Sequence-directed mutagenesis: evidence from a phylogenetic history of human alpha-interferon genes.

Abstract

We have studied the potential contribution of template-dependent events to genetic variation in mammals by examining the sequence alterations that have occurred in the recent evolution of human interferon genes. Fifteen members of the human a-interferon gene family were aligned, and a phylogenetic history was inferred. Many multiple events are inferred to have occurred in the evolution of the interferon genes and for the majority of these local DNA sequences were present that were capable of serving as templates for their occurrence. We conclude that the DNA sequence has the potential to explain many of the inferred spontaneous events and to explain complex alterations to sequences-i.e., the joint occurrence of base substitutions and insertions/deletions. Thus, such a mechanism would often cause multiple sequence changes as a result of a single mutational event and would provide additional genetic variation for evolution. Sequencedirected mutations would depend upon the local DNA sequences and, hence, would not be random at the DNA level.Inherent in the reproduction of all organisms is the potential for mutation. Such errors, though rare, provide the ultimate driving force behind evolution. It is through the genetic variation provided by mutation that natural selection and random drift can alter the genetic composition ofpopulations. The rate of mutation has been estimated to be on the order of 10-8-10-10 errors per base pair (bp) copied in a wide range of organisms (1). This high level of fidelity is astonishing considering the properties of the DNA bases, the complexity of the processes of DNA replication and repair, and the environmental threats to the integrity of the DNA.The number of potential DNA sequence changes as well as the mechanisms behind them are extensive, but they all provide opportunity for genetic variation. The relative contribution of each kind of mutational event to spontaneous mutation is not known. Such information is particularly sparse in mammals, but an analysis of 176 spontaneous lacI mutations isolated by Schaaper et al. (2) reveals that only 11% were base substitutions and just 4% involved insertion elements. The majority of events were frameshifts, deletions, and duplications. Similarly, within the flanking and intron sequences of globin it has been suggested that deletion/ insertion events and "block mutations" are prevalent compared to single-base substitutions (3,4).Mechanisms proposed to account for frameshift, deletion, and insertion events are diverse, but they share a commonality such that in the proposed mutational intermediates the bases are correctly paired in the Watson and Crick (5) sense but are misaligned because they are out of register. Misalignment mutational intermediates were first proposed by Streisinger et al. (6) to explain frameshift mutations at sites of repetitive sequences. This model was later supported by the data of Okada et al. (7) and Pribnow et al. (8) who showed that frameshift hotspots in bacteriophage T4 occur in sequences ofthe same nucl...

DNA sequences of genes encoding Acinetobacter calcoaceticus protocatechuate 3,4-dioxygenase: evidence indicating shuffling of genes and of DNA sequences within genes during their evolutionary divergence

“…The possibility of multiple alignments and the implication of common ancestry for identical residues in alternatively aligned sequences reinforce earlier suggestions that substitution of DNA sequences from one region into another may have served as a major mechanism of evolutionary divergence (18,37,52). Furthermore, the data provide grounds for exploring the possibility that DNA sequence repetitions, gained during evolutionary divergence, may maintain evolved sequences through mismatch repair (29,36).…”

DNA sequence analysis of spontaneous mutations in the SUP4-o gene of Saccharomyces cerevisiae.

“…The other two mutants (Co-31-1 and 160) both had the sequence 5'-GATCTCA-3' at +58 to +64 replaced by 5'-CCGGG-3'. It has been proposed that quasi-palindromic sequences might play a role in the production of this type of complex event by pairing out of register to stabilize mutational intermediates and template concurrent multiple changes (5,14). Intriguingly, a DNA secondary structure which could be processed to yield the replacement we detected at +58 to +64 could be formed by pairing within an inverted repeat present in the region involved (Fig.…”

Highly mutable sites for ICR-170-induced frameshift mutations are associated with potential DNA hairpin structures: studies with SUP4 and other Saccharomyces cerevisiae genes.

“…For example, Ripley and Glickman (38) suggested that the stem of imperfect hairpin structures might serve as a template during repair so that one strand of the stem is "repaired" to generate a closer complement of the other. This mechanism has been invoked to account for a variety of complex multiple-base-pair changes (38; M. Hampsey, J. Ernst, J. Stewart, and F. Sherman, submitted) and more recently was suggested as a mechanism to account, in part, for nucleotide variability in human alpha interferon gene phylogeny (18). The formation of DNA hairpin structures has also been suggested to account for varied rates of UV-induced G C-to-A T transitions (50).…”