Email updates

Keep up to date with the latest news and content from BMC Genomics and BioMed Central.

Open Access Research article

Evolution of genomic sequence inhomogeneity at mid-range scales

Ashwin Prakash17, Samuel S Shepard17, Jie He2, Benjamin Hart3, Miao Chen3, Surya P Amarachintha4, Olga Mileyeva-Biebesheimer5, Jason Bechtel6 and Alexei Fedorov67*

Author Affiliations

1 Program in Cardiovascular & Metabolic Diseases Track, Biomedical Sciences, University of Toledo Health Science Campus, Toledo, OH 43614, USA

2 University of Toledo, Department of Biology, Toledo, Ohio, USA

3 Dept of Medical Microbiology & Immunology, Infection, Immunity & Transplantation Track, University of Toledo, Health Science Campus, Toledo, OH 43614, USA

4 Department of Biological Sciences, Bowling Green State University, Bowling Green, OH - 43403, USA

5 Department of Civil Engineering, University of Toledo, Toledo, Ohio, USA

6 Program in Bioinformatics and Proteomics/Genomics, University of Toledo Health Science Campus, Toledo, OH 43614, USA

7 Department of Medicine, University of Toledo, Health Science Campus, Toledo, Ohio, USA

For all author emails, please log on.

BMC Genomics 2009, 10:513  doi:10.1186/1471-2164-10-513

Published: 5 November 2009

Abstract

Background

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. Recently it was demonstrated that MRI could be observed not only for G+C content but also for all other nucleotide pairings (e.g. A+G and G+T) as well as for individual bases. Various types of MRI regions are 4-20 times enriched in mammalian genomes compared to their occurrences in random models.

Results

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 within both MRI regions and control regions of average nucleotide composition. Over 18.8 million fixed point substitutions, 3.9 million SNPs, and indels spanning 6.9 Mb were procured and evaluated in human. They include 1.8 Mb substitutions and 1.9 Mb indels within MRI regions. Ancestral and mutant (derived) alleles for substitutions have been determined. Substitutions were grouped according to their fixation within human populations: fixed substitutions (from the human-chimp-macaca alignment), major SNPs (> 80% mutant allele frequency within humans), medium SNPs (20% - 80% mutant allele frequency), minor SNPs (3% - 20%), and rare SNPs (<3%). Data on short (< 3 bp) and medium-length (3 - 50 bp) insertions and deletions within MRI regions and appropriate control regions were analyzed for the effect of indels on the expansion or diminution of such regions as well as on changing nucleotide composition.

Conclusion

MRI regions have comparable levels of de novo mutations to the control genomic sequences with average base composition. De novo substitutions rapidly erode MRI regions, bringing their nucleotide composition toward genome-average levels. However, those substitutions that favor the maintenance of MRI properties have a higher chance to spread through the entire population. Indels have a clear tendency to maintain MRI features yet they have a smaller impact than substitutions. All in all, the observed fixation bias for mutations helps to preserve MRI regions during evolution.