Nudging the nudge

We have seen that the Alu element is poised to generate binding sites for multiple transcription factors involved in development.  Even more interesting is the manner in which the process of cytosine deamination can easily create several of these transcription factor binding sites.  It’s as if we have two nudges, working together, to facilitate the evolution of primates.

Yet there is more to the story.  Recall that the cytosine deamination events occur at CpG sites.This is simply where a cytosine (C) is followed by a guanine (G).  Why is this?

Let me quote from this site:

CpG islands are often located around the promoters of housekeeping genes (which are essential for general cell functions) or other genes frequently expressed in a cell.  At these locations, the CG sequence is not methylated.  By contrast, the CG sequences in inactive genes are usually methylated to suppress their expression.  The methylated cytosine may be converted to thymine by accidental deamination.  Unlike the cytosine to uracil mutation which is efficiently repaired, the cytosine to thymine mutation can be corrected only by the mismatch repair which is very inefficient.  Hence, over evolutionary time scales, the methylated CG sequence will be converted to the TG sequence.  This explains the deficiency of the CG sequence in inactive genes.

To this, let me add a couple of more facts.  First, transposons contain roughly 35% of the GC sequence in a genome.  Second, when transposons jump, the response from the genome is the methylate them.  By placing methyl groups on the C’s of the CG transposon sequence, the genome is effectively silencing them.  Yet the silencing of the transposon poises the system for cytosine deamination.  Built into the fabric of jumping genes is the recruitment of cytosine deamination.

And as if that was not enough, one study determined that this effect would become most pronounced in warm-blooded animals, where “CT and GA transitions occur at higher rates than other base substitutions in mammals.”  Why is this?

the rate of cytosine deamination is strongly temperature-dependent. Given a typical body temperature of 20°C in fish and amphibians versus 37°C in mammals, cytosine deamination should occur 20.6-fold more slowly in fish and amphibians (based on eq. 3 , k37°C/k20°C = (7.0 x 10-13/s)/(0.34 x 10-13/s) = 20.6). This indicates that positive feedback between cytosine deamination and GC content is insignificant in fish and amphibians, which is consistent with the lack of distinct classes of isochores in fish and amphibians. Reptiles are intermediate between cold-blooded vertebrates (i.e., fish and amphibians) and homeothermic vertebrates (i.e., birds and mammals) in terms of body temperature, remaining levels of 5-methylcytosine , presence of GC-rich isochore structures, and presence of cytological chromosome bands.

rabbit4Sit back and take it in.  The SRP, which elegantly solves a core problem for life and helps nudge into existence the eukaryotic cell plan, also happens to have an RNA component that can moonlight as a transposon – the Alu element.  The Alu element played an important role in primate and human evolution, helping to reformat the genome by, in part, recruiting transcription factors and surveillance proteins to different regions.  This reformatting function was, in turn, facilitated by cytosine deamination, which in turn was facilitated by the methylation of cytosines that comes with gene jumping, all in the context of a warm-blooded body that enhances the rate of cytosine deamination.  I guess we’re all just lucky that all these puzzle pieces fell together like that.

Well, there is more to say about the Alu element.  For example, we should explore why it is that Alu elements still can bind to the SRP proteins (do you know that Alu function depends on these proteins?).  And we should explore some uncanny similarities between the Alu elements in primates and the B1 elements in rodents.   But let’s take a break from all that Alu investigatin’ for the moment.


One response to “Nudging the nudge

  1. Pingback: Methylation – Focusing the Effects of Cytosine Deamination or a new coincidence to Darwinism? « Evolution-Oriented

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