Mutations affecting the proofreading domains of POLE and POLD1 predispose.

Many individuals with multiple or large colorectal adenomas or early-onset colorectal cancer (CRC) have no detectable germline mutations in the known cancer predisposition genes. Using whole-genome sequencing, supplemented by linkage and association analysis, we identified specific heterozygous POLE or POLD1 germline variants in several multiple-adenoma and/or CRC cases but in no controls. The variants associated with susceptibility, POLE p.Leu424Val and POLD1 p.Ser478Asn, have high penetrance, and POLD1 mutation was also associated with endometrial cancer predisposition. The mutations map to equivalent sites in the proofreading (exonuclease) domain of DNA polymerases ε and δ and are predicted to cause a defect in the correction of mispaired bases inserted during DNA replication. In agreement with this prediction, the tumors from mutation carriers were microsatellite stable but tended to acquire base substitution mutations, as confirmed by yeast functional assays. Further analysis of published data showed that the recently described group of hypermutant, microsatellite-stable CRCs is likely to be caused by somatic POLEmutations affecting the exonuclease domain.

Impacts of biofuel cultivation on mortality and crop yields

Ground-level ozone is a priority air pollutant, causing ~ 22,000 excess deaths per year in Europe¹, significant reductions in crop yields² and loss of biodiversity³. It is produced in the troposphere through photochemical reactions involving oxides of nitrogen (NO_x) and volatile organic compounds (VOCs). The biosphere is the main source of VOCs, with an estimated 1,150 TgC yr⁻¹ (~ 90% of total VOC emissions) released from vegetation globally⁴. Isoprene (2-methyl-1,3-butadiene) is the most significant biogenic VOC in terms of mass (around 500 TgC yr⁻¹) and chemical reactivity⁴ and plays an important role in the mediation of ground-level ozone concentrations⁵. Concerns about climate change and energy security are driving an aggressive expansion of bioenergy crop production and many of these plant species emit more isoprene than the traditional crops they are replacing. Here we quantify the increases in isoprene emission rates caused by cultivation of 72 Mha of biofuel crops in Europe. We then estimate the resultant changes in ground-level ozone concentrations and the impacts on human mortality and crop yields that these could cause. Our study highlights the need to consider more than simple carbon budgets when considering the cultivation of biofuel feedstock crops for greenhouse-gas mitigation.