Efficacy of computational predictions of the functional effect of idiosyncratic pharmacogenetic variants

BACKGROUND: Pharmacogenetic variation is important to drug responses through diverse and complex mechanisms. Predictions of the functional impact of missense pharmacogenetic variants primarily rely on the degree of sequence conservation between species as a primary discriminator. However, idiosyncratic or off-target drug-variant interactions sometimes involve effects that are peripheral or accessory to the central systems in which a gene functions. Given the importance of sequence conservation to functional prediction tools—these idiosyncratic pharmacogenetic variants may violate the assumptions of predictive software commonly used to infer their effect. METHODS: Here we exhaustively assess the effectiveness of eleven missense mutation functional inference tools on all known pharmacogenetic missense variants contained in the Pharmacogenomics Knowledgebase (PharmGKB) repository. We categorize PharmGKB entries into sub-classes to catalog likely off-target interactions, such that we may compare predictions across different variant annotations. RESULTS: As previously demonstrated, functional inference tools perform variably across the complete set of PharmGKB variants, with large numbers of variants incorrectly classified as ‘benign’. However, we find substantial differences amongst PharmGKB variant sub-classes, particularly in variants known to cause off-target, type B adverse drug reactions, that are largely unrelated to the main pharmacological action of the drug. Specifically, variants associated with off-target effects (hence referred to as off-target variants) were most often incorrectly classified as ‘benign’. These results highlight the importance of understanding the underlying mechanism of pharmacogenetic variants and how variants associated with off-target effects will ultimately require new predictive algorithms. CONCLUSION: In this work we demonstrate that functional inference tools perform poorly on pharmacogenetic variants, particularly on subsets enriched for variants causing off-target, type B adverse drug reactions. We describe how to identify variants associated with off-target effects within PharmGKB in order to generate a training set of variants that is needed to develop new algorithms specifically for this class of variant. Development of such tools will lead to more accurate functional predictions and pave the way for the increased wide-spread adoption of pharmacogenetics in clinical practice

Macrophage transactivation for chemokine production identified as a negative regulator of granulomatous inflammation using agent-based modeling

Cellular activation in trans by interferons, cytokines and chemokines is a commonly recognized mechanism to amplify immune effector function and limit pathogen spread. However, an optimal host response also requires that collateral damage associated with inflammation is limited. This may be particularly so in the case of granulomatous inflammation, where an excessive number and / or excessively florid granulomas can have significant pathological consequences. Here, we have combined transcriptomics, agent-based modeling and in vivo experimental approaches to study constraints on hepatic granuloma formation in a murine model of experimental leishmaniasis. We demonstrate that chemokine production by non-infected Kupffer cells in the Leishmania donovani-infected liver promotes competition with infected KCs for available iNKT cells, ultimately inhibiting the extent of granulomatous inflammation. We propose trans-activation for chemokine production as a novel broadly applicable mechanism that may operate early in infection to limit excessive focal inflammation

Thermal Adaptation of Westslope Cutthroat Trout

Populations of westslope cutthroat trout (Oncorhynchus clarkii lewisi), a State species of special concern, have declined throughout their native range. Genetic introgressions, mainly from rainbow trout (O. mykiss), but also from Yellowstone cutthroat trout (O. c. bouvieri), and habitat loss are believed to be the leading causes of this decline. Populations that remain are often small and isolated, thereby increasing their risk of inbreeding depression and extinction. Translocation projects may offer a solution by infusing new genetic material into populations and potentially increasing their probability of persistence. However, local adaptations must be considered when selecting a donor population. We investigated thermal adaptations of four wild populations of westslope cutthroat trout from the Missouri River drainage and one hatchery population from the Washoe Park Trout Hatchery, Anaconda, Montana. Two wild populations were deemed to be from warm streams and two from cold streams. Fish were spawned streamside and at the hatchery. The resulting embryos were placed in experimental systems at 8, 10, and 14 °C. Survival was monitored throughout incubation. Post-embryonic growth was measured 90 days after hatching. Relationships between population performance and natal stream thermal characteristics were examined for adaptive differences

Shallow stratigraphic control on pockmark distribution in north temperate estuaries

This paper is not subject to U.S. copyright. The definitive version was published in Marine Geology 329-331 (2012): 34-45, doi:10.1016/j.margeo.2012.09.006.Pockmark fields occur throughout northern North American temperate estuaries despite the absence of extensive thermogenic hydrocarbon deposits typically associated with pockmarks. In such settings, the origins of the gas and triggering mechanism(s) responsible for pockmark formation are not obvious. Nor is it known why pockmarks proliferate in this region but do not occur south of the glacial terminus in eastern North America. This paper tests two hypotheses addressing these knowledge gaps: 1) the region's unique sea-level history provided a terrestrial deposit that sourced the gas responsible for pockmark formation; and 2) the region's physiography controls pockmarks distribution. This study integrates over 2500 km of high-resolution swath bathymetry, Chirp seismic reflection profiles and vibracore data acquired in three estuarine pockmark fields in the Gulf of Maine and Bay of Fundy. Vibracores sampled a hydric paleosol lacking the organic-rich upper horizons, indicating that an organic-rich terrestrial deposit was eroded prior to pockmark formation. This observation suggests that the gas, which is presumably responsible for the formation of the pockmarks, originated in Holocene estuarine sediments (loss on ignition 3.5–10%), not terrestrial deposits that were subsequently drowned and buried by mud. The 7470 pockmarks identified in this study are non-randomly clustered. Pockmark size and distribution relate to Holocene sediment thickness (r2 = 0.60), basin morphology and glacial deposits. The irregular underlying topography that dictates Holocene sediment thickness may ultimately play a more important role in temperate estuarine pockmark distribution than drowned terrestrial deposits. These results give insight into the conditions necessary for pockmark formation in nearshore coastal environments.Graduate support for Brothers came from a Maine Economic Improvement Fund Dissertation Fellowship

Recurrent miscalling of missense variation from short-read genome sequence data

Background: Short-read resequencing of genomes produces abundant information of the genetic variation of individuals. Due to their numerous nature, these variants are rarely exhaustively validated. Furthermore, low levels of undetected variant miscalling will have a systematic and disproportionate impact on the interpretation of individual genome sequence information, especially should these also be carried through into in reference databases ofgenomic variation. Results: We find that sequence variation from short-read sequence data is subject to recurrent-yet-intermittent miscalling that occurs in a sequence intrinsic manner and is very sensitive to sequence read length. The miscalls arise from difficulties aligning short reads to redundant genomic regions, where the rate of sequencing error approaches the sequence diversity between redundant regions. We find the resultant miscalled variants to be sensitive to small sequence variations between genomes, and thereby are often intrinsic to an individual, pedigree, strain or human ethnic group. In human exome sequences, we identify 2–300 recurrent false positive variants per individual, almost all of which are present in public databases of human genomic variation. From the exomes of non-reference strains of inbred mice, we identify 3–5000 recurrent false positive variants per mouse – the number of which increasing with greater distance between an individual mouse strain and the reference C57BL6 mouse genome. We show that recurrently miscalled variants may be reproduced for a given genome from repeated simulation rounds of read resampling, realignment and recalling. As such, it is possible to identify more than two-thirds of false positive variation from only ten rounds of simulation. Conclusion: Identification and removal of recurrent false positive variants from specific individual variant sets will improve overall data quality. Variant miscalls arising are highly sequence intrinsic and are often specific to an individual, pedigree or ethnicity. Further, read length is a strong determinant of whether given false variants will be called for any given genome – which has profound significance for cohort studies that pool datasets collected and sequenced at different points in time

Breaking the waves: improved detection of copy number variation from microarray-based comparative genomic hybridization.

BACKGROUND: Large-scale high throughput studies using microarray technology have established that copy number variation (CNV) throughout the genome is more frequent than previously thought. Such variation is known to play an important role in the presence and development of phenotypes such as HIV-1 infection and Alzheimer's disease. However, methods for analyzing the complex data produced and identifying regions of CNV are still being refined. RESULTS: We describe the presence of a genome-wide technical artifact, spatial autocorrelation or 'wave', which occurs in a large dataset used to determine the location of CNV across the genome. By removing this artifact we are able to obtain both a more biologically meaningful clustering of the data and an increase in the number of CNVs identified by current calling methods without a major increase in the number of false positives detected. Moreover, removing this artifact is critical for the development of a novel model-based CNV calling algorithm - CNVmix - that uses cross-sample information to identify regions of the genome where CNVs occur. For regions of CNV that are identified by both CNVmix and current methods, we demonstrate that CNVmix is better able to categorize samples into groups that represent copy number gains or losses. CONCLUSION: Removing artifactual 'waves' (which appear to be a general feature of array comparative genomic hybridization (aCGH) datasets) and using cross-sample information when identifying CNVs enables more biological information to be extracted from aCGH experiments designed to investigate copy number variation in normal individuals.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Meloneis Gen. Nov., a New Epipsammic Genus of Rhaphoneidaceae (Bacillariophyceae)

The diatom family Rhaphoneidaceae is characterized by high generic diversity and low species diversity with most genera known to have long stratigraphic ranges. The genera within this family are neritic marine, and mostly epipsammic. A new modern and epipsammic genus, Meloneis gen. nov., is described herein and is compared to all genera within Rhaphoneidaceae and especially to Rhaphoneis Ehrenberg s.l. Within Meloneis three new species and one variety are distinguished and described herein: M. mimallis sp. nov., M. mimallis var. zephyria var. nov., M. akytos sp. nov., and M. gorgis sp. nov

David Quentin Bowen: A memorial

The Quaternary community lost a giant and a leader on October 5, 2020, when David Quentin Bowen, known to many as “DQ” and founding editor of Quaternary Science Reviews, passed away in Cardiff. Born on February 14, 1938 in Llanelli, SouthWales, he received his PhD at University College London. David’s 50 years of contributions to our science cannot be adequately summarized in a brief memorial but past, present, and future generations of Quaternary scientists will long remember his landmark achievements in publishing, his scientific contributions, and his personal and professional class in all his endeavors

Integrated multiple mediation analysis: A robustness–specificity trade-off in causal structure

Recent methodological developments in causal mediation analysis have addressed several issues regarding multiple mediators. However, these developed methods differ in their definitions of causal parameters, assumptions for identification, and interpretations of causal effects, making it unclear which method ought to be selected when investigating a given causal effect. Thus, in this study, we construct an integrated framework, which unifies all existing methodologies, as a standard for mediation analysis with multiple mediators. To clarify the relationship between existing methods, we propose four strategies for effect decomposition: two-way, partially forward, partially backward, and complete decompositions. This study reveals how the direct and indirect effects of each strategy are explicitly and correctly interpreted as path-specific effects under different causal mediation structures. In the integrated framework, we further verify the utility of the interventional analogues of direct and indirect effects, especially when natural direct and indirect effects cannot be identified or when cross-world exchangeability is invalid. Consequently, this study yields a robustness–specificity trade-off in the choice of strategies. Inverse probability weighting is considered for estimation. The four strategies are further applied to a simulation study for performance evaluation and for analyzing the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer data set from Taiwan to investigate the causal effect of hepatitis C virus infection on mortality