scholarly journals Biases in arginine codon usage correlate with genetic disease risk

2019 ◽  
Author(s):  
Katharina V. Schulze ◽  
Neil A. Hanchard ◽  
Michael F. Wangler
Keyword(s):  
Codon Usage ◽  
Genetic Disease ◽  
Human Disease ◽  
Disease Risk ◽  
Single Gene ◽  
Autism Spectrum ◽  
Disease Genes ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Human Genetic Disease

ABSTRACTPurposeThe persistence of hypermutable ‘CGN’ (CGG, CGA, CGC, CGU) arginine codons at high frequency suggests the possibility of negative selective pressure at these sites and that arginine codon usage could be a predictive indicator of human disease genes.MethodsWe analyzed arginine codons (CGN, AGG, AGA) from all ‘canonical’ Ensembl protein coding gene transcripts before comparing the frequency of CGN codons between genes with and without human disease associations and with gnomAD constraint metrics.ResultsThe frequency of CGN codons among a gene’s total arginine codon count was higher in genes linked to syndromic autism spectrum disorder (ASD) compared to genes not associated with ASD. A comparison of genes annotated as dominant or recessive with control genes not matching either classification revealed a progressive increase in CGN codon frequency. Moreover, CGN frequency was positively correlated with a gene’s probability of loss-of-function intolerance (pLI) score and negatively correlated with ‘observed-over-expected’ ratios for both loss of function and missense mutations.ConclusionOur findings indicate that genes utilizing CGN arginine codons rather than AGG or AGA are more likely to underlie single gene disorders, particularly for dominant phenotypes, and thus constitute candidate genes for the study of human genetic disease.

scholarly journals Biases in arginine codon usage correlate with genetic disease risk

2020 ◽  
Vol 22 (8) ◽  
pp. 1407-1412
Author(s):  
Katharina V. Schulze ◽  
Neil A. Hanchard ◽  
Michael F. Wangler
Keyword(s):  
Codon Usage ◽  
Genetic Disease ◽  
Disease Risk

COMPARATIVE ANALYSIS OF DISEASE-ASSOCIATED MUTATIONS IN THE CODING REGIONS OF ALTERNATIVELY AND CONSTITUTIVELY SPLICED HUMAN GENES

2008 ◽  
Vol 16 (02) ◽  
pp. 241-253
Author(s):  
QIANLI HUANG ◽  
YONG LI ◽  
JESSE LI-LING ◽  
HUIFANG HUANG ◽  
XUEPING CHEN ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Codon Usage ◽  
Codon Usage Bias ◽  
Human Disease ◽  
Molecular Mechanisms ◽  
Human Diseases ◽  
Disease Genes ◽  
Single Mutation ◽  
Coding Regions ◽  
Human Disease Genes

To better understand the evolutionary and molecular mechanisms of alternative splicing causing human diseases, we have systematically compared the pattern, the distribution and the density of disease-associated mutations as well as the influence of codon usage bias on the single mutation between alternatively and constitutively spliced genes through analysis of the large datasets from human disease genes. The results indicated that: 1. The most common pattern of single mutation in alternatively and constitutively spliced genes are, respectively, C/T (25.17%), (22.81%) and G/A (21.54%), (22.73%), suggesting that the two types of disease genes are prone to C → T and G → A mutations. 2. There is an overall preponderance for transitions over transversions in alternatively (62.88% versus 37.12%) and constitutively (64.41% versus 35.59%) spliced disease genes. 3. For the second base of codons, there exist significant differences in transitions and transversions between the two types of genes. 4. Our data indicated that the single mutation tends to occur preferentially when the upstream neighboring-nucleotide is C or G in human disease genes. 5. Codon usage bias and synonymous codon usage have great influence on the single mutation in both alternatively and constitutively spliced genes. The GC content and gene length also have very evident influence on such mutations. Our results seem to imply that disease-associated mutations within the coding regions of alternatively spliced human disease genes have different mechanisms from constitutively spliced genes. Such findings may facilitate understanding the molecular mechanism of alternative splicing causing human diseases, and the development of gene therapies for such diseases.

scholarly journals Varying intolerance of gene pathways to mutational classes explain genetic convergence across neuropsychiatric disorders

2016 ◽  
Author(s):  
Shahar Shohat ◽  
Eyal Ben-David ◽  
Sagiv Shifman
Keyword(s):  
Gene Expression ◽  
Genome Wide Association Study ◽  
De Novo ◽  
Expression Patterns ◽  
Neuropsychiatric Disorders ◽  
Autism Spectrum ◽  
Specific Gene ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Brain Gene Expression

AbstractGenetic susceptibility to Intellectual disability (ID), autism spectrum disorder (ASD) and schizophrenia (SCZ) often arises from mutations in the same genes, suggesting that they share common mechanisms. We studied genes with de novo mutations in the three disorders and genes implicated by SCZ genome-wide association study (GWAS). Using biological annotations and brain gene expression, we show that mutation class explains enrichment patterns more than specific disorder. Genes with loss of function mutations and genes with missense mutations were enriched with different pathways, shared with genes intolerant to mutations. Specific gene expression patterns were found for each disorder. ID genes were preferentially expressed in fetal cortex, ASD genes also in fetal cerebellum and striatum, and genes associated with SCZ were most significantly enriched in adolescent cortex. Our study suggests that convergence across neuropsychiatric disorders stems from vulnerable pathways to genetic variations, but spatiotemporal activity of genes contributes to specific phenotypes.

scholarly journals Mapping Autosomal Recessive Intellectual Disability: Combined Microarray and Exome Sequencing Identifies 26 Novel Candidate Genes in 192 Consanguineous Families

2016 ◽  
Author(s):  
Ricardo Harripaul ◽  
Nasim Vasli ◽  
Anna Mikhailov ◽  
Muhammad Arshad Rafiq ◽  
Kirti Mittal ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Autosomal Recessive ◽  
De Novo ◽  
Clinical Diagnostics ◽  
High Yield ◽  
Disease Genes ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Whole Exome

Approximately 1% of the global population is affected by intellectual disability (ID), and the majority receive no molecular diagnosis. Previous studies have indicated high levels of genetic heterogeneity, with estimates of more than 2500 autosomal ID genes, the majority of which are autosomal recessive (AR). Here, we combined microarray genotyping, homozygosity-by-descent (HBD) mapping, copy number variation (CNV) analysis, and whole exome sequencing (WES) to identify disease genes/mutations in 192 multiplex Pakistani and Iranian consanguineous families with non-syndromic ID. We identified definite or candidate mutations (or CNVs) in 51% of families in 72 different genes, including 26 not previously reported for ARID. The new ARID genes include nine with loss-of-function mutations(ABI2, MAPK8, MPDZ, PIDD1, SLAIN1, TBC1D23, TRAPPC6B, UBA7,andUSP44),and missense mutations include the first reports of variants inBDNForTET1associated with ID. The genes identified also showed overlap withde novogene sets for other neuropsychiatric disorders. Transcriptional studies showed prominent expression in the prenatal brain. The high yield of AR mutations for ID indicated that this approach has excellent clinical potential and should inform clinical diagnostics, including clinical whole exome and genome sequencing, for populations in which consanguinity is common. As with other AR disorders, the relevance will also apply to outbred populations.

scholarly journals Biophysical classification of a CACNA1D de novo mutation as a high-risk mutation for a severe neurodevelopmental disorder

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Nadja T. Hofer ◽  
Petronel Tuluc ◽  
Nadine J. Ortner ◽  
Yuliia V. Nikonishyna ◽  
Monica L. Fernándes-Quintero ◽  
...  
Keyword(s):  
High Risk ◽  
Neurodevelopmental Disorders ◽  
Developmental Disorder ◽  
De Novo ◽  
Disease Risk ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
De Novo Mutation ◽  
Loss Of Function ◽  
Gain Of Function

Abstract Background There is increasing evidence that de novo CACNA1D missense mutations inducing increased Cav1.3 L-type Ca2+-channel-function confer a high risk for neurodevelopmental disorders (autism spectrum disorder with and without neurological and endocrine symptoms). Electrophysiological studies demonstrating the presence or absence of typical gain-of-function gating changes could therefore serve as a tool to distinguish likely disease-causing from non-pathogenic de novo CACNA1D variants in affected individuals. We tested this hypothesis for mutation S652L, which has previously been reported in twins with a severe neurodevelopmental disorder in the Deciphering Developmental Disorder Study, but has not been classified as a novel disease mutation. Methods For functional characterization, wild-type and mutant Cav1.3 channel complexes were expressed in tsA-201 cells and tested for typical gain-of-function gating changes using the whole-cell patch-clamp technique. Results Mutation S652L significantly shifted the voltage-dependence of activation and steady-state inactivation to more negative potentials (~ 13–17 mV) and increased window currents at subthreshold voltages. Moreover, it slowed tail currents and increased Ca2+-levels during action potential-like stimulations, characteristic for gain-of-function changes. To provide evidence that only gain-of-function variants confer high disease risk, we also studied missense variant S652W reported in apparently healthy individuals. S652W shifted activation and inactivation to more positive voltages, compatible with a loss-of-function phenotype. Mutation S652L increased the sensitivity of Cav1.3 for inhibition by the dihydropyridine L-type Ca2+-channel blocker isradipine by 3–4-fold. Conclusions and limitations Our data provide evidence that gain-of-function CACNA1D mutations, such as S652L, but not loss-of-function mutations, such as S652W, cause high risk for neurodevelopmental disorders including autism. This adds CACNA1D to the list of novel disease genes identified in the Deciphering Developmental Disorder Study. Although our study does not provide insight into the cellular mechanisms of pathological Cav1.3 signaling in neurons, we provide a unifying mechanism of gain-of-function CACNA1D mutations as a predictor for disease risk, which may allow the establishment of a more reliable diagnosis of affected individuals. Moreover, the increased sensitivity of S652L to isradipine encourages a therapeutic trial in the two affected individuals. This can address the important question to which extent symptoms are responsive to therapy with Ca2+-channel blockers.

The role of cloned genes in the prevention of genetic disease

1988 ◽  
Vol 319 (1194) ◽  
pp. 249-261 ◽  
Keyword(s):  
Prenatal Diagnosis ◽  
Genetic Disease ◽  
Dna Analysis ◽  
Recombinant Dna ◽  
Single Gene ◽  
Recombinant Dna Technology ◽  
Human Genetic Disease ◽  
Single Gene Disorders ◽  
Current Experience

The application of recombinant DNA technology to the study of human genetic disease promises to increase the scope for carrier detection and prenatal diagnosis. Here we summarize current experience with prenatal diagnosis of single-gene disorders by DNA analysis and highlight some of the technical and organizational problems that remain to be solved.

scholarly journals FMR1 and Autism, an Intriguing Connection Revisited

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1218
Author(s):  
William Fyke ◽  
Milen Velinov
Keyword(s):  
Fragile X ◽  
Major Gene ◽  
Single Gene ◽  
Autism Spectrum ◽  
Protein Product ◽  
Loss Of Function ◽  
Cgg Repeat ◽  
Statistical Manual ◽  
The Us ◽  
The Central Nervous System

Autism Spectrum Disorder (ASD) represents a distinct phenotype of behavioral dysfunction that includes deficiencies in communication and stereotypic behaviors. ASD affects about 2% of the US population. It is a highly heritable spectrum of conditions with substantial genetic heterogeneity. To date, mutations in over 100 genes have been reported in association with ASD phenotypes. Fragile X syndrome (FXS) is the most common single-gene disorder associated with ASD. The gene associated with FXS, FMR1 is located on chromosome X. Accordingly, the condition has more severe manifestations in males. FXS results from the loss of function of FMR1 due to the expansion of an unstable CGG repeat located in the 5′′ untranslated region of the gene. About 50% of the FXS males and 20% of the FXS females meet the Diagnostic Statistical Manual 5 (DSM-5) criteria for ASD. Among the individuals with ASD, about 3% test positive for FXS. FMRP, the protein product of FMR1, is a major gene regulator in the central nervous system. Multiple pathways regulated by FMRP are found to be dysfunctional in ASD patients who do not have FXS. Thus, FXS presents the opportunity to study cellular phenomena that may have wider applications in the management of ASD and to develop new strategies for ASD therapy.

scholarly journals Loss-of-function, gain-of-function and dominant-negative mutations have profoundly different effects on protein structure: implications for variant effect prediction

2021 ◽  
Author(s):  
Lukas Gerasimavicius ◽  
Benjamin J Livesey ◽  
Joseph A Marsh
Keyword(s):  
Protein Structure ◽  
Molecular Mechanisms ◽  
Dominant Negative ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Human Genetic Disease ◽  
Gain Of Function ◽  
Protein Coding ◽  
Pathogenic Mutations ◽  
Variant Effect

Most known pathogenic mutations occur in protein-coding regions of DNA and change the way proteins are made. Taking protein structure into account has therefore provided great insight into the molecular mechanisms underlying human genetic disease. While there has been much focus on how mutations can disrupt protein structure and thus cause a loss of function (LOF), alternative mechanisms, specifically dominant-negative (DN) and gain-of-function (GOF) effects, are less understood. Here, we have investigated the protein-level effects of pathogenic missense mutations associated with different molecular mechanisms. We observe striking differences between recessive vs dominant, and LOF vs non-LOF mutations, with dominant, non-LOF disease mutations having much milder effects on protein structure, and DN mutations being highly enriched at protein interfaces. We also find that nearly all computational variant effect predictors underperform on non-LOF mutations, even those based solely on sequence conservation. However, we do find that non-LOF mutations could potentially be identified by their tendency to cluster in space. Overall, our work suggests that many pathogenic mutations that act via DN and GOF mutations are likely being missed by current variant prioritisation strategies, but that there is considerable scope to improve computational predictions through consideration of molecular disease mechanisms.

Red blood cells in Rett syndrome: oxidative stress, morphological changes and altered membrane organization

2015 ◽  
Vol 396 (11) ◽  
pp. 1233-1240 ◽  
Author(s):  
Lucia Ciccoli ◽  
Claudio De Felice ◽  
Silvia Leoncini ◽  
Cinzia Signorini ◽  
Alessio Cortelazzo ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Morphological Changes ◽  
Single Gene ◽  
Neurodevelopmental Disorder ◽  
Gene Mutations ◽  
Autism Spectrum ◽  
Current Evidence ◽  
Loss Of Function ◽  
Beneficial Effects ◽  
Spectrum Disorders

Abstract In this review, we summarize the current evidence on the erythrocyte as a previously unrecognized target cell in Rett syndrome, a rare (1:10 000 females) and devastating neurodevelopmental disorder caused by loss-of-function mutations in a single gene (i.e. MeCP2, CDKL5, or rarely FOXG1). In particular, we focus on morphological changes, membrane oxidative damage, altered membrane fatty acid profile, and aberrant skeletal organization in erythrocytes from patients with typical Rett syndrome and MeCP2 gene mutations. The beneficial effects of ω-3 polyunsaturated fatty acids (PUFAs) are also summarized for this condition to be considered as a ‘model’ condition for autism spectrum disorders.

scholarly journals In vivo Perturb-Seq reveals neuronal and glial abnormalities associated with autism risk genes

Science ◽  
2020 ◽  
Vol 370 (6520) ◽  
pp. eaaz6063 ◽  
Author(s):  
Xin Jin ◽  
Sean K. Simmons ◽  
Amy Guo ◽  
Ashwin S. Shetty ◽  
Michelle Ko ◽  
...  
Keyword(s):  
De Novo ◽  
Disease Risk ◽  
Cell Types ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Risk Genes ◽  
Cellular Effects ◽  
Gene Modules ◽  
Conserved Gene

The number of disease risk genes and loci identified through human genetic studies far outstrips the capacity to systematically study their functions. We applied a scalable genetic screening approach, in vivo Perturb-Seq, to functionally evaluate 35 autism spectrum disorder/neurodevelopmental delay (ASD/ND) de novo loss-of-function risk genes. Using CRISPR-Cas9, we introduced frameshift mutations in these risk genes in pools, within the developing mouse brain in utero, followed by single-cell RNA-sequencing of perturbed cells in the postnatal brain. We identified cell type–specific and evolutionarily conserved gene modules from both neuronal and glial cell classes. Recurrent gene modules and cell types are affected across this cohort of perturbations, representing key cellular effects across sets of ASD/ND risk genes. In vivo Perturb-Seq allows us to investigate how diverse mutations affect cell types and states in the developing organism.

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