A New Theory of Genome Evolution

May 17th, 2007 Placozoan Posted in News |

VERTEBRATE GENOMES are composed of islands of GC-rich DNA surrounded by a sea of GC-poor DNA. The GC-rich and GC-poor regions, called isochores, can be subdivided into five classes. The majority of vertebrate genes are contained in two GC-rich isochores, with the remainder spread throughout the other isochores. When compared to the genomes of fish and amphibians, the gene-rich isochores of mammals and birds are comparatively enriched in GC, while reptiles’ isochores are intermediate.

This is of interest for several reasons. First, the mutational tendency is for conversion from GC to AT as cytosine, which is commonly methylated when in a CpG dinucleotide (C followed by G), deaminates to produce thymidine. Subsequent DNA repair can then convert the GT mismatch to an AT. An increase in GC content requires a reversal of this mutational bias. Secondly, this GC increase must have occurred independently twice in order to appear in both mammals and birds.

A variety of mechanisms have been suggested for the origin of isochores, both selectionist and neutral, but no consensus has yet been reached. Now a new model has been proposed.

Bernardi proposes this week (in an open access article) that the GC content of the isochores is driven by increasing body temperature. The GC base pair has three hydrogen bonds instead of two as in the AT base pair, resulting in a higher thermal stability of the GC base pair at increasing temperature. Bernardi suggests that the gene-rich isochores are more vulnerable to thermal denaturation than the gene-poor AT regions, since the gene-poor regions are typically compacted in chromatin while the gene-rich regions must be expanded for gene transcription. Thus, increasing body temperature creates a selective force towards more thermally stable gene-rich regions high in GC. While most of the research in this area seems speculative, Bernardi offers several examples of correlation between higher body temperature and increased or stabilized GC content.

This selectionist explanation was supported (i) by the similar genome changes occurring in the independent lines of mammals and birds; (ii) by the decreases of CpG doublets and methylcytosine, which are correlated with increasing body temperatures in vertebrates ranging from Antarctic fishes to mammals (72–76); (iii) by the variable compositional heterogeneity and methylation levels (intermediate between those of fishes/amphibians and mammals/birds) of the genomes from reptiles (51, 47, 77), which are known to have different body temperatures and thermal regulations; (iv) by the mammalian-like isochore organization of the genomes of subtropical and tropical insects (Drosophila, Anopheles) (78, 79); and (v) by the increase of GC levels that accompanies the increase in optimal growth temperatures in many families of prokaryotes (80).

The result is a theory that allows neutral or nearly neutral AT -> GC conversions yet stabilizes the GC level by selection for the structure of the chromatin produced. Bernardi suggests that the GC level of an isochore is bounded by a lower and upper threshold. Within these bounds neutral mutations can occur to convert GC -> AT and AT -> GC. However, when the GC content falls below the lower threshold, adverse structural changes occur. On an evolutionary timescale trending towards higher body temperature, the threshold will ratchet up to produce an eventual elevated GC level compared to the ancestral cold-blooded organism.

Bernardi has termed this the “neoselectionist theory”. While I generally oppose the proliferation of labels, I think in this case it may be deserved as he introduces the concept of epigenetic “genomic fitness” and “genomic disease” based upon disadvantageous chromatin structure preventing proper expression of genes.

Bernardi, G. “The neoselectionist theory of genome evolution.” Proceedings of the National Academy of Sciences, USA 2007, 104, 8385.