PaperPlayer biorxiv genetics

Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.22.215988v1?rss=1

Authors: Lopez, M.-E., Cadiz, M. I., Rondeau, E., Koop, B. F., Yanez, J.

Abstract:

Animal domestication and artificial selection give rise to gradual changes at the genomic level in populations. Subsequent footprints of selection known as selection signatures or selective sweeps have been traced in the genomes of many animal livestock species by exploiting variations in linkage disequilibrium patterns and/or reduction of genetic diversity. Domestication of most aquatic species is recent in comparison with land animals, and salmonids are one of the most important fish species in aquaculture. Coho salmon (Oncorhynchus kisutch), cultivated primarily in Chile, has been subject to breeding programs to improve growth, disease resistance traits, and flesh color. This study aimed to identify selection signatures that may be involved in adaptation to culture conditions and traits of productive interest. To do so, individuals of two domestic populations cultured in Chile were genotyped with 200 thousand SNPs, and analyses were conducted using iHS, XP-EHH and CLR. Several signatures of selection on different chromosomal regions were detected across both populations. Some of the identified regions under selection contained genes such anapc2, alad, chp2 and myn that have been previously associated with body weight in Atlantic salmon or sec24d and robo1 that have been associated with disease resistance to Piscirickettsia salmonis in coho salmon. Findings in our study can contribute to an integrated genome-wide map of selection signatures, to help identify the genetic mechanisms of phenotypic diversity in coho salmon.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.22.216101v1?rss=1

Authors: Haase, M. A. B., Kominek, J., Opulente, D., Shen, X.-X., LaBella, A., Zhou, X., DeVirgilio, J., Hulfachor, A., Kurtzman, C., Rokas, A., Hittinger, C. T.

Abstract:

Dollo's law posits that evolutionary losses are irreversible, thereby narrowing the potential paths of evolutionary change. While phenotypic reversals to ancestral states have been observed, little is known about their underlying genetic causes. The genomes of budding yeasts have been shaped by extensive reductive evolution, such as reduced genome sizes and the losses of metabolic capabilities. However, the extent and mechanisms of trait reacquisition after gene loss in yeasts have not been thoroughly studied. Here, through phylogenomic analyses, we reconstructed the evolutionary history of the yeast galactose utilization pathway and observed widespread and repeated losses of the ability to utilize galactose, which occurred concurrently with the losses of GALactose (GAL) utilization genes. Unexpectedly, we detected three galactose-utilizing lineages that were deeply embedded within clades that underwent ancient losses of galactose utilization. We show that at least two, and possibly three, lineages reacquired the GAL pathway via yeast-to-yeast horizontal gene transfer. Our results show how trait reacquisition can occur tens of millions of years after an initial loss via horizontal gene transfer from distant relatives. These findings demonstrate that the losses of complex traits and even whole pathways are not always evolutionary dead-ends, highlighting how reversals to ancestral states can occur.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.22.216382v1?rss=1

Authors: Soria, L. R., Perocheau, D. P., De Sabbata, G., De Angelis, A., Bruno, G., Polishchuk, E., Gurung, S., Paris, D., Cuomo, P., Motta, A., Orford, M., Eaton, S., Waddington, S., Settembre, C., Muro, A. F., Baruteau, J., Brunetti-Pierri, N.

Abstract:

Urea cycle disorders (UCD) are inherited defects in clearance of waste nitrogen with high morbidity and mortality. Novel and more effective therapies for UCD are needed. Studies in mice with constitutive activation of autophagy unraveled Beclin-1 as druggable candidate for therapy of hyperammonemia. Next, we investigated efficacy of cell penetrating autophagy inducing Tat-Beclin-1 (TB-1) peptide for therapy of the two most common UCD, namely ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL) deficiencies. TB-1 reduced urinary orotic acid and hyperammonemia, and improved survival under protein-rich diet in spf-ash mice, a model of OTC deficiency (proximal UCD). In AslNeo/Neo mice, a model of ASL deficiency (distal UCD), TB-1 increased ureagenesis, reduced argininosuccinate, and improved survival. Moreover, it alleviated hepatocellular injury and decreased both cytoplasmic and nuclear glycogen accumulation in AslNeo/Neo mice. In conclusion, Beclin-1-dependent activation of autophagy improved biochemical and clinical phenotypes of proximal and distal defects of the urea cycle.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.23.214007v1?rss=1

Authors: Hedan, b., Cadieu, E., Rimbault, M., Vaysse, A., Devauchelle, P., Botherel, N., Abadie, J., Quignon, P., Derrien, T., Andre, C.

Abstract:

Histiocytic sarcoma (HS) is a rare but aggressive cancer in humans and dogs. The spontaneous canine model, with the clinical, epidemiological and histological similarities with human HS and specific breed predispositions, is a unique model/opportunity to unravel the genetic bases of this cancer. In this study, we aimed to identify germline risk factors associated with the development of HS in canine predisposed breeds. We used a methodology that combined several genome-wide association studies in a multi-breed and multi-cancer approach, as well as targeted next generation sequencing, and imputation combining several breeds (Bernese mountain dog, Rottweiler, flat coated retriever and golden retriever) and three haematopoietic cancers (HS, lymphoma and mast cell tumor). Results showed that we not only refined the previously identified HS risk CDKN2A locus but we identified new loci on canine chromosomes 2, 5, 12, 14, 20, 26 and X. Capture and targeted sequencing of specific loci pointed towards the existence of regulatory variants in non coding regions and/or methylation mechanisms linked to risk haplotypes, leading to strong cancer predispositions in specific dog breeds. Our results showed that these canine cancer predisposing loci appear to be due to the additive effect of several risk haplotype involved also in other haematopoietic cancers such lymphoma or mast cell tumor, illustrating the pleiotropic nature of these canine cancer loci as observed in human oncology.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.23.217166v1?rss=1

Authors: Martins, T., Martins, C., Silva Pereira, C.

Abstract:

In fungi, salicylate catabolism was believed to proceed only through the catechol branch of the 3-oxoadipate pathway, as shown e.g. in Aspergillus nidulans. However, the observation of a transient accumulation of gentisate upon cultivation of Aspergillus terreus in salicylate media questions this concept. To address this we have run a comparative analysis of the transcriptome of these two species after growth in salicylate using acetate as a control condition. The results revealed the high complexity of the salicylate metabolism in A. terreus with the concomitant positive regulation of several pathways for the catabolism of aromatic compounds. This included the unexpected joint action of two pathways: the nicotinate and the 3-hydroxyanthranilate, possibly crucial for the catabolism of aromatics in this fungus. New genes participating in the nicotinate metabolism are here proposed, whereas the 3-hydroxyanthranilate catabolic pathway in fungi is described for the first time. The transcriptome analysis showed also for the two species an intimate relationship between salicylate catabolism and secondary metabolism. This study emphasizes that the central pathways for the catabolism of aromatic hydrocarbons in fungi hold many mysteries yet to be discovered.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.23.213793v1?rss=1

Authors: de Jong, M. J., de Jong, J. F., Hoelzel, A. R., Janke, A.

Abstract:

Background: SNP datasets can be used to infer a wealth of information about natural populations, including information about their structure, genetic diversity, and the presence of loci under selection. However, SNP data analysis can be a time-consuming and challenging process, not in the least because at present many different software packages are needed to execute and depict the wide variety of mainstream population-genetic analyses. Here we present SambaR, an integrative and user-friendly R package which automates and simplifies quality control and population-genetic analyses of biallelic SNP datasets. SambaR allows users to perform mainstream population-genetic analyses and to generate a wide variety of ready to publish graphs with a minimum number of commands (less than ten). These wrapper commands call functions of existing packages (including adegenet, ape, LEA, poppr, pcadapt and StAMPP) as well as new tools uniquely implemented in SambaR. Results. We tested SambaR on online available SNP datasets and found that SambaR can process datasets of millions of SNPs and hundreds of individuals within hours, given sufficient computing power. Newly developed tools implemented in SambaR facilitate optimization of filter settings, objective interpretation of ordination analyses, enhance comparability of diversity estimates from reduced representation library SNP datasets, and generate reduced SNP panels and structure-like plots with Bayesian population assignment probabilities. Conclusion: SambaR facilitates rapid population genetic analyses on biallelic SNP datasets by removing three major time sinks: file handling, software learning, and data plotting. In addition, SambaR provides a convenient platform for SNP data storage and management, as well as several new utilities, including guidance in setting appropriate data filters.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.24.208975v1?rss=1

Authors: Storm, C. S., Kia, D. A., Almramhi, M., Bandres-Ciga, S., Finan, C., Hingorani, A. D., International Parkinson's Disease Genomics Consortium (IPDGC),, Wood, N. W.

Abstract:

Parkinson's disease (PD) is a neurodegenerative movement disorder that currently has no disease-modifying treatment, partly owing to inefficiencies in drug target identification and validation using human evidence. Here, we use Mendelian randomization to investigate more than 3000 genes that encode druggable proteins, seeking to predict their efficacy as drug targets for PD. We use expression and protein quantitative trait loci for druggable genes to mimic exposure to medications, and we examine the causal effect on PD risk (in two large case-control cohorts), PD age at onset and progression. We propose 23 potential drug targeting mechanisms for PD, of which four are repurposing opportunities of already-licensed or clinical-phase drugs. We identify two drugs which may increase PD risk. Importantly, there is remarkably little overlap between our MR-supported drug targeting mechanisms to prevent PD and those that reduce PD progression, suggesting that molecular mechanisms driving disease risk and progression differ. Drugs with genetic support are considerably more likely to be successful in clinical trials, and we provide compelling genetic evidence and an analysis pipeline that can be used to prioritise drug development efforts for PD.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.24.219295v1?rss=1

Authors: Nandanan, K. G., Pankajam, A. V., Salim, S., Shinohara, M., Lin, G., Chakraborty, P., Steinmetz, L. M., Shinohara, A., Nishant, K. T.

Abstract:

Segregation of homologous chromosomes during the first meiotic division requires at least one obligate crossover/exchange event between the homolog pairs. In the bakers yeast Saccharomyces cerevisiae and mammals, the mismatch repair-related factors, Msh4-Msh5 and Mlh1-Mlh3 generate the majority of the meiotic crossovers from programmed double-strand breaks (DSBs). To understand the mechanistic role of Msh4-Msh5 in meiotic crossing over, we performed genome-wide ChIP-sequencing and cytological analysis of the Msh5 protein in cells synchronized for meiosis. We observe that Msh5 associates with DSB hotspots, chromosome axis, and centromeres. We found that the initial recruitment of Msh4-Msh5 occurs following DSB resection. A two-step Msh5 binding pattern was observed: an early weak binding at DSB hotspots followed by enhanced late binding upon the formation of double Holliday junction structures. Msh5 association with the chromosome axis is Red1 dependent, while Msh5 association with the DSB hotspots and axis is dependent on DSB formation by Spo11. Msh5 binding was enhanced at strong DSB hotspots consistent with a role for DSB frequency in promoting Msh5 binding. These data on the in vivo localization of Msh5 during meiosis have implications for how Msh4-Msh5 may work with other crossover and synapsis promoting factors to ensure Holliday junction resolution at the chromosome axis.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.23.217273v1?rss=1

Authors: Colon-Rodriguez, A., Uribe-Salazar, J. M., Weyenberg, K. B., Sriram, A., Quezada, A., Kaya, G., Jao, E., Radke, B., Lein, P. J., Dennis, M.

Abstract:

In recent years zebrafish have become commonly used as a model for studying human traits and disorders. Their small size, high fecundity, and rapid development allow for more high-throughput experiments compared to other vertebrate models. Given that zebrafish share >70% gene homologs with humans and their genomes can be readily edited using highly efficient CRISPR methods, we are now able to rapidly generate mutations impacting practically any gene of interest. Unfortunately, our ability to phenotype mutant larvae has not kept pace. To address this challenge, we have developed a protocol that obtains multiple phenotypic measurements from individual zebrafish larvae in an automated and parallel fashion, including morphological features (i.e., body length, eye area, and head size) and movement/behavior. By assaying wild-type zebrafish in a variety of conditions, we determined optimal parameters that avoid significant developmental defects or physical damage; these include morphological imaging of larvae at two time points (3 days post fertilization (dpf) and 5 dpf) coupled with motion tracking of behavior at 5 dpf. As a proof-of-principle, we tested our approach on two novel CRISPR-generated mutant zebrafish lines carrying predicted null-alleles of syngap1b and slc7a5, orthologs to two human genes implicated in autism-spectrum disorder, intellectual disability, and epilepsy. Using our optimized high-throughput phenotyping protocol, we recapitulated previously published results from mouse and zebrafish models of these candidate genes. In summary, we describe a rapid parallel pipeline to characterize morphological and behavioral features of individual larvae in a robust and consistent fashion, thereby improving our ability to better identify genes important in human traits and disorders.

AUTHOR SUMMARYZebrafish (Danio rerio) are a well-established model organism for the study of neurodevelopmental disorders. Due to their small size, fast reproduction, and genetic homology with humans, zebrafish have been widely used for characterizing and screening candidate genes for many disorders, including autism-spectrum disorder, intellectual disability, and epilepsy. Although several studies have described the use of high-throughput morphological and behavioral assays, few combine multiple assays in a single zebrafish larva. Here, we optimized a platform to characterize morphometric features at two developmental time points in addition to behavioral traits of zebrafish larvae. We then used this approach to characterize two autism candidate genes (SYNGAP1 and SLC7A5) in two CRISPR-generated zebrafish null mutant models we developed in house. These data recapitulate previously published results related to enhanced seizure activity, while identifying additional defects not previously reported. We propose that our phenotyping platform represents a feasible method for maximizing the use of single zebrafish larvae in the characterization of additional mutants relevant to neurodevelopmental disorders.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.23.218073v1?rss=1

Authors: Turra, G. L., Schneider, L., Liedgens, L., Deponte, M.

Abstract:

Leishmania parasites include important pathogens and model organisms and are even used for the production of recombinant proteins. However, functional genomics and the characterization of essential genes are often limited in Leishmania because of low-throughput technologies for gene disruption or tagging and the absence of components for RNA interference. Here, we tested the T7 RNA polymerase-dependent CRISPR-Cas9 system by Beneke et al. and the glmS ribozyme-based knock-down system in the model parasite Leishmania tarentolae. We successfully deleted two reference genes encoding the flagellar motility factor Pf16 and the salvage-pathway enzyme adenine phosphoribosyltransferase, resulting in immotile and drug-resistant parasites, respectively. In contrast, we were unable to disrupt the gene encoding the mitochondrial flavoprotein Erv. Cultivation of L. tarentolae in standard BHI medium resulted in a constitutive down-regulation of an episomal mCherry-glmS reporter by 40 to 60%. For inducible knock-downs, we evaluated the growth of L. tarentolae in alternative media and identified supplemented MEM, IMDM and McCoys 5A medium as candidates. Cultivation in supplemented MEM allowed an inducible, glucosamine concentration-dependent down-regulation of the episomal mCherry-glmS reporter by more than 70%. However, chromosomal glmS-tagging of the genes encoding Pf16, adenine phosphoribosyltransferase or Erv did not reveal a knock-down phenotype. Our data demonstrate the suitability of the CRISPR-Cas9 system for the disruption and tagging of genes in L. tarentolae as well as the limitations of the glmS system, which was restricted to moderate efficiencies for episomal knock-downs and caused no detectable phenotype for chromosomal knock-downs.

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