Evolution Of The Isochore Structure On Human Chromosome 18

The mammalian genomes consist of large regions (>300kb, on average) of relatively homogeneous base composition, which are known as isochores. This characteristic of genome has been a fundamental problem to understand the organization of genomes. The evolution of base composition has drawn great interests recently. Studies have not only focused on the origion of the special structure, but also on the fata of the present isochore structure. It is proposed that the isochore structure is vanishing on the mammalian genomes, but it is argued by other scientists because of inaccurate methods and limited sample.Although it is believed that recombination drives the evolution of base composition, the exact mechanism is not clearly known. Two models are most likely to explain the mechanism: the Biased Gene Conversion (BGC) model proposes a biased fixation toward GC-alleles in GC/AT heterozygous site due to biased DNA mismatch repair process during meiotic recombination. This process results in an increase of GC-content in the frequent recombination region. The Regional Mutation Biased (RMB) model suggests a variation in the ratios of GC→AT and AT→GC mutation rates among genomic region to account for their specific base composition. The mutagenicity of recombination would raise the possibility that new AT→GC mutations are introduced during recombination. Then, under neutrality, the regional GC-content will be increased if the mutation process of this region is biased toward AT→GC and decreased if reverse process occurs. Supporting evidences have accumulated for both the Regional Mutation Bias model and Biased Gene Conversion model. Since the BGC model predicts a fixation bias in favor of GC alleles while the RMB model does not. We can distinguish them by studying the process of mutation bias fixation bias. Therefore to estimate their contributions to the isochore evolution.SNP is the mutation that has not been fixed, compared with the substitution among different species, it can present the mutation bias more accurate. Besides, the derived allele frequencies of the SNPs can reflect the mutation bias of different alleles. Although they are fewer compared with the substitution, with the accomplishment of the HapMap project, millions of SNPs and their allele frequencies in different populations is available in the human genome. So, SNP is a suitable material to study the evolution of the isochore.As a novel reliable method inferring the mutation direction of the SNP has been introduced and used in the research related with human and chimpanzee SNPs, we can determine the mutation direction of more SNPs. Taking the advantage of the first isochore map of human being, we did some research on the evolution of the isochore structure in a continuous region with accurate partition. A remarkable mutation bias was found which was destroying the present isochore structure, in particular, more mutations from GC to AT observed in the GC-rich regions and more mutations form AT to GC observed in the GC-poor regions, which reflects the disequilibriem of the base composition in the isochores. However, a fixation bias contributed by the BGC effect and a rising fixation probability of derived alleles with increasing GC content was extending the present isochore structure. Note, the mutation from AT to GC is easier to be fixed than that from GC to AT in all isochores. Combining the two opposing processes, the old isochore structure was declining and a more homogenous isochore structure with higher GC content was forming on the chromosome. During this process, both the CpG and genic sites, which contained in the isochore, played an important role. Besides, the recombination was confirmed to promote the GC alleles fixed in the genome whereas against the AT alleles due to the BGC effect. With little recombination occurred, AT alleles had the identical fixation probability with GC alleles in the recombination cold spots. Although it seems more mutations from AT to GC happened in the recombination hot spots, it is not statistic significant.