Are drug targets with genetic support twice as likely to be approved? Revised estimates of the impact of genetic support for drug mechanisms on the probability of drug approval. Supplementary Methods And Results, bioRxiv, 2019-01-08

Despite strong vetting for disease activity, only 10% of candidate new molecular entities in early stage clinical trials are eventually approved. Analyzing historical pipeline data, Nelson et al. 2015 (Nat. Genet.) concluded pipeline drug targets with human genetic evidence of disease association are twice as likely to lead to approved drugs. Taking advantage of recent clinical development advances and rapid growth in GWAS datasets, we extend the original work using updated data, test whether genetic evidence predicts future successes and introduce statistical models adjusting for target and indication-level properties. Our work confirms drugs with genetically supported targets were more likely to be successful in Phases II and III. When causal genes are clear (Mendelian traits and GWAS associations linked to coding variants), we find the use of human genetic evidence increases approval from Phase I by greater than two-fold, and, for Mendelian associations, the positive association holds prospectively. Our findings suggest investments into genomics and genetics are likely to be beneficial to companies deploying this strategy.

biorxiv genetics 100-200-users 2019

Microtubule 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 2019

GToTree 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 2019

A 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 2019

Ecological 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

Ecological causes of uneven diversification and richness in the mammal tree of life, bioRxiv, 2019-01-05

AbstractThe uneven distribution of species in the tree of life is rooted in unequal speciation and extinction among groups. Yet the causes of differential diversification are little known despite their relevance for sustaining biodiversity into the future. Here we investigate rates of species diversification across extant Mammalia, a compelling system that includes our own closest relatives. We develop a new phylogeny of nearly all ∼6000 species using a 31-gene supermatrix and fossil node- and tip-dating approaches to establish a robust evolutionary timescale for mammals. Our findings link the causes of uneven modern species richness with ecologically-driven variation in rates of speciation andor extinction, including 24 detected shifts in net diversification. Speciation rates are a stronger predictor of among-clade richness than clade age, countering claims of clock-like speciation in large phylogenies. Surprisingly, speciation rate heterogeneity in recent radiations shows limited association with latitude, despite the well-known increase in species richness toward the equator. Instead, we find a deeper-time association where clades of high-latitude species have the highest speciation rates, suggesting that species durations are shorter (turnover is higher) outside than inside the tropics. At shallower timescales (i.e., young clades), diurnality and low vagility are both linked to greater speciation rates and extant richness. We suggest that high turnover among small-ranged allopatric species has erased the signal of vagility in older clades, while diurnality has adaptively promoted lineage persistence. These findings highlight the underappreciated joint roles of ephemeral (turnover-based) and adaptive (persistence-based) processes of diversification, which manifest in recent and more ancient evolutionary radiations of mammals to explain modern diversity.Author SummaryThe over 6000 living species in the mammalian tree of life are distributed unevenly among branches so that similarly aged groups sometimes differ many fold in species richness (e.g., ∼2500 rodent species versus 8 pangolins). Why differential bursts of species diversification occur, and how long they persist, has implications for sustaining biodiversity. Here we develop a robust evolutionary timescale for most extant species, recovering signatures of rate-variable diversification linked to ecological factors. Mammals with low dispersal or that are day-active show the fastest recent speciation rates, consistent with mechanisms of allopatric isolation and ecological opportunity, respectively. Speciation is surprisingly faster in extra-tropical than tropical lineages, suggesting that longer species durations for tropical lineages underpin the latitudinal diversity gradient in mammal.

biorxiv evolutionary-biology 200-500-users 2019