Variation across 141,456 human exomes and genomes reveals the spectrum of loss-of-function intolerance across human protein-coding genes, bioRxiv, 2019-01-29
SummaryGenetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption genes critical for an organism’s function will be depleted for such variants in natural populations, while non-essential genes will tolerate their accumulation. However, predicted loss-of-function (pLoF) variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes. Here, we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence pLoF variants in this cohort after filtering for sequencing and annotation artifacts. Using an improved human mutation rate model, we classify human protein-coding genes along a spectrum representing tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve gene discovery power for both common and rare diseases.
biorxiv genomics 500+-users 2019Tracking the popularity and outcomes of all bioRxiv preprints, bioRxiv, 2019-01-13
AbstractResearchers in the life sciences are posting work to preprint servers at an unprecedented and increasing rate, sharing papers online before (or instead of) publication in peer-reviewed journals. Though the increasing acceptance of preprints is driving policy changes for journals and funders, there is little information about their usage. Here, we collected and analyzed data on all 37,648 preprints uploaded to bioRxiv.org, the largest biology-focused preprint server, in its first five years. We find preprints are being downloaded more than ever before (1.1 million tallied in October 2018 alone) and that the rate of preprints being posted has increased to a recent high of 2,100 per month. We also find that two-thirds of preprints posted before 2017 were later published in peer-reviewed journals, and find a relationship between journal impact factor and preprint downloads. Lastly, we developed Rxivist.org, a web application providing multiple ways of interacting with preprint metadata.
biorxiv scientific-communication-and-education 500+-users 2019Tumor 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 2019Flowers respond to pollinator sound within minutes by increasing nectar sugar concentration, bioRxiv, 2018-12-29
Can plants hear? That is, can they sense airborne sounds and respond to them? Here we show that Oenothera drummondii flowers, exposed to the playback sound of a flying bee or to synthetic sound-signals at similar frequencies, produced sweeter nectar within 3 minutes, potentially increasing the chances of cross pollination. We found that the flowers vibrated mechanically in response to these sounds, suggesting a plausible mechanism where the flower serves as the plant’s auditory sensory organ. Both the vibration and the nectar response were frequency-specific the flowers responded to pollinator sounds, but not to higher frequency sound. Our results document for the first time that plants can rapidly respond to pollinator sounds in an ecologically relevant way. Sensitivity of plants to pollinator sound can affect plant-pollinator interactions in a wide range of ways Plants could allocate their resources more adequately, focusing on the time of pollinator activity; pollinators would then be better rewarded per time unit; flower shape may be selected for its effect on hearing ability, and not only on signaling; and pollinators may evolve to make sounds that the flowers can hear. Finally, our results suggest that plants may be affected by other sounds as well, including antropogenic ones.
biorxiv ecology 500+-users 2018Plants emit informative airborne sounds under stress, bioRxiv, 2018-12-29
Stressed plants show altered phenotypes, including changes in color, smell, and shape. Yet, the possibility that plants emit airborne sounds when stressed, similarly to many animals, has not been investigated. Here we show, to our knowledge for the first time, that stressed plants emit airborne sounds that can be recorded remotely, both in acoustic chambers and in greenhouses. We recorded ~65 dBSPL ultrasonic sounds 10 cm from tomato and tobacco plants, implying that these sounds could be detected by some organisms from up to several meters away. We developed machine learning models that were capable of distinguishing between plant sounds and general noises, and identifying the condition of the plants dry, cut, or intact, based solely on the emitted sounds. Our results suggest that animals, humans, and possibly even other plants, could use sounds emitted by a plant to gain information about the plant's condition. More investigation on plant bioacoustics in general and on sound emission in plants in particular may open new avenues for understanding plants and their interactions with the environment, and it may also have a significant impact on agriculture.
biorxiv plant-biology 500+-users 2018