Academic journal article Genetics

Tree Scanning: A Method for Using Haplotype Trees in Phenotype/Genotype Association Studies

Academic journal article Genetics

Tree Scanning: A Method for Using Haplotype Trees in Phenotype/Genotype Association Studies

Article excerpt

ABSTRACT

We use evolutionary trees of haplotypes to study phenotypic associations by exhaustively examining all possible biallelic partitions of the tree, a technique we call tree scanning. If the first scan detects significant associations, additional rounds of tree scanning are used to partition the tree into three or more allelic classes. Two worked examples are presented. The first is a reanalysis of associations between haplotypes at the Alcohol Dehydrogenase locus in Drosophila melanogaster that was previously analyzed using a nested clade analysis, a more complicated technique for using haplotype trees to detect phenotypic associations. Tree scanning and the nested clade analysis yield the same inferences when permutation testing is used with both approaches. The second example is an analysis of associations between variation in various lipid traits and genetic variation at the Apolipoprotein E (APOE) gene in three human populations. Tree scanning successfully identified phenotypic associations expected from previous analyses. Tree scanning for the most part detected more associations and provided a better biological interpretative framework than single SNP analyses. We also show how prior information can be incorporated into the tree scan by starting with the traditional three electrophoretic alleles at APOE. Tree scanning detected genetically determined phenotypic heterogeneity within all three electrophoretic allelic classes. Overall, tree scanning is a simple, powerful, and flexible method for using haplotype trees to detect phenotype/genotype associations at candidate loci.

MANY studies attempt to associate trait variation with genetic variation at a candidate gene by employing separate tests at each polymorphic nucleotide site within the gene, even when the sites display extensive linkage disequilibrium. Increasingly, there is an appreciation that using haplotypes can often augment power for detecting phenotypic associations and can eliminate the difficulties of statistical dependence among polymorphic sites showing linkage disequilibrium (DRYSDALE et al. 2000; MARTIN el al. 2000; SELTMAN et al. 2001; BALCIUNIENE et al. 2002; RNOBLAUCH et al. 2002; VAN EERDEWEGH et al. 2002; ZAYKIN et al. 2002). The tendency for haplotype analyses to show increased power over single-nucleotide polymorphism (SNP) analyses is not surprising if SNPs do not always affect phenotypes in isolation but rather affect the phenotype through the joint genetic effects of two or more SNPs.

An evolutionary tree of the haplotypes at a candidate locus or DNA region can be estimated when there is little to no recombination in the DNA region. Given that there is increasing evidence for areas of low recombination separated by recombination hotspots (TEMPLETON et al 2000; JEFFREYS et al 2001; REICH et al 2002), haplotype variation in many genomic regions can be organized into haplotype trees. Just as SNPs can be placed into the context of a haplotype to increase the level of biological information, so can haplotypes be placed into their evolutionary context to further augment the amount of biological information. TEMPLETON et al. (1987) were the first to propose using haplotypes and their evolutionary trees in phenotype/genotype association studies through nested clade analysis (NCA) in which the branches of the haplotype tree are used to define a nested hierarchy of clades ("branches") of haplotypes. The fundamental premise of NCA is that any mutation having functional significance will be imbedded in the historical framework defined by the haplotype tree and therefore whole branches (clades) of this tree will show similar functional attributes. Nesting has several advantages. First, nesting categories are determined tdexclusively by the evolutionary history of the haplotypes without any consideration of phenotypic data, thereby eliminating a source of potential bias in phenotype/genotype association studies. second, the clades define a nested design that makes full and efficient use of the available degrees of freedom and performs only evolutionarily relevant contrasts. …

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