Hierarchical analysis of RNA-seq reads improves the accuracy of allele-specific expression

Raghupathy, Narayanan; Choi, Kwangbom; Vincent, Matthew; Beane, Glen L.; Sheppard, Keith; Munger, Steven C.; Korstanje, Ron; Villena, Fernando Pardo-Manual de; Churchill, Gary A.

doi:10.1093/bioinformatics/bty078

Cited by 87 publications

(82 citation statements)

References 32 publications

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“…In order to account for genetic variation, D2 ChIP-seq and ATAC-seq data were aligned to an in silico pseudogenome incorporating known variants (R78-REL1505) (Wu et al, 2010), and converted to mm10 reference coordinates using G2Gtools (accessible online at: https://github.com/churchill-lab/g2gtools). Allele-specific ChIP analysis was performed as previously described (Baker et al, 2015a) using variant-aware alignment strategy EMASE (Raghupathy et al, 2018). To identify hotspots, peaks were selected for those loci that overlap (BxC)F1 PRDM9 ChIP-seq summits.…”

Section: Discussionmentioning

confidence: 99%

HELLS and PRDM9 form a Pioneer Complex to Open Chromatin at Meiotic Recombination Hotspots

Spruce

Dlamini

Ananda

et al. 2019

Preprint

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Chromatin barriers prevent spurious interactions between regulatory elements and DNAbinding proteins. One such barrier, whose mechanism for overcoming is poorly understood, is access to recombination hotspots during meiosis. Here we show that the chromatin remodeler HELLS and DNA-binding protein PRDM9 function together to open chromatin at hotspots and provide access for the DNA double-strand break (DSB) machinery. Recombination hotspots are decorated by a unique combination of histone modifications, not found at other regulatory elements. HELLS is recruited to hotspots by PRDM9, and is necessary for both histone modifications and DNA accessibility at hotspots. In male mice lacking HELLS, DSBs are retargeted to other sites of open chromatin, leading to germ cell death and sterility. Together, these data provide a model for hotspot activation where HELLS and PRDM9 function as a pioneer complex to create a unique epigenomic environment of open chromatin, permitting correct placement and repair of DSBs.

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Section: Discussionmentioning

confidence: 99%

HELLS and PRDM9 form a Pioneer Complex to Open Chromatin at Meiotic Recombination Hotspots

Spruce

Dlamini

Ananda

et al. 2019

Preprint

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“…FastQC was used to evaluate the quality of the reads, and all samples passed the QC stage 59 . Reads were mapped to the eight collaborative cross founder transcriptomes based on build mm9 using Bowtie, and quantified using EMASE 60 . EMASE output transcript level expression estimates calculated by assigning multi-mapping reads across the genome using and expectation-maximization algorithm to allocate reads that differentiate between genes, then isoforms of a gene, and then alleles.…”

Section: Methodsmentioning

confidence: 99%

Identification of a core module for bone mineral density through the integration of a co-expression network and GWAS data

Sabik

Calabrese

Taleghani

et al. 2019

Preprint

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45Recently, the "omnigenic" model of the genetic architecture of complex traits proposed two 46 general categories of causal genes, core and peripheral. Core genes are hypothesized to play a 47 direct role in regulating disease; thus, their identification has the potential to reveal critical 48 regulators and novel therapeutic targets. Here, we sought to identify genes with "core-like" 49 characteristics for bone mineral density (BMD), one of the most significant predictors of 50 osteoporotic fracture. This was accomplished by analyzing genome-wide association study 51 (GWAS) data through the lens of a cell-type and timepoint-specific gene co-expression network 52 for mineralizing osteoblasts. We identified a single co-expression network module that was 53 enriched for genes implicated by GWAS and partitioned BMD heritability, correlated with in vitro 54 osteoblast mineralization, and enriched for genes, which when mutated in humans or mice, led 55 to a skeletal phenotype. Further characterization of this module identified four novel genes 56 (B4GALNT3, CADM1, DOCK9, and GPR133) located within BMD GWAS loci with colocalizing 57 expression quantitative trait loci (eQTL) and altered BMD in mouse knockouts, suggesting they 58 are causal genetic drivers of BMD in humans. Our network-based approach identified a "core" 59 module for BMD and provides a resource for expanding our understanding of the genetics of 60 bone mass. 61 62 63 64 65 66 67 68 69 70 3

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“…We used an expectation maximization algorithm (EMASE, https://github.com/churchill-lab/emase) to obtain estimated total read counts for each gene as a sum across alleles and isoforms (RAGHUPATHY et al 2018). We normalized read counts in each sample using upper-quantile normalization.…”

Section: Islet Rna Profilingmentioning

confidence: 99%

Genetic Drivers of Pancreatic Islet Function

et al. 2018

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The majority of gene loci that have been associated with type 2 diabetes play a role in pancreatic islet function. To evaluate the role of islet gene expression in the etiology of diabetes, we sensitized a genetically diverse mouse population with a Western diet high in fat (45%-kcal) and sucrose (34%) and carried out genome-wide association mapping of diabetes-related phenotypes. We quantified mRNA abundance in the islets and identified 18,820 expression quantitative trait loci. We applied mediation analysis to identify candidate causal driver genes at loci that affect the abundance of numerous transcripts. These include two genes previously associated with monogenic diabetes (PDX1 and HNF4A), as well as three genes with nominal association with diabetes-related traits in humans (FAM83E, IL6ST, and SAT2). We grouped transcripts into gene modules and mapped regulatory loci for modules enriched with transcripts specific for α-cells, and another specific for δ-cells. However, no single module enriched for β-cell-specific transcripts, suggesting heterogeneity of gene expression patterns within the β-cell population. A module enriched in transcripts associated with branched chain amino acid metabolism was the most strongly correlated with physiological traits that reflect insulin resistance. Although the mice in this study were not overtly diabetic, the analysis of pancreatic islet gene expression under dietary-induced stress enabled us to identify correlated variation in groups of genes that are functionally linked to diabetes-associated physiological traits. Our analysis suggests an expected degree of concordance between diabetes-associated loci in the mouse with those found in human populations and demonstrates how the mouse can provide evidence to support nominal associations found in human genome-wide association mapping.4

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Hierarchical analysis of RNA-seq reads improves the accuracy of allele-specific expression

Abstract: Supplementary data are available at Bioinformatics online.

Cited by 87 publications

References 32 publications

HELLS and PRDM9 form a Pioneer Complex to Open Chromatin at Meiotic Recombination Hotspots

HELLS and PRDM9 form a Pioneer Complex to Open Chromatin at Meiotic Recombination Hotspots

Identification of a core module for bone mineral density through the integration of a co-expression network and GWAS data

Genetic Drivers of Pancreatic Islet Function

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