RESUMO
The SARS-CoV-2 virus, the causative agent of COVID-19, is undergoing constant mutation. Here, we utilized an integrative approach combining epidemiology, virus genome sequencing, clinical phenotyping, and experimental validation to locate mutations of clinical importance. We identified 35 recurrent variants, some of which are associated with clinical phenotypes related to severity. One variant, containing a deletion in the Nsp1-coding region (Δ500-532), was found in more than 20% of our sequenced samples and associates with higher RT-PCR cycle thresholds and lower serum IFN-ß levels of infected patients. Deletion variants in this locus were found in 37 countries worldwide, and viruses isolated from clinical samples or engineered by reverse genetics with related deletions in Nsp1 also induce lower IFN-ß responses in infected Calu-3 cells. Taken together, our virologic surveillance characterizes recurrent genetic diversity and identified mutations in Nsp1 of biological and clinical importance, which collectively may aid molecular diagnostics and drug design.
Assuntos
COVID-19/imunologia , COVID-19/virologia , Interferon Tipo I/imunologia , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Proteínas não Estruturais Virais/genética , Células A549 , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Sequência de Bases , COVID-19/sangue , Linhagem Celular , Criança , Pré-Escolar , Chlorocebus aethiops , Feminino , Deleção de Genes , Genômica , Células HEK293 , Humanos , Lactente , Interferon Tipo I/sangue , Interferon beta/sangue , Interferon beta/metabolismo , Masculino , Pessoa de Meia-Idade , Epidemiologia Molecular , Genética Reversa , Células Vero , Proteínas não Estruturais Virais/imunologia , Adulto JovemRESUMO
Lysine demethylase 4D (KDM4D) encodes a histone demethylase, which can influence the androgen signaling as well as play an essential role in spermatogenesis. Recently a study has shown that the mRNA of KDM4D is the key to the successful clone of the Macaque monkeys named as "Zhongzhong" and "Huahua," which greatly increased pregnancy rates of female monkey, suggesting that the KDM4D gene may be strongly associated with reproduction. Therefore, the objective of this study was to explore possible single nucleotide polymorphisms (SNPs) within the coding region of KDM4D gene and analyze the associations with testis morphology traits of male pigs. Herein, two SNPs in exon1 of pig KDM4D gene were identifiedï¼NC_010451.4:g.1078A > G and NC_010451.4:g.1358G > Cï¼. Among them, the g.1078A > G mutation was located at the JmjN domain which located from 15 to 55 amino acids of KDM4D. Association analyses showed that the g.1078A > G mutation was strongly associated with testis long circumference (TLC), testis short girth (TSG) and testis weight (TW) of Large White (LW) as well as Landrace (LD) (p < 0.05). The AA/AG genotype had a positive effect on testis morphology traits. Briefly, the novel missense mutation g.1078A > G could be a molecular marker for improving testis morphology traits in pig breeding.