Detection of potential GDF6 regulatory elements by multispecies sequence comparisons and identification of a skeletal joint enhancer

Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Genomics (Impact Factor: 2.28). 10/2005; 86(3):295-305. DOI: 10.1016/j.ygeno.2005.05.003
Source: PubMed


The identification of noncoding functional elements within vertebrate genomes, such as those that regulate gene expression, is a major challenge. Comparisons of orthologous sequences from multiple species are effective at detecting highly conserved regions and can reveal potential regulatory sequences. The GDF6 gene controls developmental patterning of skeletal joints and is associated with numerous, distant cis-acting regulatory elements. Using sequence data from 14 vertebrate species, we performed novel multispecies comparative analyses to detect highly conserved sequences flanking GDF6. The complementary tools WebMCS and ExactPlus identified a series of multispecies conserved sequences (MCSs). Of particular interest are MCSs within noncoding regions previously shown to contain GDF6 regulatory elements. A previously reported conserved sequence at -64 kb was also detected by both WebMCS and ExactPlus. Analysis of LacZ-reporter transgenic mice revealed that a 440-bp segment from this region contains an enhancer for Gdf6 expression in developing proximal limb joints. Several other MCSs represent candidate GDF6 regulatory elements; many of these are not conserved in fish or frog, but are strongly conserved in mammals.

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    • "A study of the SCL gene region found that five of eight known mouse enhancers were present in the chick SCL region, while only two were found in Fugu rupribes, a teleost, and none were found in zebrafish (Gottgens et al., 2002). Systematic analysis of Gdf6 regulation in mouse demonstrated that many of the known regulatory regions were also conserved between mouse and chick, but fewer were present in zebrafish (Portnoy et al., 2005). Thus it seems that while comparisons with zebrafish sequence can find some regulatory regions in amniotes, there are amniote-specific regulatory elements that can only be found by comparisons between chick and mammals. "
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