Sequencing of the human genome has opened the door to the most exciting new era for studying complex genetic traits. Positional cloning is a powerful approach, and is aimed at the identification and cloning genes, based on their chromosomal location identified through linkage analysis. The past decade has seen substantial success in identifying genes responsible for monogenic disorders while progress in gene identification for more common, multifactorial diseases has been slower. With completion of human genome sequencing the relevance of this approach is growing, with the rapidly increasing information and characterization of the human genome providing the opportunity to resolve complex diseases, as demonstrated in several recent studies. Recently, we identified a susceptibility locus for human Uric Acid Nephrolithiasis (UAN) on 10q21-q22 and showed that a variant of a novel gene encoding a specific protein is associated with Uric Acid Nephrolithiasis (OMIM 605990). Inspired by this successful identification, this paper briefly summarizes the genetical basis of Uric Acid Nephrolithiasis, and the evolutionary adaptation of the predisposing gene in a complex puzzle of inherited factors that we have disclosed through a comparative genomic approach.