PaperPlayer biorxiv genetics

Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.21.213769v1?rss=1

Authors: He, Z., Beaumont, M. A., Yu, F.

Abstract:

Over the past decade there has been an increasing focus on the application of the Wright-Fisher diffusion to the inference of natural selection from genetic time series. A key ingredient for modelling the trajectory of gene frequencies through the Wright-Fisher diffusion is its transition probability density function. Recent advances in DNA sequencing techniques have made it possible to monitor genomes in great detail over time, which presents opportunities for investigating natural selection while accounting for genetic recombination and local linkage. However, most existing methods for computing the transition probability density function of the Wright-Fisher diffusion are only applicable to one-locus problems. To address two-locus problems, in this work we propose a novel numerical scheme for the Wright-Fisher stochastic differential equation of population dynamics under natural selection at two linked loci. Our key innovation is that we reformulate the stochastic differential equation in a closed form that is amenable to simulation, which enables us to avoid boundary issues and reduce computational costs. We also propose an adaptive importance sampling approach based on the proposal introduced by Fearnhead (2008) for computing the transition probability density of the Wright-Fisher diffusion between any two observed states. We show through extensive simulation studies that our approach can achieve comparable performance to the method of Fearnhead (2008) but can avoid manually tuning the parameter{rho} to deliver superior performance for different observed states.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.19.210955v1?rss=1

Authors: Onabajo, O. O., Banday, A. R., Yan, W., Obajemu, A., Stanifer, M. L., Santer, D. M., Florez-Vargas, O., Piontkivska, H., Vargas, J., Kee, C., Tyrrell, D. L., Mendoza, J. L., Boulant, S., Prokunina-Olsson, L.

Abstract:

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes COVID-19, utilizes angiotensin-converting enzyme 2 (ACE2) for entry into target cells. ACE2 has been proposed as an interferon-stimulated gene (ISG). Thus, interferon-induced variability in ACE2 expression levels could be important for susceptibility to COVID-19 or its outcomes. Here, we report the discovery of a novel, primate-specific isoform of ACE2, which we designate as deltaACE2 (dACE2). We demonstrate that dACE2, but not ACE2, is an ISG. In vitro, dACE2, which lacks 356 N-terminal amino acids, was non-functional in binding the SARS-CoV-2 spike protein and as a carboxypeptidase. Our results reconcile current knowledge on ACE2 expression and suggest that the ISG-type induction of dACE2 in IFN-high conditions created by treatments, inflammatory tumor microenvironment, or viral co-infections is unlikely to affect the cellular entry of SARS-CoV-2 and promote infection.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.20.212530v1?rss=1

Authors: Zaidi, A. A., Mathieson, I. A.

Abstract:

Large genome-wide association studies (GWAS) have identified many loci exhibiting small but statistically significant associations with complex traits and disease risk. However, control of population stratification continues to be a limiting factor, particularly when calculating polygenic scores where subtle biases can cumulatively lead to large errors. We simulated GWAS under realistic models of demographic history to study the effect of residual stratification in large GWAS. We show that when population structure is recent, it cannot be fully corrected using principal components based on common variants--the standard approach--because common variants are uninformative about recent demographic history. Consequently, polygenic scores calculated from such GWAS results are biased in that they recapitulate non-genetic environmental structure. Principal components calculated from rare variants or identity-by-descent segments largely correct for this structure if environmental effects are smooth. However, even these corrections are not effective for local or batch effects. While sibling-based association tests are immune to stratification, the hybrid approach of ascertaining variants in a standard GWAS and then re-estimating effect sizes in siblings reduces but does not eliminate bias. Finally, we show that rare variant burden tests are relatively robust to stratification. Our results demonstrate that the effect of population stratification on GWAS and polygenic scores depends not only on the frequencies of tested variants and the distribution of environmental effects but also on the demographic history of the population.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.18.209882v1?rss=1

Authors: Islam, M., Abdullah,, Zubaida, B., Shafqat, N., Masood, R., Khan, U., Waseem, S., Waheed, M. T., Haider, W., Tahir, J., Ahmed, I., Naeem, M., Ahmad, H.

Abstract:

Wheat (Triticum aestivum) is the most important staple food in Pakistan. Knowledge of its genetic diversity is critical for designing effective crop breeding programs. Here we report agro-morphological and yield data for 112 genotypes (including 7 duplicates) of wheat (Triticum aestivum) cultivars, advance lines, landraces and wild relatives, collected from several research institutes and breeders across Pakistan. We also report genotyping-by-sequencing (GBS) data for a selected sub-set of 52 genotypes. Sequencing was performed using Illumina HiSeq 2500 platform using the PE150 run. Data generated per sample ranged from 1.01 to 2.5 Gb; 90% of the short reads exhibited quality scores above 99.9%. TGACv1 wheat genome was used as a reference to map short reads from individual genotypes and to filter single nucleotide polymorphic loci (SNPs). On average, 364,074{+/-}54479 SNPs per genotype were recorded. The sequencing data has been submitted to the SRA database of NCBI (accession number SRP179096). The agro-morphological and yield data, along with the sequence data and SNPs will be invaluable resources for wheat breeding programs in future.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.19.188789v1?rss=1

Authors: Sin-Chan, P., Gosalia, N., Gao, C., Van Hout, C. V., Ye, B., Marcketta, A., Li, A. H., O'Dushlaine, C., Li, D., Overton, J. D., Reid, J. D., Baras, A., Genetics Center, R., Carey, D. J., Ledbetter, D. H., Rader, D., Ritchie, M. D., Damrauer, S. M., Milman, S., Barzilai, N., Glass, D. J., Economides, A. N., Shuldiner, A. R.

Abstract:

Aging is characterized by degeneration in cellular and organismal functions leading to increased disease susceptibility and death. Although our understanding of aging biology in model systems has increased dramatically, large-scale sequencing studies to understand human aging are now just beginning. We applied exome sequencing and association analyses (ExWAS) to identify age-related variants on 58,470 participants of the DiscovEHR cohort. Linear Mixed Model regression analyses of age at last encounter revealed variants in genes known to be linked with clonal hematopoiesis of indeterminate potential, which are associated with myelodysplastic syndromes, as top signals in our analysis, suggestive of age-related somatic mutation accumulation in hematopoietic cells despite patients lacking clinical diagnoses. In addition to APOE, we identified rare DISP2 rs183775254 (p = 7.40x10-10) and ZYG11A rs74227999 (p = 2.50x10-08) variants that were negatively associated with age in either both sexes combined and females, respectively, which were replicated with directional consistency in two independent cohorts. Epigenetic mapping showed these variants are located within cell-type-specific enhancers, suggestive of important transcriptional regulatory functions. To discover variants associated with extreme age, we performed exome-sequencing on persons of Ashkenazi Jewish descent ascertained for extensive lifespans. Case-Control analyses in 525 Ashkenazi Jews cases (Males [≥] 92 years, Females [≥] 95years) were compared to 482 controls. Our results showed variants in APOE (rs429358, rs6857), and TMTC2 (rs7976168) passed Bonferroni-adjusted p-value, as well as several nominally-associated population-specific variants. Collectively, our Age-ExWAS, the largest performed to date, confirmed and identified previously unreported candidate variants associated with human age.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.19.211078v1?rss=1

Authors: Zapata, I., Hecht, E. E., Serpell, J. E., Alvarez, C. E.

Abstract:

Genetic studies show a general factor associated with all human personality and psychopathology, but its basis is unknown. We performed genome scans of 17 normal and problem behaviors in three multi- breed dog cohorts. 21 of 90 mapped loci were supported for the same, or a related, trait in a second cohort. Several of those loci were also associated with brain structure differences across breeds; and five of the respective top-candidate genes are also associated with human brain structure and function. More broadly, the geneset of canine behavioral scans is supported by enrichment for genes mapped for human behavior, personality, psychopathology and brain structure. The biology implicated includes, neurogenesis, axon guidance, angiogenesis, brain structure, alternative splicing, disease association, Hox-family transcription factors, and subiculum expression. Because dog behavior is correlated with body size, we isolated the effect of body size/height in the dog mapping and in the comparative human UK Biobank analyses. Our dog and human findings are consistent with pleiotropy of diverse brain traits with energy metabolism, height, longevity and reproduction. We propose a genetic network underlies neuron birth and development across the life course, and is associated with evolutionary adaptation of behavior and the general psychopathology factor. This understanding has implications for all common psychiatric disorders, and suggests how their risk could be impacted by environmental effects on the IGF1/growth factor signaling-PI3K-AKT-mTOR axis.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.19.209445v1?rss=1

Authors: Osia, B. A., Alsulaiman, T., Jackson, T., Kramara, J., Oliveira, S., Malkova, A.

Abstract:

Microhomology-mediated break-induced replication (MMBIR) is a mechanism of polymerase template switching at microhomology, which can produce complex genomic rearrangements (CGRs), underlies neurological and metabolic diseases, and contributes to cancer development. Yet, the extent of MMBIR activity in genomes is poorly understood due to difficulty in directly identifying MMBIR events by whole genome sequencing (WGS). Here, by using our newly developed MMBSearch software, we directly detect MMBIR events in human genomes and report substantial differences in frequency and complexity of MMBIR events between normal and cancer cells. MMBIR events appear only as germline variants in normal human fibroblast cells but readily accumulate de novo across several cancer types. Detailed analysis of MMBIR mutations in lung adenocarcinomas revealed MMBIR-initiated chromosome fusions that disrupted potential tumor suppressor genes and induced CGRs. Our findings document MMBIR as a trigger for widespread genomic instability and highlight MMBIR as a potential driver of tumor evolution.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.19.210518v1?rss=1

Authors: Singh, P. B., Belyakin, S. N., Laktionov, P. P.

Abstract:

The hallmarks of constitutive heterochromatin, HP1 and H3K9me2/3, assemble heterochromatin-like domains/complexes outside canonical constitutively heterochromatic territories where they regulate chromatin-templated processes. Domains are more than 100kb in size; complexes less than 100kb. They are present in the genomes of organisms ranging from fission yeast to man, with an expansion in size and number in mammals. Some of the likely functions of the domains/complexes include silencing of the donor mating type region in fission yeast, regulation of mammalian imprinted genes and the phylotypic progression during vertebrate development. Far cis- and trans-contacts between micro-phase separated domains/complexes in mammalian nuclei contribute to the emergence of epigenetic compartmental domains (ECDs) detected in Hi-C maps. We speculate that a thermodynamic description of micro-phase separation of heterochromatin-like domains/complexes will require a gestalt shift away from the monomer as the "unit of incompatibility", where it is the choice of monomer that determines the sign and magnitude of the Flory-Huggins parameter, {chi}. Instead, a more dynamic structure, the oligo-nucleosomal "clutch", consisting of between 2 to 10 nucleosomes is both the long sought-after secondary structure of chromatin and its unit of incompatibility. Based on this assumption we present a simple theoretical framework that enables an estimation of {chi} for domains/complexes flanked by euchromatin and thereby an indication of their tendency to phase separate. The degree of phase separation is specified by {chi}N, where N is the number of "clutches" in a domain/complex. Our approach may provide an additional tool for understanding the biophysics of the 3D genome.

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