Abstract
We previously developed an analytical strategy based on cladistic theory to identify subsets of haplotypes that are associated with significant phenotypic deviations. Our initial approach was limited to segments of DNA in which little recombination occurs. In such cases, a cladogram can be constructed from the restriction site data to estimate the evolutionary steps that interrelate the observed haplotypes to one another. The cladogram is then used to define a nested statistical design for identifying mutational steps associated with significant phenotypic deviations. The central assumption behind this strategy is that a mutation responsible for a particular phenotypic effect is embedded within the evolutionary history that is represented by the cladogram. The power of this approach depends on the accuracy of the cladogram in portraying the evolutionary history of the DNA region. This accuracy can be diminished both by recombination and by uncertainty in the estimated cladogram topology. In a previous paper, we presented an algorithm for estimating the set of likely cladograms and recombination events. In this paper we present an algorithm for defining a nested statistical design under cladogram uncertainty and recombination. Given the nested design, phenotypic associations can be examined using either a nested analysis of variance (for haploids or homozygous strains) or permutation testing (for outcrossed, diploid gene regions). In this paper we also extend this analytical strategy to include categorical phenotypes in addition to quantitative phenotypes. Some worked examples are presented using Drosophila data sets. These examples illustrate that having some recombination may actually enhance the biological inferences that may derived from a cladistic analysis. In particular, recombination can be used to assign a physical localization to a given subregion for mutations responsible for significant phenotypic effects.
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Selected References
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- Clark A. G., Whittam T. S. Sequencing errors and molecular evolutionary analysis. Mol Biol Evol. 1992 Jul;9(4):744–752. doi: 10.1093/oxfordjournals.molbev.a040756. [DOI] [PubMed] [Google Scholar]
- Game A. Y., Oakeshott J. G. Associations between restriction site polymorphism and enzyme activity variation for esterase 6 in Drosophila melanogaster. Genetics. 1990 Dec;126(4):1021–1031. doi: 10.1093/genetics/126.4.1021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Langley C. H., Ito K., Voelker R. A. Linkage disequilibrium in natural populations of Drosophila melanogaster Seasonal variation. Genetics. 1977 Jun;86(2 Pt 1):447–454. [PMC free article] [PubMed] [Google Scholar]
- Langley C. H., Shrimpton A. E., Yamazaki T., Miyashita N., Matsuo Y., Aquadro C. F. Naturally occurring variation in the restriction map of the amy region of Drosophila melanogaster. Genetics. 1988 Jul;119(3):619–629. doi: 10.1093/genetics/119.3.619. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Prum B., Guilloud-Bataille M., Clerget-Darpoux F. On the use of chi 2 tests for nested categorized data. Ann Hum Genet. 1990 Oct;54(Pt 4):315–320. doi: 10.1111/j.1469-1809.1990.tb00387.x. [DOI] [PubMed] [Google Scholar]
- Roff D. A., Bentzen P. The statistical analysis of mitochondrial DNA polymorphisms: chi 2 and the problem of small samples. Mol Biol Evol. 1989 Sep;6(5):539–545. doi: 10.1093/oxfordjournals.molbev.a040568. [DOI] [PubMed] [Google Scholar]
- Templeton A. R., Boerwinkle E., Sing C. F. A cladistic analysis of phenotypic associations with haplotypes inferred from restriction endonuclease mapping. I. Basic theory and an analysis of alcohol dehydrogenase activity in Drosophila. Genetics. 1987 Oct;117(2):343–351. doi: 10.1093/genetics/117.2.343. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Templeton A. R., Crandall K. A., Sing C. F. A cladistic analysis of phenotypic associations with haplotypes inferred from restriction endonuclease mapping and DNA sequence data. III. Cladogram estimation. Genetics. 1992 Oct;132(2):619–633. doi: 10.1093/genetics/132.2.619. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Templeton A. R., Sing C. F., Kessling A., Humphries S. A cladistic analysis of phenotype associations with haplotypes inferred from restriction endonuclease mapping. II. The analysis of natural populations. Genetics. 1988 Dec;120(4):1145–1154. doi: 10.1093/genetics/120.4.1145. [DOI] [PMC free article] [PubMed] [Google Scholar]