A Model-Based Approach for Identifying Signatures of Ancient Balancing Selection in Genetic Data

While much effort has focused on detecting positive and negative directional selection in the human genome, relatively little work has been devoted to balancing selection. This lack of attention is likely due to the paucity of sophisticated methods for identifying sites under balancing selection. Here we develop two composite likelihood ratio tests for detecting balancing selection. Using simulations, we show that these methods outperform competing methods under a variety of assumptions and demographic models. We apply the new methods to whole-genome human data, and find a number of previously-identified loci with strong evidence of balancing selection, including several HLA genes. Additionally, we find evidence for many novel candidates, the strongest of which is FANK1, an imprinted gene that suppresses apoptosis, is expressed during meiosis in males, and displays marginal signs of segregation distortion. We hypothesize that balancing selection acts on this locus to stabilize the segregation distortion and negative fitness effects of the distorter allele. Thus, our methods are able to reproduce many previously-hypothesized signals of balancing selection, as well as discover novel interesting candidates.Author Summary: In the past, balancing selection was a topic of great theoretical interest that received much attention. However, there has been little focus toward developing methods to identify regions of the genome that are under balancing selection. In this article, we present the first set of likelihood-based methods that explicitly model the spatial distribution of polymorphism expected near a site under long-term balancing selection. Simulation results show that our methods outperform commonly-used summary statistics for identifying regions under balancing selection. Finally, we performed a scan for balancing selection in Africans and Europeans using our new methods and identified a gene called FANK1 as our top candidate outside the HLA region. We hypothesize that the maintenance of polymorphism at FANK1 is the result of segregation distortion.