Genetics

Unbiased mosaic variant assessment in sperm: a cohort study to test predictability of transmission

1. Martin W Breuss
2. Xiaoxu Yang
3. Valentina Stanley
4. Jennifer McEvoy-Venneri
5. Xin Xu
6. Arlene J Morales
7. Joseph G Gleeson

• Curated by eLife

  Evaluation Summary:

  This manuscript analyzes human blastocysts from in vitro fertilization for three subjects (a total of 55 blastocysts), demonstrating transmission of mosaic mutations at close to expected frequencies. These studies are the first of their kind and of translational relevance for the field of clinical genetics and prenatal genetic testing, with the potential to contribute to strategies to reduce genetic disease risk in future offspring.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Reviewed by eLife

Variable paralog expression underlies phenotype variation

1. Raisa Bailon-Zambrano
2. Juliana Sucharov
3. Abigail Mumme-Monheit
4. Matthew Murry
5. Amanda Stenzel
6. Anthony T Pulvino
7. Jennyfer M Mitchell
8. Kathryn L Colborn
9. James T Nichols

• Curated by eLife

  Evaluation Summary:

  In this elegant genetic study, Bailon-Zambrano and colleagues draw on classical genetic concepts to address the clinically pertinent question of how genetic variants in the same gene can yield wildly different phenotypes in different individuals. From their case study they conclude that a major contributor is variation in paralog expression. The question addressed is of great interest to evolutionary and developmental biologists in general and to those studying the evolution of developmental mechanisms in particular.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript.The reviewers remained anonymous to the authors.)

Reviewed by eLife

Conditional GWAS of non-CG transposon methylation in Arabidopsis thaliana reveals major polymorphisms in five genes

1. Eriko Sasaki
2. Joanna Gunis
3. Ilka Reichardt-Gomez
4. Viktoria Nizhynska
5. Magnus Nordborg

Reviewed by Review Commons

The ACF chromatin-remodeling complex is essential for Polycomb repression

1. Elizabeth T Wiles
2. Colleen C Mumford
3. Kevin J McNaught
4. Hideki Tanizawa
5. Eric U Selker

• Curated by eLife

  Evaluation Summary:

  The chromatin mark, H3K27me, is deposited by the Polycomb complex PRC2 and is associated with repressed genes. There are two important findings in this paper: 1) that the promoters of some H3K27me-repressed genes are regulated by nucleosome positioning and 2) the H3K27me repressed genes are a diverse group that can be derepressed by different mechanisms.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Reviewed by eLife

Rapid and specific degradation of endogenous proteins in mouse models using auxin-inducible degrons

1. Lewis Macdonald
2. Gillian C Taylor
3. Jennifer Margaret Brisbane
4. Ersi Christodoulou
5. Lucy Scott
6. Alex von Kriegsheim
7. Janet Rossant
8. Bin Gu
9. Andrew J Wood

• Curated by eLife

  Evaluation Summary:

  This manuscript will be of interest to the broad class of biologists and especially mouse geneticists who study the function of protein-coding genes. The authors confirm the utility of the auxin-inducible degron tool to rapidly degrade the target protein of interest by developing genetically modified mouse models. This expands the set of tools to study gene function in a cell/tissue type, in adults (bypassing embryonic lethality) and also to more finely dissect the different functions of pleiotropic genes.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1, Reviewer #2 and Reviewer #3 agreed to share their name with the authors.)

Reviewed by eLife

Functional evolution of SARS-COV-2 Spike protein: adaptation on translation and infection via surface charge of spike protein

1. Xiaolong Lu
2. Gong Zhang

Reviewed by ScreenIT

Quantifying concordant genetic effects of de novo mutations on multiple disorders

1. Hanmin Guo
2. Lin Hou
3. Yu Shi
4. Sheng Chih Jin
5. Xue Zeng
6. Boyang Li
7. Richard P Lifton
8. Martina Brueckner
9. Hongyu Zhao
10. Qiongshi Lu

• Curated by eLife

  Evaluation Summary:

  Lu et al. provide a new method that looks at whether disorders tend to share excess de novo mutations in genes across the genome. The authors apply the method to nine disorders including a developmental disorder, autism spectrum disorder, congenital heart disease, schizophrenia, and intellectual disability, finding statistically significant overlap between 12 pairs of disorders in de novo mutations that cause a loss of gene function. This method will be of interest to researchers working on disorders caused by de novo mutations, but further clarification of its strengths and weaknesses compared to alternative approaches (mTADA in particular) would strengthen the paper.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Reviewed by eLife

Mitotically heritable, RNA polymerase II-independent H3K4 dimethylation stimulates INO1 transcriptional memory

1. Bethany Sump
2. Donna G Brickner
3. Agustina D'Urso
4. Seo Hyun Kim
5. Jason H Brickner

• Curated by eLife

  Evaluation Summary:

  Transcriptional memory is a phenomenon via which certain genes are activated more robustly in response to repeated stimulation and in this manner, are able to "remember" previous experiences. This report dissects the molecular mechanism of inositol-driven transcriptional memory and highlights the key role of the histone mark H3K4 di-methylation, which is deposited independently from RNA Polymerase II activity. This memory-specific H3K4 di-methylation is found to be inherited over multiple cell divisions and to require specific transcription factors and chromatin machinery components to be established and maintained. The work will be of interest to those studying transcriptional regulation and epigenetics.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Reviewed by eLife

H3K9me1/2 methylation limits the lifespan of daf-2 mutants in C. elegans

1. Meng Huang
2. Minjie Hong
3. Xinhao Hou
4. Chengming Zhu
5. Di Chen
6. Xiangyang Chen
7. Shouhong Guang
8. Xuezhu Feng

• Curated by eLife

  Evaluation Summary:

  This manuscript examines how putative C. elegans H3K9me methyltransferases affect aging by investigating their effects on long-lived daf-2 mutants. They surprisingly find that modifiers of H3K9me1/2, but not H3K9me3, can synergistically extend the lifespan of daf-2 (in some cases, to three times as long as wild-type). They demonstrate that this synergistic effect on lifespan requires the DAF-16 transcription factor and some of its downstream regulatory targets, and compellingly, they show that the effects on lifespan are phenocopied by a small molecular inhibitor known to target a conserved H3K9me1/2 HMT.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)

Reviewed by eLife

Closely related type II-C Cas9 orthologs recognize diverse PAMs

1. Jingjing Wei
2. Linghui Hou
3. Jingtong Liu
4. Ziwen Wang
5. Siqi Gao
6. Tao Qi
7. Song Gao
8. Shuna Sun
9. Yongming Wang

• Curated by eLife

  Evaluation Summary:

  This work is relevant to all who are interested in genome editing. The versatile Cas9 nuclease has enabled creative genome editing applications, yet the targetable sequence space is limited by the PAM specificity of the Cas9 RNP. This manuscript expands the Cas9 toolbox by defining the PAM specificity and genome editing activity of a large group of smaller-sized type II-C Cas9s. The results also contribute to our understanding of the diversity of Cas enzymes and show that there is a significant potential in mining for non-trivial genome editing tools amongst highly similar Cas orthologs.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)

Reviewed by eLife