RegTools: Integrated analysis of genomic and transcriptomic data for the discovery of splice-associated variants in cancer

Kc, Cotto; Feng, Yue; Ramu, Avinash; Skidmore, Zachary L.; Kunisaki, Jason; Richters, Megan M.; Freshour, Sharon; Lin, Yi Pu; Wc, Chapman; Uppaluri, Ravindra; Govindan, Ramaswamy

doi:10.1101/436634

Cited by 78 publications

(61 citation statements)

References 96 publications

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“…This is an important step as we found a substantial increase in the number of false positive splicing QTL due to allelic bias in read mapping [20]. Exon-exon junctions were extracted using RegTools [60], and clustered and quantified using LeafCutter [20]. As expected, we observed that the number of exon-exon junctions identified in each sample is positively correlated with the sequencing depth in the DICE consortium ( Supplementary Figure 1).…”

Section: Data Processingsupporting

confidence: 55%

Impact of cell-type and context-dependent regulatory variants on human immune traits

Wei

Fair

et al. 2020

Preprint

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The effects of trait-associated variants are often studied in a single relevant cell-type or context. However, for many complex traits, multiple cell-types are involved. This applies particularly to immune-related traits, for which many immune cell-types and contexts play a role. Here, we studied the impact of immune gene regulatory variants on complex traits to better understand genetic risk mediated through immune cell-types. We identified 26,271 expression quantitative trait loci (QTLs) and 23,121 splicing QTLs in 18 immune cell-types, and analyzed their overlap with trait-associated loci from 72 genome-wide association studies (GWAS). We showed that effects on RNA expression and splicing in immune cells colocalize with an average of 40.4% and 27.7% GWAS loci for immune-related and non-immune traits, respectively. Notably, we found that a large number of loci (mean: 14%) colocalize with splicing QTLs but not expression QTLs. The 60% GWAS loci without colocalization harbor genes that have lower expression levels, are less tolerant to loss-of-function mutations, and more enhancerrich than genes at colocalized loci. To further investigate the 60% GWAS loci not explained by our regulatory QTLs, we collected H3K27ac CUT&Tag data from rheumatoid arthritis (RA) and healthy controls. We found several unexplained GWAS hits lying within regions with higher H3K27ac activity in RA patients. We also observed that enrichment of RA GWAS heritability is greater in H3K27ac regions in immune cell-types from RA patients compared to healthy controls. Our study paves the way for future QTL studies to elucidate the mechanisms of as yet unexplained GWAS loci.

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Section: Data Processingsupporting

confidence: 55%

Impact of cell-type and context-dependent regulatory variants on human immune traits

Wei

Fair

et al. 2020

Preprint

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“…Reads spanning the transcription regulatory sequence (TRS) sites of both leader region and the coding genes (S gene, ORF3a, 6, 7a, 8, E, M and N gene) were selected to represent the sgmRNAs. The junction sites were predicted using RegTools junctions extract [19]. The ratio of sgmRNA reads to the viral genomic RNA reads (sgmRNA ratio) was used to estimate the relative transcription activity of SARS-CoV-2.…”

Section: Profiling Of Sub-genomic Messenger Rna (Sgmrnas)mentioning

confidence: 99%

Population Bottlenecks and Intra-host Evolution during Human-to-Human Transmission of SARS-CoV-2

Wang¹,

Wang²,

Sun³

et al. 2020

Preprint

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The emergence of the novel human coronavirus, SARS-CoV-2, causes a global COVID-19 (coronavirus disease 2019) pandemic. Here, we have characterized and compared viral populations of SARS-CoV-2 among COVID-19 patients within and across households. Our work showed an active viral replication activity in the human respiratory tract and the co-existence of genetically distinct viruses within the same host. The inter-host comparison among viral populations further revealed a narrow transmission bottleneck between patients from the same households, suggesting a dominated role of stochastic dynamics in both inter-host and intra-host evolutions.Author summaryIn this study, we compared SARS-CoV-2 populations of 13 Chinese COVID-19 patients. Those viral populations contained a considerable proportion of viral sub-genomic messenger RNAs (sgmRNA), reflecting an active viral replication activity in the respiratory tract tissues. The comparison of 66 identified intra-host variants further showed a low viral genetic distance between intra-household patients and a narrow transmission bottleneck size. Despite the co-existence of genetically distinct viruses within the same host, most intra-host minor variants were not shared between transmission pairs, suggesting a dominated role of stochastic dynamics in both inter-host and intra-host evolutions. Furthermore, the narrow bottleneck and active viral activity in the respiratory tract show that the passage of a small number of virions can cause infection. Our data have therefore delivered a key genomic resource for the SARS-CoV-2 transmission research and enhanced our understanding of the evolutionary dynamics of SARS-CoV-2.

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“…in R for each sex and brain-region specific group 75 We employed an adapted protocol 76 on BAM files to extract transcript feature counts from each cortical subregion using regtools 77 and bed_to_junctions from TopHat2 78 .…”

Section: Differential Gene Expression (Dge) Dge Was Calculated Usingmentioning

confidence: 99%

Transcriptomic Organization of Human Posttraumatic Stress Disorder

Girgenti

Wang

et al. 2020

Preprint

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Posttraumatic stress disorder (PTSD) affects approximately 8% of the general population, with higher rates in extreme stress groups, including combat veterans or victims of sexual assault. Despite extensive study of the neurobiological correlates of PTSD, little is known about its molecular substrates. Here differential gene expression and network analyses of 4 prefrontal cortex (PFC) postmortem subregions of male and female PTSD subjects demonstrates extensive remodeling of the transcriptomic landscape. The data revealed a highly connected down-regulated set of interneuron transcripts in the most significant gene network associated with PTSD and integration of this data with genotype data from the largest PTSD GWAS identified the interneuron synaptic gene ELFN1 as conferring significant genetic liability for PTSD. We also identified marked sexual dimorphism in the transcriptomic signatures that could contribute to the higher rates of PTSD in women. Comparison with a matched major depressive disorder (MDD) cohort revealed significant divergence between the molecular profiles of subjects with PTSD and depression despite their high comorbidity. Our analysis provides convergent systems-level evidence of genomic networks within the PFC that contribute to the pathophysiology of PTSD in humans.

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RegTools: Integrated analysis of genomic and transcriptomic data for the discovery of splice-associated variants in cancer

Cited by 78 publications

References 96 publications

Impact of cell-type and context-dependent regulatory variants on human immune traits

Impact of cell-type and context-dependent regulatory variants on human immune traits

Population Bottlenecks and Intra-host Evolution during Human-to-Human Transmission of SARS-CoV-2

Transcriptomic Organization of Human Posttraumatic Stress Disorder

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