Biology subjects

Klein, R.

Publications and source records attributed to Klein, R..

39 records · Page 3Linked to original sources

bioRxiv2017

High-depth whole genome sequencing of a large population-specific reference panel: Enhancing sensitivity, accuracy, and imputation

BackgroundWhile increasingly large reference panels for genome-wide imputation have been recently made available, the degree to which imputation accuracy can be enhanced by population-specific reference panels remains an open question. In the present study, we sequenced at full-depth ([≥]30x) a moderately large (n=738) cohort of samples drawn from the Ashkenazi Jewish population across two platforms (Illumina X Ten and Complete Genomics, Inc.). We developed and refined a series of quality control steps to optimize sensitivity, specificity, and comprehensiveness of variant calls in the reference panel, and then tested the accuracy of imputation against target cohorts drawn from the same population.\n\nResultsFor samples sequenced on the Illumina X Ten platform, quality thresholds were identified that permitted highly accurate calling of single nucleotide variants across 94% of the genome. The Complete Genomics, Inc. platform was more conservative (fewer variants called) compared to the Illumina platform, but also demonstrated relatively greater numbers of false positives that needed to be filtered. Quality control procedures also permitted detection of novel genome reads that are not mapped to current reference or alternate assemblies. After stringent quality control, the population-specific reference panel produced more accurate and comprehensive imputation results relative to publicly available, large cosmopolitan reference panels. The population-specific reference panel also permitted enhanced filtering of clinically irrelevant variants from personal genomes.\n\nConclusionsOur primary results demonstrate enhanced accuracy of a population-specific imputation panel relative to cosmopolitan panels, especially in the range of infrequent (<5% non-reference allele frequency) and rare (<1% non-reference allele frequency) variants that may be most critical to further progress in mapping of complex phenotypes.

genomics↗

bioRxiv2017

A Strategy for Large-Scale Systematic Pan-Cancer Germline Rare Variation Analysis

Traditionally, genetic studies in cancer are focused on somatic mutations found in tumors and absent from the normal tissue. Identification of shared attributes in germline variation could aid discrimination of high-risk from likely benign mutations and narrow the search space for new cancer predisposing genes. Extraordinary progress made in analysis of common variation with GWAS methodology does not provide sufficient resolution to understand rare variation. To fulfil missing classification for rare germline variation we assembled datasets of whole exome sequences from >2,000 patients with different types of cancers: breast cancer, colon cancer and cutaneous and ocular melanomas matched to more than 7,000 non-cancer controls and analyzed germline variation in known cancer predisposing genes to identify common properties of disease associated mutations and new candidate cancer susceptibility genes. Lists of all cancer predisposing genes were divided into subclasses according to the mode of inheritance of the related cancer syndrome or contribution to known major cancer pathways. Out of all subclasses only genes linked to dominant syndromes presented significant rare germline variants enrichment in cases. Separate analysis of protein-truncating and missense variation in this subclass of genes confirmed significant prevalence of protein-truncating variants in cases only in loss-of-function tolerant genes (pLI<0.1), while ultra-rare missense mutations were significantly overrepresented in cases only in constrained genes (pLI>0.9). Taken together, our findings provide insights into the distribution and types of mutations underlying inherited cancer predisposition.

genetics↗

bioRxiv2017

Central Amygdala Circuits Modulate Food Consumption Through A Positive Valence Mechanism

The complex behaviors underlying the pursuit and consumption of rewards are integral to an organisms survival. The hypothalamus and mesolimbic dopamine system are key mediators of these behaviors, yet regulation of appetitive and consummatory behaviors outside of these regions is not well understood. The central nucleus of the amygdala (CeA) is implicated in feeding and reward behavior, but the specific neural players and circuit mechanisms that positively regulate these behaviors remain unclear. Here, we define the neuronal mechanisms by which the CeA promotes consumption of food. We show, using in vivo activity manipulations and Ca2+ imaging, that CeA GABAergic neurons expressing the serotonin receptor 2a (Htr2a) modulate food consumption in multiple contexts, promote positive reinforcement and are active in vivo during eating. We demonstrate using electrophysiology, anatomical tracing methods and in vivo optogenetics that both intra-CeA and long-range circuit mechanisms underlie these functional effects. Finally, we show that CeAHtr2a neurons are poised to regulate food consumption through inputs from feeding-relevant brain regions. Our study highlights a mechanism by which defined CeA neural circuits positively regulate food consumption.

neuroscience↗