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Human Molecular Genetics Advance Access published online on September 9, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi338
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received July 1, 2005
Revised September 6, 2005
Accepted September 6, 2005

Article

Mapping cis-regulatory domains in the human genome using multi-species conservation of synteny

Nadav Ahituv 1, Shyam Prabhakar 1, Francis Poulin 2, Edward M. Rubin 1, and Olivier Couronne 3*

1 Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA; US DOE Joint Genome Institute, Walnut Creek, CA, USA
2 Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA
3 Genomics Division, One Cyclotron Road, MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; US DOE Joint Genome Institute, Walnut Creek, CA, USA

* To whom correspondence should be addressed.
Olivier Couronne, E-mail: ocouronne{at}mac.com


  Abstract

Our inability to associate distant regulatory elements with the genes that they regulate has largely precluded their examination for sequence alterations contributing to human disease. One major obstacle is the large genomic space surrounding targeted genes in which such elements could potentially reside. In order to delineate gene regulatory boundaries we used whole-genome human-mouse-chicken (HMC) and human-mouse-frog (HMF) multiple alignments to compile conserved blocks of synteny (CBS), under the hypothesis that these blocks have been kept intact throughout evolution at least in part by the requirement of regulatory elements to stay linked to the genes that they regulate. A total of 2,116 and 1,942 CBS > 200 kb were assembled for HMC and HMF respectively, encompassing 1.53 and 0.86 Gb of human sequence. To support the existence of complex long-range regulatory domains within these CBS we analyzed the prevalence and distribution of chromosomal aberrations leading to position effects (disruption of a gene's regulatory environment), observing a clear bias not only for mapping onto CBS but also for longer CBS size. Our results provide an extensive dataset characterizing the regulatory domains of genes and the conserved regulatory elements within them.


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