Tumor mutational load predicts survival after immunotherapy across multiple cancer types, Nature Genetics, 2019-01-08
Immune checkpoint inhibitor (ICI) treatments benefit some patients with metastatic cancers, but predictive biomarkers are needed. Findings in selected cancer types suggest that tumor mutational burden (TMB) may predict clinical response to ICI. To examine this association more broadly, we analyzed the clinical and genomic data of 1,662 advanced cancer patients treated with ICI, and 5,371 non-ICI-treated patients, whose tumors underwent targeted next-generation sequencing (MSK-IMPACT). Among all patients, higher somatic TMB (highest 20% in each histology) was associated with better overall survival. For most cancer histologies, an association between higher TMB and improved survival was observed. The TMB cutpoints associated with improved survival varied markedly between cancer types. These data indicate that TMB is associated with improved survival in patients receiving ICI across a wide variety of cancer types, but that there may not be one universal definition of high TMB.
nature genetics genetics 500+-users 2019Microtubule plus-end dynamics link wound repair to the innate immune response, bioRxiv, 2019-01-07
As a first line of defence against the environment, the epidermis protect animals from infection and physical damage. In C. elegans, wounding the epidermal epithelium triggers both an immune reaction and a repair response. Exactly how these are controlled, and the degree to which they are inter-connected remains unclear. To address these questions, we established a simple system for simultaneously inflicting precise laser wounds and imaging at high spatial and temporal resolution. We show that in C. elegans, wounding provokes a rapid sealing of the plasma membrane, involving reorganisation of phosphatidylinositol 4,5-bisphosphate domains. This is followed by a radial recruitment at the wound site of EBP-2EB1, a protein that binds the plus ends of microtubules. EB1 recruitment is accompanied by a reorganisation of microtubules, required for the subsequent recruitment of actin and wound closure. It is also required for the directed trafficking towards the site of injury of the key signaling protein SNF-12. In the absence of SNF-12 recruitment, there is an abrogation of the immune response. Our results suggest that microtubule dynamics coordinate the cytoskeletal changes required for wound repair and the concomitant activation of the innate immune response.
biorxiv cell-biology 100-200-users 2019GToTree a user-friendly workflow for phylogenomics, bioRxiv, 2019-01-06
Genome-level evolutionary inference (i.e., phylogenomics) is becoming an increasingly essential step in many biologists' work - such as in the characterization of newly recovered genomes, or in leveraging available reference genomes to guide evolutionary questions. Accordingly, there are several tools available for the major steps in a phylogenomics workflow. But for the biologist whose main focus is not bioinformatics, much of the computational work required - such as accessing genomic data on large scales, integrating genomes from different file formats, performing required filtering, stitching different tools together, etc. - can be prohibitive. Here I introduce GToTree, a command-line tool that can take any combination of fasta files, GenBank files, andor NCBI assembly accessions as input and outputs an alignment file, estimates of genome completeness and redundancy, and a phylogenomic tree based on the specified single-copy gene (SCG) set. While GToTree can work with any custom hidden Markov Models (HMMs), also included are 13 newly generated SCG-set HMMs for different lineages and levels of resolution, built based on searches of ~12,000 bacterial and archaeal high-quality genomes. GToTree aims to give more researchers the capability to make phylogenomic trees.
biorxiv bioinformatics 100-200-users 2019A pitfall for machine learning methods aiming to predict across cell types, bioRxiv, 2019-01-05
AbstractMachine learning models used to predict phenomena such as gene expression, enhancer activity, transcription factor binding, or chromatin conformation are most useful when they can generalize to make accurate predictions across cell types. In this situation, a natural strategy is to train the model on experimental data from some cell types and evaluate performance on one or more held-out cell types. In this work, we show that when the training set contains examples derived from the same genomic loci across multiple cell types, the resulting model can be susceptible to a particular form of bias related to memorizing the average activity associated with each genomic locus. Consequently, the trained model may appear to perform well when evaluated on the genomic loci that it was trained on but tends to perform poorly on loci that it was not trained on. We demonstrate this phenomenon by using epigenomic measurements and nucleotide sequence to predict gene expression and chromatin domain boundaries, and we suggest methods to diagnose and avoid the pitfall. We anticipate that, as more data and computing resources become available, future projects will increasingly risk suffering from this issue.
biorxiv bioinformatics 100-200-users 2019Ecological causes of speciation and species richness in the mammal tree of life, bioRxiv, 2019-01-05
ABSTRACTBiodiversity is distributed unevenly from the poles to the equator, and among branches of the tree of life, yet how those patterns are related is unclear. We investigated global speciation-rate variation across crown Mammalia using a novel time-scaled phylogeny (N=5,911 species, ~70% with DNA), finding that trait- and latitude-associated speciation has caused uneven species richness among groups. We identify 24 branch-specific shifts in net diversification rates linked to ecological traits. Using time-slices to define clades, we show that speciation rates are a stronger predictor of clade richness than age. Mammals that are low dispersal or diurnal diversify the fastest, indicating roles for geographic and ecological speciation, respectively. Speciation is slower in tropical than extra-tropical lineages, consistent with evidence that longer tropical species durations underpin the latitudinal diversity gradient. These findings juxtapose modes of lineage diversification that are alternatively turnover-based, and thus non-adaptive, or persistence-based as associated with resource adaptations.
biorxiv evolutionary-biology 200-500-users 2019