Multigenome DNA sequence conservation identifies Hox cis-regulatory elements.
To learn how well ungapped sequence comparisons of multiple species can predict cis-regulatory elements in Caenorhabditis elegans, we made such predictions across the large, complex ceh-13/lin-39 locus and tested them transgenically. We also examined how prediction quality varied with different genomes and parameters in our comparisons. Specifically, we sequenced approximately 0.5% of the C. brenneri and C. sp. 3 PS1010 genomes, and compared five Caenorhabditis genomes (C. elegans, C. briggsae, C. brenneri, C. remanei, and C. sp. 3 PS1010) to find regulatory elements in 22.8 kb of noncoding sequence from the ceh-13/lin-39 Hox subcluster. We developed the MUSSA program to find ungapped DNA sequences with N-way transitive conservation, applied it to the ceh-13/lin-39 locus, and transgenically assayed 21 regions with both high and low degrees of conservation. This identified 10 functional regulatory elements whose activities matched known ceh-13/lin-39 expression, with 100% specificity and a 77% recovery rate. One element was so well conserved that a similar mouse Hox cluster sequence recapitulated the native nematode expression pattern when tested in worms. Our findings suggest that ungapped sequence comparisons can predict regulatory elements genome-wide.
Kuntz
Steven G
SG
Division of Biology, California Institute of Technology, Pasadena, California 91125, USA.
Schwarz
Erich M
EM
DeModena
John A
JA
De Buysscher
Tristan
T
Trout
Diane
D
Shizuya
Hiroaki
H
Sternberg
Paul W
PW
Wold
Barbara J
BJ
D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence / Q000235:genetics*; D017173:Caenorhabditis elegans / Q000235:genetics; D017124:Conserved Sequence / Q000235:genetics; D018509:DNA, Helminth / Q000235:genetics / Q000302:isolation & purification; D017238:Genes, Helminth; D005801:Genes, Homeobox; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D010802:Phylogeny; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D017422:Sequence Analysis, DNA; D019076:Transgenes
D018509:DNA, Helminth; D018398:Homeodomain Proteins