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MBE Advance Access originally published online on June 1, 2007
Molecular Biology and Evolution 2007 24(8):1792-1800; doi:10.1093/molbev/msm108
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© 2007 The Authors.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Research Articles

Context Dependence, Ancestral Misidentification, and Spurious Signatures of Natural Selection

Ryan D. Hernandez*, Scott H. Williamson* and Carlos D. Bustamante*

* Biological Statistics and Computational Biology, Cornell University

E-mail: cdb28{at}cornell.edu.

Accepted for publication May 11, 2007.

Population genetic analyses often use polymorphism data from one species, and orthologous genomic sequences from closely related outgroup species. These outgroup sequences are frequently used to identify ancestral alleles at segregating sites and to compare the patterns of polymorphism and divergence. Inherent in such studies is the assumption of parsimony, which posits that the ancestral state of each single nucleotide polymorphism (SNP) is the allele that matches the orthologous site in the outgroup sequence, and that all nucleotide substitutions between species have been observed. This study tests the effect of violating the parsimony assumption when mutation rates vary across sites and over time. Using a context-dependent mutation model that accounts for elevated mutation rates at CpG dinucleotides, increased propensity for transitional versus transversional mutations, as well as other directional and contextual mutation biases estimated along the human lineage, we show (using both simulations and a theoretical model) that enough unobserved substitutions could have occurred since the divergence of human and chimpanzee to cause many statistical tests to spuriously reject neutrality. Moreover, using both the chimpanzee and rhesus macaque genomes to parsimoniously identify ancestral states causes a large fraction of the data to be removed while not completely alleviating problem. By constructing a novel model of the context-dependent mutation process, we can correct polymorphism data for the effect of ancestral misidentification using a single outgroup.

Key Words: context-dependence • single nucleotide polymorphism • site-frequency spectrum • ancestral misidentification

Abbreviations: likelihood ratio test, LRTPoisson random field, PRFsingle nucleotide polymorphism, SNPsite-frequency spectrum, SFSstandard neutral model, SNM

John H. McDonald, Associate Editor


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