The neoselectionist theory of genome evolution

Abstract

The vertebrate genome is a mosaic of GC-poor and GC-rich isochores, megabase-sized DNA regions of fairly homogeneous base composition that differ in relative amount, gene density, gene expression, replication timing, and recombination frequency. At the emergence of warm-blooded vertebrates, the gene-rich, moderately GC-rich isochores of the cold-blooded ancestors underwent a GC increase. This increase was similar in mammals and birds and was maintained during the evolution of mammalian and avian orders. Neither the GC increase nor its conservation can be accounted for by the random fixation of neutral or nearly neutral single-nucleotide changes (i.e., the vast majority of nucleotide substitutions) or by a biased gene conversion process occurring at random genome locations. Both phenomena can be explained, however, by the neoselectionist theory of genome evolution that is presented here. This theory fully accepts Ohta's nearly neutral view of point mutations but proposes in addition (i) that the AT-biased mutational input present in vertebrates pushes some DNA regions below a certain GC threshold; (ii) that these lower GC levels cause regional changes in chromatin structure that lead to deleterious effects on replication and transcription; and (iii) that the carriers of these changes undergo negative (purifying) selection, the final result being a compositional conservation of the original isochore pattern in the surviving population. Negative selection may also largely explain the GC increase accompanying the emergence of warm-blooded vertebrates. In conclusion, the neoselectionist theory not only provides a solution to the neutralist/selectionist debate but also introduces an epigenomic component in genome evolution.

Fig. 1.

Darwin postulated the existence of deleterious, advantageous, and neutral changes. The neo-Darwinians (or selectionists) neglected neutral changes. These were reintroduced and amplified by Kimura (7, 8), who developed the neutral theory of evolution (a non-Darwinian evolution, according to ref. 9). The nearly neutral theory was proposed by Ohta (12, 13, 102) to include intermediates between neutral and advantageous, as well as between neutral and deleterious changes. In the neoselectionist theory, the critical changes are responsible for the transition from point mutations to regional changes (modified from refs. and 103).

Fig. 2.

DNA and gene distribution in the isochore families of the human genome. The major structural and functional properties associated with each gene space are listed (in blue for the genome desert and in red for the genome core). The top frames are modified from M. Costantini, F. Auletta, and G.B. (unpublished data). SINEs, short interspersed sequences; LINEs, long interspersed sequences.

Fig. 3.

Scheme of the compositional evolution of vertebrate genomes. At the transition from cold- to warm-blooded vertebrates, the gene-dense, moderately GC-rich “ancestral genome core” (pink box) became the gene-dense, GC-rich genome core (red box), but the GC-poor and gene-poor (blue box) genome desert did not undergo any major compositional change. This transitional (or shifting) mode, which was accompanied by an overall decrease of CpG doublets and methylcytosine, was followed by a conservative mode of genome evolution in which compositional patterns were maintained (modified from ref. 32).

Fig. 4.

An example of isochore conservation between syntenic chromosome regions of dog and human (from M. Costantini, F. Auletta, and G.B., unpublished data).

Fig. 5.

Time course of typical compositional changes of a GC-rich region from a warm-blooded vertebrate in the conservative mode of evolution. In an early phase, the average GC level of the region, initially visualized at its compositional optimum (arbitrarily set here at 54% GC), is decreasing because of the mutational AT bias (the vertical blue bars crossing the black DNA line represent the “excess” GC→AT changes), but remains within a tolerated range (whose arbitrary thresholds are indicated by the thick horizontal broken lines). In a late phase, the average GC level trespasses the lower threshold (arbitrarily fixed here at 52% GC), because of the last changes, the critical changes. The chromatin (red boxes) then undergoes a structural change (broken blue box) that is deleterious for transcription and replication (see text). Until then, the changes may be neutral or, more probably, nearly neutral (modified from ref. 32).

Fig. 6.

A scheme of the transitional mode of evolution describing the GC increase of a gene-dense DNA region during the emergence of homeothermy. The basic feature is an increase in the GC level of the lower threshold (broken blue line) by a ratchet mechanism, which leads to an increased GC level of the region (pink-to-red lines).