Genetics and Genomics

eLife Assessment:

In addition to identifying several components regulated by checkpoint kinases, the authors identify a novel non-canonical activation mode for the central checkpoint kinase Rad53, a phosphorylation event that does not depend on Mec1 and instead depends on proteins involved in retrograde signaling through Rtg3. The study thus reveals unanticipated complexities in the DNA replication stress response. Overall, the work is well done and the data support the main conclusions.

eLife assessment

This manuscript is of big interest to physicians and geneticists who may struggle with interpreting the clinical significance of novel or rare missense variants in the TNFAIP3 gene in patients with systemic inflammatory diseases. There is also much debate about the potential mechanisms by which these missense mutations might be pathogenic. El Khour et al. addressed these questions by using a combination of in silico analysis and in vitro functional assays. However, their conclusions require additional experimental support and should be expanded to include other reported likely pathogenic missense variants.

eLife assessment

This study presents useful information on the environmental and epigenomic associations of obesity in children and adolescents. The data were collected and analyzed using a solid and validated methodology and can be referenced at the clinics and health authorities to make a guideline and a policy strategy.

eLife assessment

This study reports a cutting-edge set of experiments examining evolutionary models of paralog function differentiation for the mammalian ribosomal proteins eS27 and eS27L. No differentiated roles were identified for either paralog, but the paralogs are differentially expressed, and they preferentially associate with different transcript classes. Reciprocal switching of their coding sequences yielded no detectable phenotypes, but loss of either paralog resulted in lethality at different developmental stages, suggesting that subfunctionalized expression patterns underlie the retention of these paralogs. The work will be of interest to colleagues studying the evolution and diversification of ribosomes.

eLife assessment

This manuscript is of interest to readers in the field of neural development and neurodegeneration. The study is important as it examines two disease-causing mutations within the homeodomain transcription factor Cone-Rod Homeobox (CRX) that causes retinopathy in humans. The data are solid and the work contributes to our understanding of the underlying pathogenetic mechanisms.

eLife assessment

This paper demonstrates the genetic architecture of heart mitochondrial proteome that influences cardiac hypertrophy, using a panel of inbred mouse strains called the Hybrid Mouse Diversity Panel (HMDP). The HDM panel is a very powerful tool to study the genetic basis of various physiological and pathological processes in mice. The authors have used this panel extensively before, and in this paper, they extend their proteomic studies to demonstrate the genetic basis of cardiac hypertrophy. The studies will allow us to better understand the genetics of hypertrophic cardiomyopathy.

eLife assessment

Muroňová et al. provide valuable information about CDCC146 as a centriole and microtubule associated protein essential for sperm flagellar formation and male fertility. Mutations were identified in human patients suffering from MMAF syndrome, but the evidence that these human mutations were causative of the abnormal phenotype is incomplete. To further explore the causality, mouse models are generated and the findings from the mouse study, support that the key roles of CCDC146 for microtubule-based structures throughout sperm development in general but requires statical analysis.

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Within this paper, the authors describe a rapid and easy-to-implement CRISPR/Cas9-mediated knock-in approach to precisely insert large transgenes in the African turquoise killifish. The established method will be instrumental for many researchers working with unusual model species, and, in particular, will expand the killifish community toolbox. It will revolutionize the field and bring the killifish, an emerging animal model in aging biology and disease modeling in vertebrates, into the spotlight even more.

eLife assessment

This valuable manuscript presents resources for genome-wide genetic perturbation in the fruitfly, Drosophila. The evidence for the usefulness is solid, with the authors demonstrating that they can identify novel genes that affect an important pathway, the mTOR pathway, which plays key roles in cell proliferation and cell death. The genetic resources are significant for their availability to colleagues in the Drosophila community seeking to to identify genes with important cellular functions.

eLife assessment

In this useful study, a GWAS-type analysis is applied to clinical Mycobacterium tuberculosis isolates to discover genetic polymorphisms linked to poor tuberculosis outcomes. The evidence for the detected associations is still incomplete, as the corresponding polymorphisms are not adequate to power a prediction model for infection outcome, although key host factors - including patient age, sex, and duration of diagnostic delay (which have stronger predictive value) - appear to enhance predictive capacity.

eLife assessment

This important work utilizes a model organism, zebrafish, to explore changes to the proteome and the role of KLHL40, a component of the ubiquitin-proteasome system, in the development of skeletal muscle disease. Using mass spectrometry, the authors demonstrate a major and selective role for proteome remodeling in development. They identify a specific role for KLHL40 deletion in regulating the expression of Sar1 - a key component of biosynthetic secretion, where the resulting elevated levels of Sar1 expression potentially lead to collagen secretion defects in the disease state. The findings are incomplete as further experimental characterization of the overall morphological changes and secretion defects, in particular ones derived from the deregulation of Sar1 levels, is required.

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This work provides a valuable allele-specific gene editing therapeutic approach to selectively target the human RHO-T17M mutation, one of the most frequent genetic causes of autosomal dominant retinitis pigmentosa. However, the current data are incomplete. Further validation of gene editing efficiency in rods at cellular level in vivo and use of Rho-T17M mice will strengthen the conclusion.

eLife assessment

The findings in this study are important as they establish a rat model of a classic form of early-onset osteoporosis and demonstrate that osteoporosis medications are effective in the model. The evidence supporting the authors' claims is compelling.

eLife assessment

This important manuscript employs a rigorous and multi-pronged comparative genomics approach to unravel how lifestyle modulates the acquisition and domestication of viral genetic elements in the genomes of hymenopteran insects. Using an extensive dataset of over 120 hymenopteran genomes, the authors provide convincing evidence that endoparasitism (where parasite development occurs within hosts) facilitates the uptake and domestication of double-stranded DNA viral elements.

eLife assessment

This important study presents valuable findings on the dissemination of plasmids. In an analysis of five major Enterobacterales genera, the authors convincingly demonstrate that similar plasmids are shared between genera, species, and clones, both within and between ecological niches. Given the size of the dataset and the very detailed level of analysis this study importantly contributes to insights into to the flow of plasmids, including those carrying antimicrobial resistance genes, across niches.

eLife assessment

This important study of mouse genetic variation in atrial septum formation, a trait correlated with the patent foramen ovale (PFO) cardiac defect, provides convincing evidence for 37 quantitative trait loci (QTL) affecting this trait, combining genetic mapping with transcriptome analysis to zero in on relevant pathways and candidate genes within the QTL, and validating the role of one gene in tissue culture. The paper provides an important resource for hypothesis generation and future studies, which could lead to novel diagnostic or therapeutic approaches that target atrial septal defects in common congenital heart disease.

eLife assessment

In this manuscript, the authors investigate the role of histone deacetylases in the spatial epigenetic control of zygotic gene expression in early gastrulation. They discover HDAC1 binding is maternally-controlled and that inhibition of histone acetylation blocks gastrulation and disrupts cell lineage integrity, tied to both positive and negative regulatory effects on gene transcription in space and time. The study contributes to a growing body of evidence that highlights a central role of histone acetylation-deacetylation dynamics in epigenetic regulation of gene expression and cell fating in early tissue patterning of the embryo.

eLife assessment

This manuscript describes a valuable method to study the mechanism of action of essential genes and novel putative drug targets. Evidence for the effectiveness of the system, which is based on engineering pre-validated targets for RNA-mediated knockdown into genes of interest, is compelling, and the method should find use as an orthogonal method for generating gene specific knockdowns.

eLife assessment

This study presents valuable findings from a study of identical twin pairs discordant and concordant for smoking to assess whether smoking has a direct effect on DNA methylation. The results are a valuable contribution as the study confirms the reported association between smoking and epigenetic profile is indeed due to the direct effects of constituents of tobacco smoke. The study design and methods applied by the authors are solid and provide a starting point for larger studies with rigorous laboratory approaches, as well as for assessing clinical impact. The work will be of broad interest to addiction researchers, genetic epidemiologists, and environmental scientists.

eLife assessment

This manuscript presents a useful meta-analysis of genes with parent-specific expression from mouse published RNA-seq datasets, focusing on genes with weak allelic bias. A combination of systematic bioinformatic analysis and experimental validation convincingly shows that the number of parentally biased genes has been overestimated and the few novel ones lie at the periphery of known imprinted loci. The work will be of interest to genomicists with an interest in imprinting and its mechanisms.