Allelic series of Huntington's disease knock-in mice reveals expression discorrelates

Human Molecular Genetics
Ashish KumarPeter J Detloff

Abstract

Identifying molecular drivers of pathology provides potential therapeutic targets. Differentiating between drivers and coincidental molecular alterations presents a major challenge. Variation unrelated to pathology further complicates transcriptomic, proteomic and metabolomic studies which measure large numbers of individual molecules. To overcome these challenges towards the goal of determining drivers of Huntington's disease (HD), we generated an allelic series of HD knock-in mice with graded levels of phenotypic severity for comparison with molecular alterations. RNA-sequencing analysis of this series reveals high numbers of transcripts with level alterations that do not correlate with phenotypic severity. These discorrelated molecular changes are unlikely to be drivers of pathology allowing an exclusion-based strategy to provide a short list of driver candidates. Further analysis of the data shows that a majority of transcript level changes in HD knock-in mice involve alteration of the rate of mRNA processing and/or degradation rather than solely being due to alteration of transcription rate. The overall strategy described can be applied to assess the influence of any molecular change on pathology for diseases where differe...Continue Reading

References

Aug 6, 1999·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·J H ChaA B Young
Jan 12, 2001·Human Molecular Genetics·C H LinP J Detloff
Jul 18, 2002·Nature Reviews. Drug Discovery·Daniela SalveminiSalvatore Cuzzocrea
Dec 6, 2002·Nature·UNKNOWN Mouse Genome Sequencing ConsortiumEric S Lander
Jun 18, 2004·Gene Expression·Karen T DixonPeter J Detloff
Feb 1, 2005·Life Sciences·Wolfgang SadéeEdward J Bilsky
May 1, 2007·Progress in Neurobiology·Jang-Ho J Cha
Aug 23, 2007·ILAR Journal·Shilpa RamaswamyJeffrey H Kordower
Aug 24, 2007·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Mary Y HengRoger L Albin
Jul 22, 2008·Neurobiology of Disease·Mary Y HengRoger L Albin
Oct 3, 2008·Proceedings of the National Academy of Sciences of the United States of America·Elizabeth A ThomasJoel M Gottesfeld
Jan 10, 2009·Neurobiology of Disease·A Jennifer MortonJames M Wight
May 30, 2009·The Journal of Comparative Neurology·Franziska RichterMarie-Françoise Chesselet
Jul 10, 2010·Human Molecular Genetics·Mary Y HengPeter J Detloff
May 7, 2011·British Journal of Pharmacology·Javier Fernández-RuizJosé A Ramos
Aug 9, 2011·Neurobiology of Disease·Tamara Seredenina, Ruth Luthi-Carter
Sep 13, 2011·International Review of Neurobiology·Anton ReinerPaula Dietrich
Sep 13, 2014·Movement Disorders : Official Journal of the Movement Disorder Society·Liliana Menalled, Daniela Brunner
Nov 2, 2014·BMC Medical Genomics·Andreas Neueder, Gillian P Bates

❮ Previous
Next ❯

Citations

Nov 12, 2017·Journal of Neural Transmission·Brooke R Snyder, Anthony W S Chan
Feb 14, 2021·Journal of Huntington's Disease·Jasmine DonaldsonLesley Jones
Jun 26, 2021·Human Molecular Genetics·James F GusellaMarcy E MacDonald

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.

Related Papers

Infection, Genetics and Evolution : Journal of Molecular Epidemiology and Evolutionary Genetics in Infectious Diseases
Taís Nóbrega de SousaCristiana Ferreira Alves de Brito
Progress in Tumor Research
Yujie Zhao, Alex A Adjei
© 2022 Meta ULC. All rights reserved