PaperPlayer biorxiv genetics

Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.31.229682v1?rss=1

Authors: Xiang, S., Koshland, D.

Abstract:

Cohesin helps mediate sister chromatid cohesion, chromosome condensation, DNA repair and transcription regulation. Cohesin can tether two regions of DNA and also extrude DNA loops. We interrogated cohesin architecture, oligomerization and function in vivo through proximity based labeling of cohesin domains. Our results suggest that the hinge and head domain of cohesin both bind DNA, and that cohesin coiled coils bend, bringing the head and hinge together to form a butterfly conformation. Our data also suggest that cohesin efficiently oligomerizes on and off DNA. The levels of oligomers and their distribution on chromosomes are cell cycle regulated. Cohesin oligomerization is blocked by mutations in distinct domains of the Smc3p and Mcd1p subunits of cohesin or in Pds5p, a cohesin regulator. These mutations also block the maintenance of cohesion but not loop extrusion, suggesting that cohesin oligomerization plays a specific role in the maintenance of cohesion.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.30.229286v1?rss=1

Authors: Wang, S., Ge, S., Colijn, C., Wang, L., Elliott, L. T.

Abstract:

Genetic similarity is a measure for the genetic relatedness among individuals. The standard method for computing similarity matrices involves the inner product of observed genetic variant matrices. Such an approach is inaccurate or impossible if genotypes are not available, or not densely sampled, or of poor quality (for example, genetic analysis of extinct species). We provide a new method for computing genetic similarities among individuals using phylogenetic trees. Our method can supplement (or stand in for) computations based on genetic sequences. We show that the genetic similarity matrices computed from trees are consistent with those computed from genotypes. Quantitative analysis on genetic traits and analysis of heritability and co-heritability can be conducted directly using genetic similarity matrices and so in the absence of genotype data, and the presence of phylogenetic trees derived from morphological data or geological dates, such analyses can be undertaken using our methods. We use simulation studies to demonstrate the advantages of our method, and we provide an application to ancient hominin data.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.30.228007v1?rss=1

Authors: Sarup, P., Edriss, V., Kristensen, N. H., Jensen, J. D., Orabi, J., Jahoor, A., Jensen, J.

Abstract:

Genomic prediction can be advantageous in barley breeding for traits such as yield and malting quality to increase selection accuracy and minimize expensive phenotyping. In this paper, we investigate the possibilities of genomic selection for malting quality traits using a limited training population. The size of the training population is an important factor in determining the prediction accuracy of a trait. We investigated the potential for genomic prediction of malting quality within breeding cycles with leave one out (LOO) cross-validation, and across breeding cycles with leave set out (LSO) cross-validation. In addition, we investigated the effect of training population size on prediction accuracy by random two, four, and ten-fold cross-validation. The material used in this study was a population of 1329 spring barley lines from four breeding cycles. We found medium to high narrow sense heritabilities of the malting traits ( 0.31 to 0.65). Accuracies of predicting breeding values from LOO tests ranged from 0.6 to 0.9 making it worth the effort to use genomic prediction within breeding cycles. Accuracies from LSO tests ranged from 0.39 to 0.70 showing that genomic prediction across the breeding cycles were possible as well. Accuracy of prediction increased when the size of the training population increased. Therefore, prediction accuracy might be increased both within and across breeding cycle by increasing size of the training population.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.29.227660v1?rss=1

Authors: Choate, L. A., Barshad, G., McMahon, P. W., Said, I., Rice, E. J., Munn, P. R., Lewis, J. J., Danko, C. G.

Abstract:

The advent of animal husbandry and hunting increased human exposure to zoonotic pathogens. To understand how a zoonotic disease influenced human evolution, we studied changes in human expression of anthrax toxin receptor 2 (ANTXR2), which encodes a cell surface protein necessary for Bacillus anthracis virulence toxins to cause anthrax disease. In immune cells, ANTXR2 was 8-fold down-regulated in all available human samples compared to non-human primates, indicating regulatory changes early in the evolution of modern humans. We also observed multiple genetic signatures consistent with recent positive selection driving a European-specific decrease in ANTXR2 expression in several non-immune tissues affected by anthrax toxins. Our observations fit a model in which humans adapted to anthrax disease following early ecological changes associated with hunting and scavenging, as well as a second period of adaptation after the rise of modern agriculture.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.28.223016v1?rss=1

Authors: Llopis-Gimenez, A., Parenti, S., Han, Y., Ros, V. I., Herrero, S.

Abstract:

Baculoviruses constitute a large group of invertebrate DNA viruses, predominantly infecting larvae of the insect order Lepidoptera. During a baculovirus infection, the virus spreads throughout the insect body producing a systemic infection in multiple larval tissues. Some behavioral and physiological changes in lepidopteran larvae have been described following a baculovirus infection and those changes could be connected with alterations in the host central nervous system (CNS). As a main component of the CNS, neuropeptides are small protein-like molecules functioning as neurohormones, neurotransmitters or neuromodulators. These peptides are involved in regulating animal physiology and behaviour and could also be targeted by baculoviruses in order to achieve host behavioural manipulations leading to increased viral fitness. In this study, we have investigated the effect of a Spodoptera exigua multiple nucleopolyhedrovirus (SeMNPV) infection on the neuropeptidome gene expression of Spodoptera exigua larval heads and brains. Expression of the gene encoding the neuropeptide proctolin was severely downregulated following infection and was chosen for further analysis. A recombinant Autographa californica multiple nucleopolyhedrovirus (AcMNPV) overexpressing the S. exigua proctolin gene was generated and used in bioassays using S. exigua larvae to study its influence on the viral infection. AcMNPV-proctolin infected larvae showed less locomotion activity and suffered a loss of weight compared to larvae infected with wild type AcMNPV or mock-infected larvae. These results provide additional information on the role of proctolin during a baculovirus infection, and offers a novel hypothesis for the molecular bases for the behavioral changes associated with a baculovirus infection.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.29.227439v1?rss=1

Authors: Deak, J. D., Clark, D. A., Liu, M., Durbin, C. E., Iacono, W. G., McGue, M., Vrieze, S. I., Hicks, B. M.

Abstract:

Importance: Molecular genetic studies of alcohol and nicotine use have identified hundreds of genome-wide risk loci. Few studies have examined the influence of aggregate genetic risk on substance use trajectories over time. Objective: We examined the predictive utility of drinking and smoking polygenic risk scores (PRS) for alcohol and nicotine use from late childhood to early adulthood, substance-specific versus broader-liability effects of the respective PRS, and if PRS performance varied between regular consumption versus pathological use. Design: Latent growth curve models with structured residuals were used to assess the predictive utility of drinks per week and regular smoking PRS for measures of alcohol and nicotine consumption and problematic use from age 14 to 34. Setting: PRS were generated from the largest discovery sample for alcohol and nicotine use to date (i.e., GSCAN), and examined for associations with alcohol and nicotine use outcomes in the Minnesota Twin Family Study (MTFS). Participants: Participants were members of the MTFS (N=3225), a longitudinal study investigating the development of substance use disorders and related conditions. Main Outcomes and Measures: Outcomes included alcohol and nicotine use disorder symptoms as defined by the Diagnostic and Statistical Manual of Mental Disorders, measures of alcohol and nicotine consumption (i.e., drinks per occasion, cigarettes per day), and composite variables for alcohol and nicotine use problems. Results: The drinks per week PRS was a significant predictor of problematic alcohol use at age 14 and increases in problematic use during young adulthood. The regular smoking PRS was a significant predictor for all nicotine use outcomes. After adjusting for the effects of both PRSs,the regular smoking PRS demonstrated incremental predictive utility for most alcohol use outcomes and remained a significant predictor of nicotine use trajectories. Conclusions and Relevance: Higher PRS for drinks per week and regular smoking were each associated with more problematic levels of substance use over time. Additionally, the regular smoking PRS seems to capture both nicotine-specific and non-specific genetic liability for substance use problems, and may index genetic risk for externalizing behavior in general. Longitudinal PRS prediction approaches may inform personalized substance use intervention approaches.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.29.227405v1?rss=1

Authors: Hicks, B. M., Clark, D. A., Deak, J. D., Liu, M., Durbin, C. E., Schafer, J. D., Wilson, S., Iacono, W. G., McGue, M., Vrieze, S.

Abstract:

Importance: Large consortia of genome wide association studies have yielded more accurate polygenic risk scores (PRS) that aggregate the small effects of many genetic variants to characterize the genetic architecture of disorders and provide a personalized measure of genetic risk. Objective: We examined whether a PRS for smoking measured genetic risk for general behavioral disinhibition by estimating its associations with externalizing and internalizing psychopathology and related personality traits. We examined these associations at multiple time points in adolescence using more refined phenotypes defined by stable characteristics across time and at young ages, which reduced potential confounds associated with cumulative exposure to substances and reverse causality. Methods: Random intercept panel models were fit to symptoms of conduct disorder, oppositional defiant disorder, major depressive disorder (MDD), and teacher ratings of externalizing and internalizing problems and personality traits at ages 11, 14, and 17 years-old in the Minnesota Twin Family Study (N = 3225). Results: The smoking PRS had strong associations with the random intercept factors for all the externalizing measures (mean standardized = .27), agreeableness (=-.22, 95% CI: -.28, -.16), and conscientiousness (=-.19, 95% CI: -.24, -.13), but was not significantly associated with the internalizing measures (mean = .06) or extraversion (=.01, 95% CI: -.05, .07). After controlling for smoking at age 17, the associations with the externalizing measures (mean = .13) and personality traits related to behavioral control (mean = -.10) remained statistically significant. Conclusions and Relevance: The smoking PRS measures genetic influences that contribute to a spectrum of phenotypes related to behavioral disinhibition including externalizing psychopathology and normal-range personality traits related to behavioral control, but not internalizing psychopathology. Continuing to identify the correlates and delineate the mechanisms of the genetic influences associated with disinhibition could have substantial impact in mitigating a variety of public health problems (e.g., mental health, academic achievement, criminality).

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.30.229914v1?rss=1

Authors: Zhao, B., Li, T., Smith, S. M., Xiong, D., Wang, X., Yang, Y., Luo, T., Zhu, Z., Shan, Y., Hauberg, M. E., Bendl, J., Fullard, J. F., Roussos, P., Lin, W., Li, Y., Stein, J. L., Zhu, H.

Abstract:

Human brain has a complex functional architecture and remains active during resting conditions. Resting-state functional magnetic resonance imaging (rsfMRI) measures brain activity at rest, which is closely linked with cognition and clinical outcomes. The role of genetics in human brain function is largely unknown. Here we utilized rsfMRI of 44,190 multi-ethnic individuals (37,339 in the UK Biobank) to discover the common genetic variants influencing intrinsic brain activity. We identified and validated hundreds of novel genetic loci associated with intrinsic functional signatures (P < 2.8 * 10^{-11}), especially for interactions of the central executive, default mode, and salience networks involved in the triple network model of psychopathology. A number of intrinsic brain activity associated loci had been implicated with brain disorders (e.g., Alzheimer's disease, Parkinson's disease, schizophrenia) and cognition, such as 17q21.31, 19q13.32, and 2p16.1. Genetic correlation analysis suggested the shared genetic influences among intrinsic brain function, brain structure, and brain structural connectivity. We also detected significant genetic correlations with 26 other complex traits, such as education, cognitive performance, ADHD, major depressive disorder, schizophrenia, sleep, and neuroticism. Heritability of intrinsic brain activity was enriched in brain tissues. The reported risk genes of Alzheimer's disease typically had stronger associations with intrinsic brain activity than brain structure, and the associated genes of intrinsic brain activity were enriched in multiple biological pathways related to nervous system and neuropathology (P < 1.8 * 10^{-9}).

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.27.223388v1?rss=1

Authors: Luzarowska, U., Russ, A.-K., Joubes, J., Batsale, M., Szymanski, J. J., Thirumalaikumar, V. P., Luzarowski, M., Wu, S., Zhu, F., Endres, N., Khedhayir, S., Schumacher, J., Correa, S. M., Skirycz, A., Fernie, A. R., Li-Beisson, Y., Fusari, C. M., Brotman, Y.

Abstract:

Due to their sessile lifestyle, plants have evolved unique mechanisms to deal with environmental challenges. Under stress, plant lipids are important as alternative sources of carbon and energy when sugars or starch are limited. Here, we applied combined heat and darkness and extended darkness to a panel of ~ 300 Arabidopsis accessions to study lipid remodeling under carbon starvation. Natural allelic variation at 3-KETOACYL-COENZYME A SYNTHASE4 (KCS4), a gene encoding for an enzyme involved fatty-acid elongation, underlies a differential accumulation of polyunsaturated triacylglycerols (TAGs) under stress. Ectopic expression in yeast and plants proved that KCS4 is a functional enzyme localized in the ER with specificity for C22 and C24 saturated acyl-CoA. Loss-of-function mutants and transient overexpression in planta revealed the role of KCS4 alleles in TAG synthesis and biomass accumulation. The region harboring KCS4 is under high selective pressure. Furthermore, allelic variation at KCS4 correlated with environmental parameters from the locales of Arabidopsis accessions. Our results provide evidence that KCS4 plays a decisive role in the subsequent fate of fatty acids released from chloroplast-membrane lipids under carbon starvation. This work sheds light on both plant response mechanisms to abiotic stress and the evolutionary events shaping the lipidome under carbon starvation.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.29.226639v1?rss=1

Authors: Jinks-Robertson, S., Gamble, D., Shaltz, S.

Abstract:

Mitotic recombination is the predominant mechanism for repairing double-strand breaks in Saccharomyces cerevisiae. Current recombination models are largely based on studies utilizing the enzyme I-SceI or HO to create a site-specific break, each of which generates broken ends with 3' overhangs. In this study sequence-diverged ectopic substrates were used to assess whether the frequent Pol {delta}-mediated removal of a mismatch 8 nucleotides from a 3' end affects recombination outcomes and whether the presence of a 3' versus 5' overhang at the break site alters outcomes. Recombination outcomes monitored were the distributions of recombination products into crossovers versus noncrossovers, and the position/length of transferred sequence (heteroduplex DNA) in noncrossover products. A terminal mismatch that was 22 nucleotides from the 3' end was rarely removed and the greater distance from the end did not affect recombination outcomes. To determine whether the recombinational repair of breaks with 3' versus 5' overhangs differs, we compared the well-studied 3' overhang created by I-SceI to a 5' overhang created by a ZFN (Zinc Finger Nuclease). Initiation with the ZFN yielded more recombinants, consistent with more efficient cleavage and potentially faster repair rate relative to I-SceI. While there were proportionally more COs among ZFN- than I-SceI-initiated events, NCOs in the two systems were indistinguishable in terms of the extent of strand transfer. These data demonstrate that the method of DSB induction and the resulting differences in end polarity have little effect on mitotic recombination outcomes despite potential differences in repair rate.

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