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Genetics. 1987 Oct; 117(2): 343–351.
PMCID: PMC1203209

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


Because some genes have been cloned that have a known biochemical or physiological function, genetic variation can be measured in a population at loci that may directly influence a phenotype of interest. With this measured genotype approach, specific alleles or haplotypes in the probed DNA region can be assigned phenotypic effects. In this paper we address several problems encountered in implementing the measured genotype approach with restriction site data. A number of analytical problems arise in part as a consequence of the linkage disequilibrium that is commonly encountered when dealing with small DNA regions: 1) different restriction site polymorphisms are not statistically independent, 2) the sites being measured are not likely to be the direct cause of the associated phenotypic effects, 3) haplotype classes may be phenotypically heterogeneous, and 4) the sites that are most strongly associated with phenotypic effects are not necessarily the most closely linked to the actual genetic cause of the effects. When recombination and gene conversion are rare, the primary cause of linkage disequilibrium is history (mutational origin, genetic drift, hitchhiking, etc.). We deal with historical association directly by producing a cladogram that partially reconstructs the evolutionary history of the present-day haplotype variability. The cladogram defines a nested analysis of variance that simultaneously detects phenotypic effects, localizes the effects within the cladogram, and identifies haplotypes that are potentially heterogeneous in their phenotypic associations. The power of this approach is illustrated by an analysis of the associations between alcohol dehydrogenase (ADH) activity and restriction site variability in a 13-kb fragment surrounding the ADH locus in Drosophila melanogaster.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Aquadro CF, Desse SF, Bland MM, Langley CH, Laurie-Ahlberg CC. Molecular population genetics of the alcohol dehydrogenase gene region of Drosophila melanogaster. Genetics. 1986 Dec;114(4):1165–1190. [PMC free article] [PubMed]
  • Boerwinkle E, Visvikis S, Welsh D, Steinmetz J, Hanash SM, Sing CF. The use of measured genotype information in the analysis of quantitative phenotypes in man. II. The role of the apolipoprotein E polymorphism in determining levels, variability, and covariability of cholesterol, betalipoprotein, and triglycerides in a sample of unrelated individuals. Am J Med Genet. 1987 Jul;27(3):567–582. [PubMed]
  • Kan YW, Dozy AM. Evolution of the hemoglobin S and C genes in world populations. Science. 1980 Jul 18;209(4454):388–391. [PubMed]

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