The fine-scale and complex architecture of human copy-number variation.
Despite considerable excitement over the potential functional significance of copy-number variants (CNVs), we still lack knowledge of the fine-scale architecture of the large majority of CNV regions in the human genome. In this study, we used a high-resolution array-based comparative genomic hybridization (aCGH) platform that targeted known CNV regions of the human genome at approximately 1 kb resolution to interrogate the genomic DNAs of 30 individuals from four HapMap populations. Our results revealed that 1020 of 1153 CNV loci (88%) were actually smaller in size than what is recorded in the Database of Genomic Variants based on previously published studies. A reduction in size of more than 50% was observed for 876 CNV regions (76%). We conclude that the total genomic content of currently known common human CNVs is likely smaller than previously thought. In addition, approximately 8% of the CNV regions observed in multiple individuals exhibited genomic architectural complexity in the form of smaller CNVs within larger ones and CNVs with interindividual variation in breakpoints. Future association studies that aim to capture the potential influences of CNVs on disease phenotypes will need to consider how to best ascertain this previously uncharacterized complexity.
Perry
George H
GH
Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
Ben-Dor
Amir
A
Tsalenko
Anya
A
Sampas
Nick
N
Rodriguez-Revenga
Laia
L
Tran
Charles W
CW
Scheffer
Alicia
A
Steinfeld
Israel
I
Tsang
Peter
P
Yamada
N Alice
NA
Park
Han Soo
HS
Kim
Jong-Il
JI
Seo
Jeong-Sun
JS
Yakhini
Zohar
Z
Laderman
Stephen
S
Bruhn
Laurakay
L
Lee
Charles
C
D018628:Gene Dosage; D014644:Genetic Variation; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D020080:Tandem Repeat Sequences