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1.
Nat Commun ; 12(1): 3418, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34103502

RESUMO

The antifungal agent 5-fluorocytosine (5-FC) is used for the treatment of several mycoses, but is unsuitable for monotherapy due to the rapid development of resistance. Here, we show that cryptococci develop resistance to 5-FC at a high frequency when exposed to concentrations several fold above the minimal inhibitory concentration. The genomes of resistant clones contain alterations in genes relevant as well as irrelevant for 5-FC resistance, suggesting that 5-FC may be mutagenic at moderate concentrations. Mutations in FCY2 (encoding a known permease for 5-FC uptake), FCY1, FUR1, UXS1 (encoding an enzyme that converts UDP-glucuronic acid to UDP-xylose) and URA6 contribute to 5-FC resistance. The uxs1 mutants accumulate UDP-glucuronic acid, which appears to down-regulate expression of permease FCY2 and reduce cellular uptake of the drug. Additional mutations in genes known to be required for UDP-glucuronic acid synthesis (UGD1) or a transcriptional factor NRG1 suppress UDP-glucuronic acid accumulation and 5-FC resistance in the uxs1 mutants.


Assuntos
Cryptococcus/efeitos dos fármacos , Farmacorresistência Fúngica , Flucitosina/farmacologia , Cromossomos Fúngicos/genética , Células Clonais , Cryptococcus/genética , Cryptococcus/crescimento & desenvolvimento , Farmacorresistência Fúngica/efeitos dos fármacos , Farmacorresistência Fúngica/genética , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Dosagem de Genes , Duplicação Gênica , Regulação Fúngica da Expressão Gênica/efeitos dos fármacos , Genes Supressores , Variação Genética , Genoma Fúngico , Espaço Intracelular/metabolismo , Testes de Sensibilidade Microbiana , Mutação/genética , Reprodutibilidade dos Testes , Uridina Difosfato Ácido Glucurônico/metabolismo
2.
Nat Commun ; 12(1): 3420, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34103535

RESUMO

Theory shows how sexual selection can exaggerate male traits beyond naturally selected optima and also how natural selection can ultimately halt trait elaboration. Empirical evidence supports this theory, but to our knowledge, there have been no experimental evolution studies directly testing this logic, and little examination of possible associated effects on female fitness. Here we use experimental evolution of replicate populations of broad-horned flour beetles to test for effects of sex-specific predation on an exaggerated sexually selected male trait (the mandibles), while also testing for effects on female lifetime reproductive success. We find that populations subjected to male-specific predation evolve smaller sexually selected mandibles and this indirectly increases female fitness, seemingly through intersexual genetic correlations we document. Predation solely on females has no effects. Our findings support fundamental theory, but also reveal unforseen outcomes-the indirect effect on females-when natural selection targets sex-limited sexually selected characters.


Assuntos
Besouros/genética , Aptidão Genética , Característica Quantitativa Herdável , Seleção Genética , Caracteres Sexuais , Animais , Evolução Biológica , Tamanho Corporal , Cruzamento , Feminino , Variação Genética , Masculino , Mandíbula/anatomia & histologia , Tamanho do Órgão , Fenótipo , Comportamento Predatório
3.
Int J Mol Sci ; 22(11)2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-34072463

RESUMO

The NBN gene has been included in breast cancer (BC) multigene panels based on early studies suggesting an increased BC risk for carriers, though not confirmed by recent research. To evaluate the impact of NBN analysis, we assessed the results of NBN sequencing in 116 BRCA-negative BC patients and reviewed the literature. Three patients (2.6%) carried potentially relevant variants: two, apparently unrelated, carried the frameshift variant c.156_157delTT and another one the c.628G>T variant. The latter was subsequently found in 4/1390 (0.3%) BC cases and 8/1580 (0.5%) controls in an independent sample, which, together with in silico predictions, provided evidence against its pathogenicity. Conversely, the rare c.156_157delTT variant was absent in the case-control set; moreover, a 50% reduction of NBN expression was demonstrated in one carrier. However, in one family it failed to co-segregate with BC, while the other carrier was found to harbor also a probably pathogenic TP53 variant that may explain her phenotype. Therefore, the c.156_157delTT, although functionally deleterious, was not supported as a cancer-predisposing defect. Pathogenic/likely pathogenic NBN variants were detected by multigene panels in 31/12314 (0.25%) patients included in 15 studies. The risk of misinterpretation of such findings is substantial and supports the exclusion of NBN from multigene panels.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Proteínas de Ciclo Celular/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Proteínas Nucleares/genética , Adulto , Alelos , Estudos de Casos e Controles , Análise Mutacional de DNA , Feminino , Regulação Neoplásica da Expressão Gênica , Estudos de Associação Genética/métodos , Testes Genéticos , Genótipo , Haplótipos , Humanos , Linhagem
4.
Int J Mol Sci ; 22(11)2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-34072607

RESUMO

Glioblastoma (GBM) is an extremely aggressive tumor originating from neural stem cells of the central nervous system, which has high histopathological and genomic diversity. Mitochondria are cellular organelles associated with the regulation of cellular metabolism, redox signaling, energy generation, regulation of cell proliferation, and apoptosis. Accumulation of mutations in mitochondrial DNA (mtDNA) leads to mitochondrial dysfunction that plays an important role in GBM pathogenesis, favoring abnormal energy and reactive oxygen species production and resistance to apoptosis and to chemotherapeutic agents. The present review summarizes the known mitochondrial DNA alterations related to GBM, their cellular and metabolic consequences, and their association with diagnosis, prognosis, and treatment.


Assuntos
DNA Mitocondrial , Variação Genética , Glioblastoma/genética , Mitocôndrias/genética , Linhagem Celular Tumoral , Metabolismo Energético , Genoma Mitocondrial , Genômica/métodos , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Lipogênese/genética , Mitocôndrias/metabolismo , Mutação
5.
Mem Inst Oswaldo Cruz ; 116: e200584, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34076074

RESUMO

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.


Assuntos
Malária Vivax , Plasmodium vivax , Brasil , Domínio Catalítico , Variação Genética/genética , Humanos , Plasmodium vivax/genética , Proteínas de Protozoários/genética
6.
BMC Genomics ; 22(1): 407, 2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34082700

RESUMO

BACKGROUND: Next-generation sequencing (NGS) is an efficient tool used for identifying pathogenic variants that cause Mendelian disorders. However, the lack of bioinformatics training of researchers makes the interpretation of identified variants a challenge in terms of precision and efficiency. In addition, the non-standardized phenotypic description of human diseases also makes it difficult to establish an integrated analysis pathway for variant annotation and interpretation. Solutions to these bottlenecks are urgently needed. RESULTS: We develop a tool named "Cruxome" to automatically annotate and interpret single nucleotide variants (SNVs) and small insertions and deletions (InDels). Our approach greatly simplifies the current burdensome task of clinical geneticists and scientists to identify the causative pathogenic variants and build personal knowledge reference bases. The integrated architecture of Cruxome offers key advantages such as an interactive and user-friendly interface and the assimilation of electronic health records of the patient. By combining a natural language processing algorithm, Cruxome can efficiently process the clinical description of diseases to HPO standardized vocabularies. By using machine learning, in silico predictive algorithms, integrated multiple databases and supplementary tools, Cruxome can automatically process SNVs and InDels variants (trio-family or proband-only cases) and clinical diagnosis records, then annotate, score, identify and interpret pathogenic variants to finally generate a standardized clinical report following American College of Medical Genetics and Genomics/ Association for Molecular Pathology (ACMG/AMP) guidelines. Cruxome also provides supplementary tools to examine and visualize the genes or variations in historical cases, which can help to better understand the genetic basis of the disease. CONCLUSIONS: Cruxome is an efficient tool for annotation and interpretation of variations and dramatically reduces the workload for clinical geneticists and researchers to interpret NGS results, simplifying their decision-making processes. We present an online version of Cruxome, which is freely available to academics and clinical researchers. The site is accessible at http://114.251.61.49:10024/cruxome/ .


Assuntos
Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Algoritmos , Biologia Computacional , Bases de Dados Genéticas , Variação Genética , Humanos , Mutação INDEL , Software
7.
BMC Genomics ; 22(1): 442, 2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-34118867

RESUMO

BACKGROUND: Rutabaga or swede (Brassica napus ssp. napobrassica (L.) Hanelt) varies in root and leaf shape and colour, flesh colour, foliage growth habits, maturity date, seed quality parameters, disease resistance and other traits. Despite these morphological differences, no in-depth molecular analyses of genetic diversity have been conducted in this crop. Understanding this diversity is important for conservation and broadening the use of this resource. RESULTS: This study investigated the genetic diversity within and among 124 rutabaga accessions from five Nordic countries (Norway, Sweden, Finland, Denmark and Iceland) using a 15 K single nucleotide polymorphism (SNP) Brassica array. After excluding markers that did not amplify genomic DNA, monomorphic and low coverage site markers, the accessions were analyzedwith 6861 SNP markers. Allelic frequency statistics, including polymorphism information content (PIC), minor allele frequency (MAF) and mean expected heterozygosity ([Formula: see text]e) and population differentiation statistics such as Wright's F-statistics (FST) and analysis of molecular variance (AMOVA) indicated that the rutabaga accessions from Norway, Sweden, Finland and Denmark were not genetically different from each other. In contrast, accessions from these countries were significantly different from the accessions from Iceland (P < 0.05). Bayesian analysis with the software STRUCTURE placed 66.9% of the rutabaga accessions into three to four clusters, while the remaining 33.1% constituted admixtures. Three multivariate analyses: principal coordinate analysis (PCoA), the unweighted pair group method with arithmetic mean (UPGMA) and neighbour-joining (NJ) clustering methods grouped the 124 accessions into four to six subgroups. CONCLUSION: Overall, the correlation of the accessions with their geographic origin was very low, except for the accessions from Iceland. Thus, Icelandic rutabaga accessions can offer valuable germplasm for crop improvement.


Assuntos
Brassica napus , Genética Populacional , Polimorfismo de Nucleotídeo Único , Teorema de Bayes , Brassica napus/genética , Dinamarca , Finlândia , Variação Genética , Islândia , Biologia Molecular , Noruega , Suécia
8.
Zhonghua Yi Xue Za Zhi ; 101(22): 1695-1699, 2021 Jun 15.
Artigo em Chinês | MEDLINE | ID: mdl-34126719

RESUMO

Objective: To study the prevalence and genetic characteristics of human respiratory syncytial virus (HRSV) in Quanzhou city, from 2018 to 2019. Methods: A total of 141 throat swabs were collected from children patients of lower respiratory tract infection in Quanzhou children Hospital, Fujian Province from November 2018 to May 2019. RT-PCR was used to amplify the 3 'end of G gene HRSV. Sequencer 5.0 and MEGA5.05 softwares were used for sequence editing, phylogenetic tree construction and genotyping analysis. Results: Twenty-five samples were positive for HRSV. Seventeen samples succeeded to obtain the target gene, including 13 of HRSVA and 4 of HRSVB. Two genotypes were identified: ON1 genotype (13 samples, HRSVA) and BA9 genotype (4 samples, HRSVB). Five strains of ON1 genotype sequences were clustered with the ON1 sequences prevalent in Beijing, Changchun and Zhejiang from 2012 to 2015 (cluster1); one strain (FJ19-02) was clustered with the sequences of ON1 genotype circulating in many regions of China from 2012 to 2015 (cluster2); Seven strains were clustered independently (cluster FJ). FJ18-02, FJ19-14 and FJ19-15 of HRSVB were clustered with the BA9 genotype sequences prevalent in Changchun, Jilin Province in 2015, while FJ19-13 was closely related to the BA9 genotype sequences prevalent in Guangzhou and Zhejiang Province in 2013. Both the ON1 and BA9 genotypes showed variations of nucleotide and amino acid in 72 and 60 insertion segments. Amino acid mutation (H266L) only occurred among the sequence of cluster-FJ, and the mutations of H261Q and Q265L only appeared in strain FJ19-13. Conclusion: BA9 and ON1 genotypes were prevalent in Quanzhou city, from 2018 to 2019. Cluster-FJ was a newly discovered independent transmission chain, which may continue to circulate in local Quanzhou area.


Assuntos
Infecções por Vírus Respiratório Sincicial , Vírus Sincicial Respiratório Humano , Pequim , Criança , China/epidemiologia , Variação Genética , Genótipo , Humanos , Lactente , Filogenia , Infecções por Vírus Respiratório Sincicial/epidemiologia , Vírus Sincicial Respiratório Humano/genética , Análise de Sequência de DNA
9.
Braz J Biol ; 82: e241110, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34133560

RESUMO

Plasmodium vivax is the most common human malaria parasite in Asian countries including Pakistan. Present study was designed to explore the genetic diversity of plasmodium vivax genotypes based on Pvmsp-3α and Pvmsp-3ßgenes using allelic specific nested PCR and RFLP assays markers from field isolates in district Mardan, Pakistan. Blood samples of 200 P. vivax malarial patients were collected after taking their written informed consent. Genetic diversity in nested PCR products was determined by Restriction Fragment Length Polymorphism (RFLP) utilizing Alu1 and PstI restriction enzymes for alpha and beta gene products digestion, respectively. For analysis the genetic diversity of the sub allelic variants of Pvmsp3α and Pvmsp3ß genes, Chi-Square test was performed by utilizing Minitab programming software 18. The P value 0.05 was considered as statistically significant. For Pvmsp-3α genes after gel electrophoresis of digested products, four distinct genotypes were obtained from total of 50 samples; type A: 35 (70%) (1.5-2.0 kb), 12 of type B (24%) (1.5-1.7 kb), 2 of type C (4%) (0.5-1.5) and one for type D (2%) (0.5-0.65 kb) which could be characterized into 9 allelic pattern (A1-A4, B1-B3, C1, D), in which A3 remained the most predominant. For Pvmsp-3ßgenes, three distinct genotypes were obtained from 50 samples; 40(80%) of type A (1.5-2.5 kb), 9 (18%) of type B (1.0-1.5kb) and 1(2%) of type C (0.65 kb) which could be characterized into 6 allelic patterns (A1-A3, B1-B2, and C1). Most dominant one in Type A was A1 alleles which were noted (46%), while in Type B, the most dominant were B1 (10%).This study is the first ever report of molecular epidemiology and genetic variation in Pvmsp-3α and Pvmsp-3ß genes of P. vivax isolates by using PCR/RFLP from District Mardan and showed a remarkable level of genetic diversity in the studied genes of circulating parasites in the study area. The results of this study will contribute in future studies about the genetic structure of parasite and vaccine development against the malaria.


Assuntos
Plasmodium vivax , Proteínas de Protozoários , Variação Genética , Genótipo , Humanos , Paquistão , Plasmodium vivax/genética , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Proteínas de Protozoários/genética
10.
Viruses ; 13(6)2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-34071984

RESUMO

The high sequence identity of the first SARS-CoV-2 samples collected in December 2019 at Wuhan did not foretell the emergence of novel variants in the United Kingdom, North and South America, India, or South Africa that drive the current waves of the pandemic. The viral spike receptor possesses two surface areas of high mutagenic plasticity: the supersite in its N-terminal domain (NTD) that is recognised by all anti-NTD antibodies and its receptor binding domain (RBD) where 17 residues make contact with the human Ace2 protein (angiotensin I converting enzyme 2) and many neutralising antibodies bind. While NTD mutations appear at first glance very diverse, they converge on the structure of the supersite. The mutations within the RBD, on the other hand, hone in on only a small number of key sites (K417, L452, E484, N501) that are allosteric control points enabling spike to escape neutralising antibodies while maintaining or even gaining Ace2-binding activity. The D614G mutation is the hallmark of all variants, as it promotes viral spread by increasing the number of open spike protomers in the homo-trimeric receptor complex. This review discusses the recent spike mutations as well as their evolution.


Assuntos
COVID-19/virologia , Variação Genética , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genética , Sítios de Ligação/genética , COVID-19/transmissão , Evolução Molecular , Genoma Viral , Humanos , Modelos Moleculares , Mutação , Conformação Proteica , Glicoproteína da Espícula de Coronavírus/química
11.
Nat Commun ; 12(1): 3263, 2021 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-34059684

RESUMO

A fundamental question in medical genetics is how the genetic background modifies the phenotypic outcome of mutations. We address this question by focusing on the seam cells, which display stem cell properties in the epidermis of Caenorhabditis elegans. We demonstrate that a putative null mutation in the GATA transcription factor egl-18, which is involved in seam cell fate maintenance, is more tolerated in the CB4856 isolate from Hawaii than the lab reference strain N2 from Bristol. We identify multiple quantitative trait loci (QTLs) underlying the difference in phenotype expressivity between the two isolates. These QTLs reveal cryptic genetic variation that reinforces seam cell fate through potentiating Wnt signalling. Within one QTL region, a single amino acid deletion in the heat shock protein HSP-110 in CB4856 is sufficient to modify Wnt signalling and seam cell development, highlighting that natural variation in conserved heat shock proteins can shape phenotype expressivity.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Diferenciação Celular/genética , Células Epidérmicas/fisiologia , Fatores de Transcrição GATA/genética , Proteínas de Choque Térmico HSP110/genética , Células-Tronco/fisiologia , Animais , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/metabolismo , Fatores de Transcrição GATA/metabolismo , Estudos de Associação Genética , Técnicas Genéticas , Variação Genética , Proteínas de Choque Térmico HSP110/metabolismo , Organismos Hermafroditas , Masculino , Mutação , Locos de Características Quantitativas , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Via de Sinalização Wnt/genética
12.
Rev Bras Parasitol Vet ; 30(2): e000321, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34076043

RESUMO

The aim of this study was to evaluate the genotypic characteristics of Toxoplasma gondii isolated from free-range chickens in the metropolitan area of Goiânia, Goiás, in Brazil's central-west region. The seroprevalence rate was found to be 96%, according to an indirect hemagglutination assay. Brain and heart samples were processed by peptic digestion for a mice bioassay. The tissues were homogenized and the resulting samples were subjected to polymerase chain reaction (PCR), which revealed that 64% of them contained the parasite's DNA. The mice bioassay revealed 15 isolates, 8 of them tachyzoites isolates from the peritoneal lavage and 7 from brain cysts. T. gondii genotypes were determined through PCR-RFLP, using the following markers: SAG1, SAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1, alt. SAG2, Apico and CS3. Three genotypes were identified, inclued ToxoDB #65, and the other two are not yet described in the literature. Hence, we conclude that the isolates obtained from the metropolitan area of Goiânia showed relatively low genetic diversity.


Assuntos
Doenças dos Roedores , Toxoplasma , Toxoplasmose Animal , Animais , Brasil , Galinhas , Variação Genética , Genótipo , Camundongos , Estudos Soroepidemiológicos , Toxoplasma/genética , Toxoplasmose Animal/diagnóstico , Toxoplasmose Animal/epidemiologia
13.
Genes (Basel) ; 12(6)2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-34072181

RESUMO

The genomic diversity of SARS-CoV-2 has been a focus during the ongoing COVID-19 pandemic. Here, we analyzed the distribution and character of emerging mutations in a data set comprising more than 95,000 virus genomes covering eight major SARS-CoV-2 lineages in the GISAID database, including genotypes arising during COVID-19 therapy. Globally, the C>U transitions and G>U transversions were the most represented mutations, accounting for the majority of single-nucleotide variations. Mutational spectra were not influenced by the time the virus had been circulating in its host or medical treatment. At the amino acid level, we observed about a 2-fold excess of substitutions in favor of hydrophobic amino acids over the reverse. However, most mutations constituting variants of interests of the S-protein (spike) lead to hydrophilic amino acids, counteracting the global trend. The C>U and G>U substitutions altered codons towards increased amino acid hydrophobicity values in more than 80% of cases. The bias is explained by the existing differences in the codon composition for amino acids bearing contrasting biochemical properties. Mutation asymmetries apparently influence the biochemical features of SARS CoV-2 proteins, which may impact protein-protein interactions, fusion of viral and cellular membranes, and virion assembly.


Assuntos
COVID-19/virologia , Genoma Viral , Interações Hidrofóbicas e Hidrofílicas , Mutação , SARS-CoV-2/genética , Proteínas Virais/química , Proteínas Virais/genética , Desaminases APOBEC , Alelos , Substituição de Aminoácidos , Aminoácidos/química , Aminoácidos/genética , Evolução Molecular , Variação Genética , Genótipo , Interações Hospedeiro-Patógeno , Humanos , Filogenia , Polimorfismo de Nucleotídeo Único , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética
14.
Int J Mol Sci ; 22(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34073702

RESUMO

The combination of phage display technology with high-throughput sequencing enables in-depth analysis of library diversity and selection-driven dynamics. We applied short-read sequencing of the mutagenized region on focused display libraries of two homologous nucleic acid modification eraser proteins-AlkB and FTO-biopanned against methylated DNA. This revealed enriched genotypes with small indels and concomitant doubtful amino acid motifs within the FTO library. Nanopore sequencing of the entire display vector showed additional enrichment of large deletions overlooked by region-specific sequencing, and further impacted the interpretation of the obtained amino acid motifs. We could attribute enrichment of these corrupted clones to amplification bias due to arduous FTO display slowing down host cell growth as well as phage production. This amplification bias appeared to be stronger than affinity-based target selection. Recommendations are provided for proper sequence analysis of phage display data, which can improve motive discovery in libraries of proteins that are difficult to display.


Assuntos
Bacteriófagos/genética , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Biblioteca de Peptídeos , Mutação INDEL , Análise de Sequência de DNA
15.
Proc Natl Acad Sci U S A ; 118(24)2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34099556

RESUMO

Human Middle East respiratory syndrome (MERS) cases were detected primarily in the Middle East before a major outbreak occurred in South Korea in 2015. The Korean outbreak was initiated by a single infected individual, allowing studies of virus evolution in the absence of further MERS-CoV introduction into human populations. In contrast, MERS is primarily a camel disease on the Arabian Peninsula and in Africa, with clinical disease in humans only in the former location. Previous work identified two mutations in the South Korean MERS-CoV, D510G and I529T on the Spike (S) protein, that led to impaired binding to the receptor. However, whether these mutations affected virulence is unknown. To address this question, we constructed isogenic viruses expressing mutations found in the S protein from Korean isolates and showed that isogenic viruses carrying the Korean MERS-CoV mutations, D510G or I529T, were attenuated in mice, resulting in greater survival, less induction of inflammatory cytokines, and less severe lung injury. In contrast, isogenic viruses expressing S proteins from African isolates were nearly fully virulent; other studies showed that West African camel isolates carry mutations in MERS-CoV accessory proteins, which may limit human transmission. These data indicate that following a single-point introduction of the virus, MERS-CoV S protein evolved rapidly in South Korea to adapt to human populations, with consequences on virulence. In contrast, the mutations in S proteins of African isolates did not change virulence, indicating that S protein variation likely does not play a major role in the lack of camel-to-human transmission in Africa.


Assuntos
Variação Genética , Geografia , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Glicoproteína da Espícula de Coronavírus/genética , Animais , Feminino , Humanos , Imunização , Inflamação/patologia , Masculino , Camundongos Transgênicos , Coronavírus da Síndrome Respiratória do Oriente Médio/isolamento & purificação , Mutação/genética , Temperatura , Virulência , Internalização do Vírus
16.
Nat Genet ; 53(5): 630-637, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33958779

RESUMO

The kidney is an organ of key relevance to blood pressure (BP) regulation, hypertension and antihypertensive treatment. However, genetically mediated renal mechanisms underlying susceptibility to hypertension remain poorly understood. We integrated genotype, gene expression, alternative splicing and DNA methylation profiles of up to 430 human kidneys to characterize the effects of BP index variants from genome-wide association studies (GWASs) on renal transcriptome and epigenome. We uncovered kidney targets for 479 (58.3%) BP-GWAS variants and paired 49 BP-GWAS kidney genes with 210 licensed drugs. Our colocalization and Mendelian randomization analyses identified 179 unique kidney genes with evidence of putatively causal effects on BP. Through Mendelian randomization, we also uncovered effects of BP on renal outcomes commonly affecting patients with hypertension. Collectively, our studies identified genetic variants, kidney genes, molecular mechanisms and biological pathways of key relevance to the genetic regulation of BP and inherited susceptibility to hypertension.


Assuntos
Predisposição Genética para Doença , Genômica , Hipertensão/genética , Rim/patologia , Processamento Alternativo/genética , Pressão Sanguínea/genética , Metilação de DNA/genética , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética
17.
Proc Biol Sci ; 288(1950): 20202958, 2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-33975471

RESUMO

The amount of genetic variation for fitness within populations tends to exceed that expected under mutation-selection-drift balance. Several mechanisms have been proposed to actively maintain polymorphism and account for this discrepancy, including antagonistic pleiotropy (AP), where allelic variants have opposing effects on different components of fitness. Here, we identify a non-coding indel polymorphism in the fruitless gene of Drosophila melanogaster and measure survival and reproductive components of fitness in males and females of replicate lines carrying each respective allele. Expressing the fruitless region in a hemizygous state reveals a pattern of AP, with one allele generating greater reproductive fitness and the other conferring greater survival to adulthood. Different fitness effects were observed in an alternative genetic background, which may reflect dominance reversal and/or epistasis. Our findings link sequence-level variation at a single locus with complex effects on a range of fitness components, thus helping to explain the maintenance of genetic variation for fitness. Transcription factors, such as fruitless, may be prime candidates for targets of balancing selection since they interact with multiple target loci and their associated phenotypic effects.


Assuntos
Drosophila melanogaster , Aptidão Genética , Alelos , Animais , Drosophila melanogaster/genética , Feminino , Variação Genética , Masculino , Mutação , Polimorfismo Genético , Seleção Genética
18.
Nat Commun ; 12(1): 2642, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976134

RESUMO

Despite its clinical importance, the SARS-CoV-2 gene set remains unresolved, hindering dissection of COVID-19 biology. We use comparative genomics to provide a high-confidence protein-coding gene set, characterize evolutionary constraint, and prioritize functional mutations. We select 44 Sarbecovirus genomes at ideally-suited evolutionary distances, and quantify protein-coding evolutionary signatures and overlapping constraint. We find strong protein-coding signatures for ORFs 3a, 6, 7a, 7b, 8, 9b, and a novel alternate-frame gene, ORF3c, whereas ORFs 2b, 3d/3d-2, 3b, 9c, and 10 lack protein-coding signatures or convincing experimental evidence of protein-coding function. Furthermore, we show no other conserved protein-coding genes remain to be discovered. Mutation analysis suggests ORF8 contributes to within-individual fitness but not person-to-person transmission. Cross-strain and within-strain evolutionary pressures agree, except for fewer-than-expected within-strain mutations in nsp3 and S1, and more-than-expected in nucleocapsid, which shows a cluster of mutations in a predicted B-cell epitope, suggesting immune-avoidance selection. Evolutionary histories of residues disrupted by spike-protein substitutions D614G, N501Y, E484K, and K417N/T provide clues about their biology, and we catalog likely-functional co-inherited mutations. Previously reported RNA-modification sites show no enrichment for conservation. Here we report a high-confidence gene set and evolutionary-history annotations providing valuable resources and insights on SARS-CoV-2 biology, mutations, and evolution.


Assuntos
COVID-19/virologia , Genoma Viral/genética , Mutação , SARS-CoV-2/genética , Betacoronavirus/classificação , Betacoronavirus/genética , Códon , Evolução Molecular , Genes Virais , Aptidão Genética , Variação Genética , Fases de Leitura Aberta , Filogenia , Glicoproteína da Espícula de Coronavírus/genética , Proteínas Virais/genética
19.
Proc Biol Sci ; 288(1950): 20201864, 2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-33977786

RESUMO

Late Quaternary climatic fluctuations in the Northern Hemisphere had drastic effects on large mammal species, leading to the extinction of a substantial number of them. The giant deer (Megaloceros giganteus) was one of the species that became extinct in the Holocene, around 7660 calendar years before present. In the Late Pleistocene, the species ranged from western Europe to central Asia. However, during the Holocene, its range contracted to eastern Europe and western Siberia, where the last populations of the species occurred. Here, we generated 35 Late Pleistocene and Holocene giant deer mitogenomes to explore the genetics of the demise of this iconic species. Bayesian phylogenetic analyses of the mitogenomes suggested five main clades for the species: three pre-Last Glacial Maximum clades that did not appear in the post-Last Glacial Maximum genetic pool, and two clades that showed continuity into the Holocene. Our study also identified a decrease in genetic diversity starting in Marine Isotope Stage 3 and accelerating during the Last Glacial Maximum. This reduction in genetic diversity during the Last Glacial Maximum, coupled with a major contraction of fossil occurrences, suggests that climate was a major driver in the dynamics of the giant deer.


Assuntos
Cervos , Genoma Mitocondrial , Animais , Teorema de Bayes , DNA Mitocondrial/genética , Cervos/genética , Europa (Continente) , Fósseis , Variação Genética , Filogenia , Filogeografia , Dinâmica Populacional
20.
Nat Commun ; 12(1): 2756, 2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-33980843

RESUMO

High-throughput splicing assays have demonstrated that many exonic variants can disrupt splicing; however, splice-disrupting variants distribute non-uniformly across genes. We propose the existence of exons that are particularly susceptible to splice-disrupting variants, which we refer to as hotspot exons. Hotspot exons are also more susceptible to splicing perturbation through drug treatment and knock-down of RNA-binding proteins. We develop a classifier for exonic splice-disrupting variants and use it to infer hotspot exons. We estimate that 1400 exons in the human genome are hotspots. Using panels of splicing reporters, we demonstrate how the ability of an exon to tolerate a mutation is inversely proportional to the strength of its neighboring splice sites.


Assuntos
Éxons/genética , Variação Genética , Splicing de RNA/genética , Processamento Alternativo/genética , Sítios de Ligação , Regulação da Expressão Gênica , Genoma Humano , Humanos , Mutação , Sítios de Splice de RNA , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo
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