Distinct changes of genomic biases in nucleotide substitution at the time of mammalian radiation

TL;DR

This study uses a maximum likelihood approach to analyze the history of nucleotide substitution patterns in the human genome, revealing a significant shift around 90 million years ago during mammalian radiation that affected genomic isochores.

Contribution

It introduces a novel maximum likelihood method to reconstruct substitution history using repetitive sequences, uncovering a key change in genomic biases at mammalian radiation.

Findings

A 4- to 8-fold increase in CpG transition rate around 90 Myr ago.

Isochores were established before mammalian radiation.

Post-radiation, substitution patterns shifted from preserving to degrading isochores.

Abstract

Differences in the regional substitution patterns in the human genome created patterns of large-scale variation of base composition known as genomic isochores. To gain insight into the origin of the genomic isochores we develop a maximum likelihood approach to determine the history of substitution patterns in the human genome. This approach utilizes the vast amount of repetitive sequence deposited in the human genome over the past ~250 MYR. Using this approach we estimate the frequencies of seven types of substitutions: the four transversions, two transitions, and the methyl-assisted transition of cytosine in CpG. Comparing substitutional patterns in repetitive elements of various ages, we reconstruct the history of the base-substitutional process in the different isochores for the past 250 Myr. At around 90 Myr ago (around the time of the mammalian radiation), we find an abrupt 4- to 8-fold increase of the cytosine transition rate in CpG pairs compared to that of the reptilian ancestor. Further analysis of nucleotide substitutions in regions with different GC-content reveals concurrent changes in the substitutional patterns. While the substitutional pattern was dependent on the regional GC-content in such ways that it preserved the regional GC-content before the mammalian radiation, it lost this dependence afterwards. The substitutional pattern changed from an isochore-preserving to an isochore-degrading one. We conclude that isochores have been established before the radiation of the eutherian mammals and have been subject to the process of homogenization since then.