Balancing Selection in the Human Genome

Andrés, Aida M.

doi:10.1002/9780470015902.a0022863

Cited by 21 publications

(26 citation statements)

References 47 publications

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“…The Non-Central Deviation (NCD) statistic Background. Owing to linkage, the signature of long-term balancing selection extends to the genetic neighborhood of the selected variant(s); therefore, patterns of polymorphism and divergence in a genomic region can be used to infer whether it evolved under LTBS (Charlesworth 2006;Andrés 2011). As mentioned, LTBS leaves two distinctive signatures in linked variation, when compared with neutral expectations: an increase in the ratio of polymorphic to divergent sites and an excess of alleles segregating at intermediate frequencies when compared to neutral expectations ( Figure 1A-B).…”

Section: Methodsmentioning

confidence: 99%

Signatures of long-term balancing selection in human genomes

Bitarello

Filippo

Teixeira

et al. 2017

Preprint

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Balancing selection maintains advantageous diversity in populations through various mechanisms. While extensively explored from a theoretical perspective, an empirical understanding of its prevalence and targets lags behind our knowledge of positive selection. Here we describe the Non-Central Deviation (NCD), a simple yet powerful statistic to detect long-term balancing selection (LTBS) that quantifies how close frequencies are to expectations under LTBS, and provides the basis for a neutrality test. NCD can be applied to a single locus or genomic data, and can be implemented considering only polymorphisms (NCD1) or also considering fixed differences with respect to an outgroup (NCD2) species. Incorporating fixed differences improves power, and NCD2 has higher power to detect LTBS in humans under different frequencies of the balanced allele(s) than other available methods. Applied to genome-wide data from African and European human populations, in both cases using chimpanzee as an outgroup, NCD2 shows that, albeit not prevalent, LTBS affects a sizable portion of the genome: about 0.6% of analyzed genomic windows and 0.8% of analyzed positions. Significant windows (p < 0.0001) contain 1.6% of SNPs in the genome, which disproportionally fall within exons and change protein sequence, but are not enriched in putatively regulatory sites. These windows overlap about 8% of the protein-coding genes, and these have larger number of transcripts than expected by chance even after controlling for gene length. Our catalog includes known targets of LTBS but a majority of them (90%) are novel. As expected, immune-related genes are among those with the strongest signatures, although most candidates are involved in other biological functions, suggesting that LTBS potentially influences diverse human phenotypes.

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Section: Methodsmentioning

confidence: 99%

Signatures of long-term balancing selection in human genomes

Bitarello

Filippo

Teixeira

et al. 2017

Preprint

View full text Add to dashboard Cite

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“…Multiple processes can lead to balancing selection. In overdominance, the heterozygous genotype has higher fitness than either of the homozygous genotypes [1,2]. In frequency-dependent balancing selection, the fitness of an allele is inversely related to its frequency in the population [2,3].…”

Section: Introductionmentioning

confidence: 99%

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

2014

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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.

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“…Biologists refer to this last case as balancing selection (e.g. Hedrick, 2006; Mitchell-Olds et al ., 2007; Hurst, 2009; Andrés, 2011). …”

Section: Introductionmentioning

confidence: 99%

On the importance of balancing selection in plants

2013

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Summary Balancing selection refers to a variety of selective regimes that maintain advantageous genetic diversity within populations. We review the history of the ideas regarding the types of selection that maintain such polymorphism in flowering plants, notably heterozygote advantage, negative frequency-dependent selection, and spatial heterogeneity. One shared feature of these mechanisms is that whether an allele is beneficial or detrimental is conditional on its frequency in the population. We highlight examples of balancing selection on a variety of discrete traits. These include the well-referenced case of self-incompatibility and recent evidence from species with nuclear-cytoplasmic gynodioecy, both of which exhibit trans-specific polymorphism, a hallmark of balancing selection. We also discuss and give examples of how spatial heterogeneity in particular, which is often thought unlikely to allow protected polymorphism, can maintain genetic variation in plants (which are rooted in place) as a result of microhabitat selection. Lastly, we discuss limitations of the protected polymorphism concept for quantitative traits, where selection can inflate the genetic variance without maintaining specific alleles indefinitely. We conclude that while discrete-morph variation provides the most unambiguous cases of protected polymorphism, they represent only a fraction of the balancing selection at work in plants.

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Balancing Selection in the Human Genome

Cited by 21 publications

References 47 publications

Signatures of long-term balancing selection in human genomes

Signatures of long-term balancing selection in human genomes

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

On the importance of balancing selection in plants

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