Correlation-based and feature-driven mutation signature analyses to identify genetic features associated with DNA mutagenic processes in cancer genomes

Mutation signatures represent unique sequence footprints of somatic mutations resulting from specific DNA mutagenic and repair processes. However, their causal associations and the potential utility for genome research remain largely unknown. In this study, we performed PanCancer-scale correlative analyses to identify the genomic features associated with tumor mutation burdens (TMB) and individual mutation signatures. We observed that TMB was correlated with tumor purity, ploidy, and the level of aneuploidy, as well as with the expression of cell proliferation-related genes representing genomic covariates in evaluating TMB. Correlative analyses of mutation signature levels with genes belonging to specific DNA damage-repair processes revealed that deficiencies of NHEJ1 and ALKBH3 may contribute to mutations in the settings of APOBEC cytidine deaminase activation and DNA mismatch repair deficiency, respectively. We further employed a strategy to identify feature-driven, de novo mutation signatures and demonstrated that mutation signatures can be reconstructed using known causal features. Using the strategy, we further identified tumor hypoxia-related mutation signatures similar to the APOBEC-related mutation signatures, suggesting that APOBEC activity mediates hypoxia-related mutational consequences in cancer genomes. Our study advances the mechanistic insights into the TMB and signature-based DNA mutagenic and repair processes in cancer genomes. We also propose that feature-driven mutation signature analysis can further extend the categories of cancer-relevant mutation signatures and their causal relationships.

Modelling G×E with historical weather information improves genomic prediction in new environments

MotivationInteraction between the genotype and the environment (G×E) has a strong impact on the yield of major crop plants. Although influential, taking G×E explicitly into account in plant breeding has remained difficult. Recently G×E has been predicted from environmental and genomic covariates, but existing works have not shown that generalization to new environments and years without access to in-season data is possible and practical applicability remains unclear. Using data from a Barley breeding programme in Finland, we construct an in silico experiment to study the viability of G×E prediction under practical constraints.ResultsWe show that the response to the environment of a new generation of untested Barley cultivars can be predicted in new locations and years using genomic data, machine learning and historical weather observations for the new locations. Our results highlight the need for models of G×E: non-linear effects clearly dominate linear ones, and the interaction between the soil type and daily rain is identified as the main driver for G×E for Barley in Finland. Our study implies that genomic selection can be used to capture the yield potential in G×E effects for future growth seasons, providing a possible means to achieve yield improvements, needed for feeding the growing population.Availability and implementationThe data accompanied by the method code (http://research.cs.aalto.fi/pml/software/gxe/bioinformatics_codes.zip) is available in the form of kernels to allow reproducing the results.Supplementary informationSupplementary data are available at Bioinformatics online.

ModellingG×Ewith historical weather information improves genomic prediction in new environments

Interaction between the genotype and the environment (G×E) has a strong impact on the yield of major crop plants. Although influential, takingG×Eexplictily into account in plant breeding has remained difficult. RecentlyG×Ehas been predicted from environmental and genomic covariates, but existing works have not shown that generalization to new environments and years without access to in-season data is possible and practical applicability remains unclear. Using data from a Barley breeding program in Finland, we construct an in-silico experiment to study the viability ofG×Eprediction under practical constraints. We show that the response to the environment of a new generation of untested Barley cultivars can be predicted in new locations and years using genomic data, machine learning and historical weather observations for the new locations. Our results highlight the need for models ofG×E: non-linear effects clearly dominate linear ones and the interaction between the soil type and daily rain is identified as the main driver forG×Efor Barley in Finland. Our study implies that genomic selection can be used to capture the yield potential inG×Eeffects for future growth seasons, providing a possible means to achieve yield improvements, needed for feeding the growing population.

Combining Clinical and Genomic Covariates via Cov-TGDR

Clinical covariates such as age, gender, tumor grade, and smoking history have been extensively used in prediction of disease occurrence and progression. On the other hand, genomic biomarkers selected from microarray measurements may provide an alternative, satisfactory way of disease prediction. Recent studies show that better prediction can be achieved by using both clinical and genomic biomarkers. However, due to different characteristics of clinical and genomic measurements, combining those covariates in disease prediction is very challenging. We propose a new regularization method, Covariate-Adjusted Threshold Gradient Directed Regularization (Cov-TGDR), for combining different type of covariates in disease prediction. The proposed approach is capable of simultaneous biomarker selection and predictive model building. It allows different degrees of regularization for different type of covariates. We consider biomedical studies with binary outcomes and right censored survival outcomes as examples. Logistic model and Cox model are assumed, respectively. Analysis of the Breast Cancer data and the Follicular lymphoma data show that the proposed approach can have better prediction performance than using clinical or genomic covariates alone.