Genetics

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

Ecdysone acts through cortex glia to regulate sleep in Drosophila

1. Yongjun Li
2. Paula Haynes
3. Shirley L Zhang
4. Zhifeng Yue
5. Amita Sehgal

• Curated by eLife

  eLife assessment

  Li and colleague report observations that constitute a potentially fundamental advance, pointing to a mechanism by which non-neural cells can influence sleep regulation by neurons, The authors provide evidence in Drosophila showing that ecdysone synthesised outside the brain regulates sleep via ecdysone receptors in cortex glia. It further suggests that steroid signalling in glia can act on sleep through lipid droplet mobilization.

Reviewed by eLife

DNMT3B PWWP mutations cause hypermethylation of heterochromatin

1. Francesca Taglini
2. Ioannis Kafetzopoulos
3. Willow Rolls
4. Kamila Irena Musialik
5. Heng Yang Lee
6. Yujie Zhang
7. Mattia Marenda
8. Lyndsay Kerr
9. Hannah Finan
10. Cristina Rubio-Ramon
11. Philippe Gautier
12. Hannah Wapenaar
13. Dhananjay Kumar
14. Hazel Davidson-Smith
15. Jimi Wills
16. Laura C Murphy
17. Ann Wheeler
18. Marcus D Wilson
19. Duncan Sproul

Reviewed by Review Commons, PREreview

The nutrient-sensing GCN2 signaling pathway is essential for circadian clock function by regulating histone acetylation under amino acid starvation

1. Xiao-Lan Liu
2. Yulin Yang
3. Yue Hu
4. Jingjing Wu
5. Chuqiao Han
6. Qiaojia Lu
7. Xihui Gan
8. Shaohua Qi
9. Jinhu Guo
10. Qun He
11. Yi Liu
12. Xiao Liu

• Curated by eLife

  eLife assessment

  This important study provides evidence for CPC-3 mediating induction of the transcription factor CPC-1 in starved Neurospora cells, with CPC-1-mediated recruitment of Gcn5 and acetylation of the FRQ promoter counteracting the function of histone deacetylase HDA1, which in turn maintains high occupancy of the transcription factor WCC and attendant circadian rhythm of FRQ expression. The findings are significant in showing how the well-established pathways for circadian rhythm centered on FRQ gene expression and cross-pathway control centered on CPC-1 induction are integrated to maintain rhythmic cell growth in the face of amino acid limitation. However, the evidence for these claims is incomplete in certain respects and additional statistical analyses and experimental evidence are needed to better support the claims of rhythmic CPC-1 binding at FRQ, of the role of GCN-5 in rhythmic FRQ transcription in starvation conditions, and of rhythmic transcription of CPC-1-regulated amino acid biosynthetic genes.

Reviewed by eLife

Timing of TORC1 inhibition dictates Pol III involvement in longevity in Caenorhabditis elegans

1. Yasir Malik
2. Isabel Goncalves Silva
3. Rene Rivera Diazgranados
4. Colin Selman
5. Nazif Alic
6. Jennifer M. A. Tullet

Reviewed by Review Commons

Identification of a weight loss-associated causal eQTL in MTIF3 and the effects of MTIF3 deficiency on human adipocyte function

1. Mi Huang
2. Daniel Coral
3. Hamidreza Ardalani
4. Peter Spegel
5. Alham Saadat
6. Melina Claussnitzer
7. Hindrik Mulder
8. Paul W Franks
9. Sebastian Kalamajski

• Curated by eLife

  eLife assessment

  The study provides a fundamental framework for linking human genome variation to targetable mechanisms of disease. The authors provide compelling evidence that a strong candidate locus associates with body weight in humans acts through adipocyte MTIF3. Thus, the generalized approaches taken in this study have the potential to inform genetic association studies in general and lay a foundation for future functional genomics studies.

Reviewed by eLife