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

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.

Evolution of the rapidly mutating human salivary agglutinin gene ( DMBT1 ) and population subsistence strategy

“…One study has highlighted DMBT1 to be a strong candidate for ancient balancing selection in the genome (49). Another recent study has identified the region upstream of DMBT1 to show unusually negative Tajima's D (in the fifth percentile genome wide) in Europeans, supporting our model of selection (50).…”

Causes of natural variation in fitness: Evidence from studies of Drosophila populations

“…This conclusion should not be taken to mean that balancing selection is ubiquitous across the genome. Population genomics results provide little evidence for balancing selection, suggesting only a scattering of loci across the genome with alleles that have been maintained at intermediate frequencies by selection for periods of time that are much larger than the mean neutral coalescence time (77,(89)(90)(91). However, it is well known that such loci contribute disproportionately to the genetic variance, so that a relatively small number could cause most of it, even if the vast majority of individual variants affecting fitness were kept at low frequencies by purifying selection (5).…”

Assembly and analysis of 100 full MHC haplotypes from the Danish population

“…The high diversity is thought to be driven by balancing selection acting on several individual genes combined with an overall small recombination rate in the MHC (DeGiorgio et al 2014). Genome-wide association studies have revealed the MHC to be the most important region in the human genome for disease associations, in particular for autoimmune diseases (Trowsdale and Knight 2013;Zhou et al 2016).…”