Biology subjects

Thorn, S.

Publications and source records attributed to Thorn, S..

3 recordsLinked to original sources

bioRxiv2022

Whole genome sequencing of 2,023 colorectal cancers reveals mutational landscapes, new driver genes and immune interactions

To characterise the somatic alterations in colorectal cancer (CRC), we conducted whole-genome sequencing analysis of 2,023 tumours. We provide the most detailed high-resolution map to date of somatic mutations in CRC, and demonstrate associations with clinicopathological features, in particular location in the large bowel. We refined the mutational processes and signatures acting in colorectal tumorigenesis. In analyses across the sample set or restricted to molecular subtypes, we identified 185 CRC driver genes, of which 117 were previously unreported. New drivers acted in various molecular pathways, including Wnt (CTNND1, AXIN1, TCF3), TGF-{beta}/BMP (TGFBR1) and MAP kinase (RASGRF1, RASA1, RAF1, and several MAP2K and MAP3K loci). Non-coding drivers included intronic neo-splice site alterations in APC and SMAD4. Whilst there was evidence of an excess of mutations in functionally active regions of the non-coding genome, no specific drivers were called with high confidence. Novel recurrent copy number changes included deletions of PIK3R1 and PWRN1, as well as amplification of CCND3 and NEDD9. Putative driver structural variants included BRD4 and SOX9 regulatory elements, and ACVR2A and ANKRD11 hotspot deletions. The frequencies of many driver mutations, including somatic Wnt and Ras pathway variants, showed a gradient along the colorectum. The Pks-pathogenic E. coli signature and TP53 mutations were primarily associated with rectal cancer. A set of unreported immune escape driver genes was found, primarily in hypermutated CRCs, most of which showed evidence of genetic evasion of the anti-cancer immune response. About 25% of cancers had a potentially actionable mutation for a known therapy. Thirty-three of the new driver genes were predicted to be essential, 17 possessed a druggable structure, and nine had a bioactive compound available. Our findings provide further insight into the genetics and biology of CRC, especially tumour subtypes defined by genomic instability or clinicopathological features.

genomics↗

bioRxiv2021

Performance of genetic imputation across commercial crop species

We show that accurate imputation can be carried out in three commercial plant species (maize, sugar beet and wheat) and that accurate imputation does not require a pedigree, although pedigree information can improve accuracy and speed. Our approach uses a hidden Markov model to build a haplotype library from individuals genotyped at high-density and then uses this library to impute low-density genotyped individuals to high-density. To build the library, we use founders when the pedigree is known, or a sample of progeny when the pedigree is unknown. Without a pedigree, and with 50 individuals genotyped at high-density and 100 low-density markers per chromosome, the median accuracies were 0.97 (maize), 0.96 (sugar beet), and 0.94 (wheat). We obtained similar accuracies with a pedigree. For biparental crosses with 100 markers per chromosome, median accuracies were 0.96 (maize), 0.96 (sugar beet) and 0.94 (wheat). For the imputation scenarios without a pedigree, we compared accuracies with those obtained by running Beagle 5.1. In all but one scenario, our method outperformed Beagle. We believe that plant breeders can effectively apply imputation in many crop species.

genetics↗

bioRxiv2021

Climate-induced forest dieback drives compositional change in insect communities that is concentrated amongst rare species

Marked decline in insect species richness, abundance and biomass have recently been quantified in Europe. We metabarcoded 224 Malaise-trap samples to investigate whether drought-induced forest dieback and subsequent salvage logging have an impact on flying insects (ca. 3000 insect species) in silver fir Pyrenean forests. We found no evidence that climate-induced forest dieback impacted species richness of flying insects but revealed compositional turnover patterns consistent with those seen during natural forest succession, given that the key covariates explaining compositional variation were canopy openness versus microhabitat diversity and deadwood amount at local and landscape scales, respectively. Importantly, most change was driven by rare species. In contrast, observed levels of salvage logging did not explain change in species richness or composition. Hence, although forest dieback appears to cause changes in species assemblages mimicking natural forest succession, it also increases the risk of catastrophic loss of rare species through homogenization of environmental conditions.

ecology↗