Multiple Instances of Ancient Balancing Selection Shared Between Humans and Chimpanzees

An image of a human and a chimpanzee. Can you see the similarities?!

Balancing selection is a mode of adaptation that conserves regions of genetic diversity within a genome even when the population or species being examined is subject to genetic drift. Genetic diversity in a population is often described as an increased number of heterozygotes. On a more molecular level, however, balancing selection and therefore increased genetic diversity is suggested when a certain number of single nucleotide polymorphisms (SNPs) or haplotypes in a population are seen more often in a region of interest than would be expected by genetic drift or mutation alone.

Evidence has suggested that balancing selection most often occurs when the region of genetic diversity increases organismal fitness evolutionarily. A common example of balancing selection in humans is sickle cell anemia. With this heterozygote advantage individuals with one normal and one sickle cell allele have a greater ability to resist malaria. Multiple studies have shown that balancing selection most often arises from predator-prey or host-pathogen interactions. Selected, closely-linked sites can be indicative of ancient balancing selection if the genetic variation in the population is accumulated over long periods of time.

An example of balancing selection. An image comparing Malaria and Sickle cell anemia in Africa and Asia from a 2012 article.

Due to recent genome sequencing technology and genome wide analysis researchers have the chance to search and compare human and chimpanzee genomes for ancient balancing selection. A recent paper by Leffler et al. published in March of 2013 titled, Multiple instances of ancient balancing selection shared between humans and chimpanzees, highlights regions of the human and chimpanzee genomes that suggest potential balancing selection that would have occurred in an ancient common ancestor before the human-chimpanzee split. In order to find areas indicative of balancing selection genome wide scans were used to search for regions of high diversity that would not likely be seen under genetic drift, mutation, or other selective pressures. While conducting this study researchers looked for ancestral polymorphisms present in both the humans and chimpanzees that are identical by descent (IBD) in order to eliminate the probability that such polymorphisms in selected regions would be due to chance alone.

When identifying shared SNPs between the two species, the complete genome sequences from 59 humans from sub-Saharan Africa and 10 Western chimpanzees were examined. From the data that was produced, the researchers found that the shared SNPs include a much higher proportion of CpGs (regions of DNA where a cytosine nucleotide occurs next to a guanine nucleotide in the linear sequence of bases along a region of DNA). This observation suggests that “most instances of shared SNPs are due to the independent occurrence of the same mutation in both species”. This indicates that the SNP similarities are identical by state rather than descent between the human and chimpanzee populations that were examined. So, one may think that balancing selection does not play a significant role in the identification of shared SNPs….

This figure depicts that after filtering measures were taken in order to weed out other factors that would cause similarities in SNPs that some sites are strictly maintained by balancing selection from the ancestral population of human and chimpanzee to present time.

Along with identifying shared SNPs, protein variants were also analyzed in order to determine the prevalence of balancing selection. The MHC stood out in the analysis. This observation in the commonality of the MHC protein variant includes six nonsynonymous and three synonymous SNPs that were not among the many cases of shared haplotypes in this region indicating a relationship between the two species’ genomes.

The most notable shared SNP found between the human and chimpanzee genome is a nonsynonymous SNP in GP1BA. This gene encodes a glycoprotein present on the membrane of platelets that is responsible for binding to the ABO antigens expressed on the Von Willebrand Factor. The specific polymorphism in this gene shared between chimps and humans affects the actual binding to the Von Willebrand Factor and is associated with platelet count. These results from the protein variant analysis leads researchers to believe that the two genes in the two species may have been targets of long-lived balancing selection.

125 regions outside the MHC with shared haplotypes were identified between chimpanzees and humans. In five of the regions that were located with shared haplotypes, there are more than two pairs of shared SNPs in significant linkage disequilibrium. This indicates that balancing selection could play a role in the incidences of shared haplotypes between the two species.

The phylogenetic tree generated based on the regions of shared haplotypes, shows that haplotypes from different species that carry the same allele are more closely related to each other than to haplotypes from the same species with the other allele. This pattern of clusters represented by the tree indicates that these cases of commonality cannot be explained solely by recurrent mutation. This investigation is another piece of evidence in support of the presence of balancing selection.

What do you think? Is there enough evidence to suggest balancing selection within the human and chimpanzee genomes? Where could researchers go from here? What should they look at next?


3 Responses to Multiple Instances of Ancient Balancing Selection Shared Between Humans and Chimpanzees

  1. Reading this paper, I thought it was interesting where SNPs were found to be in ibd between humans and chimpanzees. In previous studies, polymorphisms shared in between humans and apes were connected to immune response and blood types. Later in the study, they found that shared SNPS acted mainly on the regulatory elements of the human and ape genomes. Many SNPs were related to cell proliferation, cell adhision, and metabolism regulation. It’s not that surprising that conserved genes would be related to these essential processes, but the location of the SNPs was compelling. In figure 2A and 2B, the SNPs were found in the coding section of DNA but in figure 2C, the shared SNPs were seen in the intron. Since an intron is often removed during RNA splicing, what sort of function could these SNPs provide if they are ibd? Or did these results occur simply because most of the shared SNPs were found at CpG sites?

    On the final page of the paper, the investigators briefly talked about how balancing selection occurred at specific sites due to pathogen-host interactions. Balancing selection for the GP1BA protein makes sense because infestation of disease begins at the cellular level. I would be curious to see if they could collaborate with a Drosophila lab or another research team to induce balancing selection against a particular pathogen to verify their results. Then, the genomes of selected flies could be sequenced and analyzed for equivocal sites. Could they see these results over many generations?

  2. The phylogenetic trees presented in this paper prove the idea that balancing selection occurred in a human-chimpanzee common ancestor quite well.
    For a species to have genetic material at certain sites in the genome more in common with a different species than with other individuals within the species is extremely interesting and is rather clear proof that a common ancestor of the two species underwent some level of balancing selection.

    Furthermore, as the paper noted that the balancing selection in a human-chimpanzee common ancestor occurred mainly within genetic regions relating to disease, it would be interesting to see if by tracking divergences in chimpanzee and human disease-related alleles it could be estimated when new diseases entered the chimpanzee or human populations and began applying new selection forces.

  3. While reading the manuscript of Leffler, et al., I was really intrigued by the the methodology used by the lab to analyze and identify shared coding SNPs and haplotypes. Specifically, the pipeline that is presented in Figure 1A is mind-boggling in scope, as 9.4 million autosomal and 261,000 X chromosome SNPs from humans and 3.8 million autosomal and 102,000 X chromosome SNPs from chimpanzees were filtered and parsed to ~340 shared SNPs (excluding MHC) and 125 regions with shared haplotypes! I am usually impressed by the critical thinking and step-wise methodology used in scientific research, but the sheer volume of data being filtered by the scientists in an effort to find pertinent genetic information and ensure the quality of this information is astounding.

    Beyond my amazement at the schematic in Figure 1A, I also could not escape thinking about RNA editing, and its potential role with balanced polymorphisms. Essentially, RNA editing is exactly how it sounds, that being the editing of the transcript of other RNA form, which can ultimately lead to altered protein function. Because the researchers mention that their findings suggest that balancing selection has targeted regulatory variation in the human genome, I am curious as to whether the two SNPs found in coding regions in some way are involved in RNA editing or regulatory processes associated with it. Unfortunately, I am still very unfamiliar with RNA editing, as it has just begun to be discussed in my RNA class, but nevertheless, this question lingered as I read the paper.

Leave a Reply

Your email address will not be published. Required fields are marked *