A genome-wide view of Caenorhabditis elegans base-substitution mutation processes

Abstract

Knowledge of mutation processes is central to understanding virtually all evolutionary phenomena and the underlying nature of genetic disorders and cancers. However, the limitations of standard molecular mutation detection methods have historically precluded a genome-wide understanding of mutation rates and spectra in the nuclear genomes of multicellular organisms. We applied two high-throughput DNA sequencing technologies to identify and characterize hundreds of spontaneously arising base-substitution mutations in 10 Caenorhabditis elegans mutation-accumulation (MA)-line nuclear genomes. C. elegans mutation rate estimates were similar to previous calculations based on smaller numbers of mutations. Mutations were distributed uniformly within and among chromosomes and were not associated with recombination rate variation in the MA lines, suggesting that intragenomic variation in genetic hitchhiking and/or background selection are primarily responsible for the chromosomal distribution patterns of polymorphic nucleotides in C. elegans natural populations. A strong mutational bias from G/C to A/T nucleotides was detected in the MA lines, implicating oxidative DNA damage as a major endogenous mutagenic force in C. elegans. The observed mutational bias also suggests that the C. elegans nuclear genome cannot be at equilibrium because of mutation alone. Transversions dominate the spectrum of spontaneous mutations observed here, whereas transitions dominate patterns of allegedly neutral polymorphism in natural populations of C. elegans and many other animal species; this observation challenges the assumption that natural patterns of molecular variation in noncoding regions of the nuclear genome accurately reflect underlying mutation processes.

Fig. 1.

MA-line mutation rate estimates. (A) Mutation rate estimates specific to each of the 10 MA-line genomes analyzed (solid gray bars) and maximum-likelihood mutation rate estimates (striped bars) for the three genomes analyzed by 454 (L-ML) and the seven analyzed by Solexa (B-ML). Error bars for the 10 line-specific estimates show SEM, and those for the maximum-likelihood estimates show SD. (B) Conditional mutation rate estimates for each of the six nonstrand-specific base substitution mutation types. Error bars show SEM.

Fig. 2.

Distribution of 391 MA-line base substitutions across C. elegans chromosomes. Tick marks indicate the physical positions of MA-line mutations across the six C. elegans chromosomes; those above the chromosomes derive from the three MA lines analyzed by 454; those below the line are from the seven lines analyzed by Solexa.