PsyMuKB: An Integrative De Novo Variant Knowledge Base for Developmental Disorders

De novo variants (DNVs) are one of the most significant contributors to severe early-onset genetic disorders such as autism spectrum disorder, intellectual disability, and other developmental and neuropsychiatric (DNP) disorders. Presently, a plethora of DNVs have been identified using next-generation sequencing, and many efforts have been made to understand their impact at the gene level. However, there has been little exploration of the effects at the isoform level. The brain contains a high level of alternative splicing and regulation, and exhibits a more divergent splicing program than other tissues. Therefore, it is crucial to explore variants at the transcriptional regulation level to better interpret the mechanisms underlying DNP disorders. To facilitate a better usage and improve the isoform-level interpretation of variants, we developed NeuroPsychiatric Mutation Knowledge Base (PsyMuKB). It contains a comprehensive, carefully curated list of DNVs with transcriptional and translational annotations to enable identification of isoform-specific mutations. PsyMuKB allows a flexible search of genes or variants and provides both table-based descriptions and associated visualizations, such as expression, transcript genomic structures, protein interactions, and the mutation sites mapped on the protein structures. It also provides an easy-to-use web interface, allowing users to rapidly visualize the locations and characteristics of mutations and the expression patterns of the impacted genes and isoforms. PsyMuKB thus constitutes a valuable resource for identifying tissue-specific DNVs for further functional studies of related disorders. PsyMuKB is freely accessible at http://psymukb.net.

[1]  Jie Qiao,et al.  A single-cell RNA-seq survey of the developmental landscape of the human prefrontal cortex , 2018, Nature.

[2]  Insuk Lee,et al.  Characterising and Predicting Haploinsufficiency in the Human Genome , 2010, PLoS genetics.

[3]  Guan Ning Lin,et al.  De novo Mutations From Whole Exome Sequencing in Neurodevelopmental and Psychiatric Disorders: From Discovery to Application , 2019, Front. Genet..

[4]  Boris Yamrom,et al.  Rare De Novo and Transmitted Copy-Number Variation in Autistic Spectrum Disorders , 2011, Neuron.

[5]  G. Shaw,et al.  Fetal de novo mutations and preterm birth , 2017, PLoS genetics.

[6]  Serafim Batzoglou,et al.  Identifying a High Fraction of the Human Genome to be under Selective Constraint Using GERP++ , 2010, PLoS Comput. Biol..

[7]  Eric T. Wang,et al.  Alternative Isoform Regulation in Human Tissue Transcriptomes , 2008, Nature.

[8]  Christa Lese Martin,et al.  A Cross-Disorder Method to Identify Novel Candidate Genes for Developmental Brain Disorders. , 2016, JAMA psychiatry.

[9]  B. Frey,et al.  Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing , 2008, Nature Genetics.

[10]  Ryan L. Collins,et al.  An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder , 2018, Nature Genetics.

[11]  H. Hakonarson,et al.  ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data , 2010, Nucleic acids research.

[12]  Douglas L. Black,et al.  Neuronal regulation of alternative pre-mRNA splicing , 2007, Nature Reviews Neuroscience.

[13]  M. Lynch.  Rate, molecular spectrum, and consequences of human mutation , 2010, Proceedings of the National Academy of Sciences.

[14]  Benjamin J. Blencowe,et al.  Alternative Splicing in the Mammalian Nervous System: Recent Insights into Mechanisms and Functional Roles , 2015, Neuron.

[15]  Derek W Wright,et al.  Gateways to the FANTOM5 promoter level mammalian expression atlas , 2015, Genome Biology.

[16]  Stephan J Sanders,et al.  The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment , 2015, Nature Communications.

[17]  J. Knowles,et al.  The autism-associated gene chromodomain helicase DNA-binding protein 8 (CHD8) regulates noncoding RNAs and autism-related genes , 2015, Translational Psychiatry.

[18]  S. Horvath,et al.  Genetic programs in human and mouse early embryos revealed by single-cell RNA sequencing , 2013, Nature.

[19]  Dmitri D. Pervouchine,et al.  The human transcriptome across tissues and individuals , 2015, Science.

[20]  Kenny Q. Ye,et al.  Strong Association of De Novo Copy Number Mutations with Autism , 2007, Science.

[21]  P. Grabowski.  Alternative splicing takes shape during neuronal development. , 2011, Current opinion in genetics & development.

[22]  Zhong Sheng Sun,et al.  Genes with de novo mutations are shared by four neuropsychiatric disorders discovered from NPdenovo database , 2016, Molecular Psychiatry.

[23]  Doron Lancet,et al.  GeneHancer: genome-wide integration of enhancers and target genes in GeneCards , 2017, Database J. Biol. Databases Curation.

[24]  J. Harrow,et al.  Assessment of transcript reconstruction methods for RNA-seq , 2013, Nature Methods.

[25]  Cole Trapnell,et al.  Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. , 2010, Nature biotechnology.

[26]  Gary D. Bader,et al.  Cytoscape.js: a graph theory library for visualisation and analysis , 2015, Bioinform..

[27]  Rona S. Gertner,et al.  Single-cell transcriptomics reveals bimodality in expression and splicing in immune cells , 2013, Nature.

[28]  Mark Diekhans,et al.  MuPIT interactive: webserver for mapping variant positions to annotated, interactive 3D structures , 2013, Human Genetics.

[29]  J. Veltman,et al.  De novo mutations in human genetic disease , 2012, Nature Reviews Genetics.

[30]  Kara Dolinski,et al.  The BioGRID interaction database: 2017 update , 2016, Nucleic Acids Res..

[31]  J. Sebat,et al.  High Frequencies of De Novo CNVs in Bipolar Disorder and Schizophrenia , 2011, Neuron.

[32]  Jay Shendure,et al.  Disruptive CHD8 Mutations Define a Subtype of Autism Early in Development , 2014, Cell.

[33]  Michael D. Wilson,et al.  The Evolutionary Landscape of Alternative Splicing in Vertebrate Species , 2012, Science.

[34]  Joseph A. Gogos,et al.  Strong association of de novo copy number mutations with sporadic schizophrenia , 2008, Nature Genetics.

[35]  James Y. Zou.  Analysis of protein-coding genetic variation in 60,706 humans , 2015, Nature.

[36]  J. Sebat,et al.  From de novo mutations to personalized therapeutic interventions in autism. , 2015, Annual review of medicine.

[37]  Alexander Hoischen,et al.  New insights into the generation and role of de novo mutations in health and disease , 2016, Genome Biology.

[38]  S. Scherer,et al.  Whole-genome sequencing of quartet families with autism spectrum disorder , 2015, Nature Medicine.

[39]  Jeffrey D. Mandell,et al.  De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis , 2018, Cell reports.

[40]  Jan O. Korbel,et al.  Phenotypic impact of genomic structural variation: insights from and for human disease , 2013, Nature Reviews Genetics.

[41]  Jun S. Liu,et al.  The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans , 2015, Science.

[42]  Evan Z. Macosko,et al.  Molecular Diversity and Specializations among the Cells of the Adult Mouse Brain , 2018, Cell.

[43]  P. Bork,et al.  A method and server for predicting damaging missense mutations , 2010, Nature Methods.

[44]  Steven Henikoff,et al.  SIFT: predicting amino acid changes that affect protein function , 2003, Nucleic Acids Res..

[45]  J. Kleinman,et al.  Spatiotemporal transcriptome of the human brain , 2011, Nature.

[46]  P. Shannon,et al.  Analysis of Genetic Inheritance in a Family Quartet by Whole-Genome Sequencing , 2010, Science.

[47]  Raphael A. Bernier,et al.  denovo-db: a compendium of human de novo variants , 2016, Nucleic Acids Res..

[48]  Deciphering Developmental Disorders Study,et al.  Prevalence and architecture of de novo mutations in developmental disorders , 2017, Nature.

[49]  L. Vissers,et al.  Genome sequencing identifies major causes of severe intellectual disability , 2014, Nature.

[50]  Hannes P. Eggertsson,et al.  Parental influence on human germline de novo mutations in 1,548 trios from Iceland , 2017, Nature.

[51]  E. Banks,et al.  De novo mutations in schizophrenia implicate synaptic networks , 2014, Nature.

[52]  J. Shendure,et al.  A general framework for estimating the relative pathogenicity of human genetic variants , 2014, Nature Genetics.

[53]  Len A. Pennacchio,et al.  Genomic Patterns of De Novo Mutation in Simplex Autism , 2017, Cell.