Biology subjects

Niu, G.

Publications and source records attributed to Niu, G..

23 records · Page 2Linked to original sources

bioRxiv2020

Activation of cryptic splicing in bovine WDR19 is associated with reduced semen quality and male fertility

Cattle are ideally suited to investigate the genetics of male reproduction, because semen quality and fertility are recorded for all ejaculates of artificial insemination bulls. We analysed 26,090 ejaculates of 794 Brown Swiss bulls to assess ejaculate volume, sperm concentration, sperm motility, sperm head and tail anomalies and insemination success. The heritability of the six semen traits was between 0 and 0.26. Genome-wide association testing on 607,511 SNPs revealed a QTL on bovine chromosome 6 that was associated with sperm motility (P = 2.5 x 10-27), head (P = 2.0 x 10-44) and tail anomalies (P = 7.2 x 10-49) and insemination success (P = 9.9 x 10-13). The QTL harbors a recessive allele that compromises semen quality and male fertility. We replicated the effect of the QTL on fertility (P = 7.1 x 10-32) in an independent cohort of 2481 Brown Swiss bulls. The analysis of whole-genome sequencing data revealed that a synonymous variant (BTA6:58373887C>T, rs474302732) in WDR19 encoding WD repeat-containing protein 19 was in linkage disequilibrium with the fertility-associated haplotype. WD repeat-containing protein 19 is a constituent of the intraflagellar transport complex that is essential for the physiological function of motile cilia and flagella. Bioinformatic and transcription analyses revealed that the BTA6:58373887 T-allele activates a cryptic exonic splice site that eliminates three evolutionarily conserved amino acids from WDR19. Western blot analysis demonstrated that the BTA6:58373887 T-allele decreases protein expression. We make the remarkable observation that, in spite of negative effects on semen quality and bull fertility, the BTA6:58373887 T-allele has a frequency of 24 % in the Brown Swiss population. Our findings are the first to uncover a variant that is associated with quantitative variation in semen quality and male fertility in cattle. Author summaryIn cattle farming, artificial insemination is the most commonly used method of breeding. To ensure high fertilization rates, ejaculate quality and insemination success are closely monitored in artificial insemination bulls. We analyse semen quality, insemination success and microarray-called genotypes at more than 600,000 genome-wide SNP markers in 794 bulls to identify a recessive allele that compromises semen quality. We take advantage of whole-genome sequencing to pinpoint a variant in the coding sequence of WDR19 encoding WD repeat-containing protein 19 that activates a novel exonic splice site. Our results indicate that cryptic splicing in WDR19 is associated with reduced male reproductive performance. This is the first report of a variant that contributes to quantitative variation in bovine semen quality.

genomics↗

bioRxiv2019

Malaria transmission assisted by interaction between Plasmodium α-tubulin-1 and Anopheles FREP1 protein

Passage of Plasmodium through a mosquito midgut is essential for malaria transmission. FREP1, a peritrophic matrix protein in a mosquito midgut, binds to the parasite and mediates Plasmodium infection in Anopheles. The FREP1-mediated Plasmodium invasion pathway is highly conserved across multiple species of Plasmodium and Anopheles. Through pulldown, nine P. berghei proteins were co-precipitated with FREP1-conjugated beads. After cloning these nine genes from P. berghei and expressing them in insect cells, six of them were confirmed to interact with recombinant FREP1 protein. Among them, -tubulin-1 and heat shock protein 70 (Hsp70) were highly conserved in Plasmodium species with >95% identity. Thus, P. falciparum -tubulin-1 and Hsp70 were cloned and expressed in E. coli to stimulate antibody (Ab) in mice. Our results showed that anti-serum against P. falciparum -tubulin-1 significantly inhibited P. falciparum transmission to An. gambiae, while Ab against P. falciparum Hsp70 serum did not. The polyclonal Ab against human -tubulin did not interfere formation of ookinetes, however, significantly reduced the number of P. falciparum oocysts in An. gambiae midguts. Moreover, fluorescence microscope assays showed that anti--tubulin Ab bound to impermeable Plasmodium ookinete apical invasive apparatus. Therefore, we propose that the interaction between Anopheles FREP1 protein and Plasmodium -tubulin-1 directs the ookinete invasive apparatus towards midgut peritrophic matrix for the efficient passage of the parasite. Anopheles FREP1 and Plasmodium -tubulin-1 are potential targets for blocking malaria transmission to the mosquito host. AUTHOR SUMMARYThe molecular mechanisms of malaria transmission to mosquito are not well-understood. FREP1 proteins in mosquito midget PM has been proved to mediate malaria transmission by binding to parasite ookinetes. Here we reported that Plasmodium parasite -tubulin-1 is an FREP1 binding partner. We initially identified the -tubulin-1 through the FREP1-pulldown assay; Then we cloned P. falciparum -tubulin-1, and demonstrated that the insect cell expressed recombinant Plasmodium -tubulin-1 bound to FREP1 in vitro; Next, mouse anti-serum against P. falciparum -tubulin-1 was found to inhibit P. falciparum transmission to An. gambiae. P. falciparum -tubulin-1 shares >84% identical amino acid sequence with human -tubulin, purified Ab against human -tubulin significantly inhibited malaria transmission. Anti-human -tubulin Ab did not interfere the gametocyte-to-ookinetes conversion. Final, we found that anti--tubulin Ab bound to the apical end of impermeable ookinetes. Structurally, ookinete invasive apparatus locates at the apical opening. Therefore, we propose that the interaction between Anopheles midgut FREP1 protein and Plasmodium apical -tubulin-1 directs the ookinete invasive apparatus towards midgut PM for the efficient parasite invasion.

microbiology↗

bioRxiv2019

A literature mining method to judge whether there are uncertaintiesin empirical-dependent antineoplastic drug distribution in specificclinical scenarios.

Cancer clinical practice guidelines recommend different treatment options for different cancer types and are mainly developed by clinicians. In theory, those recommendation schemes that are supported by scientific research should provide better efficacy for patients. However, in actual clinical practice: "Is the choice of a specific antineoplastic drug for a specific cancer supported by the results of molecular biology mechanisms or based on the subjective experience of the clinician?" Answering this question is of significant importance for guiding clinical practice, but there is currently no operational method to provide objective judgment in specific cases. This paper describes a literature mining method that collates information from specific antineoplastic drug-related literature to establish an antineoplastic drug-gene association matrix for global or specific cancer scenarios, and further establishes a standard model and scenario models. Based on the parameters of these models, we constructed a linear regression analysis method to evaluate whether the models in different scenarios deviated from a random distribution. Finally, we determined the possible efficacy of an antineoplastic drug in different cancer types, which was validated by the Genomics of Drug Sensitivity in Cancer (GDSC) database. Using our mining method, we tested 18 antineoplastic drugs in 16 cancer types. We found that cisplatin used in ovarian cancer was more efficacious and may benefit patients more than when used in breast cancer, which provides a new paradigm for rational knowledge-driven drug distribution patterns in clinical practice.

bioinformatics↗

bioRxiv2019

Lipid rafts increase to facilitate ectoderm lineage specification of differentiating embryonic stem cells

Lipid rafts are packed nanoscopic domains on plasma membrane and essential signalling platforms for transducing extracellular stimuli into cellular responses. Although depletion of raft component glycoshpingolipids causes abnormality particularly in ectoderm layer formation, it remains unclear whether rafts play a role in lineage determination, a critical but less-known stage in lineage commitment. Here, inducing mouse embryonic stem cell (mESC) differentiation with retinoic acid (RA), we observed lipid rafts increased since early stage, especially in ectoderm-like cells. Stochastic optical reconstruction microscopy characterized at super-resolution the distinct raft features in mESCs and the derived differentiated cells. Furthermore, RA-induced commitment of ectoderm-like cells was significantly diminished not only by genetic ablation of rafts but by applying inhibitor for glycosphingolipids or cholesterol at early differentiation stages. Meanwhile, raft inhibition delayed RA-induced pluripotency exit, an early step required for differentiation. Therefore, lipid rafts increase and facilitate ectoderm lineage specification as well as pluripotency exit during mESC differentiation.

cell biology↗

bioRxiv2018

Germline genetics encode the resistance, risk, and lymphatic metastasis of triple-negative breast cancer in the southern Chinese population

Early identification of the risk for triple-negative breast cancer (TNBC) at the asymptomatic phase could lead to better prognosis. Here we developed a machine learning method to quantify systematic impact of all rare germline mutations on each pathway. We collected 106 TNBC patients and 287 elder healthy women controls. The spectra of activity profiles in multiple pathways were mapped and most pathway activities exhibited globally suppressed by the portfolio of individual germline mutations in TNBC patients. Accordingly, all individuals were delineated into two types: A and B. Type A patients could be differentiated from controls (AUC = 0.89) and sensitive to BRCA1/2 damages; Type B patients can be also differentiated from controls (AUC = 0.69) but probably being protected from BRCA1/2 damages. Further we found that Individuals with the lowest activity of selected pathways had extreme high relative risk (up to 21.67 in type A) and increased lymph node metastasis in these patients. Our study showed that genomic DNA contains information of unimaginable pathogenic factors. And this information is in a distributed form that could be applied to risk assessment for more cancer types. SignificanceWe identified individuals who are more susceptible to triple negative breast cancer. Our method performs much better than previous assessments based on BRCA1/2 damages, even polygenic risk scores. We disclosed previously unimaginable pathogens in a distributed form on genome and extended risk prediction to scenarios for other cancers.

cancer biology↗