Genetics and Genomics

eLife assessment

This important article presents the results of a large screen for non-genetic transgenerational effects that may influence gene expression and other phenotypes in mice. An extraordinary amount of mouse breeding, phenotyping, and RNA sequencing data provide compelling evidence that, for the phenotypes and genomic regions interrogated in these mouse strains, non-genetic transgenerational effects of appreciable magnitude are likely to be extremely rare. This paper will be of broad interest to geneticists and of particular interest to those studying epigenetic inheritance.

eLife assessment

This manuscript describes the mapping of natural DNA sequence variants that affect gene expression and its noise, as well as cell cycle timing, using as input single-cell RNA-sequencing of progeny from crosses between wild yeast strains. The method represents an important advance in the study of natural genetic variation. The findings, especially given the follow-up validation of the phenotypic impact of a mapped locus of major effect, provide convincing support for the rigor and utility of the method.

eLife assessment

This manuscript presents a detailed phenotyping of the role of dietary iron in a large number of genetically distinct mouse strains. There are exciting and convincing data that could be valuable in their impact on the fields of nutrition, iron metabolism and anemia.

eLife assessment

The findings in this manuscript are important and novel, and the genomic analyses are convincing. This study expands upon our understanding of the role of hnRNP proteins in lncRNA function and the evidence is compelling, suggesting shared mechanism(s) in the regulation of ASARs and Xist RNAs by RBPs that bind Cot1 sequences in these lncRNAs. This manuscript should be of interest to the noncoding RNA and chromatin biology communities.

eLife assessment

The findings in the manuscript are important and the strength of evidences from the genomic analyses is convincing. However, the evidence for the existence of functional MER21B/C remnants in mice, as well as for the imprinting status of Zdbf2 in rabbits and non-human primates was viewed as mainly correlative and incomplete. This manuscript will be of interest to developmental biologists and those working on possible novel mechanisms of gene regulation.

eLife assessment

This is a saturation mutagenesis screening of the CDKN2A gene, successfully assessing the functionality of the missense variants. The results seem robust, but currently, the manuscript is incomplete with a number of weaknesses. The work has the potential to serve as a valuable resource for diagnostic labs as well as cancer geneticists.

eLife assessment

This valuable study investigates likely molecular mechanisms underlying the increasingly common deletions of the hrp2 and hrp3 genes of the human malaria parasite Plasmodium falciparum, that render parasites undetectable by widely used rapid diagnostic tests. The generation of additional long-read data, alongside a new analysis of 19,000 public short-read sequenced genomes, makes this the most detailed investigation currently available on this topic. The authors provide solid evidence for chromosomal breakage with subsequent telomere healing as the mechanism for hrp2 deletion, with more complex patterns for hrp3 deletion, but further methodological details would bolster confidence in the conclusions and enable replication of the results.

eLife assessment

This valuable work investigates the role of boundary elements in the formation of 3D genome architecture. The authors established a specific model system that allowed them to manipulate boundary elements and examine the resulting genome topology. The work yielded the first demonstration of the existence of stem and circle loops in a genome and confirms a model which had been posited based on extensive prior genetic work, providing valuable insights into how 3D genome topologies affect enhancer-promoter communication. The evidence is solid, although the degree of generalization remains uncertain.

eLife assessment

This valuable work presents elegant experimental data from the Drosophila embryo supporting the notion that interactions among specific loci, called boundary elements, contribute to topologically associated domain (TAD) formation and gene regulation. Although the evidence supporting boundary elements as determinants of 3D structures is compelling, the evidence rejecting loop extrusion is incomplete. This study will be of interest to the nuclear structure community, particularly those using Drosophila as a model.

eLife assessment

This important study elucidates the function of the cohesin subunit SCC3 in impeding DNA repair between inter-sister chromatids in rice. The observation of sterility in the SCC3 weak mutant prompted an investigation of abnormal chromosome behavior during anaphase I through karyotype analysis. While the evidence presented is largely solid, the strength of support can be substantially improved in some aspects, leaving room for further investigation. This research contributes to our understanding of meiosis in rice and attracts cell biologists, reproductive biologists, and plant geneticists.

eLife assessment

This is an important study on the damage-induced checkpoint maintenance and termination in budding yeast that provides convincing evidence for a role of the spindle assembly checkpoint and mitotic exit network in halting the cell cycle after prolonged arrest in response to irreparable DNA double strand breaks (DSBs). The study identifies particular components from both checkpoints that are specifically required for the establishment and/or the maintenance of a cell cycle block triggered by such DSBs. The authors propose an interesting model for how these different checkpoints intersect and crosstalk for timely resumption of cell cycling even without repairing DNA damage with theoretical and practical implications.

eLife assessment

CCL2 is a chemokine known to have relevant immune cell chemoattractant properties, and it is believed to play a role in several chronic inflammatory diseases. The RNA-binding protein HuR controls the stability and translation of CCL2 mRNA. This paper presents solid evidence that a relatively common genetic variant tied to several disease phenotypes affects the interaction between the mRNA of CCL2 and the RNA-binding protein HuR. As CCL2 is believed to be relevant for leukocyte migration in various conditions, including chronic inflammation and cancer, this is an important finding that may be relevant to a broad audience.

eLife assessment

In this important study, a mathematical model to predict biological age by leveraging physiological traits across multiple organ systems is developed. The results presented are convincing, utilizing comprehensive data-driven approaches, although additional external validation would further strengthen its generalizability. The model provides a way to identify environmental and genetic factors impacting aging and lifespan, revealing new factors potentially affecting aging and it also shows promise for evaluating therapeutics aimed at prolonging a healthy lifespan.

eLife assessment

This useful study asks how the architecture of gene expression differences relates to the development of two alternative morphs in a marine annelid species. The dataset will be of value to the field and the work has the potential to substantially advance our understanding of life history evolution. However, in its current form, the lack of details for some methods and analyses makes the strength of the evidence incomplete. If suitably improved, the work would be of interest to anyone studying the evolution of development and life histories.

eLife assessment

This valuable study presents convincing evidence for an association between PARP-1 and H4K20me1 in transcriptional regulation, supported by biochemical and ChIP-seq analyses. The work contributes significantly to our understanding of how Parp1 associates with target genes to regulate their expression.

eLife assessment

The authors use a powerful combination of phylogenetics, structure prediction, biochemistry, and mutagenesis to provide an understanding of the mechanism that provides target specificity of Drosophila HP1 homolog Rhino vs. HP1, with Rhino specifically binding to piRNA loci. The authors show that a single amino acid substitution in the chromodomain of Rhino allows binding of the zinc finger protein Kipferl, which directs the complex to a subset of heterochromatic regions that other HP1 homologs do not. The evidence supporting the conclusions is compelling, providing an impressive level of mechanistic understanding of how the specificity of the piRNA genome defense system is defined. Also, the study highlights how a single amino acid change can change the functionality of a protein, providing fundamental insight into protein evolution.

eLife assessment

Using genomic data from ancient and modern samples, this important study investigates the genomic history of cattle in Iberia, focusing on the admixture between domestic cattle and their wild ancestors, aurochs. The authors present solid evidence for interbreeding between domestic cattle and wild aurochs since the Neolithic period, although the extent, sex bias, and directionality of genetic flow over time remain highly unclear. The authors also show that the aurochs ancestry in cattle stabilized at ~20% since ~4000 years ago and continues into modern breeds, including the Lidia breed that is bred for aggressiveness and used in bullfighting. The work will be of interest to evolutionary biologists and quantitative geneticists who seek to understand the genomic history and genetic basis of trait variation of domesticated animals.

eLife assessment

This fundamental study provides insight into the fascinating process of self- and non-self-recognition in the protist Tetrahymena thermophila, a species with seven distinct mating types. Using an elegant combination of phenotypic assays, protein studies, and imaging, the authors present convincing evidence that a large multifunctional protein complex at the cell surface mediates both self- and non-self mating-type recognition. This study extends our understanding of how more than two mating types/sexes may be specified in a species, and it will be relevant for anyone interested in sexual systems and cell-cell communication.

eLife assessment

This proof-of-concept study focuses on an A->G DNA base editing strategy that converts CAG repeats to CAA repeats in the human HTT gene, which causes Huntington's disease (HD). These studies are conducted in human HEK293 cells engineered with a 51 CAG canonical repeat and in HD knock-in mice harboring 105+ CAG repeats. The findings of this study are valuable for the HD field, applying state-of-the-art techniques. However, the key experiments have yet to be performed in neuronal systems or brains of these mice: actual disease-rectifying effects relevant to patients have yet to observed, so the evidence is incomplete.

eLife assessment

This valuable study reports on the genome evolution of a poorly studied fungal group. By combining long-read sequencing and various bioinformatics approaches, the authors show that the giant genome of Entomophthora muscae expanded due to extensive transposable element activity. The strength of evidence is largely solid, but some analyses are only partially supported due to different methodologies used to analyze the genomes that are being compared. This paper will be of relevance to fungal biologists as well as to evolutionary biologists interested in the study of genome size dynamics.