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Molecular Forces Shaping Human Genomic Composition at Mid-range Scales
Ashwin Prakash,Samuel Shepard, Jason Bechtel, Alexei Fedorov
University of Toledo-HSC, Cardiovascular sciences program
Mid-range inhomogeneity or MRI is the significant enrichment of particular nucleotides in genomic sequences extending from 30 up to several thousands of nucleotides. The best-known manifestation of MRI is CpG islands representing CG-rich regions. In 2008 we demonstrated that MRI could be observed not only for G+C content but also for other nucleotide pairings (A+G and G+T) as well as for individual bases. We also created a public resource called .Genomic MRI. for studying all types of genomic patterns of medium sizes.
This paper explores how different types of mutations change MRI-regions. Human, chimpanzee and Macaca mulatta genomes were aligned to study the projected effects of substitutions and indels on human sequence evolution both within MRI regions and regions of average nucleotide composition (used as control). Over 3.3 million fixed, point substitutions, 1.88 million indels, and 3.9 million SNPs were validated and recorded (registered?) within humans. They include 234567 substitutions and 987654 indels within MRI regions. Substitutions were grouped according to their fixation within human populations: fixed substitutions (from the human-chimp-macaca alignment), major SNPs (greater than 80% average frequency within humans), medium SNPs (20% - 80%), minor SNPs (3% - 20%), and rare SNPs (less than 3%). Data on short (less than 3 bp) and medium (3 - 50 bp) length insertions and deletions within MRI regions and appropriate control regions were analyzed for the effect of indels on enhancing or diminishing such regions as well as on changing nucleotide composition.
It was observed that MRI regions have comparable level of de novo mutations to the control genomic sequences with average base composition. De novo substitutions rapidly erode MRI regions bringing their nucleotide composition to the genome-average level. However, substitutions seemed to increasingly favor the maintenance of MRI regions the more fixed those substitutions are within human populations. With few exceptions, indels were seen to have a smaller impact on the MRI regions compared to substitutional forces and seemed to favor a contraction of MRI regions. Indels, fixed in the human populations, are in favor of enhancing MRI regions. The detected strong fixation bias for substitutions tends to support the preservation of MRI regions. From which we could infer that MRI regions are associated with functional genomic regions at various levels, and, therefore resist change.
Support: National Science Foundation Grant No. 0643542
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