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- Campbell, PJ, et al.
(författare)
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Pan-cancer analysis of whole genomes
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Tidskriftsartikel (refereegranskat)abstract
- Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1–3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10–18.
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- Niemi, MEK, et al.
(författare)
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- 2021
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swepub:Mat__t
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- Clark, DW, et al.
(författare)
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Associations of autozygosity with a broad range of human phenotypes
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4957-
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Tidskriftsartikel (refereegranskat)abstract
- In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.
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- Gao, YG, et al.
(författare)
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Single cell transcriptional zonation of human psoriasis skin identifies an alternative immunoregulatory axis conducted by skin resident cells
- 2021
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Ingår i: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 12:5, s. 450-
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Tidskriftsartikel (refereegranskat)abstract
- Psoriasis is the most common skin disease in adults. Current experimental and clinical evidences suggested the infiltrating immune cells could target local skin cells and thus induce psoriatic phenotype. However, recent studies indicated the existence of a potential feedback signaling loop from local resident skin cells to infiltrating immune cells. Here, we deconstructed the full-thickness human skins of both healthy donors and patients with psoriasis vulgaris at single cell transcriptional level, and further built a neural-network classifier to evaluate the evolutional conservation of skin cell types between mouse and human. Last, we systematically evaluated the intrinsic and intercellular molecular alterations of each cell type between healthy and psoriatic skin. Cross-checking with psoriasis susceptibility gene loci, cell-type based differential expression, and ligand-receptor communication revealed that the resident psoriatic skin cells including mesenchymal and epidermis cell types, which specifically harbored the target genes of psoriasis susceptibility loci, intensively evoked the expression of major histocompatibility complex (MHC) genes, upregulated interferon (INF), tumor necrosis factor (TNF) signalling and increased cytokine gene expression for primarily aiming the neighboring dendritic cells in psoriasis. The comprehensive exploration and pathological observation of psoriasis patient biopsies proposed an uncovered immunoregulatory axis from skin local resident cells to immune cells, thus provided a novel insight for psoriasis treatment. In addition, we published a user-friendly website to exhibit the transcriptional change of each cell type between healthy and psoriatic human skin.
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