Pioneer works by Bernardi and colleagues in the 70's have demonstrated that the base composition is spatially structured in mammalian genomes: chromosomes can be seen as mosaics of long (>300kb) GC-rich and GC-poor fragments called isochores. The sequencing of the human genome confirmed the existence of substantial variations in average GC-content among large fragments (from 33% to 62% G+C), although these isochores do not appear to be as homogeneous as was expected. The isochore structure is correlated with various genomic features, including repeat element distribution, methylation pattern, replication, recombination and, most remarkably, gene density. However, the biological significance of this large-scale variation in GC-content remains highly debated. Does the isochore organization result of a selective pressure on base composition or does it simply reflect a neutral evolutionary process ? To understand the evolution of isochores we analyzed the synonymous substitution pattern in coding sequences from closely related species in primates, cetartiodactyls, and rodents. GC-rich genes are undergoing a large excess of GC->AT substitutions over AT->GC substitutions: GC-rich isochores are slowly disappearing from the genome of these three mammalian orders. This observation questions the conclusions of previous works that assumed that base composition was at equilibrium. Analysis of allele frequency in human polymorphism data, however, confirmed that in the GC-rich parts of the genome, GC alleles have a higher probability of fixation than AT alleles (probably because of biased gene conversion, not selection). This fixation bias appears not strong enough to overcome the large excess of GC->AT mutations. Thus, whatever was the evolutionary force (neutral or selective) at the origin of GC-rich isochores, this force is no longer effective in mammals. We propose a model based on the biased gene conversion hypothesis that accounts for the origin of GC-rich isochores in the ancestral amniote genome, and for their decline in present-day mammals.
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