Evidence for Local DNA Influences on Patterns of Substitutions in the Human Alpha-interferon Gene Family

The evolutionary history of genes can be used to examine patterns of spontaneous mutation if the sequences are sufficiently extensive to provide reliable data. Many human alpha-interferon genes have been sequenced and they form a large multigene family including several pseudogenes. A phylogenetic history for 15 human interferon sequences was reconstructed and their ancestral sequences inferred using a maximum parsimony method. This evolutionary history provided a record of more than 738 spontaneous mutations that have occurred in man's recent evolution. Of these mutations, more than 267 base substitution and deletion-insertion events were analyzed to determine the possible effects of nearby DNA sequences. Many substitutions occur at the end of long runs of identical bases and some dinucleotide pairs may mutate more often than others. Because templating by local DNA sequences has been implicated in prokaryotic mutation, the sequences were also examined for nearby repeats that include the substituted nucleotide and hence are potentially capable of templating the substitution. The majority of sequence alterations examined have either a similar direct repeat or palindrome nearby. Often such templates can account for simultaneous multiple mutations. These results suggest that sequence-directed events may occur occasionally in eukaryotes and that neighbouring DNA sequences can influence both the occurrence and types of mutations in several different ways.