The problem of choosing a DNA sequence similarity measure based purely on nucleotide content matching or genealogical or cladistic distance is rooted in the fact that, ultimately, functional nucleotide content (i.e., what nucleotides and nucleotide combinations an individual possesses that impact function) determines gene activity, rather than the phylogenetic origins of those nucleotides. Thus, in theory, similarity measures that build off the functional features and functional capacities of impacted genes associated with DNA sequence (Box 2) – as shaped by particular nucleotides and nucleotide combinations – are likely to be more appropriate for association studies than measures based on either phylogenetic relationships between sequences or the mere equality of aligned nucleotides.
