Genetics

Dynamic regulation of inter-organelle communication by ubiquitylation controls skeletal muscle development and disease onset

1. Arian Mansur
2. Remi Joseph
3. Euri S Kim
4. Pierre M Jean-Beltran
5. Namrata D Udeshi
6. Cadence Pearce
7. Hanjie Jiang
8. Reina Iwase
9. Miroslav P Milev
10. Hashem A Almousa
11. Elyshia McNamara
12. Jeffrey Widrick
13. Claudio Perez
14. Gianina Ravenscroft
15. Michael Sacher
16. Philip A Cole
17. Steven A Carr
18. Vandana A Gupta

• Curated by eLife

  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.

Reviewed by eLife

Her6 and Prox1 are novel regulators of photoreceptor regeneration in the zebrafish retina

1. Kellie Veen
2. Aaron Krylov
3. Shuguang Yu
4. Jie He
5. Patrick Boyd
6. David R. Hyde
7. Theo Mantamadiotis
8. Louise Y Cheng
9. Patricia R Jusuf

Reviewed by Review Commons

Allele-specific gene-editing approach for vision loss restoration in RHO-associated retinitis pigmentosa

1. Xiaozhen Liu
2. Jing Qiao
3. Ruixuan Jia
4. Fan Zhang
5. Xiang Meng
6. Yang Li
7. Liping Yang

• Curated by eLife

  **eLife assessment
  **
  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.

Reviewed by eLife

Impaired bone strength and bone microstructure in a novel early-onset osteoporotic rat model with a clinically relevant PLS3 mutation

1. Jing Hu
2. Bingna Zhou
3. Xiaoyun Lin
4. Qian Zhang
5. Feifei Guan
6. Lei Sun
7. Jiayi Liu
8. Ou Wang
9. Yan Jiang
10. Wei-bo Xia
11. Xiaoping Xing
12. Mei Li

• Curated by eLife

  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.

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Quantitative trait and transcriptome analysis of genetic complexity underpinning cardiac interatrial septation in mice using an advanced intercross line

1. Mahdi Moradi Marjaneh
2. Edwin P Kirk
3. Ralph Patrick
4. Dimuthu Alankarage
5. David T Humphreys
6. Gonzalo Del Monte-Nieto
7. Paola Cornejo-Paramo
8. Vaibhao Janbandhu
9. Tram B Doan
10. Sally L Dunwoodie
11. Emily S Wong
12. Chris Moran
13. Ian CA Martin
14. Peter C Thomson
15. Richard P Harvey

• Curated by eLife

  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.

Reviewed by eLife

Precision RNAi using synthetic shRNAmir target sites

1. Thomas Hoffmann
2. Alexandra Hörmann
3. Maja Corcokovic
4. Jakub Zmajkovic
5. Matthias Hinterndorfer
6. Jasko Salkanovic
7. Fiona Spreitzer
8. Anna Köferle
9. Katrin Gitschtaler
10. Alexandra Popa
11. Sarah Oberndorfer
12. Florian Andersch
13. Markus Schaefer
14. Michaela Fellner
15. Nicole Budano
16. Jan G Ruppert
17. Paolo Chetta
18. Melanie Wurm
19. Johannes Zuber
20. Ralph A Neumüller

• Curated by eLife

  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.

Reviewed by eLife

Inactivation of Invs/Nphp2 in renal epithelial cells drives infantile nephronophthisis like phenotypes in mouse

1. Yuanyuan Li
2. Wenyan Xu
3. Svetlana Makova
4. Martina Brueckner
5. Zhaoxia Sun

• Curated by eLife

  eLife assessment

  Germline inactivation of NPHP2, which encodes a protein that localizes to the transition zone at the base of the primary cilium, results in infantile kidney cysts and fibrosis. In this study, the authors provide solid evidence that increased cell proliferation and fibrosis precede cyst formation in Nphp-2 mouse models, that mutant renal epithelial cells are responsible for the phenotype, and that genetic inhibition of ciliogenesis in this model reduces disease severity. They also show that valproic acid, a drug that affects a number of cellular targets and is used to treat other human conditions, slows disease progression. One limitation of the study is that it provides limited insights into the mechanisms responsible for any of its interesting observations.

Reviewed by eLife

Unique functions of two overlapping PAX6 retinal enhancers

1. Kirsty Uttley
2. Andrew S. Papanastasiou
3. Manuela Lahne
4. Jennifer M. Brisbane
5. Ryan B. MacDonald
6. Wendy A. Bickmore
7. Shipra Bhatia

Reviewed by Review Commons

The lingering effects of Neanderthal introgression on human complex traits

1. Xinzhu Wei
2. Christopher R Robles
3. Ali Pazokitoroudi
4. Andrea Ganna
5. Alexander Gusev
6. Arun Durvasula
7. Steven Gazal
8. Po-Ru Loh
9. David Reich
10. Sriram Sankararaman

• Curated by eLife

  eLife assessment

  A small proportion of the genomes of humans whose ancestors lived outside Africa traces back to an interbreeding event with Neanderthals. While we know that selection has generally acted to remove Neanderthal ancestry, intense interest has focused on understanding the contribution to current human phenotypic variation. This paper uses a new set of approaches to carefully quantify this contribution, taking into account various complicating factors. The work will be of interest to colleagues in human evolution and evolutionary biology more generally.

Reviewed by eLife

Coarsening dynamics can explain meiotic crossover patterning in both the presence and absence of the synaptonemal complex

1. John A Fozard
2. Chris Morgan
3. Martin Howard

• Curated by eLife

  eLife assessment

  During meiotic prophase I, protein complexes essential for crossover recombination are distributed non-randomly along chromosomes. With mathematical modelling and based on results from super-resolution microscopy, the authors introduce a second type of coarsening of protein ensembles between chromosome axes and nucleoplasm between chromosomes and nucleoplasm to support the random distribution of the complexes in the synapsis-defective mutant. The new model is interesting and may be applied to other chromosomal events accompanied by the formation of large protein ensembles on the chromosomes. The work is of interest to colleagues studying recombination and meiosis.

Reviewed by eLife