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      Relationships between Gene Expression and Brain Wiring in the Adult Rodent Brain

      1 , 2 , 2 , 3 , *

      PLoS Computational Biology

      Public Library of Science

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          We studied the global relationship between gene expression and neuroanatomical connectivity in the adult rodent brain. We utilized a large data set of the rat brain “connectome” from the Brain Architecture Management System (942 brain regions and over 5000 connections) and used statistical approaches to relate the data to the gene expression signatures of 17,530 genes in 142 anatomical regions from the Allen Brain Atlas. Our analysis shows that adult gene expression signatures have a statistically significant relationship to connectivity. In particular, brain regions that have similar expression profiles tend to have similar connectivity profiles, and this effect is not entirely attributable to spatial correlations. In addition, brain regions which are connected have more similar expression patterns. Using a simple optimization approach, we identified a set of genes most correlated with neuroanatomical connectivity, and find that this set is enriched for genes involved in neuronal development and axon guidance. A number of the genes have been implicated in neurodevelopmental disorders such as autistic spectrum disorder. Our results have the potential to shed light on the role of gene expression patterns in influencing neuronal activity and connectivity, with potential applications to our understanding of brain disorders. Supplementary data are available at http://www.chibi.ubc.ca/ABAMS.

          Author Summary

          We tested the idea that the “wiring diagram” of the adult brain has a relationship with where genes are expressed. We were inspired by similar work carried out by groups examining the nematode worm Caenorhabditis elegans. By using large-scale databases of brain connectivity and gene expression in rodents, we found that many genes involved in the development of the brain show correlations with anatomical connectivity patterns. Some of the genes we found have been implicated in disorders such as autism, which is suspected to affect brain wiring. While the biological causes of the patterns we found are not yet known, we believe they provide new insight into the patterns of gene expression in the brain and will spur further study of this problem.

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          Most cited references 61

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          Structural variation of chromosomes in autism spectrum disorder.

          Structural variation (copy number variation [CNV] including deletion and duplication, translocation, inversion) of chromosomes has been identified in some individuals with autism spectrum disorder (ASD), but the full etiologic role is unknown. We performed genome-wide assessment for structural abnormalities in 427 unrelated ASD cases via single-nucleotide polymorphism microarrays and karyotyping. With microarrays, we discovered 277 unbalanced CNVs in 44% of ASD families not present in 500 controls (and re-examined in another 1152 controls). Karyotyping detected additional balanced changes. Although most variants were inherited, we found a total of 27 cases with de novo alterations, and in three (11%) of these individuals, two or more new variants were observed. De novo CNVs were found in approximately 7% and approximately 2% of idiopathic families having one child, or two or more ASD siblings, respectively. We also detected 13 loci with recurrent/overlapping CNV in unrelated cases, and at these sites, deletions and duplications affecting the same gene(s) in different individuals and sometimes in asymptomatic carriers were also found. Notwithstanding complexities, our results further implicate the SHANK3-NLGN4-NRXN1 postsynaptic density genes and also identify novel loci at DPP6-DPP10-PCDH9 (synapse complex), ANKRD11, DPYD, PTCHD1, 15q24, among others, for a role in ASD susceptibility. Our most compelling result discovered CNV at 16p11.2 (p = 0.002) (with characteristics of a genomic disorder) at approximately 1% frequency. Some of the ASD regions were also common to mental retardation loci. Structural variants were found in sufficiently high frequency influencing ASD to suggest that cytogenetic and microarray analyses be considered in routine clinical workup.
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            Autism spectrum disorders: developmental disconnection syndromes.

            Autism is a common and heterogeneous childhood neurodevelopmental disorder. Analogous to broad syndromes such as mental retardation, autism has many etiologies and should be considered not as a single disorder but, rather, as 'the autisms'. However, recent genetic findings, coupled with emerging anatomical and functional imaging studies, suggest a potential unifying model in which higher-order association areas of the brain that normally connect to the frontal lobe are partially disconnected during development. This concept of developmental disconnection can accommodate the specific neurobehavioral features that are observed in autism, their emergence during development, and the heterogeneity of autism etiology, behaviors and cognition.
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              Autism and abnormal development of brain connectivity.

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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Comput Biol
                plos
                ploscomp
                PLoS Computational Biology
                Public Library of Science (San Francisco, USA )
                1553-734X
                1553-7358
                January 2011
                January 2011
                6 January 2011
                : 7
                : 1
                Affiliations
                [1 ]Bioinformatics Graduate Program, University of British Columbia, Vancouver, British Columbia, Canada
                [2 ]Centre for High-Throughput Biology, University of British Columbia, Vancouver, British Columbia, Canada
                [3 ]Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada
                Indiana University, United States of America
                Author notes

                Conceived and designed the experiments: LF PP. Performed the experiments: LF. Analyzed the data: LF. Contributed reagents/materials/analysis tools: LF PP. Wrote the paper: LF PP.

                Article
                10-PLCB-RA-2338R3
                10.1371/journal.pcbi.1001049
                3017102
                21253556
                French, Pavlidis. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 12
                Categories
                Research Article
                Genetics and Genomics/Bioinformatics
                Genetics and Genomics/Gene Expression
                Neuroscience

                Quantitative & Systems biology

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