scholarly journals The evolutionary history of the polyQ tract in huntingtin sheds light on its functional pro-neural activities

2022 ◽  
Author(s):  
Raffaele Iennaco ◽  
Giulio Formenti ◽  
Camilla Trovesi ◽  
Riccardo Lorenzo Rossi ◽  
Chiara Zuccato ◽  
...  
Keyword(s):  
Natural Selection ◽  
Embryonic Stem ◽  
Purifying Selection ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Protein Coding ◽  
Neural Activities ◽  
Cell Assays ◽  
History Of ◽  
Polyq Tract

AbstractHuntington’s disease is caused by a pathologically long (>35) CAG repeat located in the first exon of the Huntingtin gene (HTT). While pathologically expanded CAG repeats are the focus of extensive investigations, non-pathogenic CAG tracts in protein-coding genes are less well characterized. Here, we investigated the function and evolution of the physiological CAG tract in the HTT gene. We show that the poly-glutamine (polyQ) tract encoded by CAGs in the huntingtin protein (HTT) is under purifying selection and subjected to stronger selective pressures than CAG-encoded polyQ tracts in other proteins. For natural selection to operate, the polyQ must perform a function. By combining genome-edited mouse embryonic stem cells and cell assays, we show that small variations in HTT polyQ lengths significantly correlate with cells’ neurogenic potential and with changes in the gene transcription network governing neuronal function. We conclude that during evolution natural selection promotes the conservation and purity of the CAG-encoded polyQ tract and that small increases in its physiological length influence neural functions of HTT. We propose that these changes in HTT polyQ length contribute to evolutionary fitness including potentially to the development of a more complex nervous system.

scholarly journals Standard codon substitution models overestimate purifying selection for non-stationary data

2016 ◽  
Author(s):  
Benjamin D Kaehler ◽  
Von Bing Yap ◽  
Gavin A Huttley
Keyword(s):  
Natural Selection ◽  
De Novo ◽  
Purifying Selection ◽  
Neutral Evolution ◽  
Protein Coding ◽  
Synonymous Substitutions ◽  
New Model ◽  
Sequence Composition ◽  
Codon Substitution ◽  
Substitution Models

Estimation of natural selection on protein-coding sequences is a key comparative genomics approach for de novo prediction of lineage specific adaptations. Selective pressure is measured on a per-gene basis by comparing the rate of non-synonymous substitutions to the rate of neutral evolution, typically assumed to be the rate of synonymous substitutions. All published codon substitution models have been time-reversible and thus assume that sequence composition does not change over time. We previously demonstrated that if time-reversible DNA substitution models are applied blindly in the presence of changing sequence composition, the number of substitutions is systematically biased towards overestimation. We extend these findings to the case of codon substitution models and further demonstrate that the ratio of non-synonymous to synonymous rates of substitution tends to be underestimated over three data sets of insects, mammals, and vertebrates. Our basis for comparison is a non-stationary codon substitution model that allows sequence composition to change. Model selection and model fit results demonstrate that our new model tends to fit the data better. Direct measurement of non-stationarity shows that bias in estimates of natural selection and genetic distance increases with the degree of violation of the stationarity assumption. Additionally, inferences drawn under time-reversible models are systematically affected by compositional divergence. As genomic sequences accumulate at an accelerating rate, the importance of accurate de novo estimation of natural selection increases. Our results establish that our new model provides a more robust perspective on this fundamental quantity.

scholarly journals Parkinsonism with a Hint of Huntington’s from 29 CAG Repeats in HTT

2019 ◽  
Vol 9 (10) ◽  
pp. 245
Author(s):  
Sipilä JOT
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Clinical Phenotype ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Test Results ◽  
Intermediate Allele ◽  
History Of ◽  
Neurophysiological Test ◽  
History Of Parkinson’S Disease

Huntington’s disease is caused by at least 36 cytosine-adenine-guanine (CAG) repeats in an HTT gene allele, but repeat tracts in the intermediate range (27–35 repeats) also display a subtle phenotype. This patient had a slightly elongated CAG repeat tract (29 repeats), a prominent family history of Parkinson’s disease (PD), and a clinical phenotype mostly consistent with PD, but early dystonia and poor levodopa response. Neurophysiological test results were more consistent with Huntington’s disease (HD) than PD. It is suggested that the intermediate allele modulated the clinical phenotype of PD in this patient.

Association of CAG Repeat Length in the Huntington Gene With Cognitive Performance in Young Adults

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000011823
Author(s):  
Jordan L. Schultz ◽  
Carsten Saft ◽  
Peggy C. Nopoulos
Keyword(s):  
Cognitive Performance ◽  
Color Naming ◽  
Repeat Length ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Cross Sectional ◽  
History Of ◽  
Disease Threshold ◽  
Interference Tests ◽  
Sectional Analysis

Objective:To investigate the relationships between CAG repeat length in the huntingtin gene and cognitive performance in participants above and below the disease threshold for Huntington’s Disease (HD), we performed a cross-sectional analysis of the Enroll-HD database.Methods:We analyzed data from young, developing adults (≤ 30 years) without a history of depression, apathy, or cognitive deficits. We included participants with and without the gene-expansion (CAG ≥ 36) for HD. All participants had to have a Total Functional Capacity Score of 13, a diagnostic confidence level of zero, a total motor score of <10, and be more than 28.6 years from their predicted motor onset. We performed regression analyses to investigate the non-linear relationship between CAG repeat length and various cognitive measures controlling for age, sex, and education level.Results:There were significant positive relationships between CAG repeat length and the Symbol Digit Modalities, Stroop Color Naming, and Stroop Interference Tests. There were significant negative relationships between CAG repeat length and parts A and B of the Trails Making Test (p<0.05) indicating that longer CAG repeat lengths were associated with better performance.Discussion:An increasing number of CAG repeats in the huntingtin gene below disease threshold and low pathological CAG ranges was associated with some improvements in cognitive performance. These findings outline the relationship between CAG repeats within the huntingtin gene and cognitive development.Classification of Evidence:This study provides Class IV evidence that CAG repeat length is positively associated with cognitive function across a spectrum of CAG repeat lengths.

scholarly journals Interferon mediated neuroinflammation in polyglutamine disease is not caused by RNA toxicity

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Aksheev Bhambri ◽  
Akeeth Pinto ◽  
Beena Pillai
Keyword(s):  
Protein Aggregates ◽  
Cag Repeat ◽  
Site Directed Mutagenesis ◽  
Cag Repeats ◽  
Polyglutamine Disease ◽  
Messenger Rnas ◽  
Protein Coding ◽  
Interferon Stimulated Genes ◽  
Rna Sensors ◽  
Interferon Pathway

AbstractPolyglutamine diseases are neurodegenerative diseases that occur due to the expansion of CAG repeat regions in coding sequences of genes. Previously, we have shown the formation of large protein aggregates along with activation of the interferon pathway leading to apoptosis in a cellular model of SCA17. Here, we corroborate our previous results in a tetracycline-inducible model of SCA17. Interferon gamma and lambda were upregulated in 59Q-TBP expressing cells as compared to 16Q-TBP expressing cells. Besides interferon-stimulated genes, the SCA17 model and Huntington’s mice brain samples showed upregulation of RNA sensors. However, in this improved model interferon pathway activation and apoptosis preceded the formation of large polyglutamine aggregates, suggesting a role for CAG repeat RNA or soluble protein aggregates. A polyglutamine minus mutant of TBP, expressing polyCAG mRNA, was created by site directed mutagenesis of 10 potential start codons. Neither this long CAG embedded mRNA nor short polyCAG RNA could induce interferon pathway genes or cause apoptosis. polyQ-TBP induced the expression of canonical RNA sensors but the downstream transcription factor, IRF3, showed a muted response. We found that expanded CAG repeat RNA is not sufficient to account for the neuronal apoptosis. Neuronal cells sense expanded CAG repeats embedded in messenger RNAs of protein-coding genes. However, polyglutamine containing protein is responsible for the interferon-mediated neuroinflammation and cell death seen in polyglutamine disease. Thus, we delineate the inflammatory role of CAG repeats in the mRNA from the resulting polyglutamine tract in the protein. Embedded in messenger RNAs of protein-coding regions, the cell senses CAG repeat expansion and induces the expression of RNA sensors and interferon-stimulated genes.

scholarly journals OLGenie: Estimating Natural Selection to Predict Functional Overlapping Genes

2020 ◽  
Author(s):  
Chase W Nelson ◽  
Zachary Ardern ◽  
Xinzhu Wei
Keyword(s):  
Natural Selection ◽  
Protein Gene ◽  
Purifying Selection ◽  
Biological Sequences ◽  
Overlapping Genes ◽  
Protein Coding ◽  
Discriminatory Ability ◽  
Viral Genomes ◽  
Scalable Methods ◽  
Hiv 1

Abstract Purifying (negative) natural selection is a hallmark of functional biological sequences, and can be detected in protein-coding genes using the ratio of nonsynonymous to synonymous substitutions per site (dN/dS). However, when two genes overlap the same nucleotide sites in different frames, synonymous changes in one gene may be nonsynonymous in the other, perturbing dN/dS. Thus, scalable methods are needed to estimate functional constraint specifically for overlapping genes (OLGs). We propose OLGenie, which implements a modification of the Wei-Zhang method. Assessment with simulations and controls from viral genomes (58 OLGs and 176 non-OLGs) demonstrates low false positive rates and good discriminatory ability in differentiating true OLGs from non-OLGs. We also apply OLGenie to the unresolved case of HIV-1’s putative antisense protein gene, showing significant purifying selection. OLGenie can be used to study known OLGs and to predict new OLGs in genome annotation. Software and example data are freely available at https://github.com/chasewnelson/OLGenie.

scholarly journals OLGenie: Estimating Natural Selection to Predict Functional Overlapping Genes

2019 ◽  
Author(s):  
Chase W. Nelson ◽  
Zachary Ardern ◽  
Xinzhu Wei
Keyword(s):  
Natural Selection ◽  
Purifying Selection ◽  
Biological Sequences ◽  
Overlapping Genes ◽  
Protein Coding ◽  
Discriminatory Ability ◽  
Viral Genomes ◽  
Protein Coding Genes ◽  
Scalable Methods ◽  
Hiv 1

AbstractPurifying (negative) natural selection is a hallmark of functional biological sequences, and can be detected in protein-coding genes using the ratio of nonsynonymous to synonymous substitutions per site (dN/dS). However, when two genes overlap the same nucleotide sites in different frames, synonymous changes in one gene may be nonsynonymous in the other, perturbing dN/dS. Thus, scalable methods are needed to estimate functional constraint specifically for overlapping genes (OLGs). We propose OLGenie, which implements a modification of the Wei-Zhang method. Assessment with simulations and controls from viral genomes (58 OLGs and 176 non-OLGs) demonstrates low false positive rates and good discriminatory ability in differentiating true OLGs from non-OLGs. We also apply OLGenie to the unresolved case of HIV-1’s putative antisense protein gene, showing significant purifying selection. OLGenie can be used to study known OLGs and to predict new OLGs in genome annotation. Software and example data are freely available at https://github.com/chasewnelson/OLGenie.

scholarly journals Standard codon substitution models overestimate purifying selection for non-stationary data

2016 ◽  
Author(s):  
Benjamin D Kaehler ◽  
Von Bing Yap ◽  
Gavin A Huttley
Keyword(s):  
Natural Selection ◽  
De Novo ◽  
Purifying Selection ◽  
Neutral Evolution ◽  
Protein Coding ◽  
Synonymous Substitutions ◽  
New Model ◽  
Sequence Composition ◽  
Codon Substitution ◽  
Substitution Models

Estimation of natural selection on protein-coding sequences is a key comparative genomics approach for de novo prediction of lineage specific adaptations. Selective pressure is measured on a per-gene basis by comparing the rate of non-synonymous substitutions to the rate of neutral evolution, typically assumed to be the rate of synonymous substitutions. All published codon substitution models have been time-reversible and thus assume that sequence composition does not change over time. We previously demonstrated that if time-reversible DNA substitution models are applied blindly in the presence of changing sequence composition, the number of substitutions is systematically biased towards overestimation. We extend these findings to the case of codon substitution models and further demonstrate that the ratio of non-synonymous to synonymous rates of substitution tends to be underestimated over three data sets of insects, mammals, and vertebrates. Our basis for comparison is a non-stationary codon substitution model that allows sequence composition to change. Model selection and model fit results demonstrate that our new model tends to fit the data better. Direct measurement of non-stationarity shows that bias in estimates of natural selection and genetic distance increases with the degree of violation of the stationarity assumption. Additionally, inferences drawn under time-reversible models are systematically affected by compositional divergence. As genomic sequences accumulate at an accelerating rate, the importance of accurate de novo estimation of natural selection increases. Our results establish that our new model provides a more robust perspective on this fundamental quantity.

scholarly journals Precise CAG repeat contraction in a Huntington’s Disease mouse model is enabled by gene editing with SpCas9-NG

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Seiya Oura ◽  
Taichi Noda ◽  
Naoko Morimura ◽  
Seiji Hitoshi ◽  
Hiroshi Nishimasu ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Streptococcus Pyogenes ◽  
Gene Editing ◽  
Es Cells ◽  
Embryonic Stem ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Disease Mutations ◽  
Protospacer Adjacent Motif

AbstractThe clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 system is a research hotspot in gene therapy. However, the widely used Streptococcus pyogenes Cas9 (WT-SpCas9) requires an NGG protospacer adjacent motif (PAM) for target recognition, thereby restricting targetable disease mutations. To address this issue, we recently reported an engineered SpCas9 nuclease variant (SpCas9-NG) recognizing NGN PAMs. Here, as a feasibility study, we report SpCas9-NG-mediated repair of the abnormally expanded CAG repeat tract in Huntington’s disease (HD). By targeting the boundary of CAG repeats with SpCas9-NG, we precisely contracted the repeat tracts in HD-mouse-derived embryonic stem (ES) cells. Further, we confirmed the recovery of phenotypic abnormalities in differentiated neurons and animals produced from repaired ES cells. Our study shows that SpCas9-NG can be a powerful tool for repairing abnormally expanded CAG repeats as well as other disease mutations that are difficult to access with WT-SpCas9.

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