PaperPlayer biorxiv genetics

Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.27.222638v1?rss=1

Authors: Miller, J., Vienneau-Hathaway, J., Dendev, E., Lan, M., Ayoub, N.

Abstract:

Orb-web weaving spiders and their relatives spin multiple task-specific fiber types. The unique material properties of each silk type result from differences in amino acid sequence and structure of their component proteins, primarily spidroins (spider fibrous proteins). Amino acid content and gene expression measurements of spider silks suggest some spiders change expression patterns of individual protein components in response to environmental cues. We quantified mRNA abundance of three spidroin encoding genes involved in prey capture in the common house spider, Parasteatoda tepidariorum (Theridiidae), fed different diets. After 10 days of acclimation to the lab on a diet of mealworms, spiders were split into three groups: (1) individuals were immediately dissected, (2) spiders were fed high-energy crickets, or (3) spiders were fed low-energy flies, for 1 month. All spiders gained mass during the acclimation period and cricket-fed spiders continued to gain mass, while fly fed spiders either maintained or lost mass. Using quantitative PCR, we found no significant differences in the absolute or relative abundance of dragline gene transcripts, major ampullate spidroin 1 (MaSp1) and major ampullate spidroin 2 (MaSp2), among groups. In contrast, prey-wrapping minor ampullate spidroin (MiSp) gene transcripts were significantly less abundant in fly-fed than lab-acclimated spiders. However, when measured relative to actin, cricket-fed spiders showed the lowest expression of MiSp. Our results suggest that house spiders are able to maintain silk production, even in the face of a low-quality diet.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.27.223438v1?rss=1

Authors: Kraft, K., Yost, K. E., Murphy, S., Magg, A., Long, Y., Corces, R. M., Granja, J. M., Mundlos, S., Cech, T. R., Boettiger, A., Chang, H. Y.

Abstract:

Polycomb-group proteins play critical roles in gene silencing through the deposition of histone H3 lysine 27 trimethylation (H3K27me3) and chromatin compaction. This process is essential for embryonic stem cell (ESCs) pluripotency, differentiation, and development. Polycomb repressive complex 2 (PRC2) can both read and write H3K27me3, enabling progressive spread of H3K27me3 on the linear genome. Long-range Polycomb-associated DNA contacts have also been described, but their regulation and role in gene silencing remains unclear. Here, we apply H3K27me3 HiChIP, a protein-directed chromosome conformation method, and optical reconstruction of chromatin architecture to profile long-range Polycomb-associated DNA loops that span tens to hundreds of megabases across multiple topological associated domains in mouse ESCs and human induced pluripotent stem cells. We find that H3K27me3 loop anchors are enriched for Polycomb nucleation points and coincide with key developmental genes, such as Hmx1, Wnt6 and Hoxa. Genetic deletion of H3K27me3 loop anchors revealed a coupling of Polycomb-associated genome architecture and H3K27me3 deposition evidenced by disruption of spatial contact between distant loci and altered H3K27me3 in cis, both locally and megabases away on the same chromosome. Further, we find that global alterations in PRC2 occupancy resulting from an EZH2 mutant selectively deficient in RNA binding is accompanied by loss of Polycomb-associated DNA looping. Together, these results suggest PRC2 acts as a "genomic wormhole", using RNA binding to enhance long range chromosome folding and H3K27me3 spreading. Additionally, developmental gene loci have novel roles in Polycomb spreading, emerging as important architectural elements of the epigenome.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.27.222323v1?rss=1

Authors: Choi, B. Y., Lee, C. J., Oh, D.-Y., Jang, M. W., Lee, E.

Abstract:

Genes that are primarily expressed in cochlear glia-like supporting cells (GLSs) have never been clearly associated with progressive deafness. Herein, we present a novel deafness locus mapped to chromosome 3p25.1 and a new auditory neuropathy spectrum disorder (ANSD) gene TMEM43 mainly expressed in GLSs. We identify p.R372X of TMEM43 by linkage analysis and exome sequencing in two large Asian families. The knock-in (KI) mouse with p.R372X mutation recapitulates a progressive hearing loss with histological abnormalities exclusively in GLSs. Mechanistically, TMEM43 interacts with Cx26 and Cx30 gap junction channels, disrupting the passive conductance current in GLSs in a dominant-negative fashion when the p.R372X mutation is introduced. Based on the mechanistic insights, cochlear implant was performed on two patients and speech discrimination was successfully restored. Our study highlights a pathological role of cochlear GLSs by identifying a novel deafness gene and its causal relationship with ANSD.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.24.220392v1?rss=1

Authors: Reales, G., Kelemen, M., Wallace, C.

Abstract:

Polygenic scores (PGS) aim to predict complex traits at an individual level based on genetic data. Computation of PGS is based on simply ascertained genome-wide association summary statistics but typically requires an independent test dataset to tune PGS parameters, and for the more sophisticated methods, the computation of LD matrices. Internally tuned methods have recently been proposed that obviate the need for a test dataset, but they remain computationally intensive to run. Here we present RapidoPGS, a flexible and fast method to compute PGS without the need to compute LD-matrices, requiring only summary-level GWAS datasets. Based on fine-mapping principles, RapidoPGS computes the posterior probability that each variant is causal, which in turn is used to shrink effect sizes adaptively as a function of LD and strength of association. We show by summary and individual-level validation that RapidoPGS performs well in comparison with another well-established internally-trained method (median AUC difference [RapidoPGS - LDpred2-auto] = -0.02205, range = [-0.1184, 0.0217]), with at least 50-fold improved speed. RapidoPGS is implemented in R, and can work with user-supplied summary statistics or download them directly from the GWAS catalog. We propose that RapidoPGS can be used to rapidly screen a set of candidate traits for utility, before more computationally intensive methods are applied to selected traits.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.25.220913v1?rss=1

Authors: Yamamoto, E., Matsunaga, H.

Abstract:

Genotype-by-environment interactions (GEIs) are important for not only a precise understanding of genotype-phenotype relationships but also improving the environmental adaptability of crops. Although many formulae have been proposed to model GEI effects, a comprehensive comparison of their efficacy in genome-wide association studies (GWASs) has not been performed. Therefore, the advantages and disadvantages of the formulae are not well recognized. In this study, linear mixed models (LMMs) consisting of various combinations of foreground fixed genetic and background random genetic effect terms were constructed. Next, the power to detect quantitative trait loci (QTLs) with GEI effects was compared across the LMMs by using simulation. The fixed genetic effect terms of the genotype main effects and GEI (GGE) model were preferred over those based on the additive main effects and multiplicative interaction (AMMI) model because the latter showed p-value inflation, whereas the former yielded theoretically expected p-value distribution. With regard to the background random genetic effects, inclusion of genotype-by-trial interaction effects has been recommended to achieve high power and robustness when phenotype data are obtained from multiple environments and multiple trials. The recommended form of LMM was applied to GWASs performed using real agronomic trait data of tomato F1 varieties (Solanum lycopersicum L.) that were obtained from two different cropping seasons. The GWASs detected QTLs with not only persistent effects across the cropping seasons, but also cropping season-specific effects. Thus, the application of GWAS strategy to phenotypic data from multiple environments and trials allowed the detection of more QTLs with GEI effects.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.26.217802v1?rss=1

Authors: Johnston, S. E., Stoffel, M. A., Pemberton, J. M.

Abstract:

Meiotic recombination is a ubiquitous feature of sexual reproduction, ensuring proper disjunction of homologous chromosomes, and creating new combinations of alleles upon which selection can act. By identifying the genetic drivers of recombination rate variation, we can begin to understand its evolution. Here, we revisit an analysis investigating the genetic architecture of gamete autosomal crossover counts (ACC) in a wild population of Soay sheep (Ovis aries) using a much larger dataset (increasing from 3,300 to 7,235 gametes and from ~39,000 to ~415,000 SNPs for genome-wide association analysis). Animal models fitting genomic relatedness confirmed that ACC was heritable in both females (h2 = 0.18) and males (h2 = 0.12). Genome-wide association studies identified two regions associated with ACC variation. A region on chromosome 6 containing RNF212 explained 46% of heritable variation in female ACC, but was not associated with male ACC, confirming the previous finding. A region on chromosome 7 containing RNF212B explained 20-25% of variation in ACC in both males and females. Both RNF212 and RNF212B have been repeatedly associated with recombination rate in other mammal species. These findings confirm that moderate to large effect loci can underpin ACC variation in wild mammals, and provide a foundation for further studies on the evolution of recombination rates.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.23.217646v1?rss=1

Authors: Chen, J.

Abstract:

Glycaemic traits are used to diagnose and monitor type 2 diabetes, and cardiometabolic health. To date, most genetic studies of glycaemic traits have focused on individuals of European ancestry. Here, we aggregated genome-wide association studies in up to 281,416 individuals without diabetes (30% non-European ancestry) with fasting glucose, 2h-glucose post-challenge, glycated haemoglobin, and fasting insulin data. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P<5x10-8), 80% with no significant evidence of between-ancestry heterogeneity. Analyses restricted to European ancestry individuals with equivalent sample size would have led to 24 fewer new loci. Compared to single-ancestry, equivalent sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase understanding of diabetes pathophysiology by use of trans-ancestry studies for improved power and resolution.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.24.220525v1?rss=1

Authors: Acharya, P., Sampathi, S., Flaherty, D. K., Matlock, B. K., Williams, C. S., Hiebert, S. W., Stengel, K. R.

Abstract:

The ETO/MTG family of transcriptional co-repressors play a key role in adult stem cell functions in various tissues. These factors are commonly found in complex with E proteins such as E2A, HEB, and Lyl1 as well as PRDM14 and BTB/POZ domain factors. Structural studies identified a region in the first domain of MTGs that is conserved in the Drosophila homologue Nervy (Nervy Homology Domain-1, or NHR1) that is essential for ETO/MTG8 to inhibit E protein-dependent transcription. The Cancer Genome Atlas (TCGA) identified cancer associated single nucleotide variants (SNVs) near the MTG16:E protein contact site. We tested these SNVs using sensitive yeast two-hybrid association assays, which suggested that only P209T significantly affected E protein binding. We then used CRISPR-Cas9 and homology directed DNA repair to insert P209T and a known inactivating mutation, F210A, into NHR1 of Mtg16 in the germ line of mice. These mice developed normally, but in competitive bone marrow transplantation assays, the F210A-containing stem cells failed to contribute to lymphopoiesis, while P209T mutant cells were reduced in mature T cell populations. High content fluorescent activated analytical flow cytometry assays identified a defect in the multi-potent progenitor to common lymphoid progenitor transition during lymphopoiesis. These data indicate that the cancer associated changes are likely benign polymorphisms, and the MTG:E protein association is required for lymphopoiesis, but less important for myelopoiesis and stem cell functions.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.24.219758v1?rss=1

Authors: Gracia Villacampa, E., Larsson, L., Kvastad, L., Andersson, A., Carlson, J., Lundeberg, J.

Abstract:

Formalin-fixed paraffin embedding (FFPE) is the most widespread long-term tissue preservation approach. Here we present a procedure to perform genome-wide spatial analysis of mRNA in FFPE tissue sections. The procedure takes advantage of well-established, commercially available methods for imaging and spatial barcoding using slides spotted with barcoded oligo(dT) probes to capture the 3' end of mRNA molecules in tissue sections. First, we conducted expression profiling and cell type mapping in coronal sections from the mouse brain to demonstrate the method's capability to delineate anatomical regions from a molecular perspective. Second, we explored the spatial composition of transcriptomic signatures in ovarian carcinosarcoma samples using data driven analysis methods, exemplifying the method's potential to elucidate molecular mechanisms in heterogeneous clinical samples.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.22.215426v1?rss=1

Authors: Cho, Y. K., Won, D.-g., Keum, C., Seo, G. H., Lee, B. H., Lee, B.-C.

Abstract:

The American College of Medical Genetics (ACMG) and Genomics/Association for Molecular Pathology (AMP) previously reported standardized guidance for the assessment of genetic variants. One of the criteria regarding the prevalence in a case-control study, PS4, is important due to its evidence of pathogenicity. Despite recent studies approaching gene- and disease-specific probands, interpretation of a variant to PS4 still has certain limitations for rare variants. Here, we suggest a generalized method, Bayesian odds ratio (BayesianOR), applicable to PS4 via decomposing a disease to its symptoms and applying a Bayesian framework. Using this approach, we demonstrate reproducibility of the calculation of the original odds ratio from well-studied epilepsy data and verify the applicability to in-house frequencies for various rare diseases. In addition, BayesianOR showed a significant difference in tendency with different ClinVar pathogenicity, using in-house data. Thus, the novel method described here should provide an improved interpretation of sequence variants. Furthermore, we anticipate that it will enhance the diagnosis of patients with rare diseases.

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