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Detection, interpretation, and funct...

Meyer, Kacie Jo.

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Detection, interpretation, and functional consequences of genomic copy number variation in human disease.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Detection, interpretation, and functional consequences of genomic copy number variation in human disease./
Author:	Meyer, Kacie Jo.
Description:	245 p.
Notes:	Source: Dissertation Abstracts International, Volume: 72-10, Section: B, page: .
Contained By:	Dissertation Abstracts International72-10B.
Subject:	Biology, Genetics. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3461198
ISBN:	9781124743127

Detection, interpretation, and functional consequences of genomic copy number variation in human disease.
Meyer, Kacie Jo.

Detection, interpretation, and functional consequences of genomic copy number variation in human disease. - 245 p.

Source: Dissertation Abstracts International, Volume: 72-10, Section: B, page: .

Thesis (Ph.D.)--The University of Iowa, 2011.

In recent years, microarray technology has revealed the widespread presence of submicroscopic deletions and duplications throughout the human genome termed copy number variants (CNVs). CNVs have a profound effect on gene expression and are an important source of normal genetic variation. In addition, a small proportion of CNVs contribute to genetically simple and complex disease. This thesis focuses on the identification of pathogenic CNVs contributing to the etiology of diseases with "missing heritability" using a well-planned study design individually tailored to each disease cohort to optimize CNV detection and interpretation.

ISBN: 9781124743127Subjects--Topical Terms:

1017730
Biology, Genetics.

Detection, interpretation, and functional consequences of genomic copy number variation in human disease.
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020 $a 9781124743127
035 $a (UMI)AAI3461198
035 $a AAI3461198
040 $a UMI $c UMI
100 1 $a Meyer, Kacie Jo. $3 1684995
245 1 0 $a Detection, interpretation, and functional consequences of genomic copy number variation in human disease.
300 $a 245 p.
500 $a Source: Dissertation Abstracts International, Volume: 72-10, Section: B, page: .
500 $a Adviser: Thomas H. Wassink.
502 $a Thesis (Ph.D.)--The University of Iowa, 2011.
520 $a In recent years, microarray technology has revealed the widespread presence of submicroscopic deletions and duplications throughout the human genome termed copy number variants (CNVs). CNVs have a profound effect on gene expression and are an important source of normal genetic variation. In addition, a small proportion of CNVs contribute to genetically simple and complex disease. This thesis focuses on the identification of pathogenic CNVs contributing to the etiology of diseases with "missing heritability" using a well-planned study design individually tailored to each disease cohort to optimize CNV detection and interpretation.
520 $a We performed a genome-wide analysis for CNVs in five disease cohorts with genetic etiology: autism, age-related macular degeneration (AMD), glaucoma, clubfoot, and Bardet-Biedl syndrome (BBS). Our results indicate that CNVs likely account for a proportion of cases for each disease cohort reported in this thesis. Approximately 20% of our cohort of individuals with autism from trio pedigrees harbors a CNV known to confer risk to develop autism and we identified other novel and rare variants that may play a role in autism pathogenesis. We also characterized a duplication of 2p25.3 identified in two male half-siblings with autism and determined that their mother was somatic mosaic for the duplication. Our work provides evidence that this novel CNV disrupting the genes PXDN and MYT1L are the autism-causing mutation in this pedigree. A comparative cases experimental design was used in the study of AMD and glaucoma. While no common "risk CNVs" were identified for either eye disorder, we did identify several rare overlapping CNVs disrupting genes known to play a role in the eye that may confer risk to disease in a small proportion of individuals. In a fourth genetically complex disease, clubfoot, we identified a duplication of 17q23.2 disrupting the genes TBX4, NACA2, and BRIP1 that segregates with the autosomal dominant clubfoot phenotype in a large pedigree with 16 affected individuals. In addition, the duplication is within the linkage interval identified for this family. We also applied microarray technology to analyze the genomes of individuals with BBS, an autosomal recessive disorder, for the presence of CNVs in known BBS genes as well as CNVs that elucidate novel candidate genes for BBS. From 34 BBS patients with an unidentified mutation, we observed one CNV, a heterozygous deletion of BBS10, unmasking a BBS10 frameshift mutation. A promising BBS candidate gene also emerged from our studies, implicated by an intragenic deletion of the gene MARK3 predicted to result in a frameshift and premature truncation of the protein. Functional studies utilizing antisense morpholino gene knockdown in the zebrafish provide additional evidence that MARK3 is a BBS gene as knockdown of zebrafish mark3 results in a Kupffer's Vesicle defect and a melanosome transport delay, two cardinal BBS phenotypes in the zebrafish.
520 $a In addition to identifying CNVs involved in disease, the work outlined in this thesis provides valuable insight into the study design and interpretation of a genome-wide analysis of CNV. This includes the appropriate use of controls and publicly available control databases, methods for enriching for CNVs in a patient cohort to maximize efficiency and discovery, and the importance of analyzing all patient cohorts with heritable disease for the presence of CNVs disrupting known disease genes and CNVs that implicate novel genetic candidates. As the reliability and resolution of CNV detection continue to improve, allowing detection of > 1,000 CNVs in each individual genome, it becomes more important than ever to have a well-defined study design for both the detection and interpretation of CNVs.
590 $a School code: 0096.
650 4 $a Biology, Genetics. $3 1017730
650 4 $a Health Sciences, Pathology. $3 1017854
690 $a 0369
690 $a 0571
710 2 $a The University of Iowa. $b Genetics. $3 1684996
773 0 $t Dissertation Abstracts International $g 72-10B.
790 1 0 $a Wassink, Thomas H., $e advisor
790 1 0 $a Smith, Richard J. $e committee member
790 1 0 $a Kitamoto, Toshihiro $e committee member
790 1 0 $a Dawson, Deborah V. $e committee member
790 1 0 $a Nopoulos, Peggy $e committee member
790 $a 0096
791 $a Ph.D.
792 $a 2011
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3461198