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      Tissue-Specific Genetic Control of Splicing: Implications for the Study of Complex Traits

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          Abstract

          Numerous genome-wide screens for polymorphisms that influence gene expression have provided key insights into the genetic control of transcription. Despite this work, the relevance of specific polymorphisms to in vivo expression and splicing remains unclear. We carried out the first genome-wide screen, to our knowledge, for SNPs that associate with alternative splicing and gene expression in human primary cells, evaluating 93 autopsy-collected cortical brain tissue samples with no defined neuropsychiatric condition and 80 peripheral blood mononucleated cell samples collected from living healthy donors. We identified 23 high confidence associations with total expression and 80 with alternative splicing as reflected by expression levels of specific exons. Fewer than 50% of the implicated SNPs however show effects in both tissue types, reflecting strong evidence for distinct genetic control of splicing and expression in the two tissue types. The data generated here also suggest the possibility that splicing effects may be responsible for up to 13 out of 84 reported genome-wide significant associations with human traits. These results emphasize the importance of establishing a database of polymorphisms affecting splicing and expression in primary tissue types and suggest that splicing effects may be of more phenotypic significance than overall gene expression changes.

          Author Summary

          Although humans have a relatively small complement of genes, the proteins encoded by those genes and their biologic function are far more complex. The increased complexity is achieved in part through processes that create different messages from the same gene sequence (alternative splicing) and that regulate the expression of those messages in a tissue-specific fashion. These processes expand the functional capacity of the human genome, but also can create predisposition to disease when these processes go awry. In this study, we investigated how single nucleotide polymorphisms influence both overall gene expression and alternative splicing in two important cell types (brain and blood) highly relevant to human disease. Extensive and tissue-specific regulation of gene expression and alternative splicing were observed in the two tissue types, and some of these polymorphisms were shown to be connected to other polymorphsims that have been recently implicated in human diseases through genome-wide association studies. Most of these connections appeared to relate to alternative splicing as opposed to overall expression changes, suggesting that changes in splicing patterns may be more consequential for disease than those affecting only expression. These data emphasize the importance of comprehensive studies into genetic regulation of gene expression in all human tissue types in order to help understand how genetic variation influences risk of common diseases.

          Abstract

          We investigated tissue-specific genetic control of gene expression and alternative splicing in primary human cells, and we describe here the implications for understanding how genetic variation influences human disease.

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          Most cited references15

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          Genome-wide midrange transcription profiles reveal expression level relationships in human tissue specification.

          Genes are often characterized dichotomously as either housekeeping or single-tissue specific. We conjectured that crucial functional information resides in genes with midrange profiles of expression. To obtain such novel information genome-wide, we have determined the mRNA expression levels for one of the largest hitherto analyzed set of 62 839 probesets in 12 representative normal human tissues. Indeed, when using a newly defined graded tissue specificity index tau, valued between 0 for housekeeping genes and 1 for tissue-specific genes, genes with midrange profiles having 0.15 50% of all expression patterns. We developed a binary classification, indicating for every gene the I(B) tissues in which it is overly expressed, and the 12-I(B) tissues in which it shows low expression. The 85 dominant midrange patterns with I(B)=2-11 were found to be bimodally distributed, and to contribute most significantly to the definition of tissue specification dendrograms. Our analyses provide a novel route to infer expression profiles for presumed ancestral nodes in the tissue dendrogram. Such definition has uncovered an unsuspected correlation, whereby de novo enhancement and diminution of gene expression go hand in hand. These findings highlight the importance of gene suppression events, with implications to the course of tissue specification in ontogeny and phylogeny. All data and analyses are publically available at the GeneNote website, http://genecards.weizmann.ac.il/genenote/ and, GEO accession GSE803. doron.lancet@weizmann.ac.il Four tables available at the above site.
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            Newly identified loci that influence lipid concentrations and risk of coronary artery disease.

            To identify genetic variants influencing plasma lipid concentrations, we first used genotype imputation and meta-analysis to combine three genome-wide scans totaling 8,816 individuals and comprising 6,068 individuals specific to our study (1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables) and 2,758 individuals from the Diabetes Genetics Initiative, reported in a companion study in this issue. We subsequently examined promising signals in 11,569 additional individuals. Overall, we identify strongly associated variants in eleven loci previously implicated in lipid metabolism (ABCA1, the APOA5-APOA4-APOC3-APOA1 and APOE-APOC clusters, APOB, CETP, GCKR, LDLR, LPL, LIPC, LIPG and PCSK9) and also in several newly identified loci (near MVK-MMAB and GALNT2, with variants primarily associated with high-density lipoprotein (HDL) cholesterol; near SORT1, with variants primarily associated with low-density lipoprotein (LDL) cholesterol; near TRIB1, MLXIPL and ANGPTL3, with variants primarily associated with triglycerides; and a locus encompassing several genes near NCAN, with variants strongly associated with both triglycerides and LDL cholesterol). Notably, the 11 independent variants associated with increased LDL cholesterol concentrations in our study also showed increased frequency in a sample of coronary artery disease cases versus controls.
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              Association between microdeletion and microduplication at 16p11.2 and autism.

              Autism spectrum disorder is a heritable developmental disorder in which chromosomal abnormalities are thought to play a role. As a first component of a genomewide association study of families from the Autism Genetic Resource Exchange (AGRE), we used two novel algorithms to search for recurrent copy-number variations in genotype data from 751 multiplex families with autism. Specific recurrent de novo events were further evaluated in clinical-testing data from Children's Hospital Boston and in a large population study in Iceland. Among the AGRE families, we observed five instances of a de novo deletion of 593 kb on chromosome 16p11.2. Using comparative genomic hybridization, we observed the identical deletion in 5 of 512 children referred to Children's Hospital Boston for developmental delay, mental retardation, or suspected autism spectrum disorder, as well as in 3 of 299 persons with autism in an Icelandic population; the deletion was also carried by 2 of 18,834 unscreened Icelandic control subjects. The reciprocal duplication of this region occurred in 7 affected persons in AGRE families and 4 of the 512 children from Children's Hospital Boston. The duplication also appeared to be a high-penetrance risk factor. We have identified a novel, recurrent microdeletion and a reciprocal microduplication that carry substantial susceptibility to autism and appear to account for approximately 1% of cases. We did not identify other regions with similar aggregations of large de novo mutations. Copyright 2008 Massachusetts Medical Society.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS Biol
                pbio
                plbi
                plosbiol
                PLoS Biology
                Public Library of Science (San Francisco, USA )
                1544-9173
                1545-7885
                December 2008
                23 December 2008
                : 6
                : 12
                : e1000001
                Affiliations
                [1 ] Institute for Genome Sciences & Policy, Center for Human Genome Variation, Duke University, Durham, North Carolina, United States of America
                [2 ] Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University, Durham, North Carolina, United States of America
                [3 ] Human Vaccine Institute, Duke University, Durham, North Carolina, United States of America
                Genome Institute of Singapore, Singapore
                Author notes
                * To whom correspondence should be addressed. E-mail: d.goldstein@ 123456duke.edu
                Article
                08-PLBI-RA-1982R3 plbi-06-12-25
                10.1371/journal.pbio.1000001
                2605930
                19222302
                5aa200c8-2ea8-419d-8c3e-3e883d8c5208
                Copyright: © 2008 Heinzen et al. 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.
                History
                : 19 May 2008
                : 12 November 2008
                Page count
                Pages: 11
                Categories
                Research Article
                Genetics and Genomics
                Custom metadata
                Heinzen EL, Ge D, Cronin KD, Maia JM, Shianna KV, et al. (2008) Tissue-specific genetic control of splicing: Implications for the study of complex traits. PLoS Biol 6(12): e1000001. doi: 10.1371/journal.pbio.1000001

                Life sciences
                Life sciences

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