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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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- 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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- Benatar, Michael, et al.
(författare)
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Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01) : a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial
- 2024
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Ingår i: Lancet Neurology. - : Elsevier. - 1474-4422 .- 1474-4465. ; 23:7, s. 687-699
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Tidskriftsartikel (refereegranskat)abstract
- Background: Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to muscle weakness and respiratory failure. Arimoclomol, a heat-shock protein-70 (HSP70) co-inducer, is neuroprotective in animal models of amyotrophic lateral sclerosis, with multiple mechanisms of action, including clearance of protein aggregates, a pathological hallmark of sporadic and familial amyotrophic lateral sclerosis. We aimed to evaluate the safety and efficacy of arimoclomol in patients with amyotrophic lateral sclerosis.Methods: ORARIALS-01 was a multinational, randomised, double-blind, placebo-controlled, parallel-group trial done at 29 centres in 12 countries in Europe and North America. Patients were eligible if they were aged 18 years or older and met El Escorial criteria for clinically possible, probable, probable laboratory-supported, definite, or familial amyotrophic lateral sclerosis; had an ALS Functional Rating Scale-Revised score of 35 or more; and had slow vital capacity at 70% or more of the value predicted on the basis of the participant's age, height, and sex. Patients were randomly assigned (2:1) in blocks of 6, stratified by use of a stable dose of riluzole or no riluzole use, to receive oral arimoclomol citrate 1200 mg/day (400 mg three times per day) or placebo. The Randomisation sequence was computer generated centrally. Investigators, study personnel, and study participants were masked to treatment allocation. The primary outcome was the Combined Assessment of Function and Survival (CAFS) rank score over 76 weeks of treatment. The primary outcome and safety were analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03491462, and is completed.Findings: Between July 31, 2018, and July 17, 2019, 287 patients were screened, 245 of whom were enrolled in the trial and randomly assigned. The modified intention-to-treat population comprised 239 patients (160 in the arimoclomol group and 79 in the placebo group): 151 (63%) were male and 88 (37%) were female; mean age was 57·6 years (SD 10·9). CAFS score over 76 weeks did not differ between groups (mean 0·51 [SD 0·29] in the arimoclomol group vs 0·49 [0·28] in the placebo group; p=0·62). Cliff's delta comparing the two groups was 0·039 (95% CI –0·116 to 0·194). Proportions of participants who died were similar between the treatment groups: 29 (18%) of 160 patients in the arimoclomol group and 18 (23%) of 79 patients in the placebo group. Most deaths were due to disease progression. The most common adverse events were gastrointestinal. Adverse events were more often deemed treatment-related in the arimoclomol group (104 [65%]) than in the placebo group (41 [52%]) and more often led to treatment discontinuation in the arimoclomol group (26 [16%]) than in the placebo group (four [5%]).Interpretation: Arimoclomol did not improve efficacy outcomes compared with placebo. Although available biomarker data are insufficient to preclude future strategies that target the HSP response, safety data suggest that a higher dose of arimoclomol would not have been tolerated.Funding: Orphazyme.
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- Forrest, ARR, et al.
(författare)
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A promoter-level mammalian expression atlas
- 2014
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 507:7493, s. 462-
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Tidskriftsartikel (refereegranskat)
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- Callaway, EM, et al.
(författare)
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A multimodal cell census and atlas of the mammalian primary motor cortex
- 2021
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 598:7879, s. 86-102
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Tidskriftsartikel (refereegranskat)abstract
- Here we report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties and cellular resolution input–output mapping, integrated through cross-modal computational analysis. Our results advance the collective knowledge and understanding of brain cell-type organization1–5. First, our study reveals a unified molecular genetic landscape of cortical cell types that integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a consensus taxonomy of transcriptomic types and their hierarchical organization that is conserved from mouse to marmoset and human. Third, in situ single-cell transcriptomics provides a spatially resolved cell-type atlas of the motor cortex. Fourth, cross-modal analysis provides compelling evidence for the transcriptomic, epigenomic and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types. We further present an extensive genetic toolset for targeting glutamatergic neuron types towards linking their molecular and developmental identity to their circuit function. Together, our results establish a unifying and mechanistic framework of neuronal cell-type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties.
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- Noguchi, S, et al.
(författare)
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FANTOM5 CAGE profiles of human and mouse samples
- 2017
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Ingår i: Scientific data. - : Springer Science and Business Media LLC. - 2052-4463. ; 4, s. 170112-
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Tidskriftsartikel (refereegranskat)abstract
- In the FANTOM5 project, transcription initiation events across the human and mouse genomes were mapped at a single base-pair resolution and their frequencies were monitored by CAGE (Cap Analysis of Gene Expression) coupled with single-molecule sequencing. Approximately three thousands of samples, consisting of a variety of primary cells, tissues, cell lines, and time series samples during cell activation and development, were subjected to a uniform pipeline of CAGE data production. The analysis pipeline started by measuring RNA extracts to assess their quality, and continued to CAGE library production by using a robotic or a manual workflow, single molecule sequencing, and computational processing to generate frequencies of transcription initiation. Resulting data represents the consequence of transcriptional regulation in each analyzed state of mammalian cells. Non-overlapping peaks over the CAGE profiles, approximately 200,000 and 150,000 peaks for the human and mouse genomes, were identified and annotated to provide precise location of known promoters as well as novel ones, and to quantify their activities.
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