Genetics and Genomics

eLife assessment

This manuscript suggests a novel mechanism of purifying selection by which programmed cell death contributes to the selective removal of mtDNA deletion mutations in C. elegans. The evidence for this mechanism of removal is strong although questions remain regarding the underlying mechanism and the role of canonical ageing pathways. Because of the likely central role of mtDNA deletions in ageing and age-dependent diseases, this work will be of interest to scientists in the field of mitochondrial biology as well as ageing.

eLife assessment

This important paper uses a genome-wide, massively parallel reporter assay to determine how CpG methylation affects regulatory sequences that control the expression of human genes. The authors provide compelling evidence that methylation not only influences baseline activity of regulatory sequences but also the magnitude of acute responses to environmental stimuli. The findings are of broad interest, and the extensive data set will likely become a key resource for the community.

eLife assessment

This study describes important findings on how a core component of the circadian clock impacts the effect of dietary restriction (DR) on longevity and fecundity in Drosophila, which lead the authors to postulate rhythmic control of proteostasis in the fat body as a critical aspect of DR effects. The evidence presented is still incomplete, not fully supporting the conclusions of the study, as alternative hypotheses/explanations have not yet been systematically explored. The work will nevertheless be of substantial interest to researchers working in circadian and cell biology, metabolism, and aging, with an interesting hypothesis to be explored further.

eLife assessment

This important study reveals the genetic regulation of changes in cuticular hydrocarbon profiles in a Hymenopteran insect and links these changes with courtship behaviour and sexual attractiveness. It provides convincing empirical evidence, spanning genetic, chemical, and behavioural data. It adds valuable new perspectives on the mechanisms that underlie chemical recognition and communication systems in nature.

eLife assessment:

This fundamental study provides compelling evidence that long-range resection is important for recombination between distal, but not proximal, homologous sequences. It is thus proposed that a major role of long resection of a double-strand break mediated by Sgs1 and Exo1 is to activate the DNA damage checkpoint to allow the chromosomal mobility needed for the DNA ends to find a distant homologous sequence with which repair via homologous recombination, adding a new biological meaning to the role of long DNA resection in homologous recombination.

eLife assessment

Using C. elegans as a model organism, the study hones in on the role of ether lipid biosynthesis as an effector of metformin--a process previously implicated in extending lifespan in response to diet--, TOR signalling, and mitochondrial interventions. The data in this paper are compelling, and a better understanding of biguanide impact on metabolism is highly important in the field.

eLife assessment

This valuable study adds to our understanding of the DNA replication origin selection process in budding yeast. The authors provide convincing evidence that the number of possible origins of replication is much higher than previously appreciated, although many of the newly identified origins probably direct replication initiation only very rarely. This work will be of interest to those studying DNA replication and investigating protein-DNA interactions across the genome.

eLife assessment

This important work substantially advances our understanding of the interplay between genetic variation, chromatin, and genes within topologically associated domains and how this interplay regulates gene expression. The evidence supporting the conclusions is convincing, with appropriate and validated methodology in line with current state-of-the-art genomic and epigenomic techniques. The work will be of broad interest to geneticists and those working to understand the basic mechanisms of gene expression.

eLife assessment

This valuable offers insight into the relationship between floral and reproductive phenotypes and gene expression in allopolyploids. This well-reasoned experimental setup uses thorough statistical analyses to provide compelling insights into the mechanisms driving both phenotypic and gene expression evolution in allopolyploids. The work will be of interest to researchers working in plant speciation and genomics, as well as those more broadly in the effects of ploidy on phenotypic and expression evolution.

eLife assessment

The authors pair single-cell sequencing technology with the LoopSeq synthetic long-read method to examine samples of hepatocellular carcinoma and benign liver, with the goal of identifying mutations and fusion transcripts specific to cancer cells. The authors present a valuable resource, but the overall support for the major claims remains incomplete. In particular, the authors could have provided stronger support for the combination of technologies and interpretation regarding cancer-associated genomic changes.

eLife assessment

The authors present valuable findings on how to determine the genetic architecture of extreme phenotype values by using data on sibling pairs. While the authors' derivations of the method are correct, the scenarios considered are incomplete, making it difficult to have confidence in the interpretation of the results as demonstrating the influence of de-novo or Mendelian (rare, penetrant-variant) architectures. The method shows nevertheless promise and will be of interest to researchers studying complex trait genetics.

eLife assessment

In this study, the authors discuss the relevance of the tumor mutational burden (TMB) as an appropriate predictive biomarker for the effectiveness of immunotherapy. The study offers important findings that will contribute to current dialogues around the biomarkers used for therapy in cancer (and perhaps, other diseases). This is an area of substantial controversy, and the authors have gone to great lengths to support their claims with convincing evidence.

eLife assessment

This valuable study examines the effects of different co-stimulatory pathways on gene expression and chromatin accessibility in T cells, in order to link the role of co-stimulatory proteins to genetic variants associated with inflammatory bowl disease (IBD). The work provides valuable insight into the role of alternative co-stimulatory proteins in controlling T cell responses. However, the data presented and the analyses performed are still incomplete and inconclusive with regards to IBD risk factors.

eLife assessment

Overall, this manuscript presents an intriguing potential refinement of models for adult SVZ neurogenesis, and highlights the role of RNA splicing at specific stages in the lineage. As such, the findings are valuable to the field of adult neurogenesis. Yet, the reviewers found the strength of the evidence to be incomplete and in some areas inadequate to support the claims. Thus, the conclusions require additional experimental support.

eLife assessment

This important study reports the physiological role of ZMYND21 in the regulation of sperm flagellar development and male fertility. The data supporting the conclusion are solid, although the inclusion of more patients and ultrastructural studies would have further strengthened the study. This work will be of interest to clinicians and researchers who work on either sperm biology or ciliopathy due to cilial defects.

eLife assessment

This important study combines extensive phenotyping of genome-wide deletion mutants and machine learning-based prediction to generate a large scale resource for understanding the functions of thousands of fission yeast protein-coding genes. This resource is supported by convincing phenotyping data and state-of-the-art bioinformatic analyses and will be of interest to many geneticists.

eLife assessment

This valuable study combines population genetic theory and deep learning approaches to estimate the extent of assortative mating and sex bias in modern admixed populations in the Americas. The new approach provides solid evidence for their main conclusions that socially constructed hierarchies have influenced mating behaviors, though certain results would benefit from further consideration. This paper would be of interest to human population geneticists and social scientists, particularly those studying demographic processes.

eLife assessment

This valuable paper reports the development of SCA-seq, a nanopore-based multiOME mapping method for simultaneously measuring chromatin accessibility, genome 3D and CpG DNA methylation. The methods, data and analyses are solid and largely support the claims. This new tool to interrogate genome structure-function relationships will be of broad interest to geneticists and many others.

eLife assessment

This important study uses CRISPRi to silence multiple effectors in the pathogen Legionella pneumophila. The paper provides a technique that will allow researchers to address functional redundancy amongst effectors, a problem that has persisted even after decades of study. The methodology used is convincing, and further improvement can lead to the identification of novel virulence factors.

eLife assessment

This study presents an important description on the dynamics of histone variant exchange controlling the organization of the chromatin state of the Arabidopsis genome, combining the analysis of histone variants, histone modification, and chromatin states. The evidence supporting the claims of the authors is compelling. This work will be of great interest to those in the field of epigenetics and chromatin biology.