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1.
PLoS One ; 18(1): e0280282, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36626386

RESUMO

Complement Receptor Type 1 (CR1) is a malaria-associated gene that encodes a transmembrane receptor of erythrocytes and is crucial for malaria parasite invasion. The expression of CR1 contributes to the rosetting of erythrocytes in the brain bloodstream, causing cerebral malaria, the most severe form of the disease. Here, we study the history of adaptation against malaria by analyzing selection signals in the CR1 gene. We used whole-genome sequencing datasets of 907 healthy individuals from malaria-endemic and non-endemic populations. We detected robust positive selection in populations from the hyperendemic regions of East India and Papua New Guinea. Importantly, we identified a new adaptive variant, rs12034598, which is associated with a slower rate of erythrocyte sedimentation and is linked with a variant associated with low levels of CR1 expression. The combination of the variants likely drives natural selection. In addition, we identified a variant rs3886100 under positive selection in West Africans, which is also related to a low level of CR1 expression in the brain. Our study shows the fine-resolution history of positive selection in the CR1 gene and suggests a population-specific history of CR1 adaptation to malaria. Notably, our novel approach using population genomic analyses allows the identification of protective variants that reduce the risk of malaria infection without the need for patient samples or malaria individual medical records. Our findings contribute to understanding of human adaptation against cerebral malaria.


Assuntos
Malária Cerebral , Receptores de Complemento 3b , Humanos , Eritrócitos , Malária Cerebral/genética , Malária Cerebral/metabolismo , Papua Nova Guiné , Receptores de Complemento 3b/genética , Seleção Genética , Genética Populacional , Índia
2.
J Bioinform Comput Biol ; 19(6): 2140006, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34753405

RESUMO

Evolutionary mechanisms of adaptation to malaria are understudied in Asian endemic regions despite a high prevalence of malaria in the region. In our research, we performed a genome-wide screening for footprints of natural selection against malaria by comparing eight Asian population groups from malaria-endemic regions with two non-endemic population groups from Europe and Mongolia. We identified 285 adaptive genes showing robust selection signals across three statistical methods, iHS, XP-EHH, and PBS. Interestingly, most of the identified genes (82%) were found to be under selection in a single population group, while adaptive genes shared across populations were rare. This is likely due to the independent adaptation history in different endemic populations. The gene ontology (GO) analysis for the 285 adaptive genes highlighted their functional processes linked to neuronal organizations or nervous system development. These genes could be related to cerebral malaria and may reduce the inflammatory response and the severity of malaria symptoms. Remarkably, our novel population genomic approach identified population-specific adaptive genes potentially against malaria infection without the need for patient samples or individual medical records.


Assuntos
Malária , Polimorfismo de Nucleotídeo Único , Ásia/epidemiologia , Genoma , Humanos , Malária/epidemiologia , Malária/genética , Seleção Genética
3.
RNA ; 25(8): 905-920, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31088860

RESUMO

Altered splicing contributes to the pathogenesis of human blood disorders including myelodysplastic syndromes (MDS) and leukemias. Here we characterize the transcriptomic regulation of PRPF40B, which is a splicing factor mutated in a small fraction of MDS patients. We generated a full PRPF40B knockout (KO) in the K562 cell line by CRISPR/Cas9 technology and rescued its levels by transient overexpression of wild-type (WT), P383L or P540S MDS alleles. Using RNA sequencing, we identified hundreds of differentially expressed genes and alternative splicing (AS) events in the KO that are rescued by WT PRPF40B, with a majority also rescued by MDS alleles, pointing to mild effects of these mutations. Among the PRPF40B-regulated AS events, we found a net increase in exon inclusion in the KO, suggesting that this splicing factor primarily acts as a repressor. PRPF40B-regulated splicing events are likely cotranscriptional, affecting exons with A-rich downstream intronic motifs and weak splice sites especially for 5' splice sites, consistent with its PRP40 yeast ortholog being part of the U1 small nuclear ribonucleoprotein. Loss of PRPF40B in K562 induces a KLF1 transcriptional signature, with genes involved in iron metabolism and mainly hypoxia, including related pathways like cholesterol biosynthesis and Akt/MAPK signaling. A cancer database analysis revealed that PRPF40B is lowly expressed in acute myeloid leukemia, whereas its paralog PRPF40A expression is high as opposed to solid tumors. Furthermore, these factors negatively or positively correlated with hypoxia regulator HIF1A, respectively. Our data suggest a PRPF40B role in repressing hypoxia in myeloid cells, and that its low expression might contribute to leukemogenesis.


Assuntos
Processamento Alternativo , Proteínas de Transporte/genética , Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/genética , Sistemas CRISPR-Cas , Hipóxia Celular , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Técnicas de Inativação de Genes , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Células K562 , Fatores de Transcrição Kruppel-Like/genética , Mutação , Análise de Sequência de RNA/métodos
4.
FASEB J ; 27(8): 2957-66, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23620528

RESUMO

Reverse signaling through CD137 ligand (CD137L) potently activates monocytes. However, the underlying mechanism is not well elucidated. This study provides evidence that tumor necrosis factor receptor 1 (TNFR1) acts as a coreceptor for CD137L and mediates CD137L signaling. CD137L colocalizes with TNFR1 on the plasma membrane and binds directly to TNFR1 via its extracellular domain. Using the human monocytic THP-1 cell line, we demonstrate that engagement of CD137L by recombinant CD137 protein promotes cell adhesion, apoptosis, expression of CD14, and production of IL-8 and tumor necrosis factor (TNF). Concomitantly, the expression of TNFR1 protein is down-regulated in response to CD137L activation, due to enhanced extracellular release and internalization of TNFR1. Activation of TNFR1 by TNF protein additively augments CD137L-induced IL-8 expression. Conversely, inhibition of TNFR1 activity by a TNFR1-neutralizing antibody inhibits CD137L-mediated cell adhesion, cell death, CD14 expression, and IL-8 production. Taken together, these data show that TNFR1 associates with CD137L and is required for CD137L reverse signaling.


Assuntos
Ligante 4-1BB/imunologia , Monócitos/imunologia , Receptores Tipo I de Fatores de Necrose Tumoral/imunologia , Transdução de Sinais/imunologia , Ligante 4-1BB/genética , Ligante 4-1BB/metabolismo , Apoptose/imunologia , Western Blotting , Adesão Celular/imunologia , Linhagem Celular Tumoral , Membrana Celular/imunologia , Membrana Celular/metabolismo , Citometria de Fluxo , Humanos , Interleucina-8/imunologia , Interleucina-8/metabolismo , Receptores de Lipopolissacarídeos/imunologia , Receptores de Lipopolissacarídeos/metabolismo , Células MCF-7 , Microscopia Confocal , Monócitos/metabolismo , Ligação Proteica/imunologia , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Transdução de Sinais/genética , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo
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