Abstract
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.
Highlights
Balancing selection maintains variation within a population
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
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 human leukocyte antigen (HLA) region
Summary
Balancing selection maintains variation within a population. Multiple processes can lead to balancing selection. In frequency-dependent balancing selection, the fitness of an allele is inversely related to its frequency in the population [2,3]. In a fluctuating or spatiallystructured environment, balancing selection can occur when different alleles are favored in different environments over time or geography [2,4,5]. Balancing selection can be a product of opposite directed effects of segregation distortion balanced by negative selection against the distorter [6]. Segregation distortion leads to one allele increasing in frequency. If that allele is deleterious, it is reduced in frequency by negative selection. The combined effect of these opposing forces can lead to a balanced polymorphism
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