A significant difference in the distribution of a feature between two gene sets can provide insight into function or regulation. This statistical setting differs from much of hypothesis testing theory because the genome is often considered to be effectively fixed, finite and entirely known in commonly studied organisms, such as human. The Mann-Whitney U test is commonly employed in this scenario despite the assumptions of the test not being met, leading to unreliable and generally underpowered results. Permutation tests are also commonly employed for this purpose, but are computationally burdensome and are not tractable for obtaining small P values or for multiple comparisons.