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A high-resolution map of segmental DNA copy number variation in the mouse genome.

Graubert TA, Cahan P, Edwin D, Selzer RR, Richmond TA, Eis PS, Shannon WD, Li X, McLeod HL, Cheverud JM, Ley TJ - PLoS Genet. (2006)

Bottom Line: In some cases, CNVs that cause gene dosage effects have been implicated in phenotypic variation.We demonstrate that this technique can identify copy number differences associated with known polymorphic traits.The phenotype of previously uncharacterized strains can be predicted based on their copy number at these loci.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Division of Oncology, Stem Cell Biology Section, Washington University, St. Louis, Missouri, United States of America. graubert@medicine.wustl.edu

ABSTRACT
Submicroscopic (less than 2 Mb) segmental DNA copy number changes are a recently recognized source of genetic variability between individuals. The biological consequences of copy number variants (CNVs) are largely undefined. In some cases, CNVs that cause gene dosage effects have been implicated in phenotypic variation. CNVs have been detected in diverse species, including mice and humans. Published studies in mice have been limited by resolution and strain selection. We chose to study 21 well-characterized inbred mouse strains that are the focus of an international effort to measure, catalog, and disseminate phenotype data. We performed comparative genomic hybridization using long oligomer arrays to characterize CNVs in these strains. This technique increased the resolution of CNV detection by more than an order of magnitude over previous methodologies. The CNVs range in size from 21 to 2,002 kb. Clustering strains by CNV profile recapitulates aspects of the known ancestry of these strains. Most of the CNVs (77.5%) contain annotated genes, and many (47.5%) colocalize with previously mapped segmental duplications in the mouse genome. We demonstrate that this technique can identify copy number differences associated with known polymorphic traits. The phenotype of previously uncharacterized strains can be predicted based on their copy number at these loci. Annotation of CNVs in the mouse genome combined with sequence-based analysis provides an important resource that will help define the genetic basis of complex traits.

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Relationship between Genomic Distance and Overlap between Segmental Duplications and CNVsThe number of CNVs that overlap at least one segmental duplication was calculated for a range of margin sizes. At a margin size of zero (complete overlap with CNV), 38 of 80 observed CNVs overlap segmental duplications. The extent of overlap between CNVs and segmental duplications (black solid line) increases with margin size. The red dotted line (expected CNVs) indicates the colocalization of segmental duplications with randomly permuted genomic regions of lengths equal to the observed CNVs. Each point of the permuted data was calculated by determining the 95th percentile of the overlap counts. The association between CNVs and segmental duplications remains significant to the 2-Mb window size (p < 0.01) and is highlighted in the yellow rectangle.
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pgen-0030003-g006: Relationship between Genomic Distance and Overlap between Segmental Duplications and CNVsThe number of CNVs that overlap at least one segmental duplication was calculated for a range of margin sizes. At a margin size of zero (complete overlap with CNV), 38 of 80 observed CNVs overlap segmental duplications. The extent of overlap between CNVs and segmental duplications (black solid line) increases with margin size. The red dotted line (expected CNVs) indicates the colocalization of segmental duplications with randomly permuted genomic regions of lengths equal to the observed CNVs. Each point of the permuted data was calculated by determining the 95th percentile of the overlap counts. The association between CNVs and segmental duplications remains significant to the 2-Mb window size (p < 0.01) and is highlighted in the yellow rectangle.

Mentions: We also tested a range of margin sizes, defined as the number of base pairs flanking a CNV in either direction, since a direct overlap between a CNV and segmental duplication may not be necessary for CNV genesis. The association remained significant (p < 0.01) up to 2 Mb, providing an estimate of the upper limit at which segmental duplications may affect CNVs (Figure 6). The high proportion of CNVs colocalizing with segmental duplications (94% at 2 Mb) can be interpreted as a bias in our CNV identification methodology or as support for a strong, almost necessary, role of segmental duplications in CNV generation. The distance between CNVs and segmental duplications is an important parameter of the mechanism driving segmental duplication–mediated CNV creation. Because some experimental approaches search for CNVs only in segmental duplication regions [18], it is also important to know the distribution of CNV–to–segmental duplication distances so that all potential CNV-containing regions can be screened.


A high-resolution map of segmental DNA copy number variation in the mouse genome.

Graubert TA, Cahan P, Edwin D, Selzer RR, Richmond TA, Eis PS, Shannon WD, Li X, McLeod HL, Cheverud JM, Ley TJ - PLoS Genet. (2006)

Relationship between Genomic Distance and Overlap between Segmental Duplications and CNVsThe number of CNVs that overlap at least one segmental duplication was calculated for a range of margin sizes. At a margin size of zero (complete overlap with CNV), 38 of 80 observed CNVs overlap segmental duplications. The extent of overlap between CNVs and segmental duplications (black solid line) increases with margin size. The red dotted line (expected CNVs) indicates the colocalization of segmental duplications with randomly permuted genomic regions of lengths equal to the observed CNVs. Each point of the permuted data was calculated by determining the 95th percentile of the overlap counts. The association between CNVs and segmental duplications remains significant to the 2-Mb window size (p < 0.01) and is highlighted in the yellow rectangle.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1761046&req=5

pgen-0030003-g006: Relationship between Genomic Distance and Overlap between Segmental Duplications and CNVsThe number of CNVs that overlap at least one segmental duplication was calculated for a range of margin sizes. At a margin size of zero (complete overlap with CNV), 38 of 80 observed CNVs overlap segmental duplications. The extent of overlap between CNVs and segmental duplications (black solid line) increases with margin size. The red dotted line (expected CNVs) indicates the colocalization of segmental duplications with randomly permuted genomic regions of lengths equal to the observed CNVs. Each point of the permuted data was calculated by determining the 95th percentile of the overlap counts. The association between CNVs and segmental duplications remains significant to the 2-Mb window size (p < 0.01) and is highlighted in the yellow rectangle.
Mentions: We also tested a range of margin sizes, defined as the number of base pairs flanking a CNV in either direction, since a direct overlap between a CNV and segmental duplication may not be necessary for CNV genesis. The association remained significant (p < 0.01) up to 2 Mb, providing an estimate of the upper limit at which segmental duplications may affect CNVs (Figure 6). The high proportion of CNVs colocalizing with segmental duplications (94% at 2 Mb) can be interpreted as a bias in our CNV identification methodology or as support for a strong, almost necessary, role of segmental duplications in CNV generation. The distance between CNVs and segmental duplications is an important parameter of the mechanism driving segmental duplication–mediated CNV creation. Because some experimental approaches search for CNVs only in segmental duplication regions [18], it is also important to know the distribution of CNV–to–segmental duplication distances so that all potential CNV-containing regions can be screened.

Bottom Line: In some cases, CNVs that cause gene dosage effects have been implicated in phenotypic variation.We demonstrate that this technique can identify copy number differences associated with known polymorphic traits.The phenotype of previously uncharacterized strains can be predicted based on their copy number at these loci.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Division of Oncology, Stem Cell Biology Section, Washington University, St. Louis, Missouri, United States of America. graubert@medicine.wustl.edu

ABSTRACT
Submicroscopic (less than 2 Mb) segmental DNA copy number changes are a recently recognized source of genetic variability between individuals. The biological consequences of copy number variants (CNVs) are largely undefined. In some cases, CNVs that cause gene dosage effects have been implicated in phenotypic variation. CNVs have been detected in diverse species, including mice and humans. Published studies in mice have been limited by resolution and strain selection. We chose to study 21 well-characterized inbred mouse strains that are the focus of an international effort to measure, catalog, and disseminate phenotype data. We performed comparative genomic hybridization using long oligomer arrays to characterize CNVs in these strains. This technique increased the resolution of CNV detection by more than an order of magnitude over previous methodologies. The CNVs range in size from 21 to 2,002 kb. Clustering strains by CNV profile recapitulates aspects of the known ancestry of these strains. Most of the CNVs (77.5%) contain annotated genes, and many (47.5%) colocalize with previously mapped segmental duplications in the mouse genome. We demonstrate that this technique can identify copy number differences associated with known polymorphic traits. The phenotype of previously uncharacterized strains can be predicted based on their copy number at these loci. Annotation of CNVs in the mouse genome combined with sequence-based analysis provides an important resource that will help define the genetic basis of complex traits.

Show MeSH
Related in: MedlinePlus