Advantageous diversity maintained by balancing selection in humans

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Most human polymorphisms are neutral or slightly deleterious, but some genetic variation is advantageous and maintained in populations by balancing selection. Considered a rarity and overlooked for years, balanced polymorphisms have recently received renewed attention with several lines of evidence showing their relevance in human evolution. From theoretical work on its role in adaptation to empirical studies that identify its targets, recent developments have showed that balancing selection is more prevalent than previously thought. Here we review these developments and discuss their implications in our understanding of the influence of balancing selection in human evolution. We also review existing evidence on the biological functions that benefit most from advantageous diversity, and the functional consequences of these variants. Overall, we argue that balancing selection must be considered an important selective force in human evolution.

Introduction

Humans are genetically fairly homogeneous, with low levels of genetic variation that is found mostly within (rather than between) populations. The vast majority of this variation is neutral or slightly deleterious, but there are also advantageous polymorphisms maintained by natural selection. A classical example is a polymorphism in the β-globin gene. Homozygote individuals for this variant are either susceptible to malaria (HbA/HbA genotype) or suffer from sickle cell anemia (HbS/HbS), while heterozygotes have a higher chance of surviving malaria [1]. Hence, heterozygotes have higher fitness in regions where malaria is endemic, and both alleles are maintained in the population. Such heterozygote advantage (also known as overdominance or heterosis) can maintain stable polymorphisms, as can other mechanisms such as frequency-dependent selection, certain changes in selection in time or space in well-defined populations, or pleiotropy [2, 3, 4, 5•, 6, 7], all of which can be considered classical types of balancing selection.

Section snippets

Identifying balancing selection

Balanced polymorphisms will be maintained in a population as long as selection can overcome the effects of drift and prevent allele fixation. Selection that is old will maintain advantageous polymorphism and result in an older time to the most recent common ancestor (TMRCA) than expected under neutrality [8••]. This results in the accumulation of neutral, old linked variation, segregating at a frequency close to the frequency equilibrium (i.e. the frequency that maximizes fitness in the

Balancing selection shared among species

As described above, some balanced variants can be old and shared among species. Such trans-species polymorphisms exist for example in genes associated with self-incompatibility in plants [28] and heterokaryon-incompatibility in fungi [29], but in humans they were long assumed to be restricted to a few classical examples [30] such as the ABO blood group and the major histocompatibility complex (MHC). The ABO has recently been confirmed as one of the oldest trans-species haplotypes known in

Balancing selection in humans

A few genome-wide analyses have discovered previously unknown targets of balancing selection. One study identified signatures of high diversity and excess of intermediate-frequency alleles in a Sanger-based exome-wide dataset [43••], and two more studies used novel approaches to analyze a Complete Genomics dataset: (i) a study based on two likelihood ratio test methods that determine the likelihood of variants to be linked to a balanced polymorphism, given characteristics of the local

Changes in selection and short-lived balancing selection

Overall, targets of balancing selection and enriched categories are largely but not completely shared across populations. Actually, some categories involved in immunity and defense are not shared across populations at a significant level (Table S3 in [43••]) and many of the immunity-related categories are driven by signatures solely in the HLA molecules [44••]. In individual genes, several targets show similarly high diversity in all populations, yet have significant allele frequency

Biological functions enhanced by advantageous diversity

As expected, individual targets do not necessarily show perfect overlap among existing genomic studies; still similar functional categories show enrichment in candidate genes. Immunity-related categories consistently show enrichment in candidate targets of balancing selection (Figure 2) [43••, 44••], in agreement with the arms-race against pathogens and the strong influence of natural selection in immunity-related functions (reviewed in Siddle and Quintana-Murci, in this issue). Some of the

The classes of sites under balancing selection

Classical examples of balancing selection involve mostly protein-coding changes. Most candidate targets uncovered in Leffler et al. [16••] and Rasmussen et al. [8••] lie though outside yet close to protein-coding genes suggesting that they may have a regulatory role, and several other candidate targets identified overlap promoter or regulatory regions, for example [65, 66, 67]. It is thus possible that heterogeneity in expression is often more advantageous than the presence of several protein

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgments

We thank Christoph Theunert, Alexander Cagan and Lluís Quintana-Murci for useful comments on the manuscript and the MPI-EVA multimedia department for help in the production of the figures. This work was funded by the Max Planck Society. JCT is supported by Fundação para a Ciência e a Tecnologia (FCT) within the Portuguese Ministry for Science and Education (SFRH/BD/77043/2011).

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