Genetics

Homeodomain-interacting protein kinase maintains neuronal homeostasis during normal Caenorhabditis elegans aging and systemically regulates longevity from serotonergic and GABAergic neurons

1. Maria I Lazaro-Pena
2. Adam B Cornwell
3. Carlos A Diaz-Balzac
4. Ritika Das
5. Zachary C Ward
6. Nicholas Macoretta
7. Juilee Thakar
8. Andrew V Samuelson

• Curated by eLife

  eLife assessment

  This fundamental study substantially advances our understanding of how aging and stress resilience across an organism is determined by identifying a new player in this process and uncovering its mode of action. The evidence is solid as the methods, data and analyses broadly support the claims with only minor weaknesses. The work will be of broad interest to the field of aging and protein homeostasis.

Reviewed by eLife

Engineering of the endogenous HBD promoter increases HbA2

1. Mandy Y Boontanrart
2. Elia Mächler
3. Simone Ponta
4. Jan C Nelis
5. Viviana G Preiano
6. Jacob E Corn

• Curated by eLife

  eLife assessment

  This study presents the important finding that gene editing could be used to activate delta-globin expression to treat disorders of red blood cell synthesis. The evidence supporting the claims of the authors is solid, particularly in the immortalized cell lines, although inclusion of a larger number of donor patient samples may have strengthened the conclusions that were able to be drawn from the primary cell experiments. The data show this approach to have promise and identify avenues of effort that could be pursued to advance it to a clinical strategy for hemoglobinopathy treatment.

Reviewed by eLife

Mec1-independent activation of the Rad53 checkpoint kinase revealed by quantitative analysis of protein localization dynamics

1. Brandon Ho
2. Ethan J Sanford
3. Raphael Loll-Krippleber
4. Nikko P Torres
5. Marcus B Smolka
6. Grant W Brown

• Curated by eLife

  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.

Reviewed by eLife

A critical region of A20 unveiled by missense TNFAIP3 variations that lead to autoinflammation

1. Elma El Khouri
2. Farah Diab
3. Camille Louvrier
4. Eman Assrawi
5. Aphrodite Daskalopoulou
6. Alexandre Nguyen
7. William Piterboth
8. Samuel Deshayes
9. Alexandra Desdoits
10. Bruno Copin
11. Florence Dastot Le Moal
12. Sonia Athina Karabina
13. Serge Amselem
14. Achille Aouba
15. Irina Giurgea

• Curated by eLife

  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.

Reviewed by eLife

Environment- and epigenome-wide association study of obesity in ‘Children of 1997’ birth cohort

1. Jie Zhao
2. Bohan Fan
3. Jian Huang
4. Benjamin John Cowling
5. Shiu Lun Ryan Au Yeung
6. Andrea Baccarelli
7. Gabriel M Leung
8. C Mary Schooling

• Curated by eLife

  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.

Reviewed by eLife

Subfunctionalized expression drives evolutionary retention of ribosomal protein paralogs Rps27 and Rps27l in vertebrates

1. Adele Francis Xu
2. Rut Molinuevo
3. Elisa Fazzari
4. Harrison Tom
5. Zijian Zhang
6. Julien Menendez
7. Kerriann M Casey
8. Davide Ruggero
9. Lindsay Hinck
10. Jonathan K Pritchard
11. Maria Barna

• Curated by eLife

  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.

Reviewed by eLife

Genetic architecture of heart mitochondrial proteome influencing cardiac hypertrophy

1. Karthickeyan Chella Krishnan
2. Elie-Julien El Hachem
3. Mark P Keller
4. Sanjeet G Patel
5. Luke Carroll
6. Alexis Diaz Vegas
7. Isabela Gerdes Gyuricza
8. Christine Light
9. Yang Cao
10. Calvin Pan
11. Karolina Elżbieta Kaczor-Urbanowicz
12. Varun Shravah
13. Diana Anum
14. Matteo Pellegrini
15. Chi Fung Lee
16. Marcus M Seldin
17. Nadia A Rosenthal
18. Gary A Churchill
19. Alan D Attie
20. Benjamin Parker
21. David E James
22. Aldons J Lusis

• Curated by eLife

  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.

Reviewed by eLife

Rapid and precise genome engineering in a naturally short-lived vertebrate

1. Claire N Bedbrook
2. Ravi D Nath
3. Rahul Nagvekar
4. Karl Deisseroth
5. Anne Brunet

• Curated by eLife

  **eLife assessment
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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.

Reviewed by eLife

Cell type-specific interpretation of noncoding variants using deep learning-based methods

1. Maria Sindeeva
2. Nikolay Chekanov
3. Manvel Avetisian
4. Nikita Baranov
5. Elian Malkin
6. Alexander Lapin
7. Olga Kardymon
8. Veniamin Fishman

Reviewed by GigaScience

Pooled genome-wide CRISPR activation screening for rapamycin resistance genes in Drosophila cells

1. Baolong Xia
2. Raghuvir Viswanatha
3. Yanhui Hu
4. Stephanie E Mohr
5. Norbert Perrimon

• Curated by eLife

  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.

Reviewed by eLife