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1.
Braz. j. biol ; 83: e247422, 2023. tab, graf
Artigo em Inglês | LILACS, VETINDEX | ID: biblio-1285631

RESUMO

Abstract Plasmodium falciparum resistance to Chloroquine (CQ) is a significant cause of mortality and morbidity worldwide. There is a paucity of documented data on the prevalence of CQ-resistant mutant haplotypes of Pfcrt and Pfmdr1 genes from malaria-endemic war effected Federally Administered Tribal Areas of Pakistan. The objective of this study was to investigate the prevalence of P. falciparum CQ-resistance in this area. Clinical isolates were collected between May 2017 and May 2018 from North Waziristan and South Waziristan agencies of Federally Administrated Trial Area. Subsequently, Giemsa-stained blood smears were examined to detect Plasmodium falciparum. Extraction of malarial DNA was done from microscopy positive P. falciparum samples, and P. falciparum infections were confirmed by nested PCR (targeting Plasmodium small subunit ribosomal ribonucleic acid (ssrRNA) genes). All PCR confirmed P. falciparum samples were sequenced by pyrosequencing to find out mutation in Pfcrt gene at codon K76T and in pfmdr1 at codons N86Y, Y184F, N1042D, and D1246Y. Out of 121 microscopies positive P. falciparum cases, 109 samples were positive for P. falciparum by nested PCR. Pfcrt K76T mutation was found in 96% of isolates, Pfmdr1 N86Y mutation was observed in 20%, and 11% harboured Y184F mutation. All samples were wild type for Pfmdr1 codon N1042D and D1246Y. In the FATA, Pakistan, the frequency of resistant allele 76T remained high despite the removal of CQ. However, current findings of the study suggest complete fixation of P. falciparum CQ-resistant genotype in the study area.


Resumo A resistência do Plasmodium falciparum à cloroquina (CQ) é uma causa significativa de mortalidade e morbidade em todo o mundo. Há uma escassez de dados documentados sobre a prevalência de haplótipos mutantes CQ-resistentes dos genes Pfcrt e Pfmdr1 da guerra endêmica da malária em áreas tribais administradas pelo governo federal do Paquistão. O objetivo deste estudo foi investigar a prevalência de resistência a CQ de P. falciparum nesta área. Isolados clínicos foram coletados entre maio de 2017 e maio de 2018 nas agências do Waziristão do Norte e do Waziristão do Sul da Área de Ensaio Administrada Federalmente. Posteriormente, esfregaços de sangue corados com Giemsa foram examinados para detectar Plasmodium falciparum. A extração do DNA da malária foi feita a partir de amostras de P. falciparum positivas para microscopia, e as infecções por P. falciparum foram confirmadas por nested PCR (visando genes de ácido ribonucleico ribossômico de subunidade pequena de Plasmodium (ssrRNA)). Todas as amostras de P. falciparum confirmadas por PCR foram sequenciadas por pirosequenciamento para descobrir a mutação no gene Pfcrt no códon K76T e em pfmdr1 nos códons N86Y, Y184F, N1042D e D1246Y. De 121 microscopias de casos positivos de P. falciparum, 109 amostras foram positivas para P. falciparum por nested PCR. A mutação Pfcrt K76T foi encontrada em 96% dos isolados, a mutação Pfmdr1 N86Y foi observada em 20% e 11% abrigou a mutação Y184F. Todas as amostras eram do tipo selvagem para o códon N1042D e D1246Y de Pfmdr1. No FATA, Paquistão, a frequência do alelo resistente 76T permaneceu alta apesar da remoção de CQ. No entanto, as descobertas atuais do estudo sugerem a fixação completa do genótipo resistente a CQ de P. falciparum na área de estudo.


Assuntos
Plasmodium falciparum/genética , Antimaláricos/farmacologia , Paquistão , Proteínas de Membrana Transportadoras/genética , Resistência a Medicamentos/genética , Proteínas de Protozoários/genética , Cloroquina/farmacologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Alelos
2.
Gigascience ; 112022 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-35333302

RESUMO

BACKGROUND: Cassava (Manihot esculenta) is an important clonally propagated food crop in tropical and subtropical regions worldwide. Genetic gain by molecular breeding has been limited, partially because cassava is a highly heterozygous crop with a repetitive and difficult-to-assemble genome. FINDINGS: Here we demonstrate that Pacific Biosciences high-fidelity (HiFi) sequencing reads, in combination with the assembler hifiasm, produced genome assemblies at near complete haplotype resolution with higher continuity and accuracy compared to conventional long sequencing reads. We present 2 chromosome-scale haploid genomes phased with Hi-C technology for the diploid African cassava variety TME204. With consensus accuracy >QV46, contig N50 >18 Mb, BUSCO completeness of 99%, and 35k phased gene loci, it is the most accurate, continuous, complete, and haplotype-resolved cassava genome assembly so far. Ab initio gene prediction with RNA-seq data and Iso-Seq transcripts identified abundant novel gene loci, with enriched functionality related to chromatin organization, meristem development, and cell responses. During tissue development, differentially expressed transcripts of different haplotype origins were enriched for different functionality. In each tissue, 20-30% of transcripts showed allele-specific expression (ASE) differences. ASE bias was often tissue specific and inconsistent across different tissues. Direction-shifting was observed in <2% of the ASE transcripts. Despite high gene synteny, the HiFi genome assembly revealed extensive chromosome rearrangements and abundant intra-genomic and inter-genomic divergent sequences, with large structural variations mostly related to LTR retrotransposons. We use the reference-quality assemblies to build a cassava pan-genome and demonstrate its importance in representing the genetic diversity of cassava for downstream reference-guided omics analysis and breeding. CONCLUSIONS: The phased and annotated chromosome pairs allow a systematic view of the heterozygous diploid genome organization in cassava with improved accuracy, completeness, and haplotype resolution. They will be a valuable resource for cassava breeding and research. Our study may also provide insights into developing cost-effective and efficient strategies for resolving complex genomes with high resolution, accuracy, and continuity.


Assuntos
Manihot , Alelos , Cromossomos , Diploide , Haplótipos , Manihot/genética , Melhoramento Vegetal , Análise de Sequência de DNA , Transcriptoma
3.
Forensic Sci Int Genet ; 57: 102661, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35063923

RESUMO

Non-self DNA is normally present on skin due to DNA transfer occurring during daily activities. The understanding of persistence and accumulation of foreign DNA on the neck can assist in the interpretation of DNA evidence collected from an assaulted victim. Establishing the composition and level of non-self DNA present is relevant, especially in cases where the victim cohabits with other individuals, such as partner and children. This study investigated the persistence and accumulation of non-self DNA on the neck, over the course of 24 h. DNA samples were collected from the neck of 20 adult volunteers at three time-points, on two days. The detection of a partner's DNA and DNA from unknown sources was studied in relation to the living arrangement and to the activities performed by each individual. An increased number of non-self alleles were detected over time. Partner's DNA was observed to accumulate during the day and to persist when an individual was absent from the shared home environment. DNA from unknown contributors was found on the neck of individuals that used public transport, attended public spaces and had social interactions. The data acquired from this study will help to increase knowledge on the composition of DNA present on an individual's neck in a daily situation.


Assuntos
Vítimas de Crime , DNA , Adulto , Alelos , Criança , DNA/genética , Humanos , Fatores de Tempo
4.
Proc Natl Acad Sci U S A ; 119(32): e2200567119, 2022 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-35914131

RESUMO

Evolution of resistance is a major barrier to successful deployment of gene-drive systems to suppress natural populations, which could greatly reduce the burden of many vector-borne diseases. Multiplexed guide RNAs (gRNAs) that require resistance mutations in all target cut sites are a promising antiresistance strategy since, in principle, resistance would only arise in unrealistically large populations. Using stochastic simulations that accurately model evolution at very large population sizes, we explore the probability of resistance due to three important mechanisms: 1) nonhomologous end-joining mutations, 2) single-nucleotide mutants arising de novo, or 3) single-nucleotide polymorphisms preexisting as standing variation. Our results explore the relative importance of these mechanisms and highlight a complexity of the mutation-selection-drift balance between haplotypes with complete resistance and those with an incomplete number of resistant alleles. We find that this leads to a phenomenon where weakly deleterious naturally occurring variants greatly amplify the probability of multisite resistance compared to de novo mutation. This key result provides design criterion for antiresistance multiplexed systems, which, in general, will need a larger number of gRNAs compared to de novo expectations. This theory may have wider application to the evolution of resistance or evolutionary rescue when multiple changes are required before selection can act.


Assuntos
Tecnologia de Impulso Genético , Variação Genética , Modelos Genéticos , Alelos , Deriva Genética , Variação Genética/genética , Haplótipos , Mutação , Nucleotídeos/genética , Polimorfismo de Nucleotídeo Único/genética , RNA Guia/genética , Seleção Genética , Processos Estocásticos
5.
Proc Natl Acad Sci U S A ; 119(32): e2204779119, 2022 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-35914128

RESUMO

Earlier work has shown that siRNA-mediated reduction of the SUPT4H or SUPT5H proteins, which interact to form the DSIF complex and facilitate transcript elongation by RNA polymerase II (RNAPII), can decrease expression of mutant gene alleles containing nucleotide repeat expansions differentially. Using luminescence and fluorescence assays, we identified chemical compounds that interfere with the SUPT4H-SUPT5H interaction and then investigated their effects on synthesis of mRNA and protein encoded by mutant alleles containing repeat expansions in the huntingtin gene (HTT), which causes the inherited neurodegenerative disorder, Huntington's Disease (HD). Here we report that such chemical interference can differentially affect expression of HTT mutant alleles, and that a prototypical chemical, 6-azauridine (6-AZA), that targets the SUPT4H-SUPT5H interaction can modify the biological response to mutant HTT gene expression. Selective and dose-dependent effects of 6-AZA on expression of HTT alleles containing nucleotide repeat expansions were seen in multiple types of cells cultured in vitro, and in a Drosophila melanogaster animal model for HD. Lowering of mutant HD protein and mitigation of the Drosophila "rough eye" phenotype associated with degeneration of photoreceptor neurons in vivo were observed. Our findings indicate that chemical interference with DSIF complex formation can decrease biochemical and phenotypic effects of nucleotide repeat expansions.


Assuntos
Azauridina , Proteína Huntingtina , Doença de Huntington , Proteínas Mutantes , Mutação , Proteínas Nucleares , Fenótipo , Proteínas Repressoras , Fatores de Elongação da Transcrição , Alelos , Animais , Azauridina/farmacologia , Células Cultivadas , Expansão das Repetições de DNA , Modelos Animais de Doenças , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Humanos , Proteína Huntingtina/biossíntese , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Doença de Huntington/genética , Medições Luminescentes , Proteínas Mutantes/biossíntese , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Proteínas Nucleares/metabolismo , Células Fotorreceptoras de Invertebrados/efeitos dos fármacos , Proteínas Repressoras/metabolismo , Fatores de Elongação da Transcrição/metabolismo
6.
Nat Commun ; 13(1): 4478, 2022 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-35918310

RESUMO

Intracranial germ cell tumors (IGCTs) are rare brain neoplasms that mainly occur in children and adolescents with a particularly high incidence in East Asian populations. Here, we conduct a genome-wide association study (GWAS) of 133 patients with IGCTs and 762 controls of Japanese ancestry. A common 4-bp deletion polymorphism in an enhancer adjacent to BAK1 is significantly associated with the disease risk (rs3831846; P = 2.4 × 10-9, odds ratio = 2.46 [95% CI: 1.83-3.31], minor allele frequency = 0.43). Rs3831846 is in strong linkage disequilibrium with a testicular GCTs susceptibility variant rs210138. In-vitro reporter assays reveal rs3831846 to be a functional variant attenuating the enhancer activity, suggesting its contribution to IGCTs predisposition through altering BAK1 expression. Risk alleles of testicular GCTs derived from the European GWAS show significant positive correlations in the effect sizes with the Japanese IGCTs GWAS (P = 1.3 × 10-4, Spearman's ρ = 0.48). These results suggest the shared genetic susceptibility of GCTs beyond ethnicity and primary sites.


Assuntos
Neoplasias Encefálicas , Neoplasias Embrionárias de Células Germinativas , Neoplasias Testiculares , Adolescente , Alelos , Neoplasias Encefálicas/genética , Criança , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Neoplasias Embrionárias de Células Germinativas/genética , Polimorfismo de Nucleotídeo Único , Neoplasias Testiculares/genética , Proteína Killer-Antagonista Homóloga a bcl-2/genética
7.
Cell Mol Life Sci ; 79(8): 464, 2022 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-35925520

RESUMO

Classical HLA (Human Leukocyte Antigen) is the Major Histocompatibility Complex (MHC) in man. HLA genes and disease association has been studied at least since 1967 and no firm pathogenic mechanisms have been established yet. HLA-G immune modulation gene (and also -E and -F) are starting the same arduous way: statistics and allele association are the trending subjects with the same few results obtained by HLA classical genes, i.e., no pathogenesis may be discovered after many years of a great amount of researchers' effort. Thus, we believe that it is necessary to follow different research methodologies: (1) to approach this problem, based on how evolution has worked maintaining together a cluster of immune-related genes (the MHC) in a relatively short chromosome area since amniotes to human at least, i.e., immune regulatory genes (MHC-G, -E and -F), adaptive immune classical class I and II genes, non-adaptive immune genes like (C2, C4 and Bf) (2); in addition to using new in vitro models which explain pathogenetics of HLA and disease associations. In fact, this evolution may be quite reliably studied during about 40 million years by analyzing the evolution of MHC-G, -E, -F, and their receptors (KIR-killer-cell immunoglobulin-like receptor, NKG2-natural killer group 2-, or TCR-T-cell receptor-among others) in the primate evolutionary lineage, where orthology of these molecules is apparently established, although cladistic studies show that MHC-G and MHC-B genes are the ancestral class I genes, and that New World apes MHC-G is paralogous and not orthologous to all other apes and man MHC-G genes. In the present review, we outline past and possible future research topics: co-evolution of adaptive MHC classical (class I and II), non-adaptive (i.e., complement) and modulation (i.e., non-classical class I) immune genes may imply that the study of full or part of MHC haplotypes involving several loci/alleles instead of single alleles is important for uncovering HLA and disease pathogenesis. It would mainly apply to starting research on HLA-G extended haplotypes and disease association and not only using single HLA-G genetic markers.


Assuntos
Antígenos HLA-G , Complexo Principal de Histocompatibilidade , Alelos , Animais , Cromossomos , Evolução Molecular , Genes MHC Classe I , Antígenos HLA-G/genética , Haplótipos , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Complexo Principal de Histocompatibilidade/genética
8.
Sci Rep ; 12(1): 13264, 2022 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-35918447

RESUMO

PILRA (rs1859788 A > G) has been suggested to be a protective variant for Alzheimer's disease (AD) and is an entry co-receptor for herpes simplex virus-1. We conducted a nested case-control study of 360 1:1-matched AD subjects. Interactions between the PILRA-A allele, APOE risk variants (ε3/ε4 or ε4/ε4) and GM17 for AD risk were modelled. The associations were cross-validated using two independent whole-genome sequencing datasets. We found negative interactions between PILRA-A and GM17 (OR 0.72, 95% CI 0.52-1.00) and between PILRA-A and APOE risk variants (OR 0.56, 95% CI 0.32-0.98) in the discovery dataset. In the replication cohort, a joint effect of PILRA and PILRA × GM 17/17 was observed for the risk of developing AD (p .02). Here, we report a negative effect modification by PILRA on APOE and GM17 high-risk variants for future AD risk in two independent datasets. This highlights the complex genetics of AD.


Assuntos
Doença de Alzheimer , Apolipoproteína E4 , Alelos , Doença de Alzheimer/genética , Apolipoproteína E4/genética , Apolipoproteínas E/genética , Estudos de Casos e Controles , Genótipo , Humanos , Glicoproteínas de Membrana/genética , Polimorfismo Genético , Receptores Imunológicos/genética
9.
BMC Genomics ; 23(1): 550, 2022 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-35918653

RESUMO

BACKGROUND: The Qinba region is the transition region between Indica and Japonica varieties in China. It has a long history of Indica rice planting of more than 7000 years and is also a planting area for fine-quality Indica rice. The aims of this study are to explore different genetic markers applied to the analysis population structure, genetic diversity, selection and optimization of molecular markers of Indica rice, thus providing more information for the protection and utilization on germplasm resources of Indica rice. METHODS: Fifteen phenotypic traits, a core set of 48 SSR markers which originated protocol for identification of rice varieties-SSR marker method in agricultural industry standard of the People's Republic of China (Ministry of Agriculture of the PRC, NY/T1433-2014, Protocol for identification of rice varieties-SSR marker method, 2014), and SNPs data obtained by genotyping-by-sequencing (GBS, NlaIII and MseI digestion, referred to as SNPs-NlaIII and SNPs-MseI, respectively) for this panel of 93 samples using the Illumina HiSeq2000 sequencing platform, were employed to explore the genetic diversity and population structure of 93 samples. RESULTS: The average of coefficient of variation (CV) and diversity index (He) were 29.72% and 1.83 ranging from 3.07% to 137.43%, and from 1.45 to 2.03, respectively. The correlation coefficient between 15 phenotypic traits ranged from 0.984 to -0.604. The first four PCs accounted for 70.693% phenotypic variation based on phenotypic analysis. A total of 379 alleles were obtained using SSR markers, encompassing an average of 8.0 alleles per primer. Polymorphic bands (PPB) and polymorphism information content (PIC) was 88.65% and 0.77, respectively. The Mantel test showed that the correlation between the genetic distance matrix based on SNPs-NlaIII and SNPs-MseI was the largest (R2=0.88), and that based on 15 phenotypic traits and SSR was the smallest (R2=0.09). The 93 samples could be clustered into two subgroups by 3 types of genetic markers. Molecular variance analysis revealed that the genetic variation was 2% among populations and 98% within populations (the Nm was 0.16), Tajima's D value was 1.66, the FST between the two populations was 0.61 based on 72,824 SNPs. CONCLUSIONS: The population genetic variation explained by SNPs was larger than that explained by SSRs. The gene flow of 93 samples used in this study was larger than that of naturally self-pollinated crops, which may be caused by long-term breeding selection of Indica rice in the Qinba region. The genetic structure of the 93 samples was simple and lacked rare alleles.


Assuntos
Oryza , Alelos , China , Marcadores Genéticos , Variação Genética , Genótipo , Humanos , Repetições de Microssatélites/genética , Oryza/genética , Filogenia , Melhoramento Vegetal , Polimorfismo de Nucleotídeo Único
10.
Proc Natl Acad Sci U S A ; 119(32): e2208317119, 2022 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-35914137

RESUMO

The proper balance of synthesis, folding, modification, and degradation of proteins, also known as protein homeostasis, is vital to cellular health and function. The unfolded protein response (UPR) is activated when the mechanisms maintaining protein homeostasis in the endoplasmic reticulum become overwhelmed. However, prolonged or strong UPR responses can result in elevated inflammation and cellular damage. Previously, we discovered that the enzyme filamentation induced by cyclic-AMP (Fic) can modulate the UPR response via posttranslational modification of binding immunoglobulin protein (BiP) by AMPylation during homeostasis and deAMPylation during stress. Loss of fic in Drosophila leads to vision defects and altered UPR activation in the fly eye. To investigate the importance of Fic-mediated AMPylation in a mammalian system, we generated a conditional null allele of Fic in mice and characterized the effect of Fic loss on the exocrine pancreas. Compared to controls, Fic-/- mice exhibit elevated serum markers for pancreatic dysfunction and display enhanced UPR signaling in the exocrine pancreas in response to physiological and pharmacological stress. In addition, both fic-/- flies and Fic-/- mice show reduced capacity to recover from damage by stress that triggers the UPR. These findings show that Fic-mediated AMPylation acts as a molecular rheostat that is required to temper the UPR response in the mammalian pancreas during physiological stress. Based on these findings, we propose that repeated physiological stress in differentiated tissues requires this rheostat for tissue resilience and continued function over the lifetime of an animal.


Assuntos
AMP Cíclico , Proteínas de Drosophila , Drosophila melanogaster , Estresse do Retículo Endoplasmático , Nucleotidiltransferases , Estresse Fisiológico , Resposta a Proteínas não Dobradas , Alelos , Animais , AMP Cíclico/metabolismo , Proteínas de Drosophila/deficiência , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Camundongos , Nucleotidiltransferases/deficiência , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , Pâncreas/efeitos dos fármacos , Pâncreas/enzimologia , Pâncreas/metabolismo , Pâncreas/fisiopatologia , Estresse Fisiológico/efeitos dos fármacos , Resposta a Proteínas não Dobradas/efeitos dos fármacos
11.
BMC Biol ; 20(1): 173, 2022 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-35927700

RESUMO

BACKGROUND: Non-crossover (NCO) refers to a mechanism of homologous recombination in which short tracks of DNA are copied between homologue chromatids. The allelic changes are typically restricted to one or few SNPs, which potentially allow for the gradual adaptation and maturation of haplotypes. It is assumed to be a stochastic process but the analysis of archaic and modern human haplotypes revealed a striking variability in local NCO recombination rates. METHODS: NCO recombination rates of 1.9 million archaic SNPs shared with Denisovan hominids were defined by a linkage study and correlated with functional and genomic annotations as well as ChIP-Seq data from modern humans. RESULTS: We detected a strong correlation between NCO recombination rates and the function of the respective region: low NCO rates were evident in introns and quiescent intergenic regions but high rates in splice sites, exons, 5'- and 3'-UTRs, as well as CpG islands. Correlations with ChIP-Seq data from ENCODE and other public sources further identified epigenetic modifications that associated directly with these recombination events. A particularly strong association was observed for 5-hydroxymethylcytosine marks (5hmC), which were enriched in virtually all of the functional regions associated with elevated NCO rates, including CpG islands and 'poised' bivalent regions. CONCLUSION: Our results suggest that 5hmC marks may guide the NCO machinery specifically towards functionally relevant regions and, as an intermediate of oxidative demethylation, may open a pathway for environmental influence by specifically targeting recently opened gene loci.


Assuntos
Metilação de DNA , Epigênese Genética , Alelos , Ilhas de CpG , Haplótipos , Humanos
12.
Proc Natl Acad Sci U S A ; 119(28): e2118182119, 2022 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-35787055

RESUMO

X chromosome inactivation (XCI) is the process of silencing one of the X chromosomes in cells of the female mammal which ensures dosage compensation between the sexes. Although theoretically random in somatic tissues, the choice of which X chromosome is chosen to be inactivated can be biased in mice by genetic element(s) associated with the so-called X-controlling element (Xce). Although the Xce was first described and genetically localized nearly 40 y ago, its mode of action remains elusive. In the approach presented here, we identify a single long noncoding RNA (lncRNA) within the Xce locus, Lppnx, which may be the driving factor in the choice of which X chromosome will be inactivated in the developing female mouse embryo. Comparing weak and strong Xce alleles we show that Lppnx modulates the expression of Xist lncRNA, one of the key factors in XCI, by controlling the occupancy of pluripotency factors at Intron1 of Xist. This effect is counteracted by enhanced binding of Rex1 in DxPas34, another key element in XCI regulating the activity of Tsix lncRNA, the main antagonist of Xist, in the strong but not in the weak Xce allele. These results suggest that the different susceptibility for XCI observed in weak and strong Xce alleles results from differential transcription factor binding of Xist Intron 1 and DxPas34, and that Lppnx represents a decisive factor in explaining the action of the Xce.


Assuntos
RNA Longo não Codificante , Inativação do Cromossomo X , Alelos , Animais , Compensação de Dosagem (Genética) , Feminino , Mamíferos/genética , Camundongos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Cromossomo X/genética
13.
BMC Plant Biol ; 22(1): 326, 2022 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-35790923

RESUMO

BACKGROUND: Pre-harvest sprouting (PHS) is a serious limiting factor for wheat (Triticum aestivum L.) grain yield and end-use quality. Identification of reliable molecular markers and PHS-resistant germplasms is vital to improve PHS resistance by molecular marker-assisted selection (MAS), but the effects of allelic variation and haplotypes in genes conferring PHS resistance in winter wheat cultivars are less understood. RESULTS: Resistance to PHS was tested in 326 commercial winter wheat cultivars for three consecutive growing seasons from 2018-2020. The effects of alleles and haplotypes of 10 genes associated with PHS resistance were determined for all cultivars and were validated by introgressing the PHS-resistance allele and haplotype into a susceptible wheat cultivar. High level of phenotypic variation in PHS resistance was observed in this set of cultivars and 8 of them were highly resistant to PHS with stable germination index (GI) of less than 25% in each individual year. Allelic effects of nine genes and TaMFT haplotype analysis demonstrated that the haplotype Hap1 with low-GI alleles at five positions had the best PHS resistance. This haplotype has the priority to use in improving PHS resistance because of its high effectiveness and rare present in the current commercial cultivars. Among 14 main allelic combinations (ACs) identified, the AC1 carrying the haplotype Hap1 and the TaSdr-B1a allele had better PHS resistance than the other classes. The introgression of Hap1 and TaSdr-B1a is able to significantly improve the PHS resistance in the susceptible cultivar Lunxuan 13. CONCLUSIONS: The effectiveness of alleles conferring PHS resistance in winter wheat cultivars was determined and the useful alleles and haplotypes were identified, providing valuable information for parental selection and MAS aiming at improving PHS-resistance in winter wheat. The identification of the PHS-resistant cultivars without known resistance alleles offers an opportunity to explore new PHS-resistant genes.


Assuntos
Germinação , Triticum , Alelos , Germinação/genética , Haplótipos , Estações do Ano , Triticum/genética
14.
Nat Commun ; 13(1): 3902, 2022 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-35794146

RESUMO

Crozier's paradox suggests that genetic kin recognition will not be evolutionarily stable. The problem is that more common tags (markers) are more likely to be recognised and helped. This causes common tags to increase in frequency, and hence eliminates the genetic variability that is required for genetic kin recognition. It has therefore been assumed that genetic kin recognition can only be stable if there is some other factor maintaining tag diversity, such as the advantage of rare alleles in host-parasite interactions. We show that allowing for multiple social encounters before each social interaction can eliminate Crozier's paradox, because it allows individuals with rare tags to find others with the same tag. We also show that rare tags are better indicators of relatedness, and hence better at helping individuals avoid interactions with non-cooperative cheats. Consequently, genetic kin recognition provides an advantage to rare tags that maintains tag diversity, and stabilises itself.


Assuntos
Evolução Biológica , Comunicação Celular , Alelos , Interações Hospedeiro-Parasita , Humanos
15.
Commun Biol ; 5(1): 670, 2022 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-35794204

RESUMO

GBA variants carriers are at increased risk of Parkinson's disease (PD) and Lewy body dementia (LBD). The presence of pseudogene GBAP1 predisposes to structural variants, complicating genetic analysis. We present two methods to resolve recombinant alleles and other variants in GBA: Gauchian, a tool for short-read, whole-genome sequencing data analysis, and Oxford Nanopore sequencing after PCR enrichment. Both methods were concordant for 42 samples carrying a range of recombinants and GBAP1-related mutations, and Gauchian outperformed the GATK Best Practices pipeline. Applying Gauchian to sequencing of over 10,000 individuals shows that copy number variants (CNVs) spanning GBAP1 are relatively common in Africans. CNV frequencies in PD and LBD are similar to controls. Gains may coexist with other mutations in patients, and a modifying effect cannot be excluded. Gauchian detects more GBA variants in LBD than PD, especially severe ones. These findings highlight the importance of accurate GBA analysis in these patients.


Assuntos
Doença por Corpos de Lewy , Doença de Parkinson , Alelos , Glucosilceramidase/genética , Heterozigoto , Humanos , Doença por Corpos de Lewy/genética , Doença de Parkinson/genética
16.
Cell Death Dis ; 13(7): 586, 2022 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-35798703

RESUMO

Herein, we describe the clinical and hematological features of three genetically related families predisposed to myeloproliferative neoplasms (MPNs). Using whole-exome sequencing, we identified a c.1367delG mutation(p.Arg456fs) in CHST15 (NM_001270764), a gene encoding a type II transmembraneglycoproteinthat acts as a sulfotransferase and participates in the biosynthesis of chondroitin sulfate E, in germline and somatic cells in familial MPN. CHST15defects caused an increased JAK2V617F allele burden and upregulated p-Stat3 activity,leading to an increase in the proliferative and prodifferentiation potential of transgenic HEL cells. We demonstrated that mutant CHST15 is able to coimmmunoprecipitate the JAK2 protein,suggesting the presence of a CHST15-JAK2-Stat3 signaling axis in familial MPN. Gene expression profiling showed that the FREM1, IFI27 and C4B_2 genes are overexpressed in familial MPN, suggesting the activation of an "inflammatory response-extracellular matrix-immune regulation" signaling network in the CHST15 mutation background.We thus concluded that CHST15 is a novel gene that predisposes to familial MPN and increases the probability of disease development or transformation.


Assuntos
Glicoproteínas de Membrana , Transtornos Mieloproliferativos , Neoplasias , Sulfotransferases , Alelos , Mutação em Linhagem Germinativa , Humanos , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Glicoproteínas de Membrana/genética , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/metabolismo , Neoplasias/genética , Sulfotransferases/genética
17.
Proc Natl Acad Sci U S A ; 119(27): e2202862119, 2022 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-35776547

RESUMO

Identifying the genetic basis of repeatedly evolved traits provides a way to reconstruct their evolutionary history and ultimately investigate the predictability of evolution. Here, we focus on the oldfield mouse (Peromyscus polionotus), which occurs in the southeastern United States, where it exhibits considerable color variation. Dorsal coats range from dark brown in mainland mice to near white in mice inhabiting sandy beaches; this light pelage has evolved independently on Florida's Gulf and Atlantic coasts as camouflage from predators. To facilitate genomic analyses, we first generated a chromosome-level genome assembly of Peromyscus polionotus subgriseus. Next, in a uniquely variable mainland population (Peromyscus polionotus albifrons), we scored 23 pigment traits and performed targeted resequencing in 168 mice. We find that pigment variation is strongly associated with an ∼2-kb region ∼5 kb upstream of the Agouti signaling protein coding region. Using a reporter-gene assay, we demonstrate that this regulatory region contains an enhancer that drives expression in the dermis of mouse embryos during the establishment of pigment prepatterns. Moreover, extended tracts of homozygosity in this Agouti region indicate that the light allele experienced recent and strong positive selection. Notably, this same light allele appears fixed in both Gulf and Atlantic coast beach mice, despite these populations being separated by >1,000 km. Together, our results suggest that this identified Agouti enhancer allele has been maintained in mainland populations as standing genetic variation and from there, has spread to and been selected in two independent beach mouse lineages, thereby facilitating their rapid and parallel evolution.


Assuntos
Proteína Agouti Sinalizadora , Evolução Biológica , Elementos Facilitadores Genéticos , Peromyscus , Pigmentação da Pele , Proteína Agouti Sinalizadora/metabolismo , Alelos , Animais , Genes Reporter , Peromyscus/genética , Peromyscus/fisiologia , Pigmentação da Pele/genética
18.
Sci Rep ; 12(1): 11136, 2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35778471

RESUMO

Interleukin 10 (IL-10) is associated with the progression of leishmaniasis because it inhibits the leishmanicidal action of macrophages and the production of mediators such as IFN-γ and nitric oxide. Studies have shown that specific polymorphisms are associated with the regulatory role of IL-10 and the development of more relevant clinical forms of leishamaniasis. We performed a systematic review and meta-analysis to determine whether single nucleotide polymorphisms (SNPs) of IL-10 influence the progression of leishmaniasis. The selected articles were read in full and only those consistent with the eligibility criteria were included in our study. Seven studies were eligible according to the inclusion criteria and were included in the present systematic review, but only five were subjected to statistical analysis. The pooled odds ratios showed no significant association between the rs1800871 SNP and the progression of leishmaniasis in all genotype models, including the dominant, recessive, homozygote, heterozygote, and allelic models. Regarding the association between rs1800896 SNP and the progression of leishmaniasis, the pooled odds ratios showed no association under all genotype models. Hence, IL-10 SNPs did not show significant association and were not considered a risk factor for the progression of leishmaniasis.


Assuntos
Interleucina-10 , Leishmaniose , Alelos , Predisposição Genética para Doença , Humanos , Interleucina-10/genética , Leishmaniose/genética , Polimorfismo de Nucleotídeo Único
19.
Int J Mol Sci ; 23(13)2022 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-35806155

RESUMO

In tomato cultivation, a rare natural mutation in the flowering repressor antiflorigen gene SELF-PRUNING (sp-classic) induces precocious shoot termination and is the foundation in determinate tomato breeding for open field production. Heterozygous single flower truss (sft) mutants in the florigen SFT gene in the background of sp-classic provide a heterosis-like effect by delaying shoot termination, suggesting the subtle suppression of determinacy by genetic modification of the florigen-antiflorigen balance could improve yield. Here, we isolated three new sp alleles from the tomato germplasm that show modified determinate growth compared to sp-classic, including one allele that mimics the effect of sft heterozygosity. Two deletion alleles eliminated functional transcripts and showed similar shoot termination, determinate growth, and yields as sp-classic. In contrast, amino acid substitution allele sp-5732 showed semi-determinate growth with more leaves and sympodial shoots on all shoots. This translated to greater yield compared to the other stronger alleles by up to 42%. Transcriptome profiling of axillary (sympodial) shoot meristems (SYM) from sp-classic and wild type plants revealed six mis-regulated genes related to the floral transition, which were used as biomarkers to show that the maturation of SYMs in the weaker sp-5732 genotype is delayed compared to sp-classic, consistent with delayed shoot termination and semi-determinate growth. Assessing sp allele frequencies from over 500 accessions indicated that one of the strong sp alleles (sp-2798) arose in early breeding cultivars but was not selected. The newly discovered sp alleles are potentially valuable resources to quantitatively manipulate shoot growth and yield in determinate breeding programs, with sp-5732 providing an opportunity to develop semi-determinate field varieties with higher yields.


Assuntos
Lycopersicon esculentum , Alelos , Florígeno/metabolismo , Flores/metabolismo , Regulação da Expressão Gênica de Plantas , Lycopersicon esculentum/metabolismo , Meristema/genética , Mutação , Melhoramento Vegetal , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Brotos de Planta/metabolismo
20.
Int J Mol Sci ; 23(13)2022 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-35806182

RESUMO

Galectin 1 (Gal1) exerts immunomodulatory effects leading to therapeutic effects in autoimmune animal models. Patients with rheumatoid arthritis have been reported to show higher Gal1 serum levels than the healthy population. Our study aimed to find genetic variants on the Gal1 gene (LGALS1) modulating its expression and/or clinical features in patients with early arthritis (EA). LGALS1 was sequenced in 53 EA patients to characterize all genetic variants. Then, we genotyped rs9622682, rs929039, and rs4820293, which covered the main genetic variation in LGALS1, in 532 EA patients. Gal1 and IL-6 serum levels were measured by ELISA and Gal1 also by western blot (WB) in lymphocytes from patients with specific genotypes. Once disease activity improved with treatment, patients with at least one copy of the minor allele in rs9622682 and rs929039 or those with GG genotype in rs4820293 showed significantly higher Gal1 serum levels (p < 0.05). These genotypic combinations were also associated with higher Gal1 expression in lymphocytes by WB and lower IL-6 serum levels in EA patients. In summary, our study suggests that genetic variants studied in LGALS1 can explain heterogeneity in Gal1 serum levels showing that patients with higher Gal1 levels have lower serum IL-6 levels.


Assuntos
Artrite Reumatoide , Galectina 1 , Alelos , Animais , Artrite Reumatoide/genética , Galectina 1/genética , Galectina 1/metabolismo , Genótipo , Interleucina-6/genética
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