A population genetic approach to mapping neurological disorder genes using deep resequencing

Deep resequencing of functional regions in human genomes is key to identifying potentially causal rare variants for complex disorders. Here, we present the results from a large-sample resequencing (n  =  285 patients) study of candidate genes coupled with population genetics and statistical methods to identify rare variants associated with Autism Spectrum Disorder and Schizophrenia. Three genes, MAP1A, GRIN2B, and CACNA1F, were consistently identified by different methods as having significant excess of rare missense mutations in either one or both disease cohorts. In a broader context, we also found that the overall site frequency spectrum of variation in these cases is best explained by population models of both selection and complex demography rather than neutral models or models accounting for complex demography alone. Mutations in the three disease-associated genes explained much of the difference in the overall site frequency spectrum among the cases versus controls. This study demonstrates that genes associated with complex disorders can be mapped using resequencing and analytical methods with sample sizes far smaller than those required by genome-wide association studies. Additionally, our findings support the hypothesis that rare mutations account for a proportion of the phenotypic variance of these complex disorders

The Green Bank Ammonia Survey (GAS): First Results of NH3 mapping the Gould Belt

We present an overview of the first data release (DR1) and first-look science from the Green Bank Ammonia Survey (GAS). GAS is a Large Program at the Green Bank Telescope to map all Gould Belt star-forming regions with $A_V \gtrsim 7$ mag visible from the northern hemisphere in emission from NH$_3$ and other key molecular tracers. This first release includes the data for four regions in Gould Belt clouds: B18 in Taurus, NGC 1333 in Perseus, L1688 in Ophiuchus, and Orion A North in Orion. We compare the NH$_3$ emission to dust continuum emission from Herschel, and find that the two tracers correspond closely. NH$_3$ is present in over 60\% of lines-of-sight with $A_V \gtrsim 7$ mag in three of the four DR1 regions, in agreement with expectations from previous observations. The sole exception is B18, where NH$_3$ is detected toward ~ 40\% of lines-of-sight with $A_V \gtrsim 7$ mag. Moreover, we find that the NH$_3$ emission is generally extended beyond the typical 0.1 pc length scales of dense cores. We produce maps of the gas kinematics, temperature, and NH$_3$ column densities through forward modeling of the hyperfine structure of the NH$_3$ (1,1) and (2,2) lines. We show that the NH$_3$ velocity dispersion, ${\sigma}_v$, and gas kinetic temperature, $T_K$, vary systematically between the regions included in this release, with an increase in both the mean value and spread of ${\sigma}_v$ and $T_K$ with increasing star formation activity. The data presented in this paper are publicly available.Comment: 33 pages, 27 figures, accepted to ApJS. Datasets are publicly available: https://dataverse.harvard.edu/dataverse/GAS_DR

Droplets I: Pressure-Dominated Sub-0.1 pc Coherent Structures in L1688 and B18

We present the observation and analysis of newly discovered coherent structures in the L1688 region of Ophiuchus and the B18 region of Taurus. Using data from the Green Bank Ammonia Survey (GAS), we identify regions of high density and near-constant, almost-thermal, velocity dispersion. Eighteen coherent structures are revealed, twelve in L1688 and six in B18, each of which shows a sharp "transition to coherence" in velocity dispersion around its periphery. The identification of these structures provides a chance to study the coherent structures in molecular clouds statistically. The identified coherent structures have a typical radius of 0.04 pc and a typical mass of 0.4 Msun, generally smaller than previously known coherent cores identified by Goodman et al. (1998), Caselli et al. (2002), and Pineda et al. (2010). We call these structures "droplets." We find that unlike previously known coherent cores, these structures are not virially bound by self-gravity and are instead predominantly confined by ambient pressure. The droplets have density profiles shallower than a critical Bonnor-Ebert sphere, and they have a velocity (VLSR) distribution consistent with the dense gas motions traced by NH3 emission. These results point to a potential formation mechanism through pressure compression and turbulent processes in the dense gas. We present a comparison with a magnetohydrodynamic simulation of a star-forming region, and we speculate on the relationship of droplets with larger, gravitationally bound coherent cores, as well as on the role that droplets and other coherent structures play in the star formation process.Comment: Accepted by ApJ in April, 201

Developing a Common Framework for Evaluating the Implementation of Genomic Medicine Interventions in Clinical Care: The IGNITE Network’s Common Measures Working Group

Purpose Implementation research provides a structure for evaluating the clinical integration of genomic medicine interventions. This paper describes the Implementing GeNomics In PracTicE (IGNITE) Network’s efforts to promote: 1) a broader understanding of genomic medicine implementation research; and 2) the sharing of knowledge generated in the network. Methods To facilitate this goal the IGNITE Network Common Measures Working Group (CMG) members adopted the Consolidated Framework for Implementation Research (CFIR) to guide their approach to: identifying constructs and measures relevant to evaluating genomic medicine as a whole, standardizing data collection across projects, and combining data in a centralized resource for cross network analyses. Results CMG identified ten high-priority CFIR constructs as important for genomic medicine. Of those, eight didn’t have standardized measurement instruments. Therefore, we developed four survey tools to address this gap. In addition, we identified seven high-priority constructs related to patients, families, and communities that did not map to CFIR constructs. Both sets of constructs were combined to create a draft genomic medicine implementation model. Conclusion We developed processes to identify constructs deemed valuable for genomic medicine implementation and codified them in a model. These resources are freely available to facilitate knowledge generation and sharing across the field

Yeast:One cell, one reference sequence, many genomes?

The genome of Saccharomyces cerevisiae – brewer’s or baker’s yeast – was the first eukaryotic genome to be sequenced in 1996. The identity of that yeast genome has been not just a product of sequencing, but also of its use after sequencing and particularly of its mobilization in scientific literature. We ask “what is the yeast genome?” as an empirical question by investigating “the yeast genome” as a discursive entity. Analyzing publications that followed sequencing points to several “yeast genomes” existing side-by-side: genomes as physical molecules, digital texts, and a historic event. Resolving this unified-yet-multiple “genome” helps make sense of contemporary developments in yeast genomics such as the synthetic yeast project, in which apparently “the same” genome occupies multiple roles and locations, and points to the utility of examining specific non-human genomes independent of the Human Genome Project

Using non-invasive biomarkers to identify hepatic fibrosis in people with type 2 diabetes mellitus: the Edinburgh type 2 diabetes study

BACKGROUND & AIMS: It is difficult to determine the different stages of non-alcoholic fatty liver disease without the use of invasive liver biopsy. In this study we investigated five non-invasive biomarkers used previously to detect hepatic fibrosis and determined the level of agreement between them in order to inform future research. METHODS: In the Edinburgh Type 2 Diabetes Study, a population-based cohort aged 60-74 years with type 2 diabetes, 831 participants underwent ultrasound assessment for fatty liver and had serum aspartate aminotransferase to alanine aminotransferase ratio (AST/ALT), aspartate to platelet ratio index (APRI), European Liver Fibrosis panel (ELF), Fibrosis-4 Score (FIB4) and liver stiffness measurement (LSM) measured. RESULTS: Literature based cut-offs yielded marked differences in the proportions of the cohort with probable liver fibrosis in the full cohort. Agreement between the top 5% of the distribution for each biomarker pair was poor. APRI and FIB4 had the best positive agreement at 76.4%, but agreement for all of the other serum biomarker pairs was between 18% and 34%. Agreement with LSM was poor (9-16%). CONCLUSIONS: We found poor correlation between the five biomarkers of liver fibrosis studied. Using the top 5% of each biomarker resulted in good agreement on the absence of advanced liver disease but poor agreement on the presence of advanced disease. Further work is required to validate these markers against liver biopsy and to determine their predictive value for clinical liver-related endpoints, in a range of different low and high risk population groups

Ubiquitous NH3\rm NH_3 supersonic component in L1688 coherent cores

Context : Star formation takes place in cold dense cores in molecular clouds. Earlier observations have found that dense cores exhibit subsonic non-thermal velocity dispersions. In contrast, CO observations show that the ambient large-scale cloud is warmer and has supersonic velocity dispersions. Aims : We aim to study the ammonia ($\rm NH_3$) molecular line profiles with exquisite sensitivity towards the coherent cores in L1688 in order to study their kinematical properties in unprecedented detail. Methods : We used $\rm NH_3$ (1,1) and (2,2) data from the first data release (DR1) in the Green Bank Ammonia Survey (GAS). We first smoothed the data to a larger beam of 1' to obtain substantially more extended maps of velocity dispersion and kinetic temperature, compared to the DR1 maps. We then identified the coherent cores in the cloud and analysed the averaged line profiles towards the cores. Results : For the first time, we detected a faint (mean $\rm NH_3$(1,1) peak brightness $<$0.25 K in $T_{MB}$), supersonic component towards all the coherent cores in L1688. We fitted two components, one broad and one narrow, and derived the kinetic temperature and velocity dispersion of each component. The broad components towards all cores have supersonic linewidths ($\mathcal{M}_S \ge 1$). This component biases the estimate of the narrow dense core component's velocity dispersion by $\approx$28% and the kinetic temperature by $\approx$10%, on average, as compared to the results from single-component fits. Conclusions : Neglecting this ubiquitous presence of a broad component towards all coherent cores causes the typical single-component fit to overestimate the temperature and velocity dispersion. This affects the derived detailed physical structure and stability of the cores estimated from $\rm NH_3$ observations.Comment: Accepted for publication in Astronomy & Astrophysics on 06/07/2020. 15 pages, 16 figures, 1 table. Language edits from previous versio