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in category genetics

3,478 results found. For more information, click each entry to expand.

3381: Assessing Disease Experience across the Life Span for Individuals with Osteogenesis Imperfecta: Challenges and Opportunities for Patient-Reported Outcomes (PROs) Measurement
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Posted to bioRxiv 20 Sep 2018

Assessing Disease Experience across the Life Span for Individuals with Osteogenesis Imperfecta: Challenges and Opportunities for Patient-Reported Outcomes (PROs) Measurement
77 downloads genetics

Laura L Tosi, Marianne K Floor, Christina M Dollar, Austin P Gillies, Members of the Brittle Bone Disease Consortium, Tracy S Hart, David Cuthbertson, Vernon Reid Sutton, Jeffrey P Krischer

Background: Patient reported outcome (PRO) information is crucial for establishing better patient-provider communication, improving shared decision making between clinicians and patients, and assessing patient responses to therapeutic interventions and increasing satisfaction with care. We used the Brittle Bones Disease Consortium (BBDC) Contact Registry for People with OI, managed by the Rare Disease Clinical Research Network (RDCRN) to (1) to evaluate the construct validity of the Patient-Reported Outcome Measurement Information System® (PROMIS®) to record important components of the disease experience among individuals with OI; and (2) explore the feasibility of using a registry to recruit individuals with OI to report on health status. Our long-term goal is to enhance communication of health and disease management findings back to the OI community, especially those who do not have access to major OI clinical centers. Results: We demonstrated the construct validity of PROMIS instruments in OI. Our results confirm that the scores from most domains differ significantly from the general US population: individuals with OI have worse symptom burden and functioning. We found no excessive floor or ceiling effects. Our study demonstrates that the BBDC Contact Registry can be used to recruit participants for online health status surveys. However, there are numerous challenges that must be addressed: lack of self-knowledge of OI type, under-representation of men, limited ethnic diversity, and imperfect questionnaire completion rates. Conclusion: Our pilot study demonstrated the feasibility of using a contact registry to recruit respondents from the OI community and to obtain analyzable PROMIS data regarding disease experience. Because the results differ from the general population and avoid excessive floor and ceiling effects, PROMIS instruments can be used to assess response to therapeutic interventions in individuals with OI. Future directions will include (1) development and validation of an OI-specific patient-based classification system that aggregates persons with similar clinical characteristics and risks for complications to identify treatment needs; and (2) integrating these PRO tools into routine patient care and research studies.

3382: A Simple Approximation To The Bias Of Gene-Environment Interactions In Case/Control Studies With Silent Disease
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Posted to bioRxiv 17 Oct 2018

A Simple Approximation To The Bias Of Gene-Environment Interactions In Case/Control Studies With Silent Disease
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Iryna Lobach, Joshua Sampson, Siarhei Lobach, Alexander Alekseyenko, Alexandra Pryatinska, Tao He, Li Zhang

One of the most important research areas in case-control Genome-Wide Association Studies is to determine how the effect of a genotype varies across the environment or to measure the gene-environment interaction (GxE). We consider the scenario when some of the "healthy" controls actually have the disease and when the frequency of these latent cases varies by the environmental variable of interest. In this scenario, performing logistic regression of clinically defined case status on the genetic variant, environmental variable, and their interaction will result in biased estimates of GxE interaction. Here, we derive a general theoretical approximation to the bias in the estimates of the GxE interaction and show, through extensive simulation, that this approximation is accurate in finite samples. Moreover, we apply this approximation to evaluate the bias in the effect estimates of the genetic variants related to mitochondrial proteins a large-scale Prostate Cancer study.

3383: Assignment of frost tolerant coast redwood trees of unknown origin to populations within their natural range using nuclear and chloroplast microsatellite genetic markers
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Posted to bioRxiv 12 Aug 2019

Assignment of frost tolerant coast redwood trees of unknown origin to populations within their natural range using nuclear and chloroplast microsatellite genetic markers
76 downloads genetics

Natalie Breidenbach, Oliver Gailing, Konstantin V. Krutovsky

Considering climate change and expected changes in temperature and precipitation, some introduced timber species are prospective for growing in Germany or Europe to produce valuable wood products and support sustainable forestry. The Californian tree, coast redwood (Sequoia sempervirens [D. Don] Endl.) is one of such species due to its excellent wood properties and high growth rate. It is sensitive to the freezing temperatures, but several trees of unknown origin introduced to Germany decades ago demonstrated high frost tolerance, and their propagated cuttings were planted all over German botanic gardens and arboreta. The knowledge of their origin within the natural distribution range could help us identify the potential genetic resources of frost resistant coast redwood genotypes. Therefore, both trees of unknown origin in Germany (G) and two reference data sets representing the “Kuser provenance test” established in 1990 in France (F) and samples collected in California (C) with known origin were genotyped using 18 microsatellite markers including 12 nuclear and six chloroplast simple sequence repeat (cpSSR) markers. The number of haplotypes found in the data sets based on six cpSSR markers was surprisingly very high. These markers were used to assign the German frost resistant trees (G) to the two reference data sets (F and C). The genetic structure among California samples (C) based on nSSR and cpSSR markers was very weak and mainly due to northern and southern clusters separated by the San Francisco Bay as a geographic barrier between coast redwood populations confirming previously published data. It was impossible to confidently assign frost tolerant trees (G) to single native populations, but rather to either the northern or southern cluster. However, the existing frost tolerant genotypes can already be used to establish commercial coast redwood plantation for future German forestry.

3384: Thickening of the cell wall increases the resistance of S. cerevisiae to commercial formulations of glyphosate
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Posted to bioRxiv 06 Sep 2019

Thickening of the cell wall increases the resistance of S. cerevisiae to commercial formulations of glyphosate
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Apoorva Ravishankar, Amaury Pupo, Jennifer E. G. Gallagher

The use of glyphosate-based herbicides is widespread and despite its extensive use, its effects are yet to be deciphered completely. The additives in commercial formulations of glyphosate, though labeled as inert when used individually, have adverse effects when used in combination with other additives and the active ingredient. As a species, Saccharomyces cerevisiae has a wide range of resistance to glyphosate-based herbicides. To investigate the underlying genetic differences between sensitive and resistant strains, global changes in gene expression were measured when yeast were exposed to a commercial formulation of glyphosate (CFG). Changes in gene expression involved in numerous pathways such as DNA replication, MAPK signaling, meiosis, and cell wall synthesis. Because so many diverse pathways were affected, these strains were then subjected to in-lab-evolutions (ILE) to select mutations that confer increased resistance. Common fragile sites were found to play a role in adaptation mechanisms used by cells to attain resistance with long-term exposure to CFG. The cell wall structure acts as a protective barrier in alleviating the stress caused by exposure to CFG. The thicker the cell wall, the more resistant the cell is against CFG. Hence, a detailed study of the changes occurring at the genome and transcriptome level is essential to better understand the possible effects of CFG on the cell as a whole.

3385: Goodness-of-fit filtering in classical metric multidimensional scaling with large datasets
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Posted to bioRxiv 19 Jul 2019

Goodness-of-fit filtering in classical metric multidimensional scaling with large datasets
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Jan Graffelman

Metric multidimensional scaling (MDS) is a widely used multivariate method with applications in almost all scientific disciplines. Eigenvalues obtained in the analysis are usually reported in order to calculate the overall goodness-of-fit of the distance matrix. In this paper, we refine MDS goodness-of-fit calculations, proposing additional point and pairwise goodness-of-fit statistics that can be used to filter poorly represented observations in MDS maps. The proposed statistics are especially relevant for large data sets that contain outliers, with typically many poorly fitted observations, and are helpful for improving MDS output and emphasising the most important features of the dataset. Several goodness-of-fit statistics are considered, and both Euclidean and non-Euclidean distance matrices are considered. Some examples with data from demographic, genetic and geographic studies are shown.

3386: Loss of Cdc13 causes genome instability by deficiency in replication-dependent telomere capping
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Posted to bioRxiv 05 Sep 2019

Loss of Cdc13 causes genome instability by deficiency in replication-dependent telomere capping
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Rachel Langston, Dominic Palazzola, Erin Bonnell, Raymund J Wellinger, Ted Weinert

In budding yeast, Cdc13, Stn1, and Ten1 form a telomere binding heterotrimer dubbed CST. Here we investigate the role of Cdc13/CST in maintaining genome stability, using a Chr VII disome system that can generate recombinants, loss, and enigmatic unstable chromosomes. In cells expressing a temperature sensitive CDC13 allele, cdc13F684S, unstable chromosomes frequently arise due to problems in or near a telomere. Hence, when Cdc13 is defective, passage through S phase causes Exo1-dependent ssDNA and unstable chromosomes, which then are the source for whole chromosome instability events (e.g. recombinants, chromosome truncations, dicentrics, and/or loss). Specifically, genome instability arises from a defect in Cdc13's replication-dependent telomere capping function, not Cdc13s putative post-replication telomere capping function. Furthermore, the unstable chromosomes form without involvement of homologous recombination nor non-homologous end joining. Our data suggest that a Cdc13/CST defect in semi-conservative replication near the telomere leads to ssDNA and unstable chromosomes, which then are lost or subject to complex rearrangements. This system defines a links between replication-dependent chromosome capping and genome stability in the form of unstable chromosomes.

3387: Two different pathways for initiation of Trichoderma reesei Rad51-only meiotic recombination
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Posted to bioRxiv 21 May 2019

Two different pathways for initiation of Trichoderma reesei Rad51-only meiotic recombination
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Wan-Chen Li, Yu-Chien Chuang, Chia-Ling Chen, Ljudmilla Timofejeva, Wen-Li Pong, Yu-Jie Chen, Ting-Fang Wang

Meiotic recombination is mainly, but not exclusively, initiated by Spo11-induced double strand breaks (DSBs) in some sexual eukaryotes. DSBs are repaired by one or two RecA-like recombinases (ubiquitous Rad51 and meiosis-specific Dmc1). In yeast and mammals, Dmc1 is superior to Rad51 in tolerating mismatched sequences during highly polymorphic hybrid meiosis. The mechanisms underlying Rad51-only meiotic recombination remain less studied. The Rad51-only filamentous fungus Trichoderma reesei has only one spo11 gene. Removal of spo11 from T. reesei genome does not affect normal sexual development, meiosis or chromosome synapsis, but results in decrease of interhomolog recombination products to 70%, crossover homeostasis and lower genetic interference. Our results also suggest that T. reesei Rad51, like yeast and mammalian Dmc1 (but not Rad51), can tolerate mismatched sequences during meiotic recombination. Moreover, topoisomerase II might act redundantly (and predominantly) with Spo11 to initiate meiotic recombination. We suggest that T. reesei is an emerging model for studying Spo11-independent and Rad51-only meiosis.

3388: Of Microbes and Mange: Consistent changes in the skin microbiome of three canid species infected with sarcoptic mange
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Posted to bioRxiv 22 Jul 2019

Of Microbes and Mange: Consistent changes in the skin microbiome of three canid species infected with sarcoptic mange
76 downloads genetics

Alexandra L DeCandia, Kennedy N Leverett, Bridgett M. vonHoldt

Sarcoptic mange is a highly contagious skin disease caused by the ectoparasitic mite, Sarcoptes scabiei. Although it afflicts over 100 mammal species worldwide, sarcoptic mange remains a disease obscured by variability at the individual, population, and species levels. Amid this variability, it is critical to identify consistent drivers of morbidity, particularly at the skin barrier. We characterized the skin microbiome of three species of North American canids: coyotes (Canis latrans), red foxes (Vulpes vulpes), and gray foxes (Urocyon cinereoargenteus). Comparing mange-infected and uninfected individuals, we found remarkably consistent signatures of microbial dysbiosis associated with mange infection. Across genera, mange-infected canids exhibited reduced microbial diversity, altered community composition, and increased abundance of opportunistic pathogens. The primary bacteria comprising these secondary infections were Staphylococcus pseudintermedius, previously associated with canid ear and skin infections, and Corynebacterium spp, previously found among the gut flora of S. scabiei mites and hematophagous arthropods. Considered together, this evidence suggests that mange infection consistently alters the canid skin microbiome and facilitates secondary bacterial infection. These results provide valuable insights into the pathogenesis of mange at the skin barrier of North American canids and can inspire novel treatment strategies. By further adopting a "One Health" framework that considers mites, microbes, and the potential for interspecies transmission, we can better elucidate the patterns and processes underlying this ubiquitous and enigmatic disease.

3389: Genetic effect estimates in case-control studies when a continuous variable is omitted from the model
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Posted to bioRxiv 05 Sep 2019

Genetic effect estimates in case-control studies when a continuous variable is omitted from the model
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Ying Sheng, Chiung-Yu Huang, Siarhei Lobach, Lydia Zablotska, Iryna Lobach

Large-scale genome-wide analyses scans provide massive volumes of genetic variants on large number of cases and controls that can be used to estimate the genetic effects. Yet, the sets of non-genetic variables available in publicly available databases are often brief. It is known that omitting a continuous variable from a logistic regression model can result in biased estimates of odds ratios (OR) (e.g., Gail et al (1984), Neuhaus et al (1993), Hauck et al (1991), Zeger et al (1988)). We are interested to assess what information is needed to recover the bias in the OR estimate of genotype due to omitting a continuous variable in settings when the actual values of the omitted variable are not available. We derive two estimating procedures that can recover the degree of bias based on a conditional density of the omitted variable or knowing the distribution of the omitted variable. Importantly, our derivations show that omitting a continuous variable can result in either under- or over- estimation of the genetic effects. We performed extensive simulation studies to examine bias, variability, false positive rate, and power in the model that omits a continuous variable. We show the application to two genome-wide studies of Alzheimers disease.

3390: The rs6505162 C>A polymorphism in the miRNA-423 gene exhibits a protective element of coronary artery in a southern Chinese population with Kawasaki disease
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Posted to bioRxiv 04 Apr 2019

The rs6505162 C>A polymorphism in the miRNA-423 gene exhibits a protective element of coronary artery in a southern Chinese population with Kawasaki disease
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Jiawen Li, Jinxin Wang, Xiaoping Su, Zhiyong Jiang, Xing Rong, Xueping Gu, Huixian Qiu, Lanlan Zeng, Hao Zheng, Xiaoqiong Gu, Maoping Chu

Background: Manifesting as acute rash, fever and vasculitis, belonging to autoimmune syndrome, Kawasaki disease(KD) is prone to occur in infants and young children. Males and females is affected by KD at a ratio of 1.4 to 1.7 : 1. KD is known to own many common clinical manifestations and complications, like coronary artery lesion(CAL) and coronary artery aneurysm(CAA). Polymorphisms of the rs6505162 locus in the miRNA-423 gene are associated with enhancive susceptibility to coronary artery disease and the alterations of the four cytokines IL-4. , IL-10, IL-21, IL-22 in the early stages of diabetes. However, no researcher has reported whether rs6505162 is related to KD susceptibility or no. Therefore, we carried out the trial concentrating on the connection between miRNA-423 rs6505162 C>A polymorphism and KD susceptibility. Methods: To obtain the genotypes of rs6505162 in objects enrolled by 532 KD children and 623 control, we applied Taqman real-time PCR and all statistical analyses was carried out by SAS. Results: The comparison between all cases and all controls hinted that the rs6505162C>A polymorphism has no relationship with KD susceptibility. Nevertheless, a subgroup analysis revealed that the CA/AA genotypes of rs6505162 could reduce the occurrence of CAA (Adjusted age and gender odds ratio=1.30, 95%CI=1.02-1.67, P=0.037) and CAL (Adjusted OR=1.56, 95%CI=1.19-2.03, P=0.001)in KD patients. Conclusion: Our final results stated clearly that miRNA-423 rs6505162 polymorphism appears to be a protective element of CAL and CAA in southern Chinese suffers with KD.

3391: Rapid ordering of barcoded transposon insertion libraries of anaerobic bacteria
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Posted to bioRxiv 30 Sep 2019

Rapid ordering of barcoded transposon insertion libraries of anaerobic bacteria
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Anthony L Shiver, Rebecca Culver, Adam M Deutschbauer, Kerwyn Huang

Commensal bacteria from the human intestinal microbiota play important roles in health and disease. Research into the mechanisms by which these bacteria exert their effects is hampered by the complexity of the microbiota and by the strict growth requirements of the individual species. The assembly of ordered transposon insertion libraries, in which nearly all nonessential genes have been disrupted and the strains stored as independent monocultures, would be a transformative resource for research into many microbiota members. However, assembly of these libraries must be fast and inexpensive in order to empower investigation of the large number of species that typically compose gut communities. The methods used to generate ordered libraries must also be adapted to the anaerobic growth requirements of most intestinal bacteria. We have developed a protocol to assemble ordered libraries of transposon insertion mutants that is fast, cheap, and effective for even strict anaerobes. The protocol differs from currently available methods by making use of cell sorting to order the library and barcoded transposons to facilitate the localization of ordered mutations in the library. By tracking transposon insertions using barcode sequencing, our approach increases the accuracy and reduces the time and effort required to locate mutants in the library. Ordered libraries can be sorted and characterized over the course of two weeks using this approach. We expect this protocol will lower the barrier to generating comprehensive, ordered mutant libraries for many species in the human microbiota, allowing for new investigations into genotype-phenotype relationships within this important microbial ecosystem.

3392: Predicted genetic gains from introgressing chromosome segments from exotic germplasm into an elite soybean cultivar
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Posted to bioRxiv 13 Jul 2019

Predicted genetic gains from introgressing chromosome segments from exotic germplasm into an elite soybean cultivar
75 downloads genetics

Sushan Ru, Rex Bernardo

Broadening the diversity of cultivated soybean [ Glycine max (L.) Merrill] through introgression of exotic germplasm has been difficult. Our objectives were to 1) determine if introgressing specific chromosome segments (instead of quantitative trait locus alleles) from exotic soybean germplasm has potential for improving an elite cultivar, and 2) identify strategies to introgress and pyramid exotic chromosome segments into an elite cultivar. We estimated genomewide marker effects for yield and other traits in seven crosses between the elite line IA3023 and seven soybean plant introductions (PIs). We then predicted genetic gains from having ≤2 targeted recombinations per linkage group. When introgression was modeled for yield while controlling maturity in the seven PI × IA3023 populations, the predicted yield was 8 to 25% over the yield of IA3023. Correlated changes in maturity, seed traits, lodging, and plant height were generally small but were in the favorable direction. In contrast, selecting the best recombinant inbred (without targeted recombination) in each of the PI × IA3023 populations led to negative or minimal yield gains over IA3023. In one PI × IA3023 population, introgressing and pyramiding only two linkage groups from recombinant inbreds into IA3023 was predicted to achieve an 8% yield gain over IA3023 without sacrificing the performance of other traits. The probability of inheriting intact chromosomes was high enough to allow introgression and pyramiding of chromosome segments in 5-6 generations. Overall, our study suggested that introgressing specific chromosome segments is an effective way to introduce exotic soybean germplasm into an elite cultivar.

3393: Arfgef1 haploinsufficiency in mice alters neuronal endosome composition and decreases membrane surface postsynaptic GABAA receptors
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Posted to bioRxiv 08 Sep 2019

Arfgef1 haploinsufficiency in mice alters neuronal endosome composition and decreases membrane surface postsynaptic GABAA receptors
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Jia Jie Teoh, Narayan Subramanian, Maria Elena Pero, Francesca Bartolini, Ariadna Amador, Ayla Kanber, Damian Williams, Sabrina Petri, Mu Yang, Andrew S Allen, Jules Beal, Sheryl R. Haut, Wayne Frankel

ARFGEF1 encodes a guanine exchange factor involved in intracellular vesicle trafficking, and is a candidate gene for childhood genetic epilepsies. To model ARFGEF1 haploinsufficiency observed in a recent Lennox Gastaut Syndrome patient, we studied a frameshift mutation ( Arfgef1fs ) in mice. Arfgef1fs/+ pups exhibit signs of developmental delay, and Arfgef1fs/+ adults have a significantly decreased threshold to induced seizures but do not experience spontaneous seizures. Histologically, the Arfgef1fs/+ brain exhibits a disruption in the apical lining of the dentate gyrus and altered spine morphology of deep layer neurons. In primary hippocampal neuron culture, dendritic surface and synaptic but not total GABAA receptors (GABAAR) are reduced in Arfgef1fs/+ neurons with an accompanying decrease in GABAAR-containing recycling endosomes in cell body. Arfgef1fs/+ neurons also display differences in the relative ratio of Arf6+:Rab11+:TrfR+ recycling endosomes. Although the GABAAR-containing early endosomes in Arfgef1fs/+ neurons are comparable to wildtype, Arfgef1fs/+ neurons show an increase in GABAAR-containing lysosomes in dendrite and cell body. Together, the altered endosome composition and decreased neuronal surface GABAAR results suggests a mechanism whereby impaired neuronal inhibition leads to seizure susceptibility.

3394: Test Gene-Environment Interactions for Multiple Traits in Sequencing Association Studies
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Posted to bioRxiv 22 Jul 2019

Test Gene-Environment Interactions for Multiple Traits in Sequencing Association Studies
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Jianjun Zhang, Qiuying Sha, Han Hao, Shuanglin Zhang, Xiaoyi Raymond Gao, Xuexia Wang

The risk of many complex diseases is determined by a complex interplay of genetic and environmental factors. Data on multiple traits is often collected for many complex diseases in order to obtain a better understanding of the diseases. Examination of gene-environment interactions (GxEs) for multiple traits can yield valuable insights about the etiology of the disease and increase power in detecting disease associated genes. Most existing methods focus on testing gene-environment interaction (GxE) for a single trait. In this study, we develop novel approaches to test GxEs for multiple traits in sequencing association studies. We first perform transformation of multiple traits by using either principle component analysis or standardization analysis. Then, we detect the effect of GxE for each transferred phenotypic trait using novel proposed tests: testing the effect of an optimallyweighted combination of GxE (TOW-GE) and/or variable weight TOW-GE (VW-TOW-GE). Finally, we employ the Fisher's combination test to combine the p-values of TOW-GE and/or VW-TOW-GE. Extensive simulation studies based on the Genetic Analysis Workshop 17 data show that the type I error rates of the proposed methods are well controlled. Compared to the existing interaction sequence kernel association test (ISKAT), TOW-GE is more powerful when there are only rare risk and protective variants; VW-TOW-GE is more powerful when there are both rare and common risk and protective variants. Both TOW-GE and VW-TOW-GE are robust to directions of effects of causal GxEs. Application to the COPDGene Study demonstrates that our proposed methods are very powerful.

3395: Paternal Indifference and neglect in early life and Creativity: Exploring the Moderating Role of TPH1 genotype and Offspring's Gender
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Posted to bioRxiv 08 Aug 2019

Paternal Indifference and neglect in early life and Creativity: Exploring the Moderating Role of TPH1 genotype and Offspring's Gender
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Qi Yu, Si Si, Shun Zhang, Jinghuan Zhang

For further understanding the joint contribution of environment, heredity and gender to creativity, the present research examined the prospective impact of paternal indifference & neglect in early life, TPH1 rs623580, offspring's gender, and the interaction effects thereof on creativity in five hundred and thirty-nine unrelated healthy Chinese undergraduate students. Paternal indifference & neglect in early life was assessed on the Parental Bonding Instrument (PBI) and creativity on the Runco Creativity Assessment Battery (rCAB). Results showed significant paternal indifference & neglect × TPH1 genotype and TPH1 genotype × offspring's gender interaction effects when predicting creativity. Specifically, paternal indifference & neglect in early life negatively predicted creativity in youth when individuals carry A allele of TPH1 (rs623580). In addition, male individuals who carry A allele were linked with lower level of flexibility compared to TT homozygote individuals. No significant three-way interaction was found. Findings from the current study suggested that the A allele of TPH1 (rs623580) might be a risk allele for creativity, and the long-term negative influence of paternal indifference & neglect in early life on individuals' creativity in youth depending on TPH1 genotype.

3396: Genetic risks of schizophrenia identified in a matched case-control study
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Posted to bioRxiv 13 Jul 2019

Genetic risks of schizophrenia identified in a matched case-control study
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Kengo Oishi, Tomihisa Niitsu, Nobuhisa Kanahara, Yasunori Sato, Yoshimi Iwayama, TOMOKO TOYOTA, Tasuku Hashimoto, Tsuyoshi Sasaki, Masayuki Takase, Takeo Yoshikawa, Masaomi Iyo

Background: Genetic association studies of schizophrenia may be confounded by the pathological heterogeneity and multifactorial nature of this disease. We demonstrated previously that combinations of the three functional single nucleotide polymorphisms (SNPs) rs10770141 of tyrosine hydroxylase (TH) gene, rs4680 of catechol-O-methyltransferase (COMT) gene, and rs1800497 of dopamine D2 receptor (DRD2) gene may be associated with schizophrenia onset, and we tested those associations herein. Methods: We conducted a secondary study of 2,542 individuals in age- and sex-matched case-control populations. The schizophrenia diagnosis was based on the DSM-IV. To reduce the influence of confounders (age and sex), we performed a propensity score matching analysis. Genotyping and associative analyses of rs10770141, rs4680, and rs1800497 with schizophrenia were performed. Results: We analyzed 1,271 schizophrenics (male/female: 574/698; age 47.4±13.9 years) and 1,271 matched controls (male/female: 603/669; age 46.5±13.4 years). The estimated odds ratios (ORs) were 1.245 (p<0.001) for rs4680, 1.727 (p<0.0001) for rs1800497, and 1.788 (p<0.0001) for rs10770141. Double SNP analyses revealed the ORs of 2.010 (p<0.0001) for the combination of rs4680*rs1800497, 1.871 (p<0.001) for rs1800497*rs10770141, and 1.428 (p=0.068) for rs4680*rs1800497. Among the individuals with any of the three double SNP risk combinations (which accounted for 35.8% of the involved patients), the estimated OR was 2.224 (p<0.0001). Conclusions: In this validation study, the combinations of functional polymorphisms related to dopaminergic genes were associated with the development of schizophrenia. Analyzing combinations of functional polymorphisms with the control of possible confounders may provide new insights for association research.

3397: The reliability and heritability of cortical folds and their genetic correlations across hemispheres
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Posted to bioRxiv 07 Oct 2019

The reliability and heritability of cortical folds and their genetic correlations across hemispheres
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Fabrizio Pizzagalli, Guillaume Auzias, Qifan Yang, Samuel R Mathias, Joshua Faskowitz, Joshua Boyd, Armand Amini, Denis Rivière, Katie L. McMahon, Greig I. de Zubicaray, Nicholas G Martin, Jean-François Mangin, David C Glahn, John Blangero, Margaret J Wright, Paul M Thompson, Peter Kochunov, Neda Jahanshad

The structure of the brain’s cortical folds varies considerably in human populations. Specific patterns of cortical variation arise with development and aging, and cortical traits are partially influenced by genetic factors. The degree to which genetic factors affect cortical folding patterning remains unknown, yet may be estimated with large-scale in-vivo brain MRI. Using multiple MRI datasets from around the world, we estimated the reliability and heritability of sulcal morphometric characteristics including length, depth, width, and surface area, for 61 sulci per hemisphere of the human brain. Reliability was assessed across four distinct test-retest datasets. We meta-analyzed the heritability across three independent family-based cohorts (N > 3,000), and one cohort of largely unrelated individuals (N~9,000) to examine the robustness of our findings. Reliability was high (interquartile range for ICC: 0.65-0.85) for sulcal metrics. Most sulcal measures were moderately to highly heritable (heritability estimates = 0.3-0.7). These genetic influences vary regionally, with the earlier forming sulci having higher heritability estimates. The central sulcus, the subcallosal and the collateral fissure were the most highly heritable regions. For some frontal and temporal sulci, left and right genetic influences did not completely overlap, suggesting some lateralization of genetic effects on the cortex.

3398: Marked Neurospora crassa strains for competition experiments and Bayesian methods for fitness estimates
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Posted to bioRxiv 19 Aug 2019

Marked Neurospora crassa strains for competition experiments and Bayesian methods for fitness estimates
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Ilkka Kronholm, Tereza Ormsby, Kevin Joseph McNaught, Eric U Selker, Tarmo Ketola

The filamentous fungus Neurospora crassa , a model microbial eukaryote, has a life cycle with many features that make it suitable for studying experimental evolution. However, it has lacked a general tool for estimating relative fitness of different strains in competition experiments. To remedy this need, we constructed N. crassa strains that contain a modified csr-1 locus and developed an assay for detecting the proportion of the marked strain using a post PCR high resolution melting assay. DNA extraction from spore samples can be performed on 96-well plates, followed by a PCR step, which allows many samples to be processed with ease. Furthermore, we suggest a Bayesian approach for estimating relative fitness from competition experiments that takes into account the uncertainty in measured strain proportions. We show that when combining all available information from different experiments the csr-1 * allele has no detectable fitness effect, which makes it a suitable marker for competition experiments. However, there was an effect of the mating type locus, as mating type mat a has a higher fitness than mat A . As a proof of concept, we estimate the fitness effect of the qde-2 mutation, a gene in the RNA interference pathway, and show that its competitive fitness is lower than what would be expected from its mycelial growth rate alone.

3399: From rare Copy Number Variations to biological processes in ADHD
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Posted to bioRxiv 16 Sep 2019

From rare Copy Number Variations to biological processes in ADHD
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Benjamin Harich, Monique van der Voet, Marieke Klein, Michaela Fenckova, Pavel Cizek, Barbara Franke, Annette Schenck

Aim: Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable psychiatric disorder. The objective of this study was to define ADHD-associated candidate genes, and their associated molecular modules and biological themes, based on the analysis of rare genetic variants. Methods: We combined data from 11 published copy number variation (CNV) studies in 6176 individuals with ADHD and 25026 controls and prioritized genes by applying an integrative strategy based on criteria including recurrence in ADHD individuals, absence in controls, complete coverage in copy number gains, and presence in the minimal region common to overlapping CNVs, as well as on protein-protein interactions and information from cross-species genotype-phenotype annotation. Results: We localized 2241 eligible genes in the 1532 reported CNVs, of which we classified 432 as high-priority ADHD candidate genes. The high-priority ADHD candidate genes were significantly co-expressed in the brain. A network of 66 genes was supported by ADHD-relevant phenotypes in the cross-species database. In addition, four significantly interconnected protein modules were found among the high-priority ADHD genes. A total of 26 genes were observed across all applied bioinformatic methods. Look-up in the latest genome-wide association study for ADHD showed that among those 26, POLR3C and RBFOX1 were also supported by common genetic variants. Conclusions: Integration of a stringent filtering procedure in CNV studies with suitable bioinformatics approaches can identify ADHD candidate genes at increased levels of credibility. Our pipeline provides additional insight in the molecular mechanisms underlying ADHD and allows prioritization of genes for functional validation in validated model organisms.

3400: When a phenotype is not the genotype: Implications of phenotype misclassification and pedigree errors in genomics-assisted breeding of sweetpotato [Ipomoea batatas (L.) Lam.]
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Posted to bioRxiv 28 Aug 2019

When a phenotype is not the genotype: Implications of phenotype misclassification and pedigree errors in genomics-assisted breeding of sweetpotato [Ipomoea batatas (L.) Lam.]
74 downloads genetics

Dorcus Gemenet, Bert De Boeck, Guilherme Da Silva Pereira, Mercy N Kitavi, Reuben T Ssali, Obaiya Utoblo, Jolien Swanckaert, Edward Carey, Wolfgang Gruneberg, Benard Yada, Craig Yencho, Robert O.M Mwanga

Experimental error, especially through genotype misclassification and pedigree errors, negatively affects breeding decisions by creating noise that compounds the genetic signals for selection. Unlike genotype-by-environment interactions, for which different methods have been proposed to address, the effect of noise due to pedigree errors and misclassification has not received much attention in most crops. We used two case studies in sweetpotato, based on data from the International Potato Center breeding program to estimate the level of phenotype misclassification and pedigree error and to demonstrate the consequences of such errors when combining phenotypes with the respective genotypes. In the first case study, 27.7% phenotype misclassification was observed when moving genotypes from a diversity panel through in-vitro, screenhouse and field trialing. Additionally, 22.7% pedigree error was observed from misclassification between and within families. The second case study involving multi-environment testing of a full-sib population and quantitative trait loci (QTL) mapping showed reduced genetic correlations among pairs of environments in mega-environments with higher phenotype misclassification errors when compared to the mega-environments with lower phenotype misclassification errors. Additionally, no QTL could be identified in the low genetic correlation mega-environments. Simulation analysis indicated that phenotype misclassification was more detrimental to QTL detection when compared to missingness in data. The current information is important to inform current and future breeding activities involving genomic-assisted breeding decisions in sweetpotato, and to facilitate putting in place improved workflows that minimize phenotype misclassification and pedigree errors.

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