Um entendimento genômico amplo das taxas de mutação em genoma nuclear de um organismo multicelular

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

Dee R. Denvera,1, Peter C. Dolana, Larry J. Wilhelma, Way Sungb, J. Ignacio Lucas-Lledóc, Dana K. Howea, Samantha C. Lewisa, Kazu Okamotob, W. Kelley Thomasb, Michael Lynchc and Charles F. Baerd

+ Author Affiliations

aDepartment of Zoology and Center for Genome Research and Biocomputing, Oregon State University, Corvallis, OR 97331;

bHubbard Center for Genome Studies, University of New Hampshire, Durham, NH 03824;

cDepartment of Biology, Indiana University, Bloomington, IN 47405; and

dDepartment of Zoology, University of Florida, Gainesville, FL 32611

Edited by M. T. Clegg, University of California, Irvine, CA, and approved August 11, 2009 (received for review May 4, 2009)

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.

high-throughput DNA sequencing mutation accumulation

Footnotes

1To whom correspondence should be addressed. E-mail: denver@cgrb.oregonstate.edu

Author contributions: D.R.D., W.K.T., M.L., and C.F.B. designed research; D.K.H., S.C.L., and K.O. performed research; D.R.D., P.C.D., L.J.W., W.S., J.I.L.-L., and D.K.H. analyzed data; and D.R.D. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

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