Large-scale neuroimaging and genetic study reveals genetic architecture of brain white matter microstructure, bioRxiv, 2018-03-26
AbstractMicrostructural changes of white matter (WM) tracts are known to be associated with various neuropsychiatric disordersdiseases. Heritability of structural changes of WM tracts has been examined using diffusion tensor imaging (DTI) in family-based studies for different age groups. The availability of genetic and DTI data from recent large population-based studies offers opportunity to further improve our understanding of genetic contributions. Here, we analyzed the genetic architecture of WM tracts using DTI and single-nucleotide polymorphism (SNP) data of unrelated individuals in the UK Biobank (n ∼ 8000). The DTI parameters were generated using the ENIGMA-DTI pipeline. We found that DTI parameters are substantially heritable on most WM tracts. We observed a highly polygenic or omnigenic architecture of genetic influence across the genome as well as the enrichment of SNPs in active chromatin regions. Our bivariate analyses showed strong genetic correlations for several pairs of WM tracts as well as pairs of DTI parameters. We performed voxel-based analysis to illustrate the pattern of genetic effects on selected parts of the tract-based spatial statistics skeleton. Comparing the estimates from the UK Biobank to those from small population-based studies, we illustrated that sufficiently large sample size is essential for genetic architecture discovery in imaging genetics. We confirmed this finding with a simulation study.
biorxiv genetics 100-200-users 2018Ancient Fennoscandian genomes reveal origin and spread of Siberian ancestry in Europe, bioRxiv, 2018-03-22
AbstractEuropean history has been shaped by migrations of people, and their subsequent admixture. Recently, evidence from ancient DNA has brought new insights into migration events that could be linked to the advent of agriculture, and possibly to the spread of Indo-European languages. However, little is known so far about the ancient population history of north-eastern Europe, in particular about populations speaking Uralic languages, such as Finns and Saami. Here we analyse ancient genomic data from 11 individuals from Finland and Northwest Russia. We show that the specific genetic makeup of northern Europe traces back to migrations from Siberia that began at least 3,500 years ago. This ancestry was subsequently admixed into many modern populations in the region, in particular populations speaking Uralic languages today. In addition, we show that ancestors of modern Saami inhabited a larger territory during the Iron Age than today, which adds to historical and linguistic evidence for the population history of Finland.
biorxiv genomics 0-100-users 2018Marionette E. coli containing 12 highly-optimized small molecule sensors, bioRxiv, 2018-03-21
Cellular processes are carried out by many interacting genes and their study and optimization requires multiple levers by which they can be independently controlled. The most common method is via a genetically-encoded sensor that responds to a small molecule (an “inducible system”). However, these sensors are often suboptimal, exhibiting high background expression and low dynamic range. Further, using multiple sensors in one cell is limited by cross-talk and the taxing of cellular resources. Here, we have developed a directed evolution strategy to simultaneously select for less background, high dynamic range, increased sensitivity, and low crosstalk. Libraries of the regulatory protein and output promoter are built based on random and rationally-guided mutations. This is applied to generate a set of 12 high-performance sensors, which exhibit >100-fold induction with low background and cross-reactivity. These are combined to build a single “sensor array” and inserted into the genomes of E. coli MG1655 (wild-type), DH10B (cloning), and BL21 (protein expression). These “Marionette” strains allow for the independent control of gene expression using 2,4-diacetylphophloroglucinol (DAPG), cuminic acid (Cuma), 3-oxohexanoyl-homoserine lactone (OC6), vanillic acid (Van), isopropyl β-D-1-thiogalactopyranoside (IPTG), anhydrotetracycline (aTc), L-arabinose (Ara), choline chloride (Cho), naringenin (Nar), 3,4-dihydroxybenzoic acid (DHBA), sodium salicylate (Sal), and 3-hydroxytetradecanoyl-homoserine lactone (OHC14).
biorxiv synthetic-biology 0-100-users 2018Profiling of pluripotency factors in individual stem cells and early embryos, bioRxiv, 2018-03-21
SUMMARYMajor cell fate decisions are governed by sequence-specific transcription factors (TFs) that act in small cell populations within developing embryos. To understand how TFs regulate cell fate it is important to identify their genomic binding sites in these populations. However, current methods cannot profile TFs genome-wide at or near the single cell level. Here we adapt the CUT&RUN method to profile chromatin proteins in low cell numbers, mapping TF-DNA interactions in single cells and individual pre-implantation embryos for the first time. Using this method, we demonstrate that the pluripotency TF NANOG is significantly more dependent on the SWISNF family ATPase BRG1 for association with its genomic targets in vivo than in cultured cells—a finding that could not have been made using traditional approaches. Ultra-low input CUT&RUN (uliCUT&RUN) enables interrogation of TF binding from low cell numbers, with broad applicability to rare cell populations of importance in development or disease.
biorxiv genomics 0-100-users 2018Recovering signals of ghost archaic introgression in African populations, bioRxiv, 2018-03-21
AbstractWhile introgression from Neanderthals and Denisovans has been well-documented in modern humans outside Africa, the contribution of archaic hominins to the genetic variation of present-day Africans remains poorly understood. Using 405 whole-genome sequences from four sub-Saharan African populations, we provide complementary lines of evidence for archaic introgression into these populations. Our analyses of site frequency spectra indicate that these populations derive 2-19% of their genetic ancestry from an archaic population that diverged prior to the split of Neanderthals and modern humans. Using a method that can identify segments of archaic ancestry without the need for reference archaic genomes, we built genome-wide maps of archaic ancestry in the Yoruba and the Mende populations that recover about 482 and 502 megabases of archaic sequence, respectively. Analyses of these maps reveal segments of archaic ancestry at high frequency in these populations that represent potential targets of adaptive introgression. Our results reveal the substantial contribution of archaic ancestry in shaping the gene pool of present-day African populations.One sentence summaryMultiple present-day African populations inherited genes from an unknown archaic population that diverged before modern humans and Neanderthals split.
biorxiv genomics 200-500-users 2018Exploring the Impact of Analysis Software on Task fMRI Results, bioRxiv, 2018-03-20
AbstractA wealth of analysis tools are available to fMRI researchers in order to extract patterns of task variation and, ultimately, understand cognitive function. However, this ‘methodological plurality’ comes with a drawback. While conceptually similar, two different analysis pipelines applied on the same dataset may not produce the same scientific results. Differences in methods, implementations across software packages, and even operating systems or software versions all contribute to this variability. Consequently, attention in the field has recently been directed to reproducibility and data sharing. Neuroimaging is currently experiencing a surge in initiatives to improve research practices and ensure that all conclusions inferred from an fMRI study are replicable.In this work, our goal is to understand how choice of software package impacts on analysis results. We use publically shared data from three published task fMRI neuroimaging studies, reanalyzing each study using the three main neuroimaging software packages, AFNI, FSL and SPM, using parametric and nonparametric inference. We obtain all information on how to process, analyze, and model each dataset from the publications. We make quantitative and qualitative comparisons between our replications to gauge the scale of variability in our results and assess the fundamental differences between each software package. While qualitatively we find broad similarities between packages, we also discover marked differences, such as Dice similarity coefficients ranging from 0.000 - 0.743 in comparisons of thresholded statistic maps between software. We discuss the challenges involved in trying to reanalyse the published studies, and highlight our own efforts to make this research reproducible.
biorxiv neuroscience 200-500-users 2018