Why RAREs are not so rare

matrix2From this site, we learn

Retinoic acid (RA) may act as a regulator of differentiation at various stages of vertebrate embryogenesis. In particular, the results of exogeneous RA treatment have implicated RA in antero-posterior patterning both along the body axis and in developing Limb bud.

and

Retinoic Acid receptors (RARs) are nuclear receptors related to the steroid and thyroid hormone Receptors, a family of proteins that function as ligand-dependent transcription factors.

RAR’s are not membrane receptors, but instead exist as proteins in the cytoplasm.

Because retinoic acid is a hydrophobic molecule, it easily slips across the membrane.  When it binds to the RAR, it is then able to bind the DNA to alter the expression of genes involved in embryonic development, as shown in the figure below:

rar

The RAR binds to a DNA motif known as the RARE (RAR element).  There are slightly different versions of the RAREs, and one form, known as DR2, is actually found as part of the Alu element:

Notably, a motif, AGGTCAnnAGTTCG, found within most subclasses of AluS sequences, corresponds to a non-consensus DR2 element recognized by RARs, and has been shown to function as a RARE.

From: David Laperriere, Tian-Tian Wang, John H White and Sylvie Mader. 2007. Widespread Alu repeat-driven expansion of consensus DR2 retinoic acid response elements during primate evolution. BMC Genomics 8:23.

So embedded with the Alu sequence is a DNA sequence that is able to recruit RARs!  But it gets even more interesting, as the DNA motif contained within the Alu element can become an even better binding site by one of the most common mutations:

We have mapped the positions of all consensus DR-type hormone response elements in the human genome, and found that DR2 motifs, recognized by retinoic acid receptors (RARs), are heavily overrepresented (108,582 elements). 90% of these are present in Alu repeats….. 95.5% of Alu-DR2s are distributed throughout subclasses of AluS repeats, and arose largely through deamination of a methylated CpG dinucleotide in a non-consensus motif present in AluS sequences. We find that Alu-DR2 motifs are located adjacent to numerous known retinoic acid target genes, and show by chromatin immunoprecipitation assays in squamous carcinoma cells that several of these elements recruit RARs in vivo.

The researchers conclude their study by noting

We find that consensus DR2 motifs are heavily overrepresented in the human genome relative to other DR response elements due to their presence in a subset of Alu motifs, in particular in AluS sequences…. Consensus Alu-DR2 elements arose predominantly through deamination of a methylated CpG dinucleotide present in AluS elements rather than through random base substitutions.

Readers of The Design Matrix may have perked up. Did someone say deamination?  Deamination? Alu elements, reformatting the genome, also contain sequence that can be converted to a consensus RAR binding site by through the process of cytosine deamination.

The non-telic perspective has insisted, “Any engineer would have replaced cytosine, but evolution is a tinkerer not an engineer.”  But as I noted years ago:

A second possible explanation was that cytosine was chosen because of its predisposition to undergo deamination. This explanation may also intersect with the hypothesis of necessity, as a good designer often finds ways to turn a “design problem” into an opportunity. In this case, let me propose that cytosine, far from being something any engineer would replace, may actually have played an instrumental role in the front-loading of evolution. Put simply, C-to-T transitions, as a function of deamination, may have posed a form of “direction” on evolution.

We might now catch a glimpse of one possible such direction – the creation of RAR binding sites during the reformatting of vertebrate developmental programs.

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