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Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 83,933 bioRxiv papers from 361,442 authors.

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in category genetics

4,343 results found. For more information, click each entry to expand.

3381: Bi-directional Mendelian randomization of epithelial ovarian cancer and schizophrenia and uni-directional Mendelian randomization of schizophrenia on circulating glycerophosphocholine metabolites
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Posted to bioRxiv 31 May 2019

Bi-directional Mendelian randomization of epithelial ovarian cancer and schizophrenia and uni-directional Mendelian randomization of schizophrenia on circulating glycerophosphocholine metabolites
228 downloads genetics

Charleen D. Adams, Susan L. Neuhausen

Most women with epithelial ovarian cancer (EOC) present with late-stage disease. As a result, globally, EOC is responsible for more than 150,000 deaths a year. Thus, a better understanding of risk factors for developing EOC is crucial for earlier screening and detection to improve survival. To that effort, there have been suggestions that there is an association of schizophrenia and cancer, possibly because metabolic changes are a hallmark of both cancer and schizophrenia (SZ). Perturbed choline metabolism has been documented in both diseases. Our objective was to use Mendelian randomization to evaluate whether SZ increased risk for developing EOC or the converse, and, whether SZ impacted glycerophosphocholine (GPC) metabolites. We found that SZ conferred a weak but increased risk for EOC, but not the reverse (no evidence that EOC caused SZ). SZ was also causally associated with lower levels of two GPC species and with suggestively lower levels in an additional three GPCs. We postulate that perturbed choline metabolism in SZ may mimic or contribute to a “cholinic” phenotype, as observed in EOC cells.

3382: Evidence that a major subpopulation of fall armyworm found in the Western Hemisphere is rare or absent in Africa, which may limit the range of crops at risk of infestation.
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Posted to bioRxiv 29 Nov 2018

Evidence that a major subpopulation of fall armyworm found in the Western Hemisphere is rare or absent in Africa, which may limit the range of crops at risk of infestation.
228 downloads genetics

Rodney N. Nagoshi

The introduction and establishment of fall armyworm (Spodoptera frugiperda) in Africa presents a major threat to agriculture in that continent and potentially to the entire Eastern Hemisphere. The species is subdivided into two subpopulations called the R-strain and C-strain that differ in their distribution on different plant hosts. This means that the scope of the economic risk posed by invasive fall armyworm is influenced by whether one or both strains are present. Multiple studies have found mitochondrial markers diagnostic of the two strains throughout Africa but there is substantial disagreement with a nuclear strain marker that makes conclusions about strain composition uncertain. In this study the issue of whether both strains are present in Africa was tested by an assay that can detect strain-biased mating behaviors. Western Hemisphere fall armyworm consistently showed evidence of strain-specific assortative mating in the field that was not found in surveys from multiple locations in Africa. The absence of strain mating biases and the disagreements between the strain diagnostic genetic markers indicates that the R-strain is rare (<1% of the population) or absent in Africa. Instead, it appears that the African fall armyworm populations are dominated by two groups, the C-strain and the descendants of interstrain hybrids. These results suggest that plant hosts associated with the R-strain may not be at high risk of fall armyworm infestation in Africa.

3383: Genetic structure is stronger across human-impacted habitats than among islands in the coral Porites lobata
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Posted to bioRxiv 11 Mar 2019

Genetic structure is stronger across human-impacted habitats than among islands in the coral Porites lobata
228 downloads genetics

Kaho H Tisthammer, Zac H Forsman, Robert J. Toonen, Robert H Richmond

We examined genetic structure in the lobe coral Porites lobata among pairs of highly variable and high-stress nearshore sites and adjacent less variable and less impacted offshore sites on the islands of O'ahu and Maui, Hawai'i. Using an analysis of molecular variance framework, we tested whether populations were more structured by geographic distance or environmental extremes. The genetic patterns we observed followed isolation by environment, where nearshore and adjacent offshore populations showed significant genetic structure at both locations (AMOVA FST = 0.04 ~ 0.19, P < 0.001), but no significant isolation by distance between islands. In contrast, a third site with a less impacted nearshore site showed no significant structure. Strikingly, corals from the two impacted nearshore sites on different islands over 100km apart with similar environmentally stressful conditions were genetically closer (FST ~ 0, P = 0.733) than those within a single location less than 2 km apart (FST = 0.041~0.079, P < 0.01). Our results suggest that ecological boundaries appear to play a strong role in forming genetic structure in the coastal environment, and that genetic divergence in the absence of geographical barriers to gene flow may be explained by disruptive selection across contrasting habitats.

3384: The 9aaTAD activation domains in the four Yamanaka Oct4, Sox2, Myc, and Klf4 transcription factors essential during the stem cell development
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Posted to bioRxiv 15 Dec 2019

The 9aaTAD activation domains in the four Yamanaka Oct4, Sox2, Myc, and Klf4 transcription factors essential during the stem cell development
228 downloads genetics

Martin Piskacek, Kristina Jendruchova, Martina Rezacova, Marek Havelka, Norbert Gasparik, Alena Hofrova, Andrea Knight

Somatic cells can be reprogrammed by the Yamanaka factors Oct4, Sox2, Myc and Klf4 activators into induced pluripotent stem cells. Throughout their genome, the Oct4, Sox2 and Klf4 cooperate with mediators of transcription, where the DNA binding sites serve as scaffolds for the phase-separated transcriptional condensates at distinct genome loci. In this study, we identified the 9aaTAD activation domains as the common interaction interface of the Yamanaka factors for transcription machinery. All four activation domains were identified by our online 9aaTAD prediction service and experimentally confirmed as strong activators of transcription. We considered the mediator interactions granted by 9aaTADs as part of the Yamanaka factors ability to reprogram cell fate.

3385: Linear modeling reveals a predominance of cis- over trans- regulatory effects in wild and domesticated barley
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Posted to bioRxiv 06 Jun 2019

Linear modeling reveals a predominance of cis- over trans- regulatory effects in wild and domesticated barley
228 downloads genetics

Matthew Haas, Axel Himmelbach, Martin Mascher

Barley, like other crops, has experienced a series of genetic changes that have 12 impacted its architecture and growth habit to suit the needs of humans, termed 13 the domestication syndrome. Domestication also resulted in a concomitant 14 bottleneck that reduced sequence diversity in genes and regulatory regions. Little 15 is known about regulatory changes resulting from domestication in barley. We 16 used RNA-seq to examine allele-specific expression (ASE) in hybrids between wild 17 and domesticated barley. Our results show that most genes have conserved 18 regulation. In contrast to studies of allele specific expression in interspecific 19 hybrids, we find almost a complete absence of trans effects. We also find that cis 20 regulation is largely stable in response to short-term cold stress. Our study has 21 practical implications for crop improvement using wild relatives. Genes regulated 22 in cis are more likely to be expressed in a new genetic background at the same 23 level as in their native background. 24 Introduction 25

3386: Genome-wide association analysis reveals new insights into the genetic architecture of defensive, agro-morphological and quality-related traits in cassava
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Posted to bioRxiv 27 Apr 2020

Genome-wide association analysis reveals new insights into the genetic architecture of defensive, agro-morphological and quality-related traits in cassava
228 downloads genetics

Ismail Yusuf Rabbi, Siraj Ismail Kayondo, Guillaume Bauchet, Muyideen Yusuf, Cynthia Idhigu Aghogho, Kayode Ogunpaimo, Ruth Uwugiaren, Ikpan Andrew Smith, Prasad Peteti, Afolabi Agbona, Elizabeth Parkes, Ezenwaka Lydia, Marnin Wolfe, Jean-Luc Jannink, Chiedozie Egesi, Peter Kulakow

Cassava (Manihot esculenta) is one of the most important starchy root crops in the tropics due to its adaptation to marginal environments. Genetic progress in this clonally propagated crop can be accelerated through the discovery of markers and candidate genes that could be used in cassava breeding programs. We carried out a genome-wide association study (GWAS) using a panel of 5,310 clones developed at the International Institute of Tropical Agriculture - Nigeria. The population was genotyped at more than 100,000 SNP markers via genotyping-by-sequencing (GBS). Genomic regions underlying genetic variation for 14 traits classified broadly into four categories: biotic stress (cassava mosaic disease and cassava green mite severity); quality (dry matter content and carotenoid content) and plant agronomy (harvest index and plant type). We also included several agro-morphological traits related to leaves, stems and roots with high heritability. In total, 41 significant associations were uncovered. While some of the identified loci matched with those previously reported, we present additional association signals for the traits. We provide a catalogue of favourable alleles at the most significant SNP for each trait-locus combination and candidate genes occurring within the GWAS hits. These resources provide a foundation for the development of markers that could be used in cassava breeding programs and candidate genes for functional validation. ### Competing Interest Statement The authors have declared no competing interest.

3387: Repeat-specific functions for the C-terminal domain of RNA polymerase II in budding yeast
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Posted to bioRxiv 01 Mar 2018

Repeat-specific functions for the C-terminal domain of RNA polymerase II in budding yeast
228 downloads genetics

Michael Babokhov, Mohammad M Mosaheb, Richard W. Baker, Stephen M. Fuchs

The C-terminal domain (CTD) of the largest subunit of RNA polymerase II (RNAPII) is required to regulate transcription and to integrate it with other essential cellular processes. In the budding yeast Saccharomyces cerevisiae, the CTD of Rpb1p consists of 26 conserved heptad repeats that are post-translationally modified to orchestrate protein factor binding at different stages of the transcription cycle. A long-standing question in the study of the CTD is if there are any functional differences between the 26 repeats. In this study, we present evidence that repeats of identical sequence have different functions based on their position within the CTD. We assembled plasmids expressing Rpb1p with serine to alanine substitutions in three defined regions of the CTD and measured a range of phenotypes for yeast expressing these constructs. Mutations in the beginning and middle regions of the CTD had drastic, and region-specific effects, while mutating the distal region had no observable phenotype. Further mutational analysis determined that Ser5 within the first region of repeats was solely responsible for the observed growth differences and sequencing fast-growing suppressors allowed us to further define the functional regions of the CTD. This mutational analysis is consistent with current structural models for how the RNAPII holoenzyme and the CTD specifically would reside in complex with Mediator and establishes a foundation for studying regioselective binding along the repetitive RNAPII CTD.

3388: Chances and challenges of machine learning based disease classification in genetic association studies illustrated on age-related macular degeneration
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Posted to bioRxiv 08 Dec 2019

Chances and challenges of machine learning based disease classification in genetic association studies illustrated on age-related macular degeneration
228 downloads genetics

Felix Günther, Caroline Brandl, Thomas W Winkler, Veronika Wanner, Klaus Stark, Helmut Küchenhoff, Iris M Heid

Imaging technology and machine learning algorithms for disease classification set the stage for high-throughput phenotyping and promising new avenues for genome-wide association studies (GWAS). Despite emerging algorithms, there has been no successful application in GWAS so far. We established machine learning based disease classification in genetic association analysis as a misclassification problem. To evaluate chances and challenges, we performed a GWAS based on automated classification of age-related macular degeneration (AMD) in UK Biobank (images from 135,500 eyes; 68,400 persons). We quantified misclassification of automatically derived AMD in internal validation data (images from 4,001 eyes; 2,013 persons) and developed a maximum likelihood approach (MLA) to account for it when estimating genetic association. We demonstrate that our MLA guards against bias and artefacts in simulation studies. By combining a GWAS on automatically derived AMD classification and our MLA in UK Biobank data, we were able to dissect true association (ARMS2/HTRA1, CFH) from artefacts (near HERC2) and to identify eye color as relevant source of misclassification. On this example of AMD, we are able to provide a proof-of-concept that a GWAS using machine learning derived disease classification yields relevant results and that misclassification needs to be considered in the analysis. These findings generalize to other phenotypes and also emphasize the utility of genetic data for understanding misclassification structure of machine learning algorithms.

3389: Elevated polygenic burden for ASD is associated with the broad autism phenotype
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Posted to bioRxiv 12 Nov 2019

Elevated polygenic burden for ASD is associated with the broad autism phenotype
227 downloads genetics

K. Nayar, J.M. Sealock, N. Maltman, L. Bush, E.H. Cook, L.K. Davis, M. Losh

Background: Autism spectrum disorder (ASD) is a multifactorial, neurodevelopmental disorder that encompasses a complex and heterogeneous set of traits. Subclinical traits that mirror the core features of ASD, referred to as the broad autism phenotype (BAP) have been documented repeatedly in unaffected relatives and are believed to reflect underlying genetic liability to ASD. The BAP may help inform the etiology of ASD by allowing the stratification of families into more phenotypically and etiologically homogeneous subgroups. This study explored polygenic scores related to the BAP. Methods: Phenotypic and genotypic information were obtained from 2,614 trios from Simons Simplex Sample. Polygenic scores of ASD (ASD-PGS) were generated across the sample to determine the shared genetic overlap between the BAP and ASD. Maternal and Paternal ASD-PGS was explored in relation to BAP traits and their child ASD symptomatology. Results: Maternal pragmatic language was related to childs social communicative atypicalities. In fathers, rigid personality was related to increased repetitive behaviors in children. Maternal (but not paternal) ASD-PGS was related to the pragmatic language and rigid BAP domains. Conclusions: Domain- and sex-specific associations emerged between parent and child phenotypes. ASD-PGS associations emerged with BAP in mothers only, highlighting the potential for a female protective factor, and implicating the polygenic etiology of ASD-related phenotypes in the BAP.

3390: Association study of schizophrenia with variants in miR-137 binding sites
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Posted to bioRxiv 15 Jun 2017

Association study of schizophrenia with variants in miR-137 binding sites
227 downloads genetics

David Curtis, Warren Emmett

There is strong cumulative evidence for the involvement of miR-137 and its targets in the aetiology of schizophrenia. Here we test whether variants, especially rare variants, in miR-137 binding sites are associated with schizophrenia in an exome-sequenced sample of 4225 cases and 5834 controls. A weighted burden test using 372 variants was significant at p=0.024. The sample size is too small to implicate individual variants or genes but overall this finding provides further support for the hypothesis that disruption of miR-137 binding sites can increase the risk of schizophrenia, perhaps by leading to over-expression of the target gene. These findings could be followed up by genotyping these variants in larger samples and by experimentally testing whether they do indeed effect expression. When carrying out exome sequencing it is important to include UTRs so that disruption of microRNA bindings sites can be detected.

3391: MYB5a/NEGAN activates petal anthocyanin pigmentation and shapes the MBW regulatory network in Mimulus luteus var. variegatus
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Posted to bioRxiv 10 Apr 2020

MYB5a/NEGAN activates petal anthocyanin pigmentation and shapes the MBW regulatory network in Mimulus luteus var. variegatus
227 downloads genetics

Xingyu Zheng, Kuenzang Om, Kimmy A Stanton, Daniel Thomas, Philip A Cheng, Allison Eggert, Yao-Wu Yuan, Joshua R. Puzey, Arielle M. Cooley

Much of the visual diversity of angiosperms is due to the frequent evolution of novel pigmentation patterns in flowers. The gene network responsible for anthocyanin pigmentation, in particular, has become a model for investigating how genetic changes give rise to phenotypic innovation. In the monkeyflower genus Mimulus , an evolutionarily recent gain of petal lobe anthocyanin pigmentation in M. luteus var. variegatus was previously mapped to genomic region pla2 . Here, we use DNA sequence analysis and spatiotemporal patterns of gene expression to identify MYB5a - homologous to the NEGAN transcriptional activator from M. lewisii - as a likely candidate gene within the pla2 region. Transgenic manipulation of gene expression confirms that MYB5a is both necessary and sufficient for petal lobe anthocyanin pigmentation. The deployment of MYB5a/NEGAN to the petal lobe stands in contrast to its more restricted role as a nectar guide anthocyanin activator in other Mimulus species. Transcriptome sequencing of a MYB5a RNAi line reveals the degree to which other regulators of the anthocyanin pathway - including R3 MYB repressors and bHLH and WD40 co-activators - are responsive to the level of expression of MYB5a . Overall, this work reveals that a genetically simple change, which we hypothesize to be a regulatory mutation in cis to MYB5a , has cascading effects on gene expression, not only on the genes downstream of MYB5a but also on all of its known partners in the anthocyanin regulatory network. ### Competing Interest Statement The authors have declared no competing interest.

3392: Genetic interactions among Ghd7, Ghd7.1, Ghd8 and Hd1 contribute to large variation in heading date in rice
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Posted to bioRxiv 03 Dec 2018

Genetic interactions among Ghd7, Ghd7.1, Ghd8 and Hd1 contribute to large variation in heading date in rice
227 downloads genetics

Bo Zhang, Haiyang Liu, Feronique Qi, Zhanyi Zhang, Qiuping Li, Zhongmin Han, Yongzhong Xing

Several major heading date genes are sensitive to photoperiod and jointly regulate heading date in rice. However, it is not clear how these genes coordinate rice heading. In this study, a near-isogenic F2 population with Ghd7, Ghd7.1, Ghd8 and Hd1 segregating in the Zhenshan 97 (ZS97) background was used to evaluate the genetic interactions among these four genes under natural long-day (NLD) and natural short-day (NSD) conditions, and a series of Ghd7.1-segregating populations in different backgrounds were developed to estimate the genetic effects of Ghd7.1 on heading date under both conditions. Tetragenic, trigenic and digenic interactions among these four genes were observed under both conditions. In the functional Hd1 backgrounds, the strongest digenic interaction was Ghd7 by Ghd8 under NLD conditions but was Ghd7 by Ghd7.1 under NSD conditions. Interestingly, Ghd7.1 acted as a flowering suppressor under NLD conditions, while it functioned alternatively as an activator or a suppressor under NSD conditions depending on the status of the other three genes. Based on the performances of 16 homozygous four-gene combinations, a positive correlation between heading date and yield was found under NSD conditions, but changed to a negative correlation when heading date was over 90 days under NLD conditions. These results demonstrate the importance of genetic interactions in the rice flowering regulatory network and will help breeders to select favorable combinations to maximize rice yield potential for different ecological areas.

3393: Shared genetics and couple-associated environment are major contributors to the risk of both clinical and self-declared depression
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Posted to bioRxiv 21 Sep 2016

Shared genetics and couple-associated environment are major contributors to the risk of both clinical and self-declared depression
227 downloads genetics

Yanni Zeng, Pau Navarro, Charley Xia, Carmen Amador, Ana M Fernandez-Pujals, Pippa A. Thomson, Archie Campbell, Reka Nagy, Toni-Kim Clarke, Jonathan D. Hafferty, Blair H Smith, Lynne J. Hocking, Sandosh Padmanabhan, Caroline Hayward, Donald J MacIntyre, David J. Porteous, Chris S. Haley, Andrew M McIntosh

Background: both genetic and environmental contributions to risk of depression have been identified, but estimates of their effects are limited. Commonalities between major depressive disorder (MDD) and self-declared depression (SDD) are also unclear. Dissecting the genetic and environmental contributions to these traits and their correlation would inform the design and interpretation of genetic studies. Methods: using data from a large Scottish family-based cohort (GS:SFHS, N=21,387), we estimated the genetic and environmental contributions to MDD and SDD. Genetic effects associated with common genome-wide genetic variants (SNP heritability) and additional pedigree-associated genetic variation and Non-genetic effects associated with common environments were estimated using linear mixed modeling (LMM). Findings: Both MDD and SDD had significant contributions from effects of common genetic variants, the additional genetic effect of the pedigree and the common environmental effect shared by couples. The correlation between SDD and MDD was high (r=1.00, se=0.21) for common-variant-associated genetic effects and moderate for both the additional genetic effect of the pedigree (r=0.58, se=0.08) and the couple-shared environmental effect (r=0.53, se=0.22). Interpretation: Both genetics and couple-shared environmental effects were the major factors influencing liability to depression. SDD may provide a scalable alternative to MDD in studies seeking to identify common risk variants. Rarer variants and environmental effects may however differ substantially according to different definitions of depression.

3394: Identification of pathogen genomic differences that impact human immune response and disease during Cryptococcus neoformans infection
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Posted to bioRxiv 28 Mar 2019

Identification of pathogen genomic differences that impact human immune response and disease during Cryptococcus neoformans infection
227 downloads genetics

Aleeza C. Gerstein, Katrina M. Jackson, Tami R McDonald, Yina Wang, Benjamin D. Lueck, Sara Bohjanen, Kyle D. Smith, Andrew Akampurira, David B Meya, Chaoyang Xue, David R. Boulware, Kirsten Nielsen

Patient outcomes during infection are due to a complex interplay between the quality of medical care, host immunity factors, and the infecting pathogen’s characteristics. To probe the influence of pathogen genotype on human immune response and disease, we examined Cryptococcus neoformans isolates collected during the Cryptococcal Optimal ART Timing (COAT) trial in Uganda. We measured human participants’ immunologic phenotypes, meningitis disease parameters, and survival. We compared this clinical data to whole genome sequences from 38 C. neoformans isolates of the most frequently observed sequence type (ST) ST93 in our Ugandan participant population, and an additional 18 strains from 9 other sequence types representing the known genetic diversity within the Ugandan Cryptococcus clinical isolates. We focused our analyses on 652 polymorphisms that: were variable among the ST93 genomes, were not in centromeres or extreme telomeres, and were predicted to have a fitness effect. Logistic regression and principal component analyses identified 40 candidate Cryptococcus genes and 3 hypothetical RNAs associated with human immunologic response or clinical parameters. We infected mice with 17 available KN99α gene deletion strains for these candidate genes and found that 35% (6/17) directly influenced murine survival. Four of the six gene deletions that impacted murine survival were novel. Such bedside-to-bench translational research provides important candidate genes for future studies on virulence-associated traits in human Cryptococcus infections.

3395: Asthma and affective traits in adults: a genetically informative study
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Posted to bioRxiv 26 Jan 2019

Asthma and affective traits in adults: a genetically informative study
227 downloads genetics

Kelli Lehto, Nancy L. Pedersen, Catarina Almqvist, Yi Lu, Bronwyn K. Brew

Depression, anxiety and high neuroticism (affective traits) are often comorbid with asthma. A causal direction between the affective traits and asthma is difficult to determine, however, it may be that there is a common underlying pathway attributable to shared genetic factors. Our aim was to determine whether a common genetic susceptibility exists for asthma and each of the affective traits. An adult twin cohort from the Swedish Twin Register underwent questionnaire-based health assessments (n=23 693) and genotyping (n=15 908). Firstly, questionnaire-based associations between asthma and affective traits were explored. This was followed by genetic analyses: a) polygenic risk scores (PRS) for affective traits were used as predictors of asthma, and b) linkage-disequilibrium score regression based on genome-wide association results from UK Biobank was used to quantify genetic correlations. Analyses found that the questionnaire-based associations between asthma and each affective trait were associated (OR 1.7, 95%CI 1.5-1.9 major depression, OR 1.5, 95%CI 1.3-1.6 anxiety, and OR 1.6, 95% 1.4-1.8 high neuroticism). Genetic susceptibility for neuroticism explained the variance in asthma with a dose response effect; that is, those in the highest neuroticism PRS quartile were more likely to have asthma than those in the lowest quartile (OR 1.4, 95%CI 1.2- 1.6). Genetic correlations were found between depression and asthma (rg= 0.17), but not for anxiety or neuroticism score. We conclude that the observed comorbidity between asthma and the affective traits may in part be due to shared genetic influences between asthma and depression and neuroticism, but not anxiety.

3396: A versatile bulk electrotransfection protocol for mouse embryonic fibroblast and iPS cells
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Posted to bioRxiv 09 Sep 2019

A versatile bulk electrotransfection protocol for mouse embryonic fibroblast and iPS cells
227 downloads genetics

Shahin Eghbalsaied, Iqbal Hyder, Wilfried A. Kues

A square-wave pulsing protocol was developed using OptiMEM-GlutaMAX for high efficient transfection of mouse embryonic fibroblast (MEF) and induced pluripotency stem (iPS) cells. An electrotransfection efficiency of > 95% was repeated for both MEF and iPS cells using reporter-encoding plasmids. The protocol was very efficient for plasmid size ranging from 6.2 to 13.5 kb. A high rate of targeted gene knockout (> 95 %) was produced in Venus transgenic cells using indels formation. Targeted deletions in the Venus transgene were performed by co-electroporation of two gRNA-encoding plasmids. In conclusion, this plasmid electrotransfection protocol is straight-forward, cost-effective, and efficient for CRISPRing mouse primary cells.

3397: Mutation of CFAP57 causes primary ciliary dyskinesia by disrupting the asymmetric targeting of a subset of ciliary inner dynein arms
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Posted to bioRxiv 24 Sep 2019

Mutation of CFAP57 causes primary ciliary dyskinesia by disrupting the asymmetric targeting of a subset of ciliary inner dynein arms
227 downloads genetics

Ximena M. Bustamante-Marin, Amjad Horani, Mihaela Stoyanova, Wu-Lin Charng, Mathieu Bottier, Patrick R. Sears, Leigh Anne Daniels, Hailey Bowen, Donald F. Conrad, Michael R. Knowles, Lawrence E Ostrowski, Maimoona A Zariwala, SK. Dutcher

Primary ciliary dyskinesia (PCD) is characterized by chronic airway disease, male infertility, and randomization of the left/right body axis, and is caused by defects of motile cilia and sperm flagella. We screened a cohort of affected individuals that lack an obvious TEM structural phenotype for pathogenic variants using whole exome capture and next generation sequencing. The population sampling probability (PSAP) algorithm identified one subject with a homozygous nonsense variant [(c.1762C&gtT) p.(Arg588*) exon 11] in the uncharacterized CFAP57 gene. In normal human nasal epithelial cells, CFAP57 localizes throughout the ciliary axoneme. Analysis of cells from the PCD patient shows a loss of CFAP57, reduced beat frequency, and an alteration in the ciliary waveform. Knockdown of CFAP57 in human tracheobronchial epithelial cells (hTECs) recapitulates these findings. Phylogenetic analysis showed that CFAP57 is conserved in organisms that assemble motile cilia, and CFAP57 is allelic with the BOP2 gene identified previously in Chlamydomonas. Two independent, insertional fap57 Chlamydomonas mutant strains show reduced swimming velocity and altered waveforms. Tandem mass spectroscopy showed that CFAP57 is missing, and the g inner dyneins (DHC7 and DHC3) and the d inner dynein (DHC2) are reduced. Our data demonstrate that the FAP57 protein is required for the asymmetric assembly of inner dyneins on only a subset of the microtubule doublets, and this asymmetry is essential for the generation of an effective axonemal waveform. Together, our data identifies mutations in CFAP57 as a cause of PCD with a specific defect in the inner dynein arm assembly process.

3398: Genome Wide Association Study of Resistance to PstS2 and Warrior Races of Stripe (Yellow) Rust in Bread Wheat Landraces.
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Posted to bioRxiv 10 Feb 2020

Genome Wide Association Study of Resistance to PstS2 and Warrior Races of Stripe (Yellow) Rust in Bread Wheat Landraces.
227 downloads genetics

Muhammad Massub Tehseen, Fatma Aykut Tonk, Muzaffer Tosun, Ahmed Amri, Carolina P. Sansaloni, Ezgi Kurtulus, Mariana Yazbek, Khaled Al-Sham’aa, Izzet Ozseven, Luqman Bin Safdar, Ali Shehadeh, Kumarse Nazari

Stripe rust, caused by Puccinia striiformis Westend. f. sp. tritici is a major threat to wheat production worldwide. The breakdown in resistance of certain major genes and new emerging aggressive races of stripe rusts are causing serious concerns in all main wheat growing areas of the world. To search for new sources of resistance genes and associated QTL for effective utilization in future breeding programs an association mapping panel comprising of 600 bread wheat landraces collected from eight different countries conserved at ICARDA gene bank were evaluated for seedling and adult plant resistance against PstS2 and Warrior races of stripe rust at the Regional Cereal Rust Research Center (RCRRC), Izmir, Turkey during 2016, 2018 and 2019. A set of 25,169 informative SNP markers covering the whole genome were used to examine the population structure, linkage disequilibrium and marker-trait associations in the association mapping panel. The genome-wide association study (GWAS) was carried out using a Mixed Linear Model (MLM). We identified 47 SNP markers at 19 genomic regions with significant SNP-trait associations for both seedling and adult plant stage resistance, the threshold of significance for all SNP-trait associations was determined by the false discovery rate (q) ≤ 0.05. Three genomic regions (QYr.1D\_APR, QYr.3A\_seedling and QYr.7D_seedling) identified in this study are far away from any previously reported Yr gene or QTL hence, tagging novel genomic regions. The In-silico analysis of the novel QTL regions identified candidate resistance genes encoding proteins putative to plants disease resistance and defense mechanism.

3399: PQM-1 controls hypoxic survival via regulation of lipid metabolism
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Posted to bioRxiv 14 Sep 2019

PQM-1 controls hypoxic survival via regulation of lipid metabolism
227 downloads genetics

Thomas Heimbucher, Julian Hog, Coleen T. Murphy

Animals have evolved responses to low oxygen conditions to ensure their survival. Here we have identified the C. elegans zinc finger transcription factor PQM-1 as a regulator of the hypoxic stress response. PQM-1 is required for the longevity of insulin signaling mutants, but surprisingly, loss of PQM-1 increases survival under hypoxic conditions. PQM-1 functions as a metabolic regulator by controlling oxygen consumption rates, suppressing hypoxic glycogen levels, and inhibiting the expression of the sorbitol dehydrogenase-1 SODH-1, a crucial enzyme for sugar metabolism. PQM-1 promotes intestinal fat metabolism by activating the expression of the stearoyl-CoA desaturase FAT-7, an oxygen consuming, rate-limiting enzyme in fatty acid biosynthesis. PQM-1 activity enhances fat accumulation in embryos under hypoxic conditions, thereby increasing survival rates of arrested progeny during hypoxia. Thus, while pqm-1 mutants increase survival of mothers, ultimately this loss is detrimental to progeny survival. Our data support a model in which PQM-1 controls a trade-off between lipid metabolic activity in the mother and her progeny to promote the survival of the species under hypoxic conditions.

3400: Identifying candidate detoxification genes in the ecdysteroid kinase-like (EcKL) and cytochrome P450 gene families in Drosophila melanogaster by integrating evolutionary and transcriptomic data
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Posted to bioRxiv 19 Feb 2020

Identifying candidate detoxification genes in the ecdysteroid kinase-like (EcKL) and cytochrome P450 gene families in Drosophila melanogaster by integrating evolutionary and transcriptomic data
226 downloads genetics

Jack L. Scanlan, Rebecca S Gledhill-Smith, Paul Battlay, Charles Robin

The capacity to detoxify toxic compounds is essential for adaptation to the ecological niches of many organisms, especially insects. However, detoxification in insects is often viewed through the lens of mammalian detoxification research, even though the organ and enzyme systems involved have diverged for over half a billion years. Phosphorylation is a non-canonical phase II detoxification reaction that, among animals, occurs near exclusively in insects, but the enzymes responsible have never been cloned or otherwise identified. We propose the hypothesis that members of the arthropod-specific ecdysteroid kinase-like (EcKL) gene family encode detoxicative kinases. To test this hypothesis, we annotated the EcKL gene family in 12 species of Drosophila and explored their evolution within the genus. Many ancestral EcKL clades are evolutionarily unstable and have experienced repeated gene gain and loss events, while others are conserved as single copy orthologs. Leveraging multiple published gene expression datasets from D. melanogaster , and using the cytochrome P450s (a canonical detoxification family) as a test case, we demonstrate relationships between xenobiotic induction, detoxification tissue-enriched expression and evolutionary instability in the EcKLs and the P450s. We also found previously unreported genomic and transcriptomic variation in a number of EcKLs and P450s associated with toxic stress phenotypes using a targeted phenome-wide association study (PheWAS) approach. Lastly, we devised a systematic method for identifying candidate detoxification genes in large gene families that is concordant with experimentally determined functions of P450 genes in D. melanogaster . Applying this method to the EcKLs suggested a significant proportion of these genes play roles in detoxification, and that the EcKLs may constitute a detoxification gene family in insects. Additionally, we estimate that between 11-16 uncharacterised D. melanogaster P450s are strong detoxification candidates.

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