@article{742, abstract = {We give a detailed and easily accessible proof of Gromov’s Topological Overlap Theorem. Let X be a finite simplicial complex or, more generally, a finite polyhedral cell complex of dimension d. Informally, the theorem states that if X has sufficiently strong higher-dimensional expansion properties (which generalize edge expansion of graphs and are defined in terms of cellular cochains of X) then X has the following topological overlap property: for every continuous map (Formula presented.) there exists a point (Formula presented.) that is contained in the images of a positive fraction (Formula presented.) of the d-cells of X. More generally, the conclusion holds if (Formula presented.) is replaced by any d-dimensional piecewise-linear manifold M, with a constant (Formula presented.) that depends only on d and on the expansion properties of X, but not on M.}, author = {Dotterrer, Dominic and Kaufman, Tali and Wagner, Uli}, journal = {Geometriae Dedicata}, number = {1}, pages = {307–317}, publisher = {Springer}, title = {{On expansion and topological overlap}}, doi = {10.1007/s10711-017-0291-4}, volume = {195}, year = {2018}, } @article{7458, abstract = {The coupling between magnetic and electric subsystems in composites of ferromagnetic and ferroelectric phases is a product property that is facilitated by mechanical strain that arises due to magnetostriction and the piezoelectric effect in the constituent phases. Such multiferroic composites are of immense interests for studies on the physics of electromagnetic coupling and for use in a variety of applications. Here, we focus on magneto-electric (ME) coupling in nanocomposites. Particular emphasis is on core-shell particles and coaxial fibers, thin film heterostructures, and planar structures with a variety of mechanical connectivity. A brief review of models that predict strong ME effects in nanostructures is followed by synthesis and characterization. Core-shell particulate composites can be prepared by hydrothermal processes and chemical or deoxyribonucleic acid-assisted assembly. Electrospinning techniques have been utilized to prepare defect free core-shell nanofibers. Core-shell particles and fibers can be assembled into superstructures with the aid of magnetic and electric fields and characterized for possible use in advanced technologies. Chemical-vapor deposition techniques have been shown to be effective for the preparation of heterostructures of ferrites and ferroelectrics. Exotic planar multiferroic structures with potential for enhancing ME coupling strengths are also considered. Scanning probe microscopy techniques are ideal for probing the nature of direct- and converse-ME coupling in individual nanostructures. Magnetoelectric characterization of assemblies of nanocomposites can be done by ME voltage coefficient, magnetic field induced polarization, and magneto-dielectric effects. We conclude with a brief discussion on possible avenues for strengthening the product properties in the nanocomposites.}, author = {Viehland, Dwight and Li, Jie Fang and Yang, Yaodong and Costanzo, Tommaso and Yourdkhani, Amin and Caruntu, Gabriel and Zhou, Peng and Zhang, Tianjin and Li, Tianqian and Gupta, Arunava and Popov, Maksym and Srinivasan, Gopalan}, issn = {0021-8979}, journal = {Journal of Applied Physics}, number = {6}, publisher = {AIP}, title = {{Tutorial: Product properties in multiferroic nanocomposites}}, doi = {10.1063/1.5038726}, volume = {124}, year = {2018}, } @unpublished{75, abstract = {We prove that any convex body in the plane can be partitioned into m convex parts of equal areas and perimeters for any integer m≥2; this result was previously known for prime powers m=pk. We also give a higher-dimensional generalization.}, author = {Akopyan, Arseniy and Avvakumov, Sergey and Karasev, Roman}, publisher = {arXiv}, title = {{Convex fair partitions into arbitrary number of pieces}}, doi = {10.48550/arXiv.1804.03057}, year = {2018}, } @article{76, abstract = {Consider a fully-connected synchronous distributed system consisting of n nodes, where up to f nodes may be faulty and every node starts in an arbitrary initial state. In the synchronous C-counting problem, all nodes need to eventually agree on a counter that is increased by one modulo C in each round for given C>1. In the self-stabilising firing squad problem, the task is to eventually guarantee that all non-faulty nodes have simultaneous responses to external inputs: if a subset of the correct nodes receive an external “go” signal as input, then all correct nodes should agree on a round (in the not-too-distant future) in which to jointly output a “fire” signal. Moreover, no node should generate a “fire” signal without some correct node having previously received a “go” signal as input. We present a framework reducing both tasks to binary consensus at very small cost. For example, we obtain a deterministic algorithm for self-stabilising Byzantine firing squads with optimal resilience f<n/3, asymptotically optimal stabilisation and response time O(f), and message size O(log f). As our framework does not restrict the type of consensus routines used, we also obtain efficient randomised solutions.}, author = {Lenzen, Christoph and Rybicki, Joel}, journal = {Distributed Computing}, publisher = {Springer}, title = {{Near-optimal self-stabilising counting and firing squads}}, doi = {10.1007/s00446-018-0342-6}, year = {2018}, } @article{7698, abstract = {Motor output varies along the rostro-caudal axis of the tetrapod spinal cord. At limb levels, ∼60 motor pools control the alternation of flexor and extensor muscles about each joint, whereas at thoracic levels as few as 10 motor pools supply muscle groups that support posture, inspiration, and expiration. Whether such differences in motor neuron identity and muscle number are associated with segmental distinctions in interneuron diversity has not been resolved. We show that select combinations of nineteen transcription factors that specify lumbar V1 inhibitory interneurons generate subpopulations enriched at limb and thoracic levels. Specification of limb and thoracic V1 interneurons involves the Hox gene Hoxc9 independently of motor neurons. Thus, early Hox patterning of the spinal cord determines the identity of V1 interneurons and motor neurons. These studies reveal a developmental program of V1 interneuron diversity, providing insight into the organization of inhibitory interneurons associated with differential motor output.}, author = {Sweeney, Lora Beatrice Jaeger and Bikoff, Jay B. and Gabitto, Mariano I. and Brenner-Morton, Susan and Baek, Myungin and Yang, Jerry H. and Tabak, Esteban G. and Dasen, Jeremy S. and Kintner, Christopher R. and Jessell, Thomas M.}, issn = {0896-6273}, journal = {Neuron}, number = {2}, pages = {341--355.e3}, publisher = {Elsevier}, title = {{Origin and segmental diversity of spinal inhibitory interneurons}}, doi = {10.1016/j.neuron.2017.12.029}, volume = {97}, year = {2018}, } @article{77, abstract = {Holes confined in quantum dots have gained considerable interest in the past few years due to their potential as spin qubits. Here we demonstrate two-axis control of a spin 3/2 qubit in natural Ge. The qubit is formed in a hut wire double quantum dot device. The Pauli spin blockade principle allowed us to demonstrate electric dipole spin resonance by applying a radio frequency electric field to one of the electrodes defining the double quantum dot. Coherent hole spin oscillations with Rabi frequencies reaching 140 MHz are demonstrated and dephasing times of 130 ns are measured. The reported results emphasize the potential of Ge as a platform for fast and electrically tunable hole spin qubit devices.}, author = {Watzinger, Hannes and Kukucka, Josip and Vukusic, Lada and Gao, Fei and Wang, Ting and Schäffler, Friedrich and Zhang, Jian and Katsaros, Georgios}, journal = {Nature Communications}, number = {3902 }, publisher = {Nature Publishing Group}, title = {{A germanium hole spin qubit}}, doi = {10.1038/s41467-018-06418-4}, volume = {9}, year = {2018}, } @article{7712, abstract = {Male pattern baldness (MPB) is a sex-limited, age-related, complex trait. We study MPB genetics in 205,327 European males from the UK Biobank. Here we show that MPB is strongly heritable and polygenic, with pedigree-heritability of 0.62 (SE = 0.03) estimated from close relatives, and SNP-heritability of 0.39 (SE = 0.01) from conventionally-unrelated males. We detect 624 near-independent genome-wide loci, contributing SNP-heritability of 0.25 (SE = 0.01), of which 26 X-chromosome loci explain 11.6%. Autosomal genetic variance is enriched for common variants and regions of lower linkage disequilibrium. We identify plausible genetic correlations between MPB and multiple sex-limited markers of earlier puberty, increased bone mineral density (rg = 0.15) and pancreatic β-cell function (rg = 0.12). Correlations with reproductive traits imply an effect on fitness, consistent with an estimated linear selection gradient of -0.018 per MPB standard deviation. Overall, we provide genetic insights into MPB: a phenotype of interest in its own right, with value as a model sex-limited, complex trait.}, author = {Yap, Chloe X. and Sidorenko, Julia and Wu, Yang and Kemper, Kathryn E. and Yang, Jian and Wray, Naomi R. and Robinson, Matthew Richard and Visscher, Peter M.}, issn = {2041-1723}, journal = {Nature Communications}, publisher = {Springer Nature}, title = {{Dissection of genetic variation and evidence for pleiotropy in male pattern baldness}}, doi = {10.1038/s41467-018-07862-y}, volume = {9}, year = {2018}, } @article{7713, abstract = {There are mean differences in complex traits among global human populations. We hypothesize that part of the phenotypic differentiation is due to natural selection. To address this hypothesis, we assess the differentiation in allele frequencies of trait-associated SNPs among African, Eastern Asian, and European populations for ten complex traits using data of large sample size (up to ~405,000). We show that SNPs associated with height (P=2.46×10−5), waist-to-hip ratio (P=2.77×10−4), and schizophrenia (P=3.96×10−5) are significantly more differentiated among populations than matched “control” SNPs, suggesting that these trait-associated SNPs have undergone natural selection. We further find that SNPs associated with height (P=2.01×10−6) and schizophrenia (P=5.16×10−18) show significantly higher variance in linkage disequilibrium (LD) scores across populations than control SNPs. Our results support the hypothesis that natural selection has shaped the genetic differentiation of complex traits, such as height and schizophrenia, among worldwide populations.}, author = {Guo, Jing and Wu, Yang and Zhu, Zhihong and Zheng, Zhili and Trzaskowski, Maciej and Zeng, Jian and Robinson, Matthew Richard and Visscher, Peter M. and Yang, Jian}, issn = {2041-1723}, journal = {Nature Communications}, publisher = {Springer Nature}, title = {{Global genetic differentiation of complex traits shaped by natural selection in humans}}, doi = {10.1038/s41467-018-04191-y}, volume = {9}, year = {2018}, } @article{7714, abstract = {Health risk factors such as body mass index (BMI) and serum cholesterol are associated with many common diseases. It often remains unclear whether the risk factors are cause or consequence of disease, or whether the associations are the result of confounding. We develop and apply a method (called GSMR) that performs a multi-SNP Mendelian randomization analysis using summary-level data from genome-wide association studies to test the causal associations of BMI, waist-to-hip ratio, serum cholesterols, blood pressures, height, and years of schooling (EduYears) with common diseases (sample sizes of up to 405,072). We identify a number of causal associations including a protective effect of LDL-cholesterol against type-2 diabetes (T2D) that might explain the side effects of statins on T2D, a protective effect of EduYears against Alzheimer’s disease, and bidirectional associations with opposite effects (e.g., higher BMI increases the risk of T2D but the effect of T2D on BMI is negative).}, author = {Zhu, Zhihong and Zheng, Zhili and Zhang, Futao and Wu, Yang and Trzaskowski, Maciej and Maier, Robert and Robinson, Matthew Richard and McGrath, John J. and Visscher, Peter M. and Wray, Naomi R. and Yang, Jian}, issn = {2041-1723}, journal = {Nature Communications}, publisher = {Springer Nature}, title = {{Causal associations between risk factors and common diseases inferred from GWAS summary data}}, doi = {10.1038/s41467-017-02317-2}, volume = {9}, year = {2018}, } @article{7715, abstract = {Preference for mates with similar phenotypes; that is, assortative mating, is widely observed in humans1,2,3,4,5 and has evolutionary consequences6,7,8. Under Fisher's classical theory6, assortative mating is predicted to induce a signature in the genome at trait-associated loci that can be detected and quantified. Here, we develop and apply a method to quantify assortative mating on a specific trait by estimating the correlation (θ) between genetic predictors of the trait from single nucleotide polymorphisms on odd- versus even-numbered chromosomes. We show by theory and simulation that the effect of assortative mating can be quantified in the presence of population stratification. We applied this approach to 32 complex traits and diseases using single nucleotide polymorphism data from ~400,000 unrelated individuals of European ancestry. We found significant evidence of assortative mating for height (θ = 3.2%) and educational attainment (θ = 2.7%), both of which were consistent with theoretical predictions. Overall, our results imply that assortative mating involves multiple traits and affects the genomic architecture of loci that are associated with these traits, and that the consequence of mate choice can be detected from a random sample of genomes.}, author = {Yengo, Loic and Robinson, Matthew Richard and Keller, Matthew C. and Kemper, Kathryn E. and Yang, Yuanhao and Trzaskowski, Maciej and Gratten, Jacob and Turley, Patrick and Cesarini, David and Benjamin, Daniel J. and Wray, Naomi R. and Goddard, Michael E. and Yang, Jian and Visscher, Peter M.}, issn = {2397-3374}, journal = {Nature Human Behaviour}, number = {12}, pages = {948--954}, publisher = {Springer Nature}, title = {{Imprint of assortative mating on the human genome}}, doi = {10.1038/s41562-018-0476-3}, volume = {2}, year = {2018}, } @article{7716, abstract = {Genomic prediction has the potential to contribute to precision medicine. However, to date, the utility of such predictors is limited due to low accuracy for most traits. Here theory and simulation study are used to demonstrate that widespread pleiotropy among phenotypes can be utilised to improve genomic risk prediction. We show how a genetic predictor can be created as a weighted index that combines published genome-wide association study (GWAS) summary statistics across many different traits. We apply this framework to predict risk of schizophrenia and bipolar disorder in the Psychiatric Genomics consortium data, finding substantial heterogeneity in prediction accuracy increases across cohorts. For six additional phenotypes in the UK Biobank data, we find increases in prediction accuracy ranging from 0.7% for height to 47% for type 2 diabetes, when using a multi-trait predictor that combines published summary statistics from multiple traits, as compared to a predictor based only on one trait.}, author = {Maier, Robert M. and Zhu, Zhihong and Lee, Sang Hong and Trzaskowski, Maciej and Ruderfer, Douglas M. and Stahl, Eli A. and Ripke, Stephan and Wray, Naomi R. and Yang, Jian and Visscher, Peter M. and Robinson, Matthew Richard}, issn = {2041-1723}, journal = {Nature Communications}, publisher = {Springer Nature}, title = {{Improving genetic prediction by leveraging genetic correlations among human diseases and traits}}, doi = {10.1038/s41467-017-02769-6}, volume = {9}, year = {2018}, } @article{7717, abstract = {Background: DNA methylation levels change along with age, but few studies have examined the variation in the rate of such changes between individuals. Methods: We performed a longitudinal analysis to quantify the variation in the rate of change of DNA methylation between individuals using whole blood DNA methylation array profiles collected at 2–4 time points (N = 2894) in 954 individuals (67–90 years). Results: After stringent quality control, we identified 1507 DNA methylation CpG sites (rsCpGs) with statistically significant variation in the rate of change (random slope) of DNA methylation among individuals in a mixed linear model analysis. Genes in the vicinity of these rsCpGs were found to be enriched in Homeobox transcription factors and the Wnt signalling pathway, both of which are related to ageing processes. Furthermore, we investigated the SNP effect on the random slope. We found that 4 out of 1507 rsCpGs had one significant (P < 5 × 10−8/1507) SNP effect and 343 rsCpGs had at least one SNP effect (436 SNP-probe pairs) reaching genome-wide significance (P < 5 × 10−8). Ninety-five percent of the significant (P < 5 × 10−8) SNPs are on different chromosomes from their corresponding probes. Conclusions: We identified CpG sites that have variability in the rate of change of DNA methylation between individuals, and our results suggest a genetic basis of this variation. Genes around these CpG sites have been reported to be involved in the ageing process.}, author = {Zhang, Qian and Marioni, Riccardo E and Robinson, Matthew Richard and Higham, Jon and Sproul, Duncan and Wray, Naomi R and Deary, Ian J and McRae, Allan F and Visscher, Peter M}, issn = {1756-994X}, journal = {Genome Medicine}, number = {1}, publisher = {Springer Nature}, title = {{Genotype effects contribute to variation in longitudinal methylome patterns in older people}}, doi = {10.1186/s13073-018-0585-7}, volume = {10}, year = {2018}, } @article{7718, abstract = {Flores Island, Indonesia, was inhabited by the small-bodied hominin species Homo floresiensis, which has an unknown evolutionary relationship to modern humans. This island is also home to an extant human pygmy population. Here we describe genome-scale single-nucleotide polymorphism data and whole-genome sequences from a contemporary human pygmy population living on Flores near the cave where H. floresiensis was found. The genomes of Flores pygmies reveal a complex history of admixture with Denisovans and Neanderthals but no evidence for gene flow with other archaic hominins. Modern individuals bear the signatures of recent positive selection encompassing the FADS (fatty acid desaturase) gene cluster, likely related to diet, and polygenic selection acting on standing variation that contributed to their short-stature phenotype. Thus, multiple independent instances of hominin insular dwarfism occurred on Flores.}, author = {Tucci, Serena and Vohr, Samuel H. and McCoy, Rajiv C. and Vernot, Benjamin and Robinson, Matthew Richard and Barbieri, Chiara and Nelson, Brad J. and Fu, Wenqing and Purnomo, Gludhug A. and Sudoyo, Herawati and Eichler, Evan E. and Barbujani, Guido and Visscher, Peter M. and Akey, Joshua M. and Green, Richard E.}, issn = {0036-8075}, journal = {Science}, number = {6401}, pages = {511--516}, publisher = {American Association for the Advancement of Science}, title = {{Evolutionary history and adaptation of a human pygmy population of Flores Island, Indonesia}}, doi = {10.1126/science.aar8486}, volume = {361}, year = {2018}, } @article{7721, abstract = {The availability of genome-wide genetic data on hundreds of thousands of people has led to an equally rapid growth in methodologies available to analyse these data. While the motivation for undertaking genome-wide association studies (GWAS) is identification of genetic markers associated with complex traits, once generated these data can be used for many other analyses. GWAS have demonstrated that complex traits exhibit a highly polygenic genetic architecture, often with shared genetic risk factors across traits. New methods to analyse data from GWAS are increasingly being used to address a diverse set of questions about the aetiology of complex traits and diseases, including psychiatric disorders. Here, we give an overview of some of these methods and present examples of how they have contributed to our understanding of psychiatric disorders. We consider: (i) estimation of the extent of genetic influence on traits, (ii) uncovering of shared genetic control between traits, (iii) predictions of genetic risk for individuals, (iv) uncovering of causal relationships between traits, (v) identifying causal single-nucleotide polymorphisms and genes or (vi) the detection of genetic heterogeneity. This classification helps organise the large number of recently developed methods, although some could be placed in more than one category. While some methods require GWAS data on individual people, others simply use GWAS summary statistics data, allowing novel well-powered analyses to be conducted at a low computational burden.}, author = {Maier, R. M. and Visscher, P. M. and Robinson, Matthew Richard and Wray, N. R.}, issn = {0033-2917}, journal = {Psychological Medicine}, number = {7}, pages = {1055--1067}, publisher = {Cambridge University Press}, title = {{Embracing polygenicity: A review of methods and tools for psychiatric genetics research}}, doi = {10.1017/s0033291717002318}, volume = {48}, year = {2018}, } @article{7722, abstract = {We develop a Bayesian mixed linear model that simultaneously estimates single-nucleotide polymorphism (SNP)-based heritability, polygenicity (proportion of SNPs with nonzero effects), and the relationship between SNP effect size and minor allele frequency for complex traits in conventionally unrelated individuals using genome-wide SNP data. We apply the method to 28 complex traits in the UK Biobank data (N = 126,752) and show that on average, 6% of SNPs have nonzero effects, which in total explain 22% of phenotypic variance. We detect significant (P < 0.05/28) signatures of natural selection in the genetic architecture of 23 traits, including reproductive, cardiovascular, and anthropometric traits, as well as educational attainment. The significant estimates of the relationship between effect size and minor allele frequency in complex traits are consistent with a model of negative (or purifying) selection, as confirmed by forward simulation. We conclude that negative selection acts pervasively on the genetic variants associated with human complex traits.}, author = {Zeng, Jian and de Vlaming, Ronald and Wu, Yang and Robinson, Matthew Richard and Lloyd-Jones, Luke R. and Yengo, Loic and Yap, Chloe X. and Xue, Angli and Sidorenko, Julia and McRae, Allan F. and Powell, Joseph E. and Montgomery, Grant W. and Metspalu, Andres and Esko, Tonu and Gibson, Greg and Wray, Naomi R. and Visscher, Peter M. and Yang, Jian}, issn = {1061-4036}, journal = {Nature Genetics}, number = {5}, pages = {746--753}, publisher = {Springer Nature}, title = {{Signatures of negative selection in the genetic architecture of human complex traits}}, doi = {10.1038/s41588-018-0101-4}, volume = {50}, year = {2018}, } @article{7723, abstract = {Genome-wide association studies (GWAS) have identified thousands of loci that are robustly associated with complex diseases. The use of linear mixed model (LMM) methodology for GWAS is becoming more prevalent due to its ability to control for population structure and cryptic relatedness and to increase power. The odds ratio (OR) is a common measure of the association of a disease with an exposure (e.g., a genetic variant) and is readably available from logistic regression. However, when the LMM is applied to all-or-none traits it provides estimates of genetic effects on the observed 0–1 scale, a different scale to that in logistic regression. This limits the comparability of results across studies, for example in a meta-analysis, and makes the interpretation of the magnitude of an effect from an LMM GWAS difficult. In this study, we derived transformations from the genetic effects estimated under the LMM to the OR that only rely on summary statistics. To test the proposed transformations, we used real genotypes from two large, publicly available data sets to simulate all-or-none phenotypes for a set of scenarios that differ in underlying model, disease prevalence, and heritability. Furthermore, we applied these transformations to GWAS summary statistics for type 2 diabetes generated from 108,042 individuals in the UK Biobank. In both simulation and real-data application, we observed very high concordance between the transformed OR from the LMM and either the simulated truth or estimates from logistic regression. The transformations derived and validated in this study improve the comparability of results from prospective and already performed LMM GWAS on complex diseases by providing a reliable transformation to a common comparative scale for the genetic effects.}, author = {Lloyd-Jones, Luke R. and Robinson, Matthew Richard and Yang, Jian and Visscher, Peter M.}, issn = {0016-6731}, journal = {Genetics}, number = {4}, pages = {1397--1408}, publisher = {Genetics Society of America}, title = {{Transformation of summary statistics from linear mixed model association on all-or-none traits to odds ratio}}, doi = {10.1534/genetics.117.300360}, volume = {208}, year = {2018}, } @article{7724, abstract = {Modern molecular genetic datasets, primarily collected to study the biology of human health and disease, can be used to directly measure the action of natural selection and reveal important features of contemporary human evolution. Here we leverage the UK Biobank data to test for the presence of linear and nonlinear natural selection in a contemporary population of the United Kingdom. We obtain phenotypic and genetic evidence consistent with the action of linear/directional selection. Phenotypic evidence suggests that stabilizing selection, which acts to reduce variance in the population without necessarily modifying the population mean, is widespread and relatively weak in comparison with estimates from other species.}, author = {Sanjak, Jaleal S. and Sidorenko, Julia and Robinson, Matthew Richard and Thornton, Kevin R. and Visscher, Peter M.}, issn = {0027-8424}, journal = {Proceedings of the National Academy of Sciences}, number = {1}, pages = {151--156}, publisher = {Proceedings of the National Academy of Sciences}, title = {{Evidence of directional and stabilizing selection in contemporary humans}}, doi = {10.1073/pnas.1707227114}, volume = {115}, year = {2018}, } @article{7754, abstract = {Creating a selective gel that filters particles based on their interactions is a major goal of nanotechnology, with far-reaching implications from drug delivery to controlling assembly pathways. However, this is particularly difficult when the particles are larger than the gel’s characteristic mesh size because such particles cannot passively pass through the gel. Thus, filtering requires the interacting particles to transiently reorganize the gel’s internal structure. While significant advances, e.g., in DNA engineering, have enabled the design of nano-materials with programmable interactions, it is not clear what physical principles such a designer gel could exploit to achieve selective permeability. We present an equilibrium mechanism where crosslink binding dynamics are affected by interacting particles such that particle diffusion is enhanced. In addition to revealing specific design rules for manufacturing selective gels, our results have the potential to explain the origin of selective permeability in certain biological materials, including the nuclear pore complex.}, author = {Goodrich, Carl Peter and Brenner, Michael P. and Ribbeck, Katharina}, issn = {2041-1723}, journal = {Nature Communications}, publisher = {Springer Nature}, title = {{Enhanced diffusion by binding to the crosslinks of a polymer gel}}, doi = {10.1038/s41467-018-06851-5}, volume = {9}, year = {2018}, } @unpublished{7783, abstract = {The Drosophila Genetic Reference Panel (DGRP) serves as a valuable resource to better understand the genetic landscapes underlying quantitative traits. However, such DGRP studies have so far only focused on nuclear genetic variants. To address this, we sequenced the mitochondrial genomes of >170 DGRP lines, identifying 229 variants including 21 indels and 7 frameshifts. We used our mitochondrial variation data to identify 12 genetically distinct mitochondrial haplotypes, thus revealing important population structure at the mitochondrial level. We further examined whether this population structure was reflected on the nuclear genome by screening for the presence of potential mito-nuclear genetic incompatibilities in the form of significant genotype ratio distortions (GRDs) between mitochondrial and nuclear variants. In total, we detected a remarkable 1,845 mito-nuclear GRDs, with the highest enrichment observed in a 40 kb region around the gene Sex-lethal (Sxl). Intriguingly, downstream phenotypic analyses did not uncover major fitness effects associated with these GRDs, suggesting that a large number of mito-nuclear GRDs may reflect population structure at the mitochondrial level rather than actual genomic incompatibilities. This is further supported by the GRD landscape showing particular large genomic regions associated with a single mitochondrial haplotype. Next, we explored the functional relevance of the detected mitochondrial haplotypes through an association analysis on a set of 259 assembled, non-correlating DGRP phenotypes. We found multiple significant associations with stress- and metabolism-related phenotypes, including food intake in males. We validated the latter observation by reciprocal swapping of mitochondrial genomes from high food intake DGRP lines to low food intake ones. In conclusion, our study uncovered important mitochondrial population structure and haplotype-specific metabolic variation in the DGRP, thus demonstrating the significance of incorporating mitochondrial haplotypes in geno-phenotype relationship studies.}, author = {Bevers, Roel P.J. and Litovchenko, Maria and Kapopoulou, Adamandia and Braman, Virginie S. and Robinson, Matthew Richard and Auwerx, Johan and Hollis, Brian and Deplancke, Bart}, booktitle = {bioRxiv}, pages = {49}, publisher = {Cold Spring Harbor Laboratory}, title = {{Extensive mitochondrial population structure and haplotype-specific phenotypic variation in the Drosophila Genetic Reference Panel}}, year = {2018}, } @inproceedings{78, abstract = {We provide a procedure for detecting the sub-segments of an incrementally observed Boolean signal ω that match a given temporal pattern ϕ. As a pattern specification language, we use timed regular expressions, a formalism well-suited for expressing properties of concurrent asynchronous behaviors embedded in metric time. We construct a timed automaton accepting the timed language denoted by ϕ and modify it slightly for the purpose of matching. We then apply zone-based reachability computation to this automaton while it reads ω, and retrieve all the matching segments from the results. Since the procedure is automaton based, it can be applied to patterns specified by other formalisms such as timed temporal logics reducible to timed automata or directly encoded as timed automata. The procedure has been implemented and its performance on synthetic examples is demonstrated.}, author = {Bakhirkin, Alexey and Ferrere, Thomas and Nickovic, Dejan and Maler, Oded and Asarin, Eugene}, isbn = {978-3-030-00150-6}, location = {Bejing, China}, pages = {215 -- 232}, publisher = {Springer}, title = {{Online timed pattern matching using automata}}, doi = {10.1007/978-3-030-00151-3_13}, volume = {11022}, year = {2018}, }