TY - JOUR AB - The nature and extent of mitochondrial DNA variation in a population and how it affects traits is poorly understood. Here we resequence the mitochondrial genomes of 169 Drosophila Genetic Reference Panel lines, identifying 231 variants that stratify along 12 mitochondrial haplotypes. We identify 1,845 cases of mitonuclear allelic imbalances, thus implying that mitochondrial haplotypes are reflected in the nuclear genome. However, no major fitness effects are associated with mitonuclear imbalance, suggesting that such imbalances reflect population structure at the mitochondrial level rather than genomic incompatibilities. Although mitochondrial haplotypes have no direct impact on mitochondrial respiration, some haplotypes are associated with stress- and metabolism-related phenotypes, including food intake in males. Finally, through reciprocal swapping of mitochondrial genomes, we demonstrate that a mitochondrial haplotype associated with high food intake can rescue a low food intake phenotype. Together, our findings provide new insight into population structure at the mitochondrial level and point to the importance of incorporating mitochondrial haplotypes in genotype–phenotype relationship studies. AU - Bevers, Roel P. J. AU - Litovchenko, Maria AU - Kapopoulou, Adamandia AU - Braman, Virginie S. AU - Robinson, Matthew Richard AU - Auwerx, Johan AU - Hollis, Brian AU - Deplancke, Bart ID - 7711 IS - 12 JF - Nature Metabolism SN - 2522-5812 TI - Mitochondrial haplotypes affect metabolic phenotypes in the Drosophila Genetic Reference Panel VL - 1 ER - TY - GEN AB - As genome-wide association studies (GWAS) increased in size, numerous gene-environment interactions (GxE) have been discovered, many of which however explore only one environment at a time and may suffer from statistical artefacts leading to biased interaction estimates. Here we propose a maximum likelihood method to estimate the contribution of GxE to complex traits taking into account all interacting environmental variables at the same time, without the need to measure any. This is possible because GxE induces fluctuations in the conditional trait variance, the extent of which depends on the strength of GxE. The approach can be applied to continuous outcomes and for single SNPs or genetic risk scores (GRS). Extensive simulations demonstrated that our method yields unbiased interaction estimates and excellent confidence interval coverage. We also offer a strategy to distinguish specific GxE from general heteroscedasticity (scale effects). Applying our method to 32 complex traits in the UK Biobank reveals that for body mass index (BMI) the GRSxE explains an additional 1.9% variance on top of the 5.2% GRS contribution. However, this interaction is not specific to the GRS and holds for any variable similarly correlated with BMI. On the contrary, the GRSxE interaction effect for leg impedance Embedded Image is significantly (P < 10−56) larger than it would be expected for a similarly correlated variable Embedded Image. We showed that our method could robustly detect the global contribution of GxE to complex traits, which turned out to be substantial for certain obesity measures. AU - Sulc, Jonathan AU - Mounier, Ninon AU - Günther, Felix AU - Winkler, Thomas AU - Wood, Andrew R. AU - Frayling, Timothy M. AU - Heid, Iris M. AU - Robinson, Matthew Richard AU - Kutalik, Zoltán ID - 7782 T2 - bioRxiv TI - Maximum likelihood method quantifies the overall contribution of gene-environment interaction to continuous traits: An application to complex traits in the UK Biobank ER - TY - JOUR AU - Currin, Christopher B. AU - Khoza, Phumlani N. AU - Antrobus, Alexander D. AU - Latham, Peter E. AU - Vogels, Tim P AU - Raimondo, Joseph V. ID - 8013 IS - 7 JF - PLOS Computational Biology SN - 1553-7358 TI - Think: Theory for Africa VL - 15 ER - TY - JOUR AB - Working memory, the ability to keep recently accessed information available for immediate manipulation, has been proposed to rely on two mechanisms that appear difficult to reconcile: self-sustained neural firing, or the opposite—activity-silent synaptic traces. Here we review and contrast models of these two mechanisms, and then show that both phenomena can co-exist within a unified system in which neurons hold information in both activity and synapses. Rapid plasticity in flexibly-coding neurons allows features to be bound together into objects, with an important emergent property being the focus of attention. One memory item is held by persistent activity in an attended or “focused” state, and is thus remembered better than other items. Other, previously attended items can remain in memory but in the background, encoded in activity-silent synaptic traces. This dual functional architecture provides a unified common mechanism accounting for a diversity of perplexing attention and memory effects that have been hitherto difficult to explain in a single theoretical framework. AU - Manohar, Sanjay G. AU - Zokaei, Nahid AU - Fallon, Sean J. AU - Vogels, Tim P AU - Husain, Masud ID - 8014 JF - Neuroscience and Biobehavioral Reviews SN - 0149-7634 TI - Neural mechanisms of attending to items in working memory VL - 101 ER - TY - CONF AB - We study edge asymptotics of poissonized Plancherel-type measures on skew Young diagrams (integer partitions). These measures can be seen as generalizations of those studied by Baik--Deift--Johansson and Baik--Rains in resolving Ulam's problem on longest increasing subsequences of random permutations and the last passage percolation (corner growth) discrete versions thereof. Moreover they interpolate between said measures and the uniform measure on partitions. In the new KPZ-like 1/3 exponent edge scaling limit with logarithmic corrections, we find new probability distributions generalizing the classical Tracy--Widom GUE, GOE and GSE distributions from the theory of random matrices. AU - Betea, Dan AU - Bouttier, Jérémie AU - Nejjar, Peter AU - Vuletíc, Mirjana ID - 8175 T2 - Proceedings on the 31st International Conference on Formal Power Series and Algebraic Combinatorics TI - New edge asymptotics of skew Young diagrams via free boundaries ER -