Biology subjects

Bi, K.

Publications and source records attributed to Bi, K..

5 recordsLinked to original sources

bioRxiv2021

VCFcontam: A Machine Learning Approach to Estimate Cross-Sample Contamination from Variant Call Data

The quality of genotyping calls resulting from DNA sequencing is reliant on high quality starting genetic material. One factor that can reduce sample quality and lead to misleading genotyping results is genetic contamination of a sample by another source, such as cells or DNA from another sample of the same or different species. Cross-sample contamination by individuals of the same species is particularly difficult to detect in DNA sequencing data, because the contaminating sequence reads look very similar to those of the intended base sample. We introduce a new method that uses a support vector regression model trained on in silico contaminated datasets to predict empirical contamination using a collection of variables drawn from VCF files, including the fraction of sites that are heterozygous, the fraction of heterozygous sites with imbalanced allele counts, and parameters describing distributions fit to heterozygous allele fractions in a sample. We use the method described here to train a model that can accurately predict the extent of cross-sample contamination within 1% of the actual fraction, for simulated contaminated samples in the 0-5% contamination range, directly from the VCF file. DefinitionsO_ST_ABSLesser alleleC_ST_ABSThe allele in a heterozygous position that received less sequencing read support (which may be either the REF or ALT allele). Lesser allele fraction (LAF)The number of sequencing reads supporting the less frequently observed allele divided by the sum of reads supporting both alleles in the genotype at a given genomic position.

bioinformatics↗

bioRxiv2020

A holobiont view of island biogeography: unraveling patterns driving the nascent diversification of a Hawaiian spider and its microbial associates

The diversification of a host lineage can be influenced by both the external environment and its assemblage of microbes. Here, we use a young lineage of spiders, distributed along a chronologically arranged series of volcanic mountains, to determine the parallels between the evolutionary histories of the host spiders and their associated microbial communities, together forming the "holobiont". Using the stick spider Ariamnes waikula (Araneae, Theridiidae) on the island of Hawaii, and outgroup taxa on older islands, we tested whether each component of the holobiont (the spider hosts, the intracellular endosymbionts, and the gut microbial communities) showed correlated signatures of diversity due to sequential colonization from older to younger volcanoes. In order to investigate this, we generated ddRAD data for the host spiders and 16S rRNA gene amplicon data from their microbiota. We expected sequential colonizations to result in a (phylo)genetic structuring of the host spiders and in a diversity gradient in microbial communities. Results showed that the host A. waikula is indeed structured by geographic isolation, suggesting sequential colonization from older to younger volcanoes. Similarly, the endosymbiont communities were markedly different between Ariamnes species on different islands, but more homogeneous among A. waikula populations on the island of Hawaii. Conversely, the gut microbiota was largely conserved across all populations and species, which we suspect are generally environmentally derived. Our results highlight that the different components of the holobiont have responded in distinct ways to the dynamic environment of the volcanic archipelago, showing the necessity of understanding the interplay between components to better characterize holobiont evolution.

evolutionary biology↗

bioRxiv2020

The Botrytis cinerea Crh transglycosylae is a cytoplasmic effector triggering plant cell death and defense response

Crh proteins catalyze crosslinking of chitin and glucan polymers in the fugal cell wall. We revealed a novel and unexpected role of Botrytis cinerea BcCrh1 as a cytoplasmic effector and elicitor of plant defense. During saprophytic growth the BcCrh1 protein is localized in vacuoles and ER. Upon plant infection the protein accumulates to high levels in infection cushions, it is then secreted to the apoplast and translocated into plant cells, where it induces cell death and defense responses. Two regions of 53 and 35 amino acids were found sufficient for protein uptake and cell death induction, respectively. Dimerization of BcCrh proteins was necessary for the transglycosylation activity and proper fungal development, while the monomeric proteins was sufficient for induction of cell death. Arabidopsis lines expressing the bccrh1 gene had reduced sensitivity to B. cinerea, demonstrating the potential use of the protein in plant immunization against necrotrophic pathogens.

microbiology↗

bioRxiv2020

Integrative Molecular Characterization of Sarcomatoid and Rhabdoid Renal Cell Carcinoma Reveals Determinants of Poor Prognosis and Response to Immune Checkpoint Inhibitors

Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors1-3, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings shed light on the molecular drivers of aggressivity and responsiveness to immune checkpoint inhibitors of S/R RCC tumors.

cancer biology↗

bioRxiv2020

Transcriptional mediators of treatment resistance in lethal prostate cancer

Metastatic castration resistant prostate cancer (mCRPC) is primarily treated with therapies that prevent transcriptional activity of the androgen receptor (AR), cause DNA damage, or prevent cell division. Clinical resistance to these therapies, including second-generation androgen-targeting compounds such as enzalutamide and abiraterone, is nearly universal. Other treatment modalities, including immune checkpoint inhibitors, have provided minimal benefit except in rare subsets of patients1,2. Both tumour intrinsic and extrinsic cellular programs contributing to therapeutic resistance remain areas of active investigation. Here we use full-length single-cell RNA-sequencing (scRNA-seq) to identify the transcriptional states of cancer and immune cells in the mCRPC microenvironment. Within cancer cells, we identified transcriptional patterns that mediate a significant proportion of inherited risk for prostate cancer, extensive heterogeneity in AR splicing within and between tumours, and vastly divergent regulatory programs between adenocarcinoma and small cell carcinoma. Moreover, upregulation of TGF-{beta} signalling and epithelial-mesenchymal transition (EMT) were both associated with resistance to enzalutamide. We found that some lymph node metastases, but no bone metastases, were heavily infiltrated by dysfunctional CD8+ T cells, including cells undergoing dramatic clonal expansion during enzalutamide treatment. Our findings suggest avenues for rational therapeutic approaches targeting both tumour-intrinsic and immunological pathways to combat resistance to current treatment options.

genomics↗