Identification of type 2 diabetes loci in 433,540 East Asian individuals, bioRxiv, 2019-06-29

SUMMARYMeta-analyses of genome-wide association studies (GWAS) have identified >240 loci associated with type 2 diabetes (T2D), however most loci have been identified in analyses of European-ancestry individuals. To examine T2D risk in East Asian individuals, we meta-analyzed GWAS data in 77,418 cases and 356,122 controls. In the main analysis, we identified 298 distinct association signals at 178 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 56 loci newly implicated in T2D predisposition. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. New associations include signals innear GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect muscle and adipose differentiation. At another locus, eQTLs at two overlapping T2D signals act through two genes, NKX6-3 and ANK1, in different tissues. Association studies in diverse populations identify additional loci and elucidate disease genes, biology, and pathways.Type 2 diabetes (T2D) is a common metabolic disease primarily caused by insufficient insulin production andor secretion by the pancreatic β cells and insulin resistance in peripheral tissues1. Most genetic loci associated with T2D have been identified in populations of European (EUR) ancestry, including a recent meta-analysis of genome-wide association studies (GWAS) of nearly 900,000 individuals of European ancestry that identified >240 loci influencing the risk of T2D2. Differences in allele frequency between ancestries affect the power to detect associations within a population, particularly among variants rare or monomorphic in one population but more frequent in another3,4. Although smaller than studies in European populations, a recent T2D meta-analysis in almost 200,000 Japanese individuals identified 28 additional loci4. The relative contributions of different pathways to the pathophysiology of T2D may also differ between ancestry groups. For example, in East Asian (EAS) populations, T2D prevalence is greater than in European populations among people of similar body mass index (BMI) or waist circumference5. We performed the largest meta-analysis of East Asian individuals to identify new genetic associations and provide insight into T2D pathogenesis.

biorxiv genetics 100-200-users 2019

Mutational signatures are jointly shaped by DNA damage and repair, bioRxiv, 2019-06-29

SummaryMutations arise when DNA lesions escape DNA repair. To delineate the contributions of DNA damage and DNA repair deficiency to mutagenesis we sequenced 2,721 genomes of 54 C. elegans strains, each deficient for a specific DNA repair gene and wild-type, upon exposure to 12 different genotoxins. Combining genotoxins and repair deficiency leads to differential mutation rates or new mutational signatures in more than one third of experiments. Translesion synthesis polymerase deficiencies show dramatic and diverging effects. Knockout of Polκ dramatically exacerbates the mutagenicity of alkylating agents; conversely, Polζ deficiency reduces alkylation- and UV-induced substitution rates. Examples of DNA damage-repair deficiency interactions are also found in cancer genomes, although cases of hypermutation are surprisingly rare despite signs of positive selection in a number of DNA repair genes. Nevertheless, cancer risk may be substantially elevated even by small increases in mutagenicity according to evolutionary multi-hit theory. Overall, our data underscore how mutagenesis is a joint product of DNA damage and DNA repair, implying that mutational signatures may be more variable than currently anticipated.Highlights<jatslist list-type=bullet><jatslist-item>Combining exposure to DNA damaging agents and DNA repair deficiency in C. elegans leads to altered mutation rates and new mutational signatures<jatslist-item><jatslist-item>Mutagenic effects of genotoxic exposures are generally exacerbated by DNA repair deficiency<jatslist-item><jatslist-item>Mutagenesis of UVB and alkylating agents is reduced in translesion synthesis polymerase deficiencies<jatslist-item><jatslist-item>Human cancer genomes contain examples of DNA damagerepair interactions, but mutations in DNA repair genes usually only associate with moderate mutator phenotypes, in line with evolutionary theory<jatslist-item>

biorxiv genomics 100-200-users 2019

The mutational footprints of cancer therapies, bioRxiv, 2019-06-28

Some cancer therapies damage DNA and cause mutations both in cancer and healthy cells of the patient1. These therapy-induced mutations may underlie some of the long-term and late side effects of the treatment, such as mental disabilities, organ toxicities and secondary neoplasms. Currently we ignore the mutation pattern and burden caused by different cancer treatments. Here we identify mutational signatures, or footprints of six widely-used anti-cancer therapies with the study of whole-genomes from more than 3500 metastatic tumors originated in different organs. These include previously known and new mutational signatures generated by platinum-based drugs, and a novel signature of treatment with nucleoside metabolic inhibitors. Exploiting these mutational footprints, we estimate the contribution of different treatments to the mutation burden of tumors and their risk of causing coding and likely driver mutations in the genome. In summary, the mutational footprints identified here open a window to precisely appraise the mutational risk of different cancer therapies to understand their late side effects.

biorxiv genomics 100-200-users 2019

An individual interneuron participates in many kinds of inhibition and spans much of the mouse visual thalamus, bioRxiv, 2019-06-27

SUMMARYIn principle, one way to define the functional role of a neuron would be to identify all the synaptic input it receives and all synaptic output it confers onto its targets. With serial electron microscopy we annotated all the input synapses (862) and output synapses (626) associated with one inhibitory interneuron in the visual thalamus of the mouse. This neuron’s neurites covered a broad swath of lateral geniculate nucleus and spanned multiple functionally distinct regions. Every one of its neurites formed synapses onto hundreds of thalamocortical cells of several different types. All but one small neurite also had dendrite-like properties and received input from retinal ganglion cell axons. Pre- and postsynaptic associations with other inhibitory interneurons were also distributed throughout the interneuron’s territory. We observed a diverse array of local synaptic motifs and three fundamentally different types of inhibitory neurites. Many thalamocortical cells were innervated weakly by this interneuron by single en passant shaft synapses. But a subset of the interneuron’s thalamocortical cell targets received multiple synaptic inputs from targeted inhibitory neurites that climbed along the thalamocortical cell’s dendrite with an assemblage of fasciculated retinal ganglion cell axons. Because of the diverse range of synaptic relationships exhibited by this one neuron, this cell defies a single functional label and seems rather to be using extremely local synaptic processing to participate in many different functions.

biorxiv neuroscience 100-200-users 2019

Astrocytes Contribute to Remote Memory Formation by Modulating Hippocampal-Cortical Communication During Learning, bioRxiv, 2019-06-27

ABSTRACTThe consolidation and retrieval of remote memories depend on the coordinated activity of the hippocampus and frontal cortices. However, the exact time at which these regions are recruited to support memory and the interactions between them are still debated. Astrocytes can sense and modify neuronal activity with great precision, but their role in cognitive function has not been extensively explored. To investigate the role of astrocytes in remote memory we expressed the Gi-coupled receptor hM4Di in CA1 astrocytes, allowing their manipulation by a designer drug. We discovered that astrocytic modulation during learning resulted in a specific impairment in remote, but not recent, memory recall, accompanied by decreased neuronal activity in the anterior cingulate cortex (ACC) during retrieval. We revealed a massive recruitment of ACC-projecting neurons in CA1 during memory acquisition, accompanied by activation of ACC neurons. Astrocytic Gi activation disrupted CA3 to CA1 communication in-vivo, and reduced the downstream response in the ACC. This same manipulation in behaving mice induced a projection-specific inhibition of ACC-projecting CA1 neurons during learning, consequently preventing the recruitment of the ACC. Our findings suggest that the foundation of remote memory is established in the ACC during acquisition, engaging a distinct process from the one supporting consolidation of recent memory. Furthermore, the mechanism underlying remote memory involves projection-specific functions of astrocytes in regulating neuronal activity.

biorxiv neuroscience 100-200-users 2019

DNA-loop extruding condensin complexes can traverse one another, bioRxiv, 2019-06-27

Condensin, a key member of the Structure Maintenance of Chromosome (SMC) protein complexes, has recently been shown to be a motor that extrudes loops of DNA1. It remains unclear, however, how condensin complexes work together to collectively package DNA into the chromosomal architecture. Here, we use time-lapse single-molecule visualization to study mutual interactions between two DNA-loop-extruding yeast condensins. We find that these one-side-pulling motor proteins are able to dynamically change each other’s DNA loop sizes, even when located large distances apart. When coming into close proximity upon forming a loop within a loop, condensin complexes are, surprisingly, able to traverse each other and form a new type of loop structure, which we term Z loop – three double-stranded DNA helices aligned in parallel with one condensin at each edge. These Z-loops can fill gaps left by single loops and can form symmetric dimer motors that reel in DNA from both sides. These new findings indicate that condensin may achieve chromosomal compaction using a variety of looping structures.

biorxiv biophysics 100-200-users 2019