Abstract
Unraveling the evolutionary forces responsible for variations of neutral substitution patterns among taxa or along genomes is a major issue for detecting selection within sequences. Mammalian genomes show large-scale regional variations of GC-content (the isochores), but the substitution processes at the origin of this structure are poorly understood. We analyzed the pattern of neutral substitutions in 1 Gb of primate non-coding regions. We show that the GC-content toward which sequences are evolving is strongly negatively correlated to the distance to telomeres and positively correlated to the rate of crossovers (R2 = 47%). This demonstrates that recombination has a major impact on substitution patterns in human, driving the evolution of GC-content. The evolution of GC-content correlates much more strongly with male than with female crossover rate, which rules out selectionist models for the evolution of isochores. This effect of recombination is most probably a consequence of the neutral process of biased gene conversion (BGC) occurring within recombination hotspots. We show that the predictions of this model fit very well with the observed substitution patterns in the human genome. This model notably explains the positive correlation between substitution rate and recombination rate. Theoretical calculations indicate that variations in population size or density in recombination hotspots can have a very strong impact on the evolution of base composition. Furthermore, recombination hotspots can create strong substitution hotspots. This molecular drive affects both coding and non-coding regions. We therefore conclude that along with mutation, selection and drift, BGC is one of the major factors driving genome evolution. Our results also shed light on variations in the rate of crossover relative to non-crossover events, along chromosomes and according to sex, and also on the conservation of hotspot density between human and chimp.
Highlights
Genomic landscapes are not uniform across vertebrate chromosomes
The present base composition of a genomic fragment reflects the average pattern of substitutions to which it has been exposed during evolutionary times
To better understand the evolutionary forces that have been responsible for the strong regional variations in base composition along mammalian genomes, we studied the pattern of substitution in the human lineage, by comparison with chimpanzee and using macaque as an outgroup to orientate changes
Summary
Genomic landscapes are not uniform across vertebrate chromosomes. The genomes of amniotes (mammals, birds and reptiles) show a very strong heterogeneity of base composition along chromosomes (the so-called isochores) (for review, [1]). These Mb-scale variations in GC-content result from variations of substitution patterns that have affected both coding and noncoding regions. These genomic landscapes are correlated with many other important features (gene density, intron size, distribution of transposable elements, replication timing). Isochores clearly reflect some fundamental aspects of genome organization. Isochores have been discovered more than 30 years ago [2], the reason for their origin is still highly debated: are they the result of selection [3,4,5,6,7,8], or do they reflect variations in neutral substitution patterns [9,10,11,12,13,14,15]?
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