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Ben Lehner and colleagues report an analysis of the published genome sequences of 19 S. cerevisiae strains together with the results of growth experiments using 15 strains across 20 environmental conditions. They define sets of genes influencing growth under these different conditions and use their data to make predictions about the phenotypes of individual strains.

Mutation rates in cancer genomes are closely related to chromatin organization, indicating that the arrangement of the genome into heterochromatin- and euchromatin-like domains may be a dominant influence on variation in regional mutation rate in human somatic cells.

Maternal age is found to be a major source of phenotypic variation in isogenic C. elegans populations living in a controlled environment, with the progeny of young mothers impaired for multiple fitness traits.

An analysis of how regional mutation rates vary across 652 tumours identifies variable DNA mismatch repair as the basis of the characteristic regional variation in mutation rates seen across the human genome; the results show that differential DNA repair, rather than differential mutation supply, is likely to be the primary cause of this variation.

Mutations sometimes only affect a subset of genetically identical individuals; here, variation in the expression of chaperones and gene duplicates is shown to predict mutation outcome in C. elegans.

Ben Lehner and colleagues analyze data from matched exomes and transcriptomes from tumors across 27 cancer types to elucidate rules linking premature termination codon location to nonsense-mediated mRNA decay (NMD). They propose a model that explains variability in NMD efficiency and find evidence of positive and negative selection on NMD-initiating mutations in tumors.

Genotype–phenotype landscapes are an important characteristic for understanding the evolution of traits. Here the authors construct the local landscape for the alternative splicing of FAS/CD95 exon 6, revealing the regulation of splicing and the evolution of regulatory information between species.

By comprehensively mapping the impact that different classes of mutations (substitutions, insertions, deletions) have on the ability of the amyloid beta peptide to nucleate amyloids, the authors identify a large set of likely pathogenic variants of amyloid beta that are specifically enriched at its polar N-terminal region.

An approach that combines deep mutational scanning with neural network-based thermodynamic modelling is used to provide comprehensive maps of the energetic and allosteric effects of mutations in two common protein domains.

In the classic two-hit model, both alleles of a tumour suppressor gene need to be inactivated in order to promote cancer. Here, the authors challenge this model, finding that many cancer genes can be either one-hit or two-hit drivers depending on the context and other mutations in a tumor.

A gene conferring puromycin resistance can be used for antibiotic selection in C. elegans and C. briggsae. This will permit easy maintenance of transgenic lines and facilitate single-copy insertion of transgenes. Also in this issue, a related paper reports nematode selection using neomycin.

In quantitative genetics, it is widely assumed that mutations combine additively or epistasis can be predicted with statistical or mechanistic models. Here, the authors use the phage lambda repressor model to show how biophysical ambiguity and non-monotonic functions confound phenotypic prediction.

The impact of germline variants on somatic alterations in cancer remains to be explored in large-scale datasets. Here, the authors study the association of rare germline variants with somatic mutational processes in more than 15,000 tumors, and reveal that damaging variants in newly-identifed genes are prevalent in the population.

TDP43 aggregates are a hallmark of amyotrophic lateral sclerosis. By using deep mutagenesis to measure the toxicity of more than 50,000 mutations in the prion domain of TDP43, the authors conclude that mutations that increase toxicity promote formation of liquid-like condensates, while aggregation of TDP43 is protective for the cell.

Quantifying the effects of noise in gene expression is difficult since noise and mean expression are coupled. Here the authors determine fitness landscapes in mean-noise expression space to uncouple these two parameters and show that changes in noise and mean expression are similarly detrimental to fitness.

The effects of mutations in proteins can depend on the occurrence of previous mutations. It emerges that such historical contingency is also important during the evolution of gene regulatory networks. See Letter p.361

Some mutations in tumour cells play no part in causing cancer, but they generate cellular weak spots that may allow tumour cells to be selectively killed by drugs. See Article p.337

Non-additive genetic interactions are plastic and can complicate genetic prediction. Here, using deep mutagenesis of the lambda repressor, Li et al. reveal that changes in gene expression can alter the strength and direction of genetic interactions between mutations in many genes and develop mathematical models for predicting them.

Studying how genetic variants in different genes interact and their combinatorial output is experimentally and analytically challenging. Here, the authors quantify the effects of more than 5000 mutation pairs in the yeast GAL regulatory system, finding that many combinations can be predicted with statistical models.

This method predicts three-dimensional protein structures based on the activity of mutant variants. The approach relies on quantifying genetic interactions between mutations to infer direct contacts between residues.

Inherited germline variants and somatic mutations contribute to cancer. Here, the authors present the statistical method ALFRED that tests the two-hit hypothesis of tumorigenesis and apply it to ~10,000 tumor exomes to identify rare germline variants that affect putative cancer predisposition genes, contributing substantially to cancer risk.

Ancestral experience of mitochondrial stress is now found to render progeny of the roundworm Caenorhabditis elegans more resistant to the same insult for up to four generations. A DNA modification, N6-methyldeoxyadenine, is implicated in the inheritance of this stress adaptation.

Mutagenesis of a yeast tRNA shows that the effects of mutations and how they interact varies both in magnitude and sign between genotypes.

The authors explore the impact of nonsense-mediated mRNA decay (NMD) on human genetic disease and cancer immunotherapy by applying the rules of NMD across the genome as a resource called NMDetective.

A key challenge in genetics is predicting variation in phenotypic traits from the genome sequences of individuals. Work in model organisms indicates that a combination of genetic information andin vivomeasurements of biological states will be essential for useful phenotypic predictions, including in humans.

A comprehensive study into the effects of polymorphisms on gene expression dynamics during a 12-hour development period of Caenorhabditis elegans shows that both cis and trans expression quantitative trait loci (eQTLs) can increase and decrease gene expression, depending on the time point, and that trans eQTLs can act as modifiers of expression during a given period of development.

Perez and Lehner summarize recent discoveries regarding epigenetic inheritance across generations and review the molecular mechanisms underlying non-DNA sequence-based transmissions.