Systematic analysis of the effects of genetic variants on chromatin accessibility to decipher functional variants in non-coding regions

Wang, Dongyang; Wu, Xiaohong; Jiang, Guanghui; Yang, Jianye; Yu, Zhanhui; Yang, Yanbo; Yang, Wenqian; Niu, Xiaohui; Tang, Ke; Gong, Jing

doi:10.3389/fonc.2022.1035855

Cited by 3 publications

(1 citation statement)

References 48 publications

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“…We first assessed enrichment of VIP genes in regions of LRLD, relative to a null distribution in which regions of the same size were repeatedly randomly distributed around the genome, an approach widely used to assess the significance of associations of one genomic feature with another (e.g. (29, 30)). DNA virus VIP genes showed no enrichment of LRLD, consistent with the previous finding of no signals of selection at these VIPs.…”

Section: Discussionmentioning

confidence: 99%

Natural selection exerted by historical coronavirus epidemic(s): comparative genetic analysis in China Kadoorie Biobank and UK Biobank

Morris,

Lin,

Millwood

et al. 2024

Preprint

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BackgroundPathogens have been one of the primary sources of natural selection affecting modern humans. The footprints of historical selection events – “selective sweeps” – can be detected in the genomes of present-day individuals. Previous analyses of 629 samples from the 1000 Genomes Project suggested that an ancient coronavirus epidemic ∼20,000 years ago drove multiple selective sweeps in the ancestors of present-day East Asians, but not in other worldwide populations.ResultsUsing a much larger genetic dataset of 76,719 unrelated individuals from each of the China Kadoorie Biobank (CKB) and UK Biobank (UKB) to identify regions of long-range linkage disequilibrium, we further investigated signatures of past selective sweeps and how they reflect previous viral epidemics. Using independently-curated lists of human host proteins which interact physically or functionally with viruses (virus-interacting proteins; VIPs), we found enrichment in CKB for regions of long-range linkage disequilibrium at genes encoding VIPs for coronaviruses, but not DNA viruses. By contrast, we found no clear evidence for any VIP enrichment in UKB. These findings were supported by additional analyses using saltiLASSi, a selection-scan method robust to false positives caused by demographic events. By contrast, for GWAS signals for SARS-Cov2 susceptibility (critical illness, hospitalisation, and reported infection), there was no difference between UKB and CKB in the number located at or near signals of selection, as expected for a novel virus which has had no opportunity to impact the CKB/UKB study populations.ConclusionsTogether, these results provide evidence of selection events consistent with historical coronavirus epidemic(s) originating in East Asia. These results show how biobank-scale datasets and evolutionary genomics theory can provide insight into the study of past epidemics. The results also highlights how historic infectious diseases epidemics can shape the genetic architecture of present-day human populations.

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Section: Discussionmentioning

confidence: 99%

Natural selection exerted by historical coronavirus epidemic(s): comparative genetic analysis in China Kadoorie Biobank and UK Biobank

Morris,

Lin,

Millwood

et al. 2024

Preprint

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Pancan-MNVQTLdb: systematic identification of multi-nucleotide variant quantitative trait loci in 33 cancer types

et al. 2022

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Multi-nucleotide variants (MNVs) are defined as clusters of two or more nearby variants existing on the same haplotype in an individual. Recent studies have identified millions of MNVs in human populations, but their functions remain largely unknown. Numerous studies have demonstrated that single-nucleotide variants could serve as quantitative trait loci (QTLs) by affecting molecular phenotypes. Therefore, we propose that MNVs can also affect molecular phenotypes by influencing regulatory elements. Using the genotype data from The Cancer Genome Atlas (TCGA), we first identified 223 759 unique MNVs in 33 cancer types. Then, to decipher the functions of these MNVs, we investigated the associations between MNVs and six molecular phenotypes, including coding gene expression, miRNA expression, lncRNA expression, alternative splicing, DNA methylation and alternative polyadenylation. As a result, we identified 1 397 821 cis-MNVQTLs and 402 381 trans-MNVQTLs. We further performed survival analysis and identified 46 173 MNVQTLs associated with patient overall survival. We also linked the MNVQTLs to genome-wide association studies (GWAS) data and identified 119 762 MNVQTLs that overlap with existing GWAS loci. Finally, we developed Pancan-MNVQTLdb (http://gong_lab.hzau.edu.cn/mnvQTLdb/) for data retrieval and download. Pancan-MNVQTLdb will help decipher the functions of MNVs in different cancer types and be an important resource for genetic and cancer research.

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Towards functional maps of non-coding variants in cancer

Wang,

Hon

2024

Front. Genome Ed.

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Large scale cancer genomic studies in patients have unveiled millions of non-coding variants. While a handful have been shown to drive cancer development, the vast majority have unknown function. This review describes the challenges of functionally annotating non-coding cancer variants and understanding how they contribute to cancer. We summarize recently developed high-throughput technologies to address these challenges. Finally, we outline future prospects for non-coding cancer genetics to help catalyze personalized cancer therapy.

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Systematic analysis of the effects of genetic variants on chromatin accessibility to decipher functional variants in non-coding regions

Cited by 3 publications

References 48 publications

Natural selection exerted by historical coronavirus epidemic(s): comparative genetic analysis in China Kadoorie Biobank and UK Biobank

Natural selection exerted by historical coronavirus epidemic(s): comparative genetic analysis in China Kadoorie Biobank and UK Biobank

Pancan-MNVQTLdb: systematic identification of multi-nucleotide variant quantitative trait loci in 33 cancer types

Towards functional maps of non-coding variants in cancer

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