PubMed, Web of Science, Cochrane Library, CNKI, and Embase electronic databases from inception to December 2019. The strength of the association of miRNA polymorphisms with the risk of RA and SLE was assessed by odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Eligible 20 articles (36 studies) involving 5 miRNAs were enrolled in the meta-analysis. For RA, the polled result showed that there was no significant relationship between miR-146a rs2910164 and RA, but subgroup analysis based on ethnicity demonstrated that CC genotype may be a genetic protect factor for RA in Caucasians (CC vs CG+GG, OR = 0.825, 95% CI: 0.684-0.996, Pz = .045, Ph = .166). Besides, statistical significance of miR-499 rs3746444 (T/C) with susceptibility to RA was observed as well in the overall population, and the association was only significant in Caucasians but not Asians. For SLE, the associations of miR-146a rs2431697 T allele/T-carrier with increased risk of SLE were observed. CONCLUSIONS: Our results highlight that miR-499 rs3746444 may contribute to RA susceptibility, particularly in Caucasians. In addition, CC genotype in miR-146a rs2910164 may act as a protector of RA in Caucasians. For SLE, miR-146a rs2431697 (C/T) is most likely to the increased the risk of SLE. These findings do not support the genetic association between miR-196a2 rs11614913 and RA/SLE susceptibility, as well as the association of miR-146a rs2910164, miR-146a rs57095329, miR-499 rs3746444 with SLE.


Asunto(s)
Artritis Reumatoide/genética , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Lupus Eritematoso Sistémico/genética , MicroARNs/genética , Grupo de Ascendencia Continental Asiática/genética , Estudios de Casos y Controles , Grupo de Ascendencia Continental Europea/genética , Genotipo , Humanos , Oportunidad Relativa
13.
Int J Food Microbiol ; 347: 109197, 2021 Jun 02.
Artículo en Inglés | MEDLINE | ID: mdl-33895597

RESUMEN

Shiga toxin-producing Escherichia coli (STEC) can cause severe human illness, which are frequently linked to the consumption of contaminated beef or dairy products. However, recent outbreaks associated with contaminated flour and undercooked dough in the United States and Canada, highlight the potential of plant based food as transmission routes for STEC. In Germany STEC has been isolated from flour, but no cases of illness have been linked to flour. In this study, we characterized 123 STEC strains isolated from flour and flour products collected between 2015 and 2019 across Germany. In addition to determination of serotype and Shiga toxin subtype, whole genome sequencing (WGS) was used for isolates collected in 2018 to determine phylogenetic relationships, sequence type (ST), and virulence-associated genes (VAGs). We found a high diversity of serotypes including those frequently associated with human illness and outbreaks, such as O157:H7 (stx2c/d, eae), O145:H28 (stx2a, eae), O146:H28 (stx2b), and O103:H2 (stx1a, eae). Serotypes O187:H28 (ST200, stx2g) and O154:H31 (ST1892, stx1d) were most prevalent, but are rarely linked to human cases. However, WGS analysis revealed that these strains, as well as, O156:H25 (ST300, stx1a) harbour high numbers of VAGs, including eae, nleB and est1a/sta1. Although STEC-contaminated flour products have yet not been epidemiologically linked to human clinical cases in Germany, this study revealed that flour can serve as a vector for STEC strains with a high pathogenic potential. Further investigation is needed to determine the sources of STEC contamination in flour and flour products particularly in regards to these rare serotypes.


Asunto(s)
Escherichia coli O157/genética , Escherichia coli O157/aislamiento & purificación , Harina/microbiología , Contaminación de Alimentos/análisis , Toxina Shiga/genética , Animales , Canadá , Bovinos , Brotes de Enfermedades , Infecciones por Escherichia coli/transmisión , Escherichia coli O157/patogenicidad , Proteínas de Escherichia coli/genética , Microbiología de Alimentos , Variación Genética/genética , Genoma Bacteriano/genética , Alemania , Humanos , Filogenia , Virulencia/genética , Factores de Virulencia/genética , Secuenciación Completa del Genoma
14.
Int J Mol Sci ; 22(8)2021 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-33921709

RESUMEN

BACKGROUND: Disruption of alternative splicing (AS) is frequently observed in cancer and might represent an important signature for tumor progression and therapy. Exon skipping (ES) represents one of the most frequent AS events, and in non-small cell lung cancer (NSCLC) MET exon 14 skipping was shown to be targetable. METHODS: We constructed neural networks (NN/CNN) specifically designed to detect MET exon 14 skipping events using RNAseq data. Furthermore, for discovery purposes we also developed a sparsely connected autoencoder to identify uncharacterized MET isoforms. RESULTS: The neural networks had a Met exon 14 skipping detection rate greater than 94% when tested on a manually curated set of 690 TCGA bronchus and lung samples. When globally applied to 2605 TCGA samples, we observed that the majority of false positives was characterized by a blurry coverage of exon 14, but interestingly they share a common coverage peak in the second intron and we speculate that this event could be the transcription signature of a LINE1 (Long Interspersed Nuclear Element 1)-MET (Mesenchymal Epithelial Transition receptor tyrosine kinase) fusion. CONCLUSIONS: Taken together, our results indicate that neural networks can be an effective tool to provide a quick classification of pathological transcription events, and sparsely connected autoencoders could represent the basis for the development of an effective discovery tool.


Asunto(s)
Aprendizaje Profundo , Exones/genética , Variación Genética/genética , Humanos , Redes Neurales de la Computación
15.
Int J Mol Sci ; 22(9)2021 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-33925997

RESUMEN

Sphingomyelin phosphodiesterase (SMPD1) is a key enzyme in the sphingolipid metabolism. Genetic SMPD1 variants have been related to the Niemann-Pick lysosomal storage disorder, which has different degrees of phenotypic severity ranging from severe symptomatology involving the central nervous system (type A) to milder ones (type B). They have also been linked to neurodegenerative disorders such as Parkinson and Alzheimer. In this paper, we leveraged structural, evolutionary and stability information on SMPD1 to predict and analyze the impact of variants at the molecular level. We developed the SMPD1-ZooM algorithm, which is able to predict with good accuracy whether variants cause Niemann-Pick disease and its phenotypic severity; the predictor is freely available for download. We performed a large-scale analysis of all possible SMPD1 variants, which led us to identify protein regions that are either robust or fragile with respect to amino acid variations, and show the importance of aromatic-involving interactions in SMPD1 function and stability. Our study also revealed a good correlation between SMPD1-ZooM scores and in vitro loss of SMPD1 activity. The understanding of the molecular effects of SMPD1 variants is of crucial importance to improve genetic screening of SMPD1-related disorders and to develop personalized treatments that restore SMPD1 functionality.


Asunto(s)
Enfermedades de Niemann-Pick/genética , Esfingomielina Fosfodiesterasa/genética , Simulación por Computador , Bases de Datos Genéticas , Exones/genética , Variación Genética/genética , Humanos , Mutación/genética , Enfermedades de Niemann-Pick/metabolismo , Fenotipo , Índice de Severidad de la Enfermedad , Esfingolípidos/genética , Esfingolípidos/metabolismo , Esfingomielina Fosfodiesterasa/metabolismo
16.
Mem Inst Oswaldo Cruz ; 116: e200528, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33656141

RESUMEN

Panstrongylus geniculatus (Latreille, 1811) is the triatomine with the largest geographic distribution in Latin America. It has been reported in 18 countries from southern Mexico to northern Argentina, including the Caribbean islands. Although most reports indicate that P. geniculatus has wild habitats, this species has intrusive habits regarding human dwellings mainly located in intermediate deforested areas. It is attracted by artificial light from urban and rural buildings, raising the risk of transmission of Trypanosoma cruzi. Despite the wide body of published information on P. geniculatus, many knowledge gaps exist about its biology and epidemiological potential. For this reason, we analysed the literature for P. geniculatus in Scopus, PubMed, Scielo, Google Scholar and the BibTriv3.0 databases to update existing knowledge and provide better information on its geographic distribution, life cycle, genetic diversity, evidence of intrusion and domiciliation, vector-related circulating discrete taxonomic units, possible role in oral T. cruzi transmission, and the effect of climate change on its biology and epidemiology.


Asunto(s)
Enfermedad de Chagas/transmisión , Insectos Vectores/parasitología , Panstrongylus/genética , Panstrongylus/parasitología , Triatoma/parasitología , Trypanosoma cruzi , Animales , Biología , Ecología , Genes de Insecto , Variación Genética/genética , Genotipo , Geografía , Humanos , Insectos Vectores/genética , América Latina , Panstrongylus/fisiología , Filogenia , Trypanosoma cruzi/aislamiento & purificación
17.
Medicine (Baltimore) ; 100(13): e25265, 2021 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-33787610

RESUMEN

RATIONALE: Complement deficiency are known to be predisposed to disseminated gonococcal infection (DGI). We herein present a case of DGI involving a Japanese man who latently had a complement 7 deficiency with compound heterozygous variants. PATIENT CONCERNS: A previously healthy 51-year-old Japanese man complained of sudden-onset high fever. Physical examination revealed various skin lesions including red papules on his trunk and extremities, an impetigo-like pustule on left forearm, and tendinitis of his right forefinger. DIAGNOSIS: Blood culture testing detected gram-negative cocci, which was confirmed to be Neisseria gonorrhoeae based on mass spectrometry and a pathogen-specific PCR test. INTERVENTIONS: Screening tests for underlying immunocompromised factors uncovered that complement activities (CH50) was undetectable. With a suspicion of a congenital complement deficiency, genetic analysis revealed rare single nucleotide variants in complement 7 (C7), including c.281-1G>T and a novel variant c.1454C>T (p.A485V). CH50 was normally recovered by adding purified human C7 to the patient's serum, supporting that the patient has C7 deficiency with compound heterozygous variants. OUTCOMES: Under a diagnosis of DGI, the patient underwent an antibiotic treatment with cefotaxime for a week and was discharged without any sequela. LESSONS: DGI is a rare sexually-transmitted infection that potentially induces systemic complications. Complement immunity usually defeats N. gonorrhoeae and prevents the organism from causing DGI. This case highlighted the importance of suspecting a complement deficiency when a person develops DGI.


Asunto(s)
Complemento C7/deficiencia , Variación Genética/genética , Gonorrea/genética , Enfermedades por Deficiencia de Complemento Hereditario/genética , Enfermedades por Deficiencia de Complemento Hereditario/microbiología , Neisseria gonorrhoeae , Complemento C7/genética , Femenino , Gonorrea/microbiología , Humanos , Japón , Masculino , Persona de Mediana Edad
18.
BMC Bioinformatics ; 22(1): 164, 2021 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-33773584

RESUMEN

BACKGROUND: Heritability is a central measure in genetics quantifying how much of the variability observed in a trait is attributable to genetic differences. Existing methods for estimating heritability are most often based on random-effect models, typically for computational reasons. The alternative of using a fixed-effect model has received much more limited attention in the literature. RESULTS: In this paper, we propose a generic strategy for heritability inference, termed as "boosting heritability", by combining the advantageous features of different recent methods to produce an estimate of the heritability with a high-dimensional linear model. Boosting heritability uses in particular a multiple sample splitting strategy which leads in general to a stable and accurate estimate. We use both simulated data and real antibiotic resistance data from a major human pathogen, Sptreptococcus pneumoniae, to demonstrate the attractive features of our inference strategy. CONCLUSIONS: Boosting is shown to offer a reliable and practically useful tool for inference about heritability.


Asunto(s)
Variación Biológica Poblacional , Variación Genética , Modelos Genéticos , Variación Genética/genética , Humanos , Modelos Lineales , Fenotipo , Carácter Cuantitativo Heredable
19.
Am J Hum Genet ; 108(4): 620-631, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33691092

RESUMEN

Phenotype prediction is a key goal for medical genetics. Unfortunately, most genome-wide association studies are done in European populations, which reduces the accuracy of predictions via polygenic scores in non-European populations. Here, we use population genetic models to show that human demographic history and negative selection on complex traits can result in population-specific genetic architectures. For traits where alleles with the largest effect on the trait are under the strongest negative selection, approximately half of the heritability can be accounted for by variants in Europe that are absent from Africa, leading to poor performance in phenotype prediction across these populations. Further, under such a model, individuals in the tails of the genetic risk distribution may not be identified via polygenic scores generated in another population. We empirically test these predictions by building a model to stratify heritability between European-specific and shared variants and applied it to 37 traits and diseases in the UK Biobank. Across these phenotypes, ∼30% of the heritability comes from European-specific variants. We conclude that genetic association studies need to include more diverse populations to enable the utility of phenotype prediction in all populations.


Asunto(s)
Predisposición Genética a la Enfermedad , Genética de Población , Modelos Genéticos , Herencia Multifactorial/genética , Fenotipo , Selección Genética/genética , África/etnología , Simulación por Computador , Conjuntos de Datos como Asunto , Europa (Continente)/etnología , Variación Genética/genética , Humanos , Crecimiento Demográfico , Reino Unido
20.
Am J Hum Genet ; 108(4): 608-619, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33740458

RESUMEN

The number and distribution of recessive alleles in the population for various diseases are not known at genome-wide-scale. Based on 6,447 exome sequences of healthy, genetically unrelated Europeans of two distinct ancestries, we estimate that every individual is a carrier of at least 2 pathogenic variants in currently known autosomal-recessive (AR) genes and that 0.8%-1% of European couples are at risk of having a child affected with a severe AR genetic disorder. This risk is 16.5-fold higher for first cousins but is significantly more increased for skeletal disorders and intellectual disabilities due to their distinct genetic architecture.


Asunto(s)
Consanguinidad , Grupo de Ascendencia Continental Europea/genética , Composición Familiar , Genes Recesivos/genética , Variación Genética/genética , Fenotipo , Estudios de Cohortes , Europa (Continente)/etnología , Exoma/genética , Femenino , Pruebas Genéticas , Salud , Heterocigoto , Humanos , Discapacidad Intelectual/genética , Masculino
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