Robustness Supplement

The zip file contains all supplemental files, including supplemental figures, a C program (with README.txt file) for computing false positive, false negative, etc. clades for an estimated tree and reference tree, and list of alignment lengths for loci in the 8881-locus great ape dataset

Performance of , , HKA, and Tajima's under the demographic models in Figure 2 with selection parameter and dominance parameter .

<p>The first column is the divergence model in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004561#pgen-1004561-g002" target="_blank">Figure 2<i>A</i></a>. The second column is the divergence model in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004561#pgen-1004561-g002" target="_blank">Figure 2<i>B</i></a> with a recent bottleneck within the ingroup species. The third column is the divergence model in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004561#pgen-1004561-g002" target="_blank">Figure 2<i>C</i></a> with recent population growth within the ingroup species.</p

Performance of , , HKA, and Tajima's under the bottleneck and growth demographic models in Figure 2 with selection parameter and dominance parameter .

<p>The left panel is the divergence model in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004561#pgen-1004561-g002" target="_blank">Figure 2<i>B</i></a> with a recent bottleneck within the ingroup species. The right panel is the divergence model in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004561#pgen-1004561-g002" target="_blank">Figure 2<i>C</i></a> with recent population growth within the ingroup species. The population sizes for the bottleneck and growth demographic histories have been scaled so that they produce the same number of segregating sites as a constant size population with diploid effective size individuals.</p

Performance of , , HKA, and Tajima's under the demographic models in Figure 2 with selection parameter and dominance parameter .

<p>The first column is the divergence model in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004561#pgen-1004561-g002" target="_blank">Figure 2<i>A</i></a>. The second column is the divergence model in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004561#pgen-1004561-g002" target="_blank">Figure 2<i>B</i></a> with a recent bottleneck within the ingroup species. The third column is the divergence model in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004561#pgen-1004561-g002" target="_blank">Figure 2<i>C</i></a> with recent population growth within the ingroup species.</p

Signals of balancing selection within the HLA region for the CEU (blue) and YRI (orange) populations using the test statistic.

<p>From bottom to top, the horizontal dotted gray lines indicate the , , , and empirical cutoffs, respectively.</p

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

<div><p>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 <i>FANK1</i>, 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.</p></div

Performance of , , HKA, and Tajima's under the bottleneck and growth demographic models in Figure 2 with selection parameter and dominance parameter .

<p>The left panel is the divergence model in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004561#pgen-1004561-g002" target="_blank">Figure 2<i>B</i></a> with a recent bottleneck within the ingroup species. The right panel is the divergence model in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004561#pgen-1004561-g002" target="_blank">Figure 2<i>C</i></a> with recent population growth within the ingroup species. The population sizes for the bottleneck and growth demographic histories have been scaled so that they produce the same number of segregating sites as a constant size population with diploid effective size individuals.</p

Calculation of probabilities of polymorphism and substitution under a model of balancing selection and the incorporation of these probabilities into a genome scan.

<p>(<i>A</i>) Relationship among tree length , tree height and inter-specific coalescence time . (<i>B</i>) A site is polymorphic if a mutation occurred on the length of branches until the most recent common ancestor of the ingroup sample (red region). (<i>C</i>) A site is a substitution if a mutation occurred on the length of branches that represent the divergence between the outgroup species and the most recent common ancestor of the ingroup species (blue region). (<i>D</i>) Height and length of genealogies in relationship to their spatial proximity to a selected site and how the shapes of these genealogies affect the pattern of polymorphism around the site. The composite likelihood ratio is high near a selected site as there is an excess of polymorphisms close to the site and a deficit far from the site.</p

Demographic models used in simulations in which a selected allele arises after the split a pair of species.

<p>(<i>A</i>) Divergence model. Model parameters are a diploid effective population size , divergence time of the ingroup and outgroup species, and the time when the selected allele arises. (<i>B</i>) Divergence model with a recent bottleneck within the ingroup species. Additional model parameters are the diploid effective population size during the bottleneck, the time when the bottleneck began, and the time when the bottleneck ended. (<i>C</i>) Divergence model with recent population growth within the ingroup species. Additional model parameters are the current diploid effective population size after recent growth and the time when the growth occurred.</p

Signal of balancing selection at the <i>FANK1</i> gene for the CEU (blue) and YRI (orange) populations using the test statistic.

<p>From bottom to top, the horizontal dotted gray lines indicate the , , , and empirical cutoffs, respectively. SNPs (rsIDs) correspond to markers showing significant levels of transmission distortion within the Meyer <i>et al.</i> study <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004561#pgen.1004561-Meyer1" target="_blank">[37]</a>.</p