The Genetic History of France, bioRxiv, 2019-07-24
ABSTRACTThe study of the genetic structure of different countries within Europe has provided significant insights into their demographic history and their actual stratification. Although France occupies a particular location at the end of the European peninsula and at the crossroads of migration routes, few population genetic studies have been conducted so far with genome-wide data. In this study, we analyzed SNP-chip genetic data from 2 184 individuals born in France who were enrolled in two independent population cohorts. Using FineStructure, six different genetic clusters of individuals were found that were very consistent between the two cohorts. These clusters match extremely well the geography and overlap with historical and linguistic divisions of France. By modeling the relationship between genetics and geography using EEMS software, we were able to detect gene flow barriers that are similar in the two cohorts and corresponds to major French rivers or mountains. Estimations of effective population sizes using IBDNe program also revealed very similar patterns in both cohorts with a rapid increase of effective population sizes over the last 150 generations similar to what was observed in other European countries. A marked bottleneck is also consistently seen in the two datasets starting in the fourteenth century when the Black Death raged in Europe. In conclusion, by performing the first exhaustive study of the genetic structure of France, we fill a gap in the genetic studies in Europe that would be useful to medical geneticists but also historians and archeologists.
biorxiv genetics 100-200-users 2019The histone chaperone FACT induces Cas9 multi-turnover behavior and modifies genome manipulation in human cells, bioRxiv, 2019-07-24
SummaryCas9 is a prokaryotic RNA-guided DNA endonuclease that binds substrates tightly in vitro but turns over rapidly when used to manipulate genomes in eukaryotic cells. Little is known about the factors responsible for dislodging Cas9 or how they influence genome engineering. Using a proximity labeling system for unbiased detection of transient protein interactions in cell-free Xenopus laevis egg extract, we identified the dimeric histone chaperone FACT as an interactor of substrate-bound Cas9. Immunodepletion of FACT subunits from extract potently inhibits Cas9 unloading and converts Cas9’s activity from multi-turnover to single-turnover. In human cells, depletion of FACT delays genome editing and alters the balance between indel formation and homology directed repair. Depletion of FACT also increases epigenetic marking by dCas9-based transcriptional effectors with concomitant enhancement of transcriptional modulation. FACT thus shapes the intrinsic cellular response to Cas9-based genome manipulation most likely by determining Cas9 residence times.
biorxiv cell-biology 0-100-users 2019Evidence that APP gene copy number changes reflect recombinant vector contamination, bioRxiv, 2019-07-23
AbstractMutations that occur in cells of the body, called somatic mutations, cause human diseases including cancer and some neurological disorders1. In a recent study published in Nature, Lee et al.2 (hereafter “the Lee study”) reported somatic copy number gains of the APP gene, a known risk locus of Alzheimer’s disease (AD), in the neurons of AD-patients and controls (69% vs 25% of neurons with at least one APP copy gain on average). The authors argue that the mechanism of these copy number gains was somatic integration of APP mRNA into the genome, creating what they called genomic cDNA (gencDNA). We reanalyzed the data from the Lee study, revealing evidence that APP gencDNA originates mainly from contamination by exogenous APP recombinant vectors, rather from true somatic retrotransposition of endogenous APP. Our reanalysis of two recent whole exome sequencing (WES) datasets—one by the authors of the Lee study3 and the other by Park et al.4—revealed that reads claimed to support APP gencDNA in AD samples resulted from contamination by PCR products and mRNA, respectively. Lastly, we present our own single-cell whole genome sequencing (scWGS) data that show no evidence for somatic APP retrotransposition in AD neurons or in neurons from normal individuals of various ages.
biorxiv genomics 0-100-users 2019Differential gene expression and gene variants drive color and pattern development in divergent color morphs of a mimetic poison frog, bioRxiv, 2019-07-22
AbstractEvolutionary biologists have long investigated the ecological contexts, evolutionary forces, and proximate mechanisms that produce the diversity of animal coloration we see in the natural world. In aposematic species, color and pattern is directly tied to survival and thus understanding the origin of the phenotype has been a focus of both theoretical and empirical inquiry. In order to better understand this diversity, we examined gene expression in skin tissue during development in four different color morphs of the aposematic mimic poison frog, Ranitomeya imitator. We identified a suite of candidate color-related genes a priori and identified the pattern of expression in these genes over time, differences in expression of these genes between the mimetic morphs, and genetic variants that differ between color morphs. We identified several candidate color genes that are differentially expressed over time or across populations, as well as a number of color genes with fixed genetic variants between color morphs. Many of the color genes we discovered in our dataset are involved in the canonical Wnt signaling pathway, including several fixed SNPs between color morphs. Further, many genes in this pathway were differentially expressed at different points in development (e.g., lef1, tyr, tyrp1). Importantly, Wnt signaling pathway genes are overrepresented relative to expression in Xenopus tropicalis. Taken together, this provides evidence that the Wnt signaling pathway is contributing to color pattern production in R. imitator, and is an excellent candidate for producing some of the differences in color pattern between morphs. In addition, we found evidence that sepiapterin reductase is likely important in the production of yellow-green coloration in this adaptive radiation. Finally, two iridophore genes (arfap1, gart) draw a strong parallel to previous work in another dendrobatid, indicating that these genes are also strong candidates for differential color production. We have used high throughput sequencing throughout development to examine the evolution of coloration in a rapid mimetic adaptive radiation and found that these divergent color patterns are likely to be affected by a combination of developmental patterns of gene expression, color morph-specific gene expression, and color morph-specific gene variants.
biorxiv evolutionary-biology 0-100-users 2019Why we publish where we do Faculty publishing values and their relationship to review, promotion and tenure expectations, bioRxiv, 2019-07-21
AbstractUsing an online survey of academics at 55 randomly selected institutions across the US and Canada, we explore priorities for publishing decisions and their perceived importance within review, promotion, and tenure (RPT). We find that respondents most value journal readership, while they believe their peers most value prestige and related metrics such as impact factor when submitting their work for publication. Respondents indicated that total number of publications, number of publications per year, and journal name recognition were the most valued factors in RPT. Older and tenured respondents (most likely to serve on RPT committees) were less likely to value journal prestige and metrics for publishing, while untenured respondents were more likely to value these factors. These results suggest disconnects between what academics value versus what they think their peers value, and between the importance of journal prestige and metrics for tenured versus untenured faculty in publishing and RPT perceptions.
biorxiv scientific-communication-and-education 200-500-users 2019RootNav 2.0 Deep Learning for Automatic Navigation of Complex Plant Root Architectures, bioRxiv, 2019-07-20
AbstractWe present a new image analysis approach that provides fully-automatic extraction of complex root system architectures from a range of plant species in varied imaging setups. Driven by modern deep-learning approaches, RootNav 2.0 replaces previously manual and semi-automatic feature extraction with an extremely deep multi-task Convolutional Neural Network architecture. The network has been designed to explicitly combine local pixel information with global scene information in order to accurately segment small root features across high-resolution images. In addition, the network simultaneously locates seeds, and first and second order root tips to drive a search algorithm seeking optimal paths throughout the image, extracting accurate architectures without user interaction. The proposed method is evaluated on images of wheat (Triticum aestivum L.) from a seedling assay. The results are compared with semi-automatic analysis via the original RootNav tool, demonstrating comparable accuracy, with a 10-fold increase in speed. We then demonstrate the ability of the network to adapt to different plant species via transfer learning, offering similar accuracy when transferred to an Arabidopsis thaliana plate assay. We transfer for a final time to images of Brassica napus from a hydroponic assay, and still demonstrate good accuracy despite many fewer training images. The tool outputs root architectures in the widely accepted RSML standard, for which numerous analysis packages exist (<jatsext-link xmlnsxlink=httpwww.w3.org1999xlink ext-link-type=uri xlinkhref=httprootsystemml.github.io>httprootsystemml.github.io<jatsext-link>), as well as segmentation masks compatible with other automated measurement tools.
biorxiv bioinformatics 0-100-users 2019