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MBE Advance Access published online on September 12, 2008
Molecular Biology and Evolution, doi:10.1093/molbev/msn202
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© The Author 2008. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

How segmental duplications shape our genome: recent evolution of ABCC6 and PKD1 Mendelian disease genes

Orsolya Symmons, András Váradi and Tamás Arányi

Institute of Enzymology, Hungarian Academy of Sciences

Corresponding author: Tamás Arányi, mailing address: Institute of Enzymology, Hungarian Academy of Sciences, 1113 Budapest, Karolina út 29, Hungary, E-mail: aranyi{at}enzim.hu, Tel.: +3612793149, Fax:+3614665465

Received for publication May 22, 2008. Revision received September 2, 2008. Accepted for publication September 8, 2008.

The completion of the Human Genome Project has brought the understanding that our genome contains an unexpectedly large proportion of segmental duplications. This poses the challenge of elucidating the consequences of recent duplications on physiology. We have conducted an in-depth study of a subset of segmental duplications on chromosome 16. We focused on PKD1 and ABCC6 duplications, because mutations affecting these genes are responsible for the Mendelian disorders autosomal dominant polycystic kidney disease and pseudoxanthoma elasticum, respectively. We establish that duplications of PKD1 and ABCC6 are associated to low copy repeat 16a and show that such duplications have occured several times independently in different primate species. We demonstrate that partial duplication of PKD1 and ABCC6 has numerous consequences: the pseudogenes give rise to new transcripts and mediate gene conversion, which not only results in disease-causing mutations but serves as a reservoir for sequence variation. The duplicated segments are also involved in submicroscopic and microscopic genomic rearrangements, contributing to structural variation in human and chromosomal breakpoints in the gibbon. In conclusion, our data shed light on the recent and ongoing evolution of chromosome 16 mediated by segmental duplication, and deepen our understanding of the history of two Mendelian disorder genes.

Key Words: primate evolution • non-allelic homologous recombination • morpheus • segmental duplication • copy-number variation • Mendelian disease genes


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