An abrupt change of nucleotide substitution patterns at the time 
 of mammalian radiation
 
 The Human genome shows large regional variation in GC-content (from 30% to
 60%) at scales exceeding hundreds of kilobases. This variation is due to
 differences in substitutional processes that affect evolution of both
 coding and noncoding sequences. The origin, timing, and implications of
 this large-scale GC variation remain controversial. To gain insight into
 this question, we use a novel computational approach to estimate
 substitutional patterns across the human genome at different ages going
 back approximately 200 Myr. We demonstrate that large-scale variation in
 GC-content in the human genome was generated through substitutional biases
 prior to the radiation of eutherian mammals. Approximately at the time of
 mammalian radiation, the patterns of substitutions changed abruptly and
 dramatically. The new mammalian pattern of substitution is expected to
 largely homogenize GC content across the human genome over time. Eutherian
 mammals are also predicted to share a newly evolved, 4- to 8-fold higher
 rate of methylation-induced cytosine transition in 5'-CG-3' pairs compared
 to the reptilian ancestor.