Human tri - allelic sites : evidence for a new mutational mechanism ? Alan

Most SNPs in the human genome are bi-allelic, however there are some sites that are tri-allelic. We show here that there are approximately twice as many tri-allelic sites as we would expect by chance. This excess does not appear to be caused by natural selection or mutational hotspots. Instead we propose that a new mutation can induce another mutation either within the same individual, or subsequently during recombination. We provide evidence for this model by showing that the rarer two alleles at tri-allelic sites tend to cluster on phylogenetic trees of human haplotypes. However, we find no association between the density of tri-allelic sites and the rate of recombination, which leads us to suggest that tri-allelic sites might be generated by the simultaneous production of new two mutations within the same individual on the same genetic background. Under this model we estimate that simultaneous mutation contributes approximately 3% of all distinct SNPs. We also show that there is a twofold excess of adjacent SNPs. Approximately half of these seem to be generated simultaneously since they have identical minor allele frequencies. We estimate that the mutation of adjacent nucleotides accounts for a little less than 1% of all SNPs.