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Genetics. Published Articles Ahead of Print: November 19, 2005, Copyright © 2005
doi:10.1534/genetics.105.049718

A more recent version of this article appeared on February 1, 2006.
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REGULAR RESEARCH PAPERS

Assessing the fidelity of ancient DNA sequences amplified from nuclear genes

Jonas Binladen 1, Carsten Wiuf 2, M. Thomas P Gilbert 3, Michael Bunce 4, Ross Barnett 5, Greger Larson 5, Alex D Greenwood 6, James Haile 5, Simon Y. W. Ho 5, Anders J. Hansen 1 and Eske Willerslev 1*

1 University of Copenhagen
2 University of Aarhus
3 University of Arizona
4 McMaster University
5 University of Oxford
6 American Museum of Natural History

* To whom correspondence should be addressed. E-mail: ewillerslev{at}gfy.ku.dk.

Submitted on August 17, 2005
Revised on September 30, 2005
Accepted on 25 October 2005


  Abstract
To date, the field of ancient DNA has relied almost exclusively on mitochondrial DNA (mtDNA) sequences. However, a number of recent studies have reported the successful recovery of ancient nuclear DNA (nuDNA) sequences, thereby allowing the characterization of genetic loci directly involved in phenotypic traits of extinct taxa. It is well documented that post-mortem damage in ancient mtDNA can lead to the generation of artifactual sequences. However, as yet no one has thoroughly investigated the damage spectrum in ancient nuDNA. By the comparison of clone sequences from 23 fossil specimens, recovered from environments ranging from permafrost to desert, we demonstrate the presence of miscoding lesion damage in both the mtDNA and nuDNA resulting in insertion of erroneous bases during amplification. Interestingly, no significant differences in the frequency of miscoding lesion damage are recorded between mtDNA and nuDNA despite great differences in cellular copy numbers. For both mtDNA and nuDNA, we find significant positive correlations between total sequence heterogeneity and the rates of Type 1 transitions (adenine -> guanine and thymine -> cytosine), and Type 2 transitions (cytosine -> thymine and guanine -> adenine), respectively. Type 2 transitions are by far the most dominant, and increase relative to those of Type 1 with damage load. The results suggest that the deamination of cytosine (and 5-methyl cytosine) to uracil (and thymine) is the main cause of miscoding lesions in both ancient mtDNA and nuDNA sequences. We argue that the problems presented by post-mortem damage, as well as with contamination from exogenous sources of conserved nuclear genes, allelic variation, and the reliance of single nucleotide polymorphisms, call for great caution in studies relying on ancient nuDNA sequences.

Key Words: Ancient DNA, damage, mitochondria DNA, nuclear DNA




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