Genetic meta-analysis identifies 9 novel loci and functional pathways for Alzheimer’s disease risk, bioRxiv, 2018-02-21
AbstractLate onset Alzheimer’s disease (AD) is the most common form of dementia with more than 35 million people affected worldwide, and no curative treatment available. AD is highly heritable and recent genome-wide meta-analyses have identified over 20 genomic loci associated with AD, yet only explaining a small proportion of the genetic variance indicating that undiscovered loci exist. Here, we performed the largest genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 AD cases, 383,378 controls). AD-by-proxy status is based on parental AD diagnosis, and showed strong genetic correlation with AD (rg=0.81). Genetic meta analysis identified 29 risk loci, of which 9 are novel, and implicating 215 potential causative genes. Independent replication further supports these novel loci in AD. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver and microglia). Furthermore, gene-set analyses indicate the genetic contribution of biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomisation results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying more of the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD to guide new drug development.
biorxiv genetics 100-200-users 2018Understanding 6th-Century Barbarian Social Organization and Migration through Paleogenomics, bioRxiv, 2018-02-21
ABSTARCTDespite centuries of research, much about the barbarian migrations that took place between the fourth and sixth centuries in Europe remains hotly debated. To better understand this key era that marks the dawn of modern European societies, we obtained ancient genomic DNA from 63 samples from two cemeteries (from Hungary and Northern Italy) that have been previously associated with the Longobards, a barbarian people that ruled large parts of Italy for over 200 years after invading from Pannonia in 568 CE. Our dense cemetery-based sampling revealed that each cemetery was primarily organized around one large pedigree, suggesting that biological relationships played an important role in these early Medieval societies. Moreover, we identified genetic structure in each cemetery involving at least two groups with different ancestry that were very distinct in terms of their funerary customs. Finally, our data was consistent with the proposed long-distance migration from Pannonia to Northern Italy.
biorxiv genetics 100-200-users 2018Population Replacement in Early Neolithic Britain, bioRxiv, 2018-02-19
The roles of migration, admixture and acculturation in the European transition to farming have been debated for over 100 years. Genome-wide ancient DNA studies indicate predominantly Anatolian ancestry for continental Neolithic farmers, but also variable admixture with local Mesolithic hunter-gatherers1–9. Neolithic cultures first appear in Britain c. 6000 years ago (kBP), a millennium after they appear in adjacent areas of northwestern continental Europe. However, the pattern and process of the British Neolithic transition remains unclear10–15. We assembled genome-wide data from six Mesolithic and 67 Neolithic individuals found in Britain, dating from 10.5-4.5 kBP, a dataset that includes 22 newly reported individuals and the first genomic data from British Mesolithic hunter-gatherers. Our analyses reveals persistent genetic affinities between Mesolithic British and Western European hunter-gatherers over a period spanning Britain’s separation from continental Europe. We find overwhelming support for agriculture being introduced by incoming continental farmers, with small and geographically structured levels of additional hunter-gatherer introgression. We find genetic affinity between British and Iberian Neolithic populations indicating that British Neolithic people derived much of their ancestry from Anatolian farmers who originally followed the Mediterranean route of dispersal and likely entered Britain from northwestern mainland Europe.
biorxiv evolutionary-biology 200-500-users 2018Emerging Evidence of Chromosome Folding by Loop Extrusion, bioRxiv, 2018-02-17
AbstractChromosome organization poses a remarkable physical problem with many biological consequences how can molecular interactions between proteins at the nanometer scale organize micron-long chromatinized DNA molecules, insulating or facilitating interactions between specific genomic elements? The mechanism of active loop extrusion holds great promise for explaining interphase and mitotic chromosome folding, yet remains difficult to assay directly. We discuss predictions from our polymer models of loop extrusion with barrier elements, and review recent experimental studies that provide strong support for loop extrusion, focusing on perturbations to CTCF and cohesin assayed via Hi-C in interphase. Finally, we discuss a likely molecular mechanism of loop extrusion by SMC complexes.
biorxiv genomics 100-200-users 2018Motor cortex is an input-driven dynamical system controlling dexterous movement, bioRxiv, 2018-02-16
AbstractSkillful control of movement is central to our ability to sense and manipulate the world. A large body of work in nonhuman primates has demonstrated that motor cortex provides flexible, time-varying activity patterns that control the arm during reaching and grasping. Previous studies have suggested that these patterns are generated by strong local recurrent dynamics operating autonomously from inputs during movement execution. An alternative possibility is that motor cortex requires coordination with upstream brain regions throughout the entire movement in order to yield these patterns. Here, we developed an experimental preparation in the mouse to directly test these possibilities using optogenetics and electrophysiology during a skilled reach-to-grab-to-eat task. To validate this preparation, we first established that a specific, time-varying pattern of motor cortical activity was required to produce coordinated movement. Next, in order to disentangle the contribution of local recurrent motor cortical dynamics from external input, we optogenetically held the recurrent contribution constant, then observed how motor cortical activity recovered following the end of this perturbation. Both the neural responses and hand trajectory varied from trial to trial, and this variability reflected variability in external inputs. To directly probe the role of these inputs, we used optogenetics to perturb activity in the thalamus. Thalamic perturbation at the start of the trial prevented movement initiation, and perturbation at any stage of the movement prevented progression of the hand to the target; this demonstrates that input is required throughout the movement. By comparing motor cortical activity with and without thalamic perturbation, we were able to estimate the effects of external inputs on motor cortical population activity. Thus, unlike pattern-generating circuits that are local and autonomous, such as those in the spinal cord that generate left-right alternation during locomotion, the pattern generator for reaching and grasping is distributed across multiple, strongly-interacting brain regions.
biorxiv neuroscience 100-200-users 2018End-to-end differentiable learning of protein structure, bioRxiv, 2018-02-15
AbstractPredicting protein structure from sequence is a central challenge of biochemistry. Co‐evolution methods show promise, but an explicit sequence‐to‐structure map remains elusive. Advances in deep learning that replace complex, human‐designed pipelines with differentiable models optimized end‐to‐end suggest the potential benefits of similarly reformulating structure prediction. Here we report the first end‐to‐end differentiable model of protein structure. The model couples local and global protein structure via geometric units that optimize global geometry without violating local covalent chemistry. We test our model using two challenging tasks predicting novel folds without co‐evolutionary data and predicting known folds without structural templates. In the first task the model achieves state‐of‐the‐art accuracy and in the second it comes within 1‐2Å; competing methods using co‐evolution and experimental templates have been refined over many years and it is likely that the differentiable approach has substantial room for further improvement, with applications ranging from drug discovery to protein design.
biorxiv bioinformatics 200-500-users 2018