Multiple instances of ancient balancing selection shared between humans and chimpanzees

Abstract

Instances in which natural selection maintains genetic variation in a population over millions of years are thought to be extremely rare. We conducted a genome-wide scan for long-lived balancing selection by looking for combinations of SNPs shared between humans and chimpanzees. In addition to the major histocompatibility complex, we identified 125 regions in which the same haplotypes are segregating in the two species, all but two of which are noncoding. In six cases, there is evidence for an ancestral polymorphism that persisted to the present in humans and chimpanzees. Regions with shared haplotypes are significantly enriched for membrane glycoproteins, and a similar trend is seen among shared coding polymorphisms. These findings indicate that ancient balancing selection has shaped human variation and point to genes involved in host-pathogen interactions as common targets.

Figure 1. Analysis pipeline

A) Diagram of the pipeline to identify shared coding SNPs and shared haplotypes. See (16) for details of the filtering and validation. B) Two possible scenarios of ancient balancing selection that may be detected by our approach. In (i), only one site is under balancing selection and a second mutation is neutral, but persisted as a polymorphism until the present in both species because of tight linkage to the selected site. In (ii), two or more epistatically-interacting polymorphic sites are maintained by balancing selection from the ancestral population of human and chimpanzee to the present time. In this case, the ancestral segment could be substantially longer because there is selection against recombinant haplotypes.

Figure 2. Functional information for three regions with a polymorphism shared identical by descent in humans and chimpanzees

We show the nearby genes and direction of transcription, then a close up of the region with shared polymorphisms between humans and chimpanzees. The original shared SNPs used to identify shared haplotypes are shown as solid circles. The region resequenced in the validation experiment is indicated with a solid black bar and the length of the shared haplotypes with a dashed black bar (16). For sources of the functional annotation tracks shown, see (16). In the last panel, we focus on a shared SNP (hg19, chr4:144658471, chr5:8023976, and chr4:57918492, respectively) and show the average pairwise difference between allelic classes for humans (in blue) and chimpanzees (in red), for a 500 bp sliding window; the average pairwise difference within an allelic class in humans is in gray. We further indicate the average genome-wide divergence between human and chimpanzee (1.2%; (39)) with a dotted black line. For divergence between more distant ape species and a zoom out of diversity levels in each region, see Figs. S7 and S9. A) FREM3. A duplication in chimpanzees that includes the GYPE gene is shown above the gene structure in humans (26). The shared SNPs and eQTLs for GYPE in monocytes (40) are in almost perfect LD, with a pairwise r² ranging from 0.98 to 1. B) MTRR. The shared SNP represented by a triangle is also seen in a sample of seven gorillas obtained by Sanger resequencing (see (16)); pairwise differences between allelic classes in gorillas is shown in turquoise for the resequenced region. The maximum pairwise r² between a shared SNP and the eQTL for MTRR in monocytes is 0.47 (40) (16). The FAIRE signal is enriched in six cell lines. C) IGFBP7. In the scan for shared haplotypes, five shared SNPs were found in the four kb region, occurring in two clusters with three and two SNPs, respectively, which are not in LD with each other in humans. Two of the shared SNPs found in the resequencing and a SNP outside the resequenced region constitute an additional instance of shared haplotypes. The FAIRE signal is enriched in four cell lines. Using a focal SNP in the second cluster yields similar results (see Fig. S7).

Figure 2. Functional information for three regions with a polymorphism shared identical by descent in humans and chimpanzees

We show the nearby genes and direction of transcription, then a close up of the region with shared polymorphisms between humans and chimpanzees. The original shared SNPs used to identify shared haplotypes are shown as solid circles. The region resequenced in the validation experiment is indicated with a solid black bar and the length of the shared haplotypes with a dashed black bar (16). For sources of the functional annotation tracks shown, see (16). In the last panel, we focus on a shared SNP (hg19, chr4:144658471, chr5:8023976, and chr4:57918492, respectively) and show the average pairwise difference between allelic classes for humans (in blue) and chimpanzees (in red), for a 500 bp sliding window; the average pairwise difference within an allelic class in humans is in gray. We further indicate the average genome-wide divergence between human and chimpanzee (1.2%; (39)) with a dotted black line. For divergence between more distant ape species and a zoom out of diversity levels in each region, see Figs. S7 and S9. A) FREM3. A duplication in chimpanzees that includes the GYPE gene is shown above the gene structure in humans (26). The shared SNPs and eQTLs for GYPE in monocytes (40) are in almost perfect LD, with a pairwise r² ranging from 0.98 to 1. B) MTRR. The shared SNP represented by a triangle is also seen in a sample of seven gorillas obtained by Sanger resequencing (see (16)); pairwise differences between allelic classes in gorillas is shown in turquoise for the resequenced region. The maximum pairwise r² between a shared SNP and the eQTL for MTRR in monocytes is 0.47 (40) (16). The FAIRE signal is enriched in six cell lines. C) IGFBP7. In the scan for shared haplotypes, five shared SNPs were found in the four kb region, occurring in two clusters with three and two SNPs, respectively, which are not in LD with each other in humans. Two of the shared SNPs found in the resequencing and a SNP outside the resequenced region constitute an additional instance of shared haplotypes. The FAIRE signal is enriched in four cell lines. Using a focal SNP in the second cluster yields similar results (see Fig. S7).

Figure 2. Functional information for three regions with a polymorphism shared identical by descent in humans and chimpanzees

We show the nearby genes and direction of transcription, then a close up of the region with shared polymorphisms between humans and chimpanzees. The original shared SNPs used to identify shared haplotypes are shown as solid circles. The region resequenced in the validation experiment is indicated with a solid black bar and the length of the shared haplotypes with a dashed black bar (16). For sources of the functional annotation tracks shown, see (16). In the last panel, we focus on a shared SNP (hg19, chr4:144658471, chr5:8023976, and chr4:57918492, respectively) and show the average pairwise difference between allelic classes for humans (in blue) and chimpanzees (in red), for a 500 bp sliding window; the average pairwise difference within an allelic class in humans is in gray. We further indicate the average genome-wide divergence between human and chimpanzee (1.2%; (39)) with a dotted black line. For divergence between more distant ape species and a zoom out of diversity levels in each region, see Figs. S7 and S9. A) FREM3. A duplication in chimpanzees that includes the GYPE gene is shown above the gene structure in humans (26). The shared SNPs and eQTLs for GYPE in monocytes (40) are in almost perfect LD, with a pairwise r² ranging from 0.98 to 1. B) MTRR. The shared SNP represented by a triangle is also seen in a sample of seven gorillas obtained by Sanger resequencing (see (16)); pairwise differences between allelic classes in gorillas is shown in turquoise for the resequenced region. The maximum pairwise r² between a shared SNP and the eQTL for MTRR in monocytes is 0.47 (40) (16). The FAIRE signal is enriched in six cell lines. C) IGFBP7. In the scan for shared haplotypes, five shared SNPs were found in the four kb region, occurring in two clusters with three and two SNPs, respectively, which are not in LD with each other in humans. Two of the shared SNPs found in the resequencing and a SNP outside the resequenced region constitute an additional instance of shared haplotypes. The FAIRE signal is enriched in four cell lines. Using a focal SNP in the second cluster yields similar results (see Fig. S7).

Figure 3

Phylogenetic trees of haplotypes labeled with the same focal SNP considered in Fig. 2 or Fig. S8 for (A) FREM3, (B) MTRR, (C) IGFBP7, (D) HUS1, (E) PROKR2 and (F) ST3GAL1. Trees were generated from our resequencing data using MrBayes, with the median posterior probability of the clade over two runs reported in red (16). Results are for the entire resequenced regions for FREM3 and MTRR, and for the largest regions for which we found strong support in other cases. For FREM3, MTRR and IGFBP7, the regions on which the trees are based are long (>800 bps), providing strong support for a polymorphism shared identical by descent (16). For HUS1, the tree still clusters by allele when considering 1 kb (with posterior probability 0.58), but for ST3GAL1 and PROKR2, this is not the case (for more details, see (16)).

Figure 3

Phylogenetic trees of haplotypes labeled with the same focal SNP considered in Fig. 2 or Fig. S8 for (A) FREM3, (B) MTRR, (C) IGFBP7, (D) HUS1, (E) PROKR2 and (F) ST3GAL1. Trees were generated from our resequencing data using MrBayes, with the median posterior probability of the clade over two runs reported in red (16). Results are for the entire resequenced regions for FREM3 and MTRR, and for the largest regions for which we found strong support in other cases. For FREM3, MTRR and IGFBP7, the regions on which the trees are based are long (>800 bps), providing strong support for a polymorphism shared identical by descent (16). For HUS1, the tree still clusters by allele when considering 1 kb (with posterior probability 0.58), but for ST3GAL1 and PROKR2, this is not the case (for more details, see (16)).