Evolution of genomic sequence inhomogeneity at mid-range scales

Area of Science:

• Genomics
• Molecular Biology
• Evolutionary Biology

Background:

• Mid-range inhomogeneity (MRI) describes nucleotide enrichment in genomic sequences (30 bp to thousands of bp).
• CpG islands are a well-known example of MRI, characterized by CG-rich regions.
• MRI is not limited to G+C content but extends to other nucleotide pairings and individual bases, showing 4-20 times enrichment in mammalian genomes.

Purpose of the Study:

• To investigate the impact of various mutation types on MRI regions.
• To analyze the effects of substitutions and indels on human sequence evolution within MRI and control regions.
• To understand how mutations influence the nucleotide composition and size of MRI regions.

Main Methods:

• Comparative genomics using aligned human, chimpanzee, and Macaca mulatta genomes.
• Analysis of over 18.8 million fixed point substitutions, 3.9 million SNPs, and 6.9 Mb of indels in the human genome.
• Categorization of substitutions based on fixation within human populations (fixed, major, medium, minor, rare SNPs) and analysis of indels by length (<3 bp and 3-50 bp).

Main Results:

• MRI regions exhibit similar de novo mutation rates to control regions with average base composition.
• De novo substitutions tend to reduce MRI regions, shifting their composition towards genome-average levels.
• Substitutions favoring MRI properties are more likely to become fixed in the population, while indels show a tendency to maintain MRI features with a lesser impact than substitutions.

Conclusions:

• Mutations, particularly substitutions, play a crucial role in shaping MRI regions.
• A fixation bias exists for mutations that either erode or maintain MRI properties.
• Despite the erosive effects of some mutations, evolutionary processes, including mutation fixation bias, effectively preserve MRI regions over time.