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Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.

Cell | Oct 6, 2016

Comparative analyses have identified genomic regions potentially involved in human evolution but do not directly assess function. Human accelerated regions (HARs) represent conserved genomic loci with elevated divergence in humans. If some HARs regulate human-specific social and behavioral traits, then mutations would likely impact cognitive and social disorders. Strikingly, rare biallelic point mutations-identified by whole-genome and targeted "HAR-ome" sequencing-showed a significant excess in individuals with ASD whose parents share common ancestry compared to familial controls, suggesting a contribution in 5% of consanguineous ASD cases. Using chromatin interaction sequencing, massively parallel reporter assays (MPRA), and transgenic mice, we identified disease-linked, biallelic HAR mutations in active enhancers for CUX1, PTBP2, GPC4, CDKL5, and other genes implicated in neural function, ASD, or both. Our data provide genetic evidence that specific HARs are essential for normal development, consistent with suggestions that their evolutionary changes may have altered social and/or cognitive behavior. PAPERCLIP.

Pubmed ID: 27667684 RIS Download

Mesh terms: Alleles | Animals | Autism Spectrum Disorder | Cerebral Cortex | Cognition | Gene Dosage | Genetic Predisposition to Disease | Genetic Variation | Genome, Human | Homeodomain Proteins | Humans | Introns | Mice | Mice, Transgenic | Neurogenesis | Nuclear Proteins | Point Mutation | Quantitative Trait Loci | Regulatory Elements, Transcriptional | Repressor Proteins | Social Behavior

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This is a list of tools and resources that we have found mentioned in this publication.


UCSC Genome Browser

A collection of genomes which include reference sequences and working draft assemblies, as well as a variety of tools to explore these sequences. The Genome Browser zooms and scrolls over chromosomes, showing the work of annotators worldwide. The Gene Sorter shows expression, homology and other information on groups of genes that can be related in many ways. Blat quickly maps your sequence to the genome. The Table Browser provides access to the underlying database. VisiGene lets you browse through a large collection of in situ mouse and frog images to examine expression patterns. Genome Graphs allows you to upload and display genome-wide data sets. Also provided is a portal to the Encyclopedia of DNA Elements (ENCODE) and Neandertal projects.

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Primer3Plus

A web interface to the Primer3 primer design program as an enhanced alternative for the CGI- scripts that come with Primer3.

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CLC Genomics Workbench

A comprehensive and user-friendly analysis package for analyzing, comparing, and visualizing next generation sequencing data.

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PolyPhen-2

A tool which predicts possible impact of an amino acid substitution on the structure and function of a human protein using straightforward physical and comparative considerations. It is a second version of PolyPhen:Polymorphism Phenotyping.

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PHAST

A freely available software package for comparative and evolutionary genomics that consists of about half a dozen major programs, plus more than a dozen utilities for manipulating sequence alignments, phylogenetic trees, and genomic annotations. For the most part, PHAST focuses on two kinds of applications: the identification of novel functional elements, including protein-coding exons and evolutionarily conserved sequences; and statistical phylogenetic modeling, including estimation of model parameters, detection of signatures of selection, and reconstruction of ancestral sequences. It consists of over 60,000 lines of C code.

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BEDTools

A powerful toolset for genome arithmetic allowing one to address common genomics tasks such as finding feature overlaps and computing coverage. Bedtools allows one to intersect, merge, count, complement, and shuffle genomic intervals from multiple files in widely-used genomic file formats such as BAM, BED, GFF/GTF, VCF. While each individual tool is designed to do a relatively simple task (e.g., intersect two interval files), quite sophisticated analyses can be conducted by combining multiple bedtools operations on the UNIX command line.

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Enrichr

A web-based gene list enrichment analysis tool that provides various types of visualization summaries of collective functions of gene lists. It includes new gene-set libraries, an alternative approach to rank enriched terms, and various interactive visualization approaches to display enrichment results using the JavaScript library, Data Driven Documents (D3). The software can also be embedded into any tool that performs gene list analysis. System-wide profiling of genes and proteins in mammalian cells produce lists of differentially expressed genes / proteins that need to be further analyzed for their collective functions in order to extract new knowledge. Once unbiased lists of genes or proteins are generated from such experiments, these lists are used as input for computing enrichment with existing lists created from prior knowledge organized into gene-set libraries.

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ANNOVAR

An efficient software tool to utilize update-to-date information to functionally annotate genetic variants detected from diverse genomes (including human genome hg18, hg19, as well as mouse, worm, fly, yeast and many others). Given a list of variants with chromosome, start position, end position, reference nucleotide and observed nucleotides, ANNOVAR can perform: 1. gene-based annotation. 2. region-based annotation. 3. filter-based annotation. 4. other functionalities. (entry from Genetic Analysis Software)

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EMBOSS CpGPlot/CpGReport/Isochore

This portal allows for the detection of regions of genomic sequences that are rich in the CpG pattern is important because such regions are resistant to methylation and tend to be associated with genes which are frequently switched on. Regions rich in the CpG pattern are known as CpG islands. The function of the program cpgplot is to plot CpG rich areas, and cpgreport to report all CpG rich regions. The nuclear genomes of vertebrates are mosaics of isochores, very long stretches of DNA that are homogeneous in base composition and are compositionally correlated with the coding sequences that they embed. Isochores can be partitioned in a small number of families that cover a range of GC levels. Program isochore plots GC content over a sequence. Sponsors: This resource is supported by European Bioinformatics Institute. Keywords: Software, Plotting, Pattern, CpG, Gene, Function, Isochore, DNA, Genome, Homogeneous, Coding, Sequence, Family, Sequencing,

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SAMTOOLS

Software tool for manipulating alignments in SAM format for storing nucleotide sequence alignment, including sorting, merging, indexing and generating alignments in per position format. Parts that are relevant to genetic analysis include SNP and indel callings.

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TRANSFAC

Database that contains data on eukaryotic transcription factors, their experimentally-proven binding sites, consensus binding sequences (positional weight matrices) and regulated genes. Its broad compilation of binding sites allows the derivation of positional weight matrices. The TRANSFAC programs use the integrated matrices and site sequences in TRANSFAC to perform matrix-or pattern-based searches of factor binding sites in regulatory DNA sequences. Thus, it is possible to make predictions for most gene promoters, which have not been studied in detail yet. TRANSFAC also includes a tool to automatically visualize gene-regulatory networks being based on interlinked factor and gene entries in the database (gene regulation and gene expression). In addition, TRANSFAC contains * Extensive information on transcription factors and their structures, functions, expression patterns * In-vivo binding sequences from ChIP on chip experiments

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SICER

A clustering software package for identification of enriched domains from histone modification ChIP-Seq data.

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BWA

Software for aligning sequencing reads against large reference genome. Consists of three algorithms: one for sequence reads up to 100bp, and other two for longer sequences ranged from 70bp to 1Mbp.

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SIFT

Data analysis service to predict whether an amino acid substitution affects protein function based on sequence homology and the physical properties of amino acids. SIFT can be applied to naturally occurring nonsynonymous polymorphisms and laboratory-induced missense mutations. (entry from Genetic Analysis Software) Web service is also available.

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Database for Annotation Visualization and Integrated Discovery

A database which provides a comprehensive set of functional annotation tools for investigators to understand biological meaning behind large list of genes. For any given gene list, DAVID tools are able to perform a variety of actions such as identifying enriched biological themes (particularly GO terms), discovering enriched functional-related gene groups, clustering redundant annotation terms, and visualizing genes on BioCarta and KEGG pathway maps.

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FASTX-Toolkit

Source codes of command line software for Short-Reads FASTA/FASTQ files preprocessing.

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Roadmap Epigenomics Project

A public resource of human epigenomic data from experimental pipelines built around next-generation sequencing technologies to map DNA methylation, histone modifications, chromatin accessibility and small RNA transcripts in stem cells and primary ex vivo tissues selected to represent the normal counterparts of tissues and organ systems frequently involved in human disease. The Consortium expects to deliver a collection of normal epigenomes that will provide a framework or reference for comparison and integration within a broad array of future studies. The Consortium also aims to close the gap between data generation and its public dissemination by rapid release of raw sequence data, profiles of epigenomics features and higher-level integrated maps to the scientific community. The Consortium is also committed to the development, standardization and dissemination of protocols, reagents and analytical tools to enable the research community to utilize, integrate and expand upon this body of data. Epigenetics is an emerging frontier of science that involves the study of changes in the regulation of gene activity and expression that are not dependent on gene sequence. For purposes of this program, epigenetics refers to both heritable changes in gene activity and expression (in the progeny of cells or of individuals) and also stable, long-term alterations in the transcriptional potential of a cell that are not necessarily heritable. While epigenetics refers to the study of single genes or sets of genes, epigenomics refers to more global analyses of epigenetic changes across the entire genome. The overall hypothesis of the NIH Roadmap Epigenomics Program is that the origins of health and susceptibility to disease are, in part, the result of epigentic regulation of the genetic blueprint. Specifically, epigenetic mechanisms that control stem cell differentiation and organogensis contribute to the biological response to endogenous and exogenous forms of stimuli that result in disease. The Roadmap Epigenomics Program proposes to: (1) create an international committee; (2) develop standardized platforms, procedures, and reagents for epigenomics research; (3) conduct demonstration projects to evaluate how epigenomes change; (4) develop new technologies for single cell epigenomic analysis and in vivo imaging of epigenetic activity; and (5) create a public data resource to accelerate the application of epigenomics approaches. Transforming biomedical research in the following ways:* Develop comprehensive reference epigenome maps * Develop new technologies for comprehensive epigenomic analyses A series of five interrelated initiatives are currently being developed under this program.

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Geneious

Software for beautiful sequence alignment, assembly and analysis.

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MutationTaster

Evaluates disease-causing potential of sequence alterations.

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PolyPhen: Polymorphism Phenotyping

Software tool which predicts possible impact of an amino acid substitution on the structure and function of a human protein using straightforward physical and comparative considerations. PolyPhen-2 is a new development of the PolyPhen tool for annotating coding nonsynonymous SNPs.

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Encode

Consortium to build a comprehensive parts list of functional elements in the human genome. This includes elements that act at the protein and RNA levels, and regulatory elements that control cells and circumstances in which a gene is active.

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