scholarly journals Unified inference of missense variant effects and gene constraints in the human genome

2019 ◽  
Author(s):  
Yi-Fei Huang
Keyword(s):  
Negative Selection ◽  
Random Effect ◽  
Evolutionary Model ◽  
Missense Variant ◽  
Autism Spectrum ◽  
Human Populations ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Selective Constraints ◽  
Gene Level

A challenge in medical genomics is to identify variants and genes associated with severe genetic disorders. Based on the premise that severe, early-onset disorders often result in a reduction of evolutionary fitness, several statistical methods have been developed to predict pathogenic variants or constrained genes based on the signatures of negative selection in human populations. However, we currently lack a statistical framework to jointly predict deleterious variants and constrained genes from both variant-level features and gene-level selective constraints. Here we present such a unified approach, UNEECON, based on deep learning and population genetics. UNEECON treats the contributions of variant-level features and gene-level constraints as a variant-level fixed effect and a gene-level random effect, respectively. The sum of the fixed and random effects is then combined with an evolutionary model to infer the strength of negative selection at both variant and gene levels. Compared with previously published methods, UNEECON shows unmatched performance in predicting missense variants and protein-coding genes associated with autosomal dominant disorders, and feature importance analysis suggests that both gene-level selective constraints and variant-level predictors are important for accurate variant prioritization. Furthermore, based on UNEECON, we observe an unexpected low correlation between gene-level intolerance to missense mutations and that to loss-of-function mutations, which can be partially explained by the prevalence of disordered protein regions that are highly tolerant to missense mutations. Finally, we show that genes intolerant to both missense and loss-of-function mutations play key roles in the central nervous system and the autism spectrum disorders. Overall, UNEECON is a promising framework for both variant and gene prioritization.

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 A Novel Missense Variant of HOXD13 Caused Atypical Synpolydactyly by Impairing the Downstream Gene Expression and Literature Review for Genotype–Phenotype Correlations

2021 ◽  
Vol 12 ◽  
Author(s):  
Ruiji Guo ◽  
Xia Fang ◽  
Hailei Mao ◽  
Bin Sun ◽  
Jiateng Zhou ◽  
...  
Keyword(s):  
Limb Development ◽  
Missense Variant ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Phenotype Correlation ◽  
Mutation Site ◽  
Genotype Phenotype Correlation ◽  
Α Helix ◽  
Severe Degree ◽  
Hands And Feet

Synpolydactyly (SPD) is a hereditary congenital limb malformation with distinct syndactyly designated as SPD1, SPD2, and SPD3. SPD1 is caused by mutations of HOXD13, which is a homeobox transcription factor crucial for limb development. More than 143 SPD patients have been reported to carry HOXD13 mutations, but there is a lack of genotype–phenotype correlation. We report a novel missense mutation of c. 925A > T (p.I309F) in an individual with atypical synpolydactyly inherited from her father with mild clinodactyly and three other different alanine insertion mutations in HOXD13 identified by whole exome sequencing (WES) in 12 Chinese SPD families. Unlike polyalanine extension, which tends to form α-helix and causes protein aggregation in the cytoplasm as shown by molecular simulation and immunofluorescence, the c. 925A > T mutation impairs downstream transcription of EPHA7. We compiled literature findings and analyzed genotype–phenotype features in 173 SPD individuals of 53 families, including 12 newly identified families. Among the HOXD13-related individuals, mutations were distributed in three regions: polyalanine, homeobox, and non-homeobox. Polyalanine extension was the most common variant (45%), followed by missense mutations (32%) mostly in the homeobox compared with the loss-of-function (LOF) variants more likely in non-homeobox. Furthermore, a more severe degree and classic SPD were associated with polyalanine mutations although missense variants were associated with brachydactyly and syndactyly in hands and feet and LOF variants with clinodactyly in hands. Our study broadens the HOXD13 mutation spectrum and reveals the profile of three different variants and their severity of SPD, the genotype–phenotype correlation related to the HOXD13 mutation site provides clinical insight, including for genetic counseling.

scholarly journals Evolutionary Action of de novo Missense Variants across Pathways Prioritizes Genes Linked to Autism and Predicts Patient Phenotypic Severity

2017 ◽  
Author(s):  
Amanda Koire ◽  
Christie Buchovecky ◽  
Panagiotis Katsonis ◽  
Young Won Kim ◽  
Stephen J. Wilson ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Synaptic Transmission ◽  
De Novo ◽  
Missense Variant ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Integrative Approach ◽  
Missense Mutations ◽  
Functional Impact ◽  
Missense Variants

AbstractThe pathogenicity of individual de novo missense mutations in autism spectrum disorder remains difficult to validate. Here we asked in 2,384 probands whether these variants exhibited collective functional impact biases across pathways. As measured with Evolutionary Action (EA) in 368 gene groupings, we found significant biases in axonogenesis, synaptic transmission, and other neurodevelopmental pathways. Strikingly, both de novo and inherited missense variants in prioritized genes correlated with patient IQ. This general integrative approach thus detects missense variants most likely to contribute to autism pathogenesis and is the first, to our knowledge, to link missense variant impact to autism phenotypic severity.

scholarly journals Systematic phenomics analysis of autism-associated genes reveals parallel networks underlying reversible impairments in habituation

2019 ◽  
Vol 117 (1) ◽  
pp. 656-667 ◽  
Author(s):  
Troy A. McDiarmid ◽  
Manuel Belmadani ◽  
Joseph Liang ◽  
Fabian Meili ◽  
Eleanor A. Mathews ◽  
...  
Keyword(s):  
Vision System ◽  
Missense Variant ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
C Elegans ◽  
Learning Impairments ◽  
Functional Assays ◽  
Epistasis Analysis ◽  
Parallel Networks

A major challenge facing the genetics of autism spectrum disorders (ASDs) is the large and growing number of candidate risk genes and gene variants of unknown functional significance. Here, we usedCaenorhabditis elegansto systematically functionally characterize ASD-associated genes in vivo. Using our custom machine vision system, we quantified 26 phenotypes spanning morphology, locomotion, tactile sensitivity, and habituation learning in 135 strains each carrying a mutation in an ortholog of an ASD-associated gene. We identified hundreds of genotype–phenotype relationships ranging from severe developmental delays and uncoordinated movement to subtle deficits in sensory and learning behaviors. We clustered genes by similarity in phenomic profiles and used epistasis analysis to discover parallel networks centered onCHD8•chd-7andNLGN3•nlg-1that underlie mechanosensory hyperresponsivity and impaired habituation learning. We then leveraged our data for in vivo functional assays to gauge missense variant effect. Expression of wild-type NLG-1 innlg-1mutantC. elegansrescued their sensory and learning impairments. Testing the rescuing ability of conserved ASD-associated neuroligin variants revealed varied partial loss of function despite proper subcellular localization. Finally, we used CRISPR-Cas9 auxin-inducible degradation to determine that phenotypic abnormalities caused by developmental loss of NLG-1 can be reversed by adult expression. This work charts the phenotypic landscape of ASD-associated genes, offers in vivo variant functional assays, and potential therapeutic targets for ASD.

scholarly journals Systematic phenomics analysis of ASD-associated genes reveals shared functions and parallel networks underlying reversible impairments in habituation learning

2019 ◽  
Author(s):  
Troy A. McDiarmid ◽  
Manuel Belmadani ◽  
Joseph Liang ◽  
Fabian Meili ◽  
Eleanor A. Mathews ◽  
...  
Keyword(s):  
Vision System ◽  
Missense Variant ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
C Elegans ◽  
Learning Impairments ◽  
Functional Assays ◽  
Epistasis Analysis ◽  
Parallel Networks

SUMMARYA major challenge facing the genetics of Autism Spectrum Disorders (ASD) is the large and growing number of candidate risk genes and gene variants of unknown functional significance. Here, we used Caenorhabditis elegans to systematically functionally characterize ASD-associated genes in vivo. Using our custom machine vision system we quantified 26 phenotypes spanning morphology, locomotion, tactile sensitivity, and habituation learning in 87 strains each carrying a mutation in an ortholog of an ASD-associated gene. We identified hundreds of novel genotype-phenotype relationships ranging from severe developmental delays and uncoordinated movement to subtle deficits in sensory and learning behaviors. We clustered genes by similarity in phenomic profiles and used epistasis analysis to discover parallel networks centered on CHD8•chd-7 and NLGN3•nlg-1 that underlie mechanosensory hyper-responsivity and impaired habituation learning. We then leveraged our data for in vivo functional assays to gauge missense variant effect. Expression of wild-type NLG-1 in nlg-1 mutant C. elegans rescued their sensory and learning impairments. Testing the rescuing ability of all conserved ASD-associated neuroligin variants revealed varied partial loss-of-function despite proper subcellular localization. Finally, we used CRISPR-Cas9 auxin inducible degradation to determine that phenotypic abnormalities caused by developmental loss of NLG-1 can be reversed by adult expression. This work charts the phenotypic landscape of ASD-associated genes, offers novel in vivo variant functional assays, and potential therapeutic targets for ASD.

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 Common homozygosity for predicted loss-of-function variants reveals both redundant and advantageous effects of dispensable human genes

2020 ◽  
Vol 117 (24) ◽  
pp. 13626-13636 ◽  
Author(s):  
Antonio Rausell ◽  
Yufei Luo ◽  
Marie Lopez ◽  
Yoann Seeleuthner ◽  
Franck Rapaport ◽  
...  
Keyword(s):  
Olfactory Receptor ◽  
Human Population ◽  
Parasitic Infections ◽  
Human Populations ◽  
Loss Of Function ◽  
Selective Constraints ◽  
Manual Curation ◽  
Y Chromosomes ◽  
Human Genes ◽  
Olfactory Receptor Genes

Humans homozygous or hemizygous for variants predicted to cause a loss of function (LoF) of the corresponding protein do not necessarily present with overt clinical phenotypes. We report here 190 autosomal genes with 207 predicted LoF variants, for which the frequency of homozygous individuals exceeds 1% in at least one human population from five major ancestry groups. No such genes were identified on the X and Y chromosomes. Manual curation revealed that 28 variants (15%) had been misannotated as LoF. Of the 179 remaining variants in 166 genes, only 11 alleles in 11 genes had previously been confirmed experimentally to be LoF. The set of 166 dispensable genes was enriched in olfactory receptor genes (41 genes). The 41 dispensable olfactory receptor genes displayed a relaxation of selective constraints similar to that observed for other olfactory receptor genes. The 125 dispensable nonolfactory receptor genes also displayed a relaxation of selective constraints consistent with greater redundancy. Sixty-two of these 125 genes were found to be dispensable in at least three human populations, suggesting possible evolution toward pseudogenes. Of the 179 LoF variants, 68 could be tested for two neutrality statistics, and 8 displayed robust signals of positive selection. These latter variants included a knownFUT2variant that confers resistance to intestinal viruses, and anAPOL3variant involved in resistance to parasitic infections. Overall, the identification of 166 genes for which a sizeable proportion of humans are homozygous for predicted LoF alleles reveals both redundancies and advantages of such deficiencies for human survival.

scholarly journals Multi-model functionalization of disease-associated PTEN missense mutations identifies multiple molecular mechanisms underlying protein dysfunction

2019 ◽  
Author(s):  
Kathryn L. Post ◽  
Manuel Belmadani ◽  
Payel Ganguly ◽  
Fabian Meili ◽  
Riki Dingwall ◽  
...  
Keyword(s):  
Protein Function ◽  
Molecular Mechanisms ◽  
Autism Spectrum ◽  
Model Systems ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Neuronal Morphogenesis ◽  
Full Characterization ◽  
Protein Functions ◽  
Mutation Impact

ABSTRACTFunctional variomics provides the foundation for personalized medicine by linking genetic variation to disease expression, outcome and treatment, yet its utility is dependent on appropriate assays to evaluate mutation impact on protein function. To fully assess the effects of 106 missense and nonsense variants of PTEN associated with autism spectrum disorder, somatic cancer and PHTS, we take a deep phenotypic profiling approach using 18 assays in 5 model systems spanning diverse cellular environments ranging from molecular function to neuronal morphogenesis and behavior. Variants inducing instability occurred across the protein, resulting in partial to complete loss of function (LoF), which was well correlated across models. However, assays were selectively sensitive to variants located in substrate binding and catalytic domains, which exhibited complete LoF or dominant negativity independent of effects on stability. Our results indicate that full characterization of variant impact requires assays sensitive to instability and a range of protein functions.

scholarly journals Evidence of mild founder LMOD3 mutations causing nemaline myopathy 10 in Germany and Austria

Neurology ◽  
2018 ◽  
Vol 91 (18) ◽  
pp. e1690-e1694 ◽  
Author(s):  
Ulrich A. Schatz ◽  
Simone Weiss ◽  
Stephan Wenninger ◽  
Benedikt Schoser ◽  
Wolfgang H. Muss ◽  
...  
Keyword(s):  
Early Death ◽  
Missense Variant ◽  
Nemaline Myopathy ◽  
Severe Form ◽  
Missense Mutations ◽  
Disease Course ◽  
Loss Of Function ◽  
Mild Disease ◽  
Upper Austria ◽  
Severe Clinical Picture

ObjectiveTo expand the clinical and genetic spectrum of nemaline myopathy 10 by a series of Austrian and German patients with a milder disease course and missense mutations in LMOD3.MethodsWe characterized the clinical features and the genetic status of 4 unrelated adolescent or adult patients with nemaline myopathy.ResultsThe 4 patients showed a relatively mild disease course. They all have survived into adulthood, 3 of 4 have remained ambulatory, and all showed marked facial weakness. Muscle biopsy specimens gave evidence of nemaline bodies. All patients were unrelated but originated from Austria (Tyrol and Upper Austria) and Southern Germany (Bavaria). All patients carried the missense variant c.1648C>T, p.(Leu550Phe) in the LMOD3 gene, either on both alleles or in trans with another missense variant (c.1004A>G, p.Gln335Arg). Both variants were not reported previously.ConclusionsIn 2014, a severe form of congenital nemaline myopathy caused by disrupting mutations in LMOD3 was identified and denoted as NEM10. Unlike the previously reported patients, who had a severe clinical picture with a substantial risk of early death, our patients showed a relatively mild disease course. As the missense variant c.1648C>T is located further downstream compared to all previously published LMOD3 mutations, it might be associated with higher protein expression compared to the reported loss-of-function mutations. The apparent clusters of 2 mild mutations in Germany and Austria in 4 unrelated families may be explained by a founder effect.

scholarly journals High Functioning Autism with Missense Mutations in Synaptotagmin-Like Protein 4 (SYTL4) and Transmembrane Protein 187 (TMEM187) Genes: SYTL4- Protein Modeling, Protein-Protein Interaction, Expression Profiling and MicroRNA Studies

2019 ◽  
Vol 20 (13) ◽  
pp. 3358 ◽  
Author(s):  
Syed K. Rafi ◽  
Alberto Fernández-Jaén ◽  
Sara Álvarez ◽  
Owen W. Nadeau ◽  
Merlin G. Butler
Keyword(s):  
Autism Spectrum Disorder ◽  
High Functioning Autism ◽  
Transmembrane Protein ◽  
Missense Variant ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Target Cells ◽  
Missense Mutations ◽  
Sequence Alignments ◽  
High Functioning

We describe a 7-year-old male with high functioning autism spectrum disorder (ASD) and maternally-inherited rare missense variant of Synaptotagmin-like protein 4 (SYTL4) gene (Xq22.1; c.835C>T; p.Arg279Cys) and an unknown missense variant of Transmembrane protein 187 (TMEM187) gene (Xq28; c.708G>T; p. Gln236His). Multiple in-silico predictions described in our study indicate a potentially damaging status for both X-linked genes. Analysis of predicted atomic threading models of the mutant and the native SYTL4 proteins suggest a potential structural change induced by the R279C variant which eliminates the stabilizing Arg279-Asp60 salt bridge in the N-terminal half of the SYTL4, affecting the functionality of the protein’s critical RAB-Binding Domain. In the European (Non-Finnish) population, the allele frequency for this variant is 0.00042. The SYTL4 gene is known to directly interact with several members of the RAB family of genes, such as, RAB27A, RAB27B, RAB8A, and RAB3A which are known autism spectrum disorder genes. The SYTL4 gene also directly interacts with three known autism genes: STX1A, SNAP25 and STXBP1. Through a literature-based analytical approach, we identified three of five (60%) autism-associated serum microRNAs (miRs) with high predictive power among the total of 298 mouse Sytl4 associated/predicted microRNA interactions. Five of 13 (38%) miRs were differentially expressed in serum from ASD individuals which were predicted to interact with the mouse equivalent Sytl4 gene. TMEM187 gene, like SYTL4, is a protein-coding gene that belongs to a group of genes which host microRNA genes in their introns or exons. The novel Q236H amino acid variant in the TMEM187 in our patient is near the terminal end region of the protein which is represented by multiple sequence alignments and hidden Markov models, preventing comparative structural analysis of the variant harboring region. Like SYTL4, the TMEM187 gene is expressed in the brain and interacts with four known ASD genes, namely, HCFC1; TMLHE; MECP2; and GPHN. TMM187 is in linkage with MECP2, which is a well-known determinant of brain structure and size and is a well-known autism gene. Other members of the TMEM gene family, TMEM132E and TMEM132D genes are associated with bipolar and panic disorders, respectively, while TMEM231 is a known syndromic autism gene. Together, TMEM187 and SYTL4 genes directly interact with recognized important ASD genes, and their mRNAs are found in extracellular vesicles in the nervous system and stimulate target cells to translate into active protein. Our evidence shows that both these genes should be considered as candidate genes for autism. Additional biological testing is warranted to further determine the pathogenicity of these gene variants in the causation of autism.

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