Evolutionary consequences of nonrandom damage and repair of chromatin domains

Abstract

Some evolutionary consequences of different rates and trends in DNA damage and repair are explained. Different types of DNA damaging agents cause nonrandom lesions along the DNA. The type of DNA sequence motifs to be preferentially attacked depends upon the chemical or physical nature of the assaulting agent and the DNA base composition. Higher-order chromatin structure, the nonrandom nucleosome positioning along the DNA, the absence of nucleosomes from the promoter regions of active genes, curved DNA, the presence of sequence-specific binding proteins, and the torsional strain on the DNA induced by an increased transcriptional activity all are expected to affect rates of damage of individual genes. Furthermore, potential Z-DNA, H-DNA, slippage, and cruciform structures in the regulatory region of some genes or in other genomic loci induced by torsional strain on the DNA are more prone to modification by genotoxic agents. A specific actively transcribed gene may be preferentially damaged over nontranscribed genes only in specific cell types that maintain this gene in active chromatin fractions because of (1) its decondensed chromatin structure, (2) torsional strain in its DNA, (3) absence of nucleosomes from its regulatory region, and (4) altered nucleosome structure in its coding sequence due to the presence of modified histones and HMG proteins. The situation in this regard of germ cell lineages is, of course, the only one to intervene in evolution. Most lesions in DNA such as those caused by UV or DNA alkylating agents tend to diminish the GC content of genomes. Thus, DNA sequences not bound by selective constraints, such as pseudogenes, will show an increase in their AT content during evolution as evidenced by experimental observations. On the other hand, transcriptionally active parts may be repaired at rates higher than inactive parts of the genome, and proliferating cells may display higher repair activities than quiescent cells. This might arise from a tight coupling of the repair process with both transcription and replication, all these processes taking place on the nuclear matrix. Repair activities differ greatly among species, and there is a good correlation between life span and repair among mammals. It is predicted that genes that are transcriptionally active in germ-cell lineages have a lower mutation rate than bulk DNA, a circumstance that is expected to be reflected in evolution. Exception to this rule might be genes containing potential Z-DNA, H-DNA, or cruciform structures in their coding or regulatory regions that appear to be refractory to repair.(ABSTRACT TRUNCATED AT 400 WORDS)

Patterns of Base Composition Within the Genes of Drosophila melanogaster

“…An alternative explanation is variation in the efficiency of DNA repair (Filipski 1987(Filipski , 1988Eyre-Walker 1994). Various types of DNA repair are known to vary in their efficiency over the scale of a gene (Bohr et al 1987;Boulikas 1992) and this could generate variation in the pattern of mutation (Eyre-Walker 1994). Selection could also be responsible for the variation in base composition within genes.…”

The size differences among mammalian introns are due to the accumulation of small deletions

“…This may be attributed to the conditions that surround DNA, such as mutagenic agents and the DNA repairing system. Different local chromatin structures can induce an attack of different types of DNA damaging agents [24]. The condensation and decondensation of chromatin structures, which is accompanied by inactivation and activation of a gene, are related to the sensitivity to a nuclease involved in the repairing system [25,26].…”

Evolution Rates of Genes on Leading and Lagging DNA Strands

“…It has been found that mutational patterns vary across mammalian chromosomes and different chromosomal regions evolve at different rates (e.g. Filipski 1988;Wolfe et al 1989;Boulikas 1992;Eyre-Walker 1992;Holmquist and Filipski 1994;Matassi et al 1999). Variations in mutation rates across chromosomes correlate with replication timing and could be related to the different efficiency of DNA repair mechanisms.…”