Cytosine Deamination Plays a Primary Role in the Evolution of Mammalian Isochores

Abstract

DNA melting is rate-limiting for cytosine deamination, from which we infer that the rate of cytosine deamination should decline twofold for each 10% increase in GC content. Analysis of human DNA sequence data confirms that this is the case for 5-methylcytosine. Several lines of evidence further confirm that it is also the case for unmethylated cytosine and that cytosine deamination causes the majority of all C→T and G→A transitions in mammals. Thus, cytosine deamination and DNA base composition each affect the other, forming a positive feedback loop that facilitates divergent genetic drift to high or low GC content. Because a 10ЊC increase in temperature in vitro increases the rate of cytosine deamination 5.7-fold, cytosine deamination must be highly dependent on body temperature, which is consistent with the dramatic differences between the isochores of warm-blooded versus coldblooded vertebrates. Because this process involves both DNA melting and positive feedback, it would be expected to spread progressively (in evolutionary time) down the length of the chromosome, which is consistent with the large size of isochores in modern mammals.

DNA methylation is widespread and associated with differential gene expression in castes of the honeybee, Apis mellifera

“…Previous studies have shown a positive correlation between GC content and CpG O/E (17,26,27). We also find that the GC content and CpG content are strongly correlated in the A. mellifera genome (Kendall's correlation coefficient, ϭ 0.32; P Ͻ 10 Ϫ15 ).…”

Covariation in Frequencies of Substitution, Deletion, Transposition, and Recombination During Eutherian Evolution

“…(These GC ranges divide the data roughly into equal thirds.) Because hypermutable CpG dinucleotides can sometimes skew estimates of the levels of conservation (Fryxell and Zuckerkand 2000), we also recalculated the percent identities after removing all sites that are in a CpG either in human or in mouse. This increased them to 74.4% in low-GC regions, 74.1% in medium-GC regions, and 73.6%, in high-GC regions.…”

Rational de novo gene synthesis by rapid polymerase chain assembly (PCA) and expression of endothelial protein-C and thrombin receptor genes

“…Cytosine deamination is slowest at pH 8-8.5; the rate increases sharply at higher pH and more gradually at lower pH (when a small positive salt effect is also exhibited). The deamination rates are different for ssDNA and dsDNA; Fryxell and Zuckerkandl (2000) used data from three different sources to obtain the following dsDNA deamination rate: C deamination of double stranded DNA k Cds =2.66 × 10 10 e −32/RT s −1 (R=0.00198 kcal/mol K) (1) Lindahl and Nyberg (Lindahl and Nyberg, 1974) measured cytosine deamination rates in denatured E. coli DNA. At 95 °C and 80 °C, the rates are 2.2 × 10 −7 s −1 and 1.3 × 10 −8 s −1 , respectively.…”