Genetics

Variation in human herpesvirus 6B telomeric integration, excision, and transmission between tissues and individuals

1. Michael L Wood
2. Colin D Veal
3. Rita Neumann
4. Nicolás M Suárez
5. Jenna Nichols
6. Andrei J Parker
7. Diana Martin
8. Simon PR Romaine
9. Veryan Codd
10. Nilesh J Samani
11. Adriaan A Voors
12. Maciej Tomaszewski
13. Louis Flamand
14. Andrew J Davison
15. Nicola J Royle

• Curated by eLife

  Evaluation Summary:

  Human Herpesvirus 6A (HHV6A) and 6B are common herpesviruses that establish lifelong infection in latent form and can cause severe disease upon reactivation. They are spread by acquired infection of free virus and by germ-line transmission of inherited chromosomally-integrated HHV-6A/6B in telomeres. The authors develop an approach to analyse a hypervariable region of the HHV-6B genome and exploit it to investigate the relationship between acquired and inherited virus, presenting evidence that HHV-6B can readily transition between telomere-integrated and free virus forms.

  (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

Translational control of polyamine metabolism by CNBP is required for Drosophila locomotor function

1. Sonia Coni
2. Federica A Falconio
3. Marta Marzullo
4. Marzia Munafò
5. Benedetta Zuliani
6. Federica Mosti
7. Alessandro Fatica
8. Zaira Ianniello
9. Rosa Bordone
10. Alberto Macone
11. Enzo Agostinelli
12. Alessia Perna
13. Tanja Matkovic
14. Stephan Sigrist
15. Gabriella Silvestri
16. Gianluca Canettieri
17. Laura Ciapponi

• Curated by eLife

  Evaluation Summary:

  This paper is of interest and relevance to clinicians and researchers in the field of muscular dystrophy, a condition that causes loss of muscle function and mobility primarily in older patients. The presented experiments suggest that at least part of the pathology of DM2, a certain form of muscular dystrophy, is caused by defects in a gene that is required for the production of small molecules, called polyamines which are known to support muscle health and function. Interestingly, in a Drosophila model of DM2, feeding with polyamines can restore muscle function. The paper gains broad interest by the demonstration that consistent with the findings in Drosophila, muscle biopsies from human DM2 patients show decreased ODC and polyamine levels, raising the possibility of using polyamines for therapy or prevention.

  (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

Regulatory dissection of the severe COVID-19 risk locus introgressed by Neanderthals

1. Evelyn Jagoda
2. Davide Marnetto
3. Gayani Senevirathne
4. Victoria Gonzalez
5. Kaushal Baid
6. Francesco Montinaro
7. Daniel Richard
8. Darryl Falzarano
9. Emmanuelle V LeBlanc
10. Che C Colpitts
11. Arinjay Banerjee
12. Luca Pagani
13. Terence D Capellini

• Curated by eLife

  eLife assessment

  Scientists had previously discovered that humans and neanderthals mated leading to parts of neanderthal DNA becoming part of the human genome today. More recently, it was found that a genetic region, carrying which has been associated with manifestation of severe COVID-19 symptoms, is one that was "introgressed" into humans from neanderthals. This region contains many genetic variants, and this study set out to identify which of these genetic variants may be causally involved in creating severe symptoms in response to COVID-19 infection. The main critiques of the study stem from details of the functional assays to establish the regulatory role of the 4 variants in creating severe COVID-19 symptoms. In particular, the two genes (critical chemokine receptor genes: CCR1 and CCR5) that the authors identify as down-regulated by these variants are actually up-regulated in severe COVID-19 patients, leading to doubt about the role of these variants in changing response to COVID-19 through the regulation of these genes. In that regard, it seems necessary to conduct follow-up experimental and computational analyses to establish the role of these variants in altering CCR1 and CCR5 gene expression.

Reviewed by eLife, ScreenIT

Intronic regulation of SARS-CoV-2 receptor (ACE2) expression mediated by immune signaling and oxidative stress pathways

1. Daniel Richard
2. Pushpanathan Muthuirulan
3. Jennifer Aguiar
4. Andrew C. Doxey
5. Arinjay Banerjee
6. Karen Mossman
7. Jeremy Hirota
8. Terence D. Capellini

Reviewed by ScreenIT

Improving statistical power in severe malaria genetic association studies by augmenting phenotypic precision

1. James A Watson
2. Carolyne M Ndila
3. Sophie Uyoga
4. Alexander Macharia
5. Gideon Nyutu
6. Shebe Mohammed
7. Caroline Ngetsa
8. Neema Mturi
9. Norbert Peshu
10. Benjamin Tsofa
11. Kirk Rockett
12. Stije Leopold
13. Hugh Kingston
14. Elizabeth C George
15. Kathryn Maitland
16. Nicholas PJ Day
17. Arjen M Dondorp
18. Philip Bejon
19. Thomas N Williams
20. Chris C Holmes
21. Nicholas J White

• Curated by eLife

  Evaluation Summary:

  The fundamental premise of genome wide association studies for severe malaria is to take a population with confirmed severe malaria and compare with a control group who do not have severe malaria. This paper presents a novel and valuable method for improving power for severe malaria genetic association studies. The method would also be useful for studies of other disease where there is a clinical definition that sometimes includes people who do not truly have the disease.

  (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 #2 agreed to share their name with the authors.)

Reviewed by eLife

Genetic variant in 3’ untranslated region of the mouse pycard gene regulates inflammasome activity

1. Brian Ritchey
2. Qimin Hai
3. Juying Han
4. John Barnard
5. Jonathan D Smith

• Curated by eLife

  Evaluation Summary:

  Genetic differences in outbred species such as humans and differences in the epigenomic structure form the basis of the large variability in the immune response. This work demonstrates that a single nucleotide change in the gene encoding for the universal inflammasome adaptor protein ASC regulates mRNA stability of Pycard and thereby inflammasome function. A particular strength of the work is that the authors managed to show, using genetic alterations, that a single SNP in the Pycard gene sequence (rs33183533) between AKR and DBA/2 mice causes variation in inflammasome activity. Given the relevance of inflammasome for various human pathologies, this work is important for a broad readership.

  (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

Missense variants in human ACE2 strongly affect binding to SARS-CoV-2 Spike providing a mechanism for ACE2 mediated genetic risk in Covid-19: A case study in affinity predictions of interface variants

1. Stuart A. MacGowan
2. Michael I. Barton
3. Mikhail Kutuzov
4. Omer Dushek
5. P. Anton van der Merwe
6. Geoffrey J. Barton

Reviewed by ScreenIT

The Shu complex prevents mutagenesis and cytotoxicity of single-strand specific alkylation lesions

1. Braulio Bonilla
2. Alexander J Brown
3. Sarah R Hengel
4. Kyle S Rapchak
5. Debra Mitchell
6. Catherine A Pressimone
7. Adeola A Fagunloye
8. Thong T Luong
9. Reagan A Russell
10. Rudri K Vyas
11. Tony M Mertz
12. Hani S Zaher
13. Nima Mosammaparast
14. Ewa P Malc
15. Piotr A Mieczkowski
16. Steven A Roberts
17. Kara A Bernstein

• Curated by eLife

  Evaluation Summary:

  This paper is of potential interest to an audience of DNA repair and cancer biologists because it seeks to refine the mechanism by which cells respond to DNA damage. By combining a number of genetic experiments based on cell survival of different mutant combinations and mutation analysis, their results support the view that Shu is critical for 3meC damage tolerance in yeast. Notably, expression of human ALKBH2, responsible for the repair of 3meC rescues the MMS-sensitivity of Shu mutants but not that of homologous recombination mutants. The study supports the existence of a new pathway for the removal of an important DNA lesion that seems essential in yeast, but likely contributes in other organisms, and helps clarify the distinctive role of homologous recombination in DSB repair and post-replicative repair. A few additional experiments are suggested to strengthen the mechanistic conclusions and better support the central model.

  (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

Genetic variants in TMPRSS2 and Structure of SARS-CoV-2 spike glycoprotein and TMPRSS2 complex

1. Ravikanth Vishnubhotla
2. Naveen Vankadari
3. Vijayasarathy Ketavarapu
4. Ramars Amanchy
5. Steffie Avanthi
6. Govardhan Bale
7. Duvvur Nageshwar Reddy
8. Mitnala Sasikala

Reviewed by ScreenIT

Elucidation of remdesivir cytotoxicity pathways through genome-wide CRISPR-Cas9 screening and transcriptomics

1. Ersin Akinci
2. Minsun Cha
3. Lin Lin
4. Grace Yeo
5. Marisa C. Hamilton
6. Callie J. Donahue
7. Heysol C. Bermudez-Cabrera
8. Larissa C. Zanetti
9. Maggie Chen
10. Sammy A. Barkal
11. Benyapa Khowpinitchai
12. Nam Chu
13. Minja Velimirovic
14. Rikita Jodhani
15. James D. Fife
16. Miha Sovrovic
17. Philip A. Cole
18. Robert A. Davey
19. Christopher A. Cassa
20. Richard I. Sherwood

Reviewed by Rapid Reviews Infectious Diseases, ScreenIT