Abstract: A general method is described for screening cDNAs, genes or genome segments to directly isolate and characterize sequences associated with particular phenotypes. In the case of the human genome, a simplification of the starting material is needed, and a specific method to generate highly polymorphic genome subsets for this purpose is presented. The general screening method identifies DNA sequences containing allele frequency differences when groups with dissimilar phenotypes are compared. The approach is based on mathematical principles of inequality. A change in the abundance ratio of homoduplexes of perfectly matched sequences to heteroduplexes of perfectly matched sequences, or, conversely, of mismatched homoduplexes to mismatched heteroduplexes, serves as an indicator of allele frequency difference.