Cardelino Integrating whole exomes and single-cell transcriptomes to reveal phenotypic impact of somatic variants, bioRxiv, 2018-09-12

AbstractDecoding the clonal substructures of somatic tissues sheds light on cell growth, development and differentiation in health, ageing and disease. DNA-sequencing, either using bulk or using single-cell assays, has enabled the reconstruction of clonal trees from frequency and co-occurrence patterns of somatic variants. However, approaches to systematically characterize phenotypic and functional variations between individual clones are not established. Here we present cardelino (<jatsext-link xmlnsxlink=httpwww.w3.org1999xlink ext-link-type=uri xlinkhref=httpsgithub.comPMBiocardelino>httpsgithub.comPMBiocardelino<jatsext-link>), a computational method for inferring the clone of origin of individual cells that have been assayed using single-cell RNA-seq (scRNA-seq). After validating our model using simulations, we apply cardelino to matched scRNA-seq and exome sequencing data from 32 human dermal fibroblast lines, identifying hundreds of differentially expressed genes between cells from different somatic clones. These genes are frequently enriched for cell cycle and proliferation pathways, indicating a key role for cell division genes in non-neutral somatic evolution.Key findings<jatslist list-type=bullet><jatslist-item>A novel approach for integrating DNA-seq and single-cell RNA-seq data to reconstruct clonal substructure for single-cell transcriptomes.<jatslist-item><jatslist-item>Evidence for non-neutral evolution of clonal populations in human fibroblasts.<jatslist-item><jatslist-item>Proliferation and cell cycle pathways are commonly distorted in mutated clonal populations.<jatslist-item>

biorxiv genomics 100-200-users 2018

The genomic view of diversification, bioRxiv, 2018-09-11

ABSTRACTEvolutionary relationships between species are traditionally represented in the form of a tree, called the species tree. The reconstruction of the species tree from molecular data is hindered by frequent conflicts between gene genealogies. A standard way of dealing with this issue is to postulate the existence of a unique species tree where disagreements between gene trees are explained by incomplete lineage sorting (ILS) due to random coalescences of gene lineages inside the edges of the species tree. This paradigm, known as the multi-species coalescent (MSC), is constantly violated by the ubiquitous presence of gene flow revealed by empirical studies, leading to topological incongruences of gene trees that cannot be explained by ILS alone. Here we argue that this paradigm should be revised in favor of a vision acknowledging the importance of gene flow and where gene histories shape the species tree rather than the opposite. We propose a new, plastic framework for modeling the joint evolution of gene and species lineages relaxing the hierarchy between the species tree and gene trees. We implement this framework in two mathematical models called the gene-based diversification models (GBD) 1) GBD-forward, following all evolving genomes and thus very intensive computationally and 2) GBD-backward, based on coalescent theory and thus more efficient. Each model features four parameters tuning colonization, mutation, gene flow and reproductive isolation. We propose a quick inference method based on the differences between gene trees and use it to evaluate the amount of gene flow in two empirical data-sets. We find that in these data-sets, gene tree distributions are better explained by the best fitting GBD model than by the best fitting MSC model. This work should pave the way for approaches of diversification using the richer signal contained in genomic evolutionary histories rather than in the mere species tree.

biorxiv evolutionary-biology 100-200-users 2018

A data-driven approach to the automated mapping of functional brain topographies across species, bioRxiv, 2018-09-09

AbstractBehavioral neuroscience has made great strides in developing animal models of human behavior and psychiatric disorders. Animal models allow for the formulation of hypotheses regarding the mechanisms underlying psychiatric disorders, and the opportunity to test these hypotheses using procedures that are too invasive for human participants. However, recent scientific reviews have highlighted the low success rate of translating results from animal models into clinical interventions in humans. A potential roadblock is that bidirectional functional mappings between the human and rodent brain are incomplete. To narrow this gap, we created a framework, Neurobabel, for performing large-scale automated synthesis of human neuroimaging data and behavioral neuroscience data. By leveraging the semantics of how researchers within each field describe their studies, this framework enables region to region mapping of brain regions across species, as well as cross-species mapping of psychological functions. As a proof of concept, we utilize the framework to create a functional cross-species mapping between the amygdala and hippocampus for fear-related and spatial memories, respectively. We then proceed to address two open questions in the field (1) Do rodents have a dorsolateral prefrontal cortex? (2) Which human brain region corresponds to the rodent prelimbic cortex?

biorxiv neuroscience 0-100-users 2018

 

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