| 1. |
- Ramilowski, JA, et al.
(författare)
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Functional annotation of human long noncoding RNAs via molecular phenotyping
- 2020
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Ingår i: Genome research. - : Cold Spring Harbor Laboratory. - 1549-5469 .- 1088-9051. ; 30:7, s. 1060-1072
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Tidskriftsartikel (refereegranskat)abstract
- Long noncoding RNAs (lncRNAs) constitute the majority of transcripts in the mammalian genomes, and yet, their functions remain largely unknown. As part of the FANTOM6 project, we systematically knocked down the expression of 285 lncRNAs in human dermal fibroblasts and quantified cellular growth, morphological changes, and transcriptomic responses using Capped Analysis of Gene Expression (CAGE). Antisense oligonucleotides targeting the same lncRNAs exhibited global concordance, and the molecular phenotype, measured by CAGE, recapitulated the observed cellular phenotypes while providing additional insights on the affected genes and pathways. Here, we disseminate the largest-to-date lncRNA knockdown data set with molecular phenotyping (over 1000 CAGE deep-sequencing libraries) for further exploration and highlight functional roles for ZNF213-AS1 and lnc-KHDC3L-2.
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| 2. |
- Mahajan, Anubha, et al.
(författare)
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Trans-ethnic Fine Mapping Highlights Kidney-Function Genes Linked to Salt Sensitivity
- 2016
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 99:3, s. 636-646
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Tidskriftsartikel (refereegranskat)abstract
- We analyzed genome-wide association studies (GWASs), including data from 71,638 individuals from four ancestries, for estimated glomerular filtration rate (eGFR), a measure of kidney function used to define chronic kidney disease (CKD). We identified 20 loci attaining genome-wide-significant evidence of association (p < 5 × 10(-8)) with kidney function and highlighted that allelic effects on eGFR at lead SNPs are homogeneous across ancestries. We leveraged differences in the pattern of linkage disequilibrium between diverse populations to fine-map the 20 loci through construction of "credible sets" of variants driving eGFR association signals. Credible variants at the 20 eGFR loci were enriched for DNase I hypersensitivity sites (DHSs) in human kidney cells. DHS credible variants were expression quantitative trait loci for NFATC1 and RGS14 (at the SLC34A1 locus) in multiple tissues. Loss-of-function mutations in ancestral orthologs of both genes in Drosophila melanogaster were associated with altered sensitivity to salt stress. Renal mRNA expression of Nfatc1 and Rgs14 in a salt-sensitive mouse model was also reduced after exposure to a high-salt diet or induced CKD. Our study (1) demonstrates the utility of trans-ethnic fine mapping through integration of GWASs involving diverse populations with genomic annotation from relevant tissues to define molecular mechanisms by which association signals exert their effect and (2) suggests that salt sensitivity might be an important marker for biological processes that affect kidney function and CKD in humans.
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| 3. |
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| 4. |
- Morris, John A., et al.
(författare)
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Discovery of target genes and pathways at GWAS loci by pooled single-cell CRISPR screens
- 2023
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 380:6646
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Tidskriftsartikel (refereegranskat)abstract
- Most variants associated with complex traits and diseases identified by genome-wide association studies (GWAS) map to noncoding regions of the genome with unknown effects. Using ancestrally diverse, biobank-scale GWAS data, massively parallel CRISPR screens, and single-cell transcriptomic and proteomic sequencing, we discovered 124 cis-target genes of 91 noncoding blood trait GWAS loci. Using precise variant insertion through base editing, we connected specific variants with gene expression changes. We also identified trans-effect networks of noncoding loci when cis target genes encoded transcription factors or microRNAs. Networks were themselves enriched for GWAS variants and demonstrated polygenic contributions to complex traits. This platform enables massively parallel characterization of the target genes and mechanisms of human noncoding variants in both cis and trans.
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| 5. |
- Wallace, Megan A., et al.
(författare)
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The discovery, distribution, and diversity of DNA viruses associated with Drosophila melanogaster in Europe
- 2021
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Ingår i: Virus Evolution. - : Oxford University Press (OUP). - 2057-1577. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Drosophila melanogaster is an important model for antiviral immunity in arthropods, but very few DNA viruses have been described from the family Drosophilidae. This deficiency limits our opportunity to use natural host-pathogen combinations in experimental studies, and may bias our understanding of the Drosophila virome. Here, we report fourteen DNA viruses detected in a metagenomic analysis of 6668 pool-sequenced Drosophila, sampled from forty-seven European locations between 2014 and 2016. These include three new nudiviruses, a new and divergent entomopoxvirus, a virus related to Leptopilina boulardi filamentous virus, and a virus related to Musca domestica salivary gland hypertrophy virus. We also find an endogenous genomic copy of galbut virus, a double-stranded RNA partitivirus, segregating at very low frequency. Remarkably, we find that Drosophila Vesanto virus, a small DNA virus previously described as a bidnavirus, may be composed of up to twelve segments and thus represent a new lineage of segmented DNA viruses. Two of the DNA viruses, Drosophila Kallithea nudivirus and Drosophila Vesanto virus are relatively common, found in 2 per cent or more of wild flies. The others are rare, with many likely to be represented by a single infected fly. We find that virus prevalence in Europe reflects the prevalence seen in publicly available datasets, with Drosophila Kallithea nudivirus and Drosophila Vesanto virus the only ones commonly detectable in public data from wild-caught flies and large population cages, and the other viruses being rare or absent. These analyses suggest that DNA viruses are at lower prevalence than RNA viruses in D.melanogaster, and may be less likely to persist in laboratory cultures. Our findings go some way to redressing an earlier bias toward RNA virus studies in Drosophila, and lay the foundation needed to harness the power of Drosophila as a model system for the study of DNA viruses.
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