Perspective: Detecting Adaptive Molecular Polymorphism: Lessons From the MHC

Garrigan, Daniel; Hedrick, Philip W.

doi:10.1111/j.0014-3820.2003.tb00580.x

Cited by 417 publications

(336 citation statements)

References 107 publications

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“…Our empirical and simulation results suggest that intense periodic balancing selection at the MHC may have allowed the persistence of variation in San Nicolas foxes despite strong genetic drift. This result adds significantly to the small number of studies showing evidence for balancing selection as a mechanism to maintain genetic variation (41)(42)(43)(44)(45). In effect, periodic selection has rescued genetic variation at the MHC and, potentially, other fitness-related genes.…”

Section: Resultsmentioning

confidence: 70%

High MHC diversity maintained by balancing selection in an otherwise genetically monomorphic mammal

Aguilar

Roemer

Debenham

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

375

353

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The San Nicolas Island fox (Urocyon littoralis dickeyi) is genetically the most monomorphic sexually reproducing animal population yet reported and has no variation in hypervariable genetic markers. Such low levels of variation imply lower resistance to pathogens, reduced fitness, and problems in distinguishing kin from non-kin. In vertebrates, the MHC contains genes that influence disease resistance and kin recognition and may be under intense balancing selection in some populations. Hence, genetic variation at the MHC might persist despite the extreme monomorphism shown by neutral markers. We examine variation of five loci within the MHC of San Nicolas Island foxes and find remarkably high levels of variation. Further, we show by simulation that genetic monomorphism at neutral loci and high MHC variation could arise only through an extreme population bottleneck of <10 individuals, Ϸ10 -20 generations ago, accompanied by unprecedented selection coefficients of >0.5 on MHC loci. These results support the importance of balancing selection as a mechanism to maintain variation in natural populations and expose the difficulty of using neutral markers as surrogates for variation in fitness-related loci.T he island fox (Urocyon littoralis) is an endemic North American canid that inhabits six of the eight Channel Islands off the coast of southern California (Fig. 1). As suggested by the archeological record and molecular genetic data, foxes colonized the three northern Channel Islands (San Miguel, Santa Rosa, and Santa Cruz) Ϸ16,000 years ago and, subsequently, were transported by Native Americans to the three southern Channel Islands (San Nicolas, Santa Catalina, and San Clemente) 800 to 4,300 years ago (1-4) ( Fig. 1). Effective population size varies with island area and ranges from Ͻ200 to Ϸ1,000 individuals (Table 1). Levels of genetic variation reflect population size and colonization history, with the San Nicolas Island population having the second smallest effective population size and a recent colonization history (4) ( Fig. 1 and Table 1). No variation has been discovered for any of four independent genetic marker classes in the San Nicolas Island population, including supposedly neutral hypervariable microsatellite loci (5) and multilocus fingerprints (2), for which the probability of genetic identity is commonly Ͻ1 in several million (6). Recently, because of dramatic declines, populations on the three Northern Islands and Santa Catalina Island have been proposed for listing under the U.S. Endangered Species Act (7).The MHC contains the most variable set of coding genes in vertebrates, with as many as 349 alleles described for a single locus (8) and heterozygosity values that generally exceed those predicted by neutrality (9). Class I and II MHC molecules are responsible for the presentation to T cells of intracellular (endogenous) and extracellular (exogenous) peptides, respectively (10). High levels of heterozygosity at the MHC may be maintained by balancing selection through pathogen-mediated selection, ...

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Section: Resultsmentioning

confidence: 70%

High MHC diversity maintained by balancing selection in an otherwise genetically monomorphic mammal

Aguilar

Roemer

Debenham

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

375

353

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“…First, the evolution of the DQA1 promoter region may have been inf luenced by its proximity, i.e., physical linkage, to the highly polymorphic second exon of the gene, a coding sequence located 4 kb downstream that is known to be evolving under balancing selection (7). Balancing selection on one locus increases levels of neutral variation at closely linked sites, as a function of the physical distance between the two loci, intensity of selection, recombination rate, effective population size, and mutation rate (33, 34, 51, 52).…”

Section: Discussionmentioning

confidence: 99%

“…Because there is uncertainty in the phylogenetic reconstruction of any single tree, we analyzed the 100 most frequently sampled DQA1 promoter topologies from the Bayesian analysis and obtained a mean of 37.8 deep coalescent events (95% credible interval of 32-44 events). Under the simplest models of neutrality and drift, there should be complete congruence between gene and species trees, and a set of species separated by Ͼ4 N e generations should have (n Ϫ 1) interspecific coalescent events, where n is the number of species sampled (7,39). Therefore, the mean of 37.8 interspecific coalescent events observed in our DQA1 analysis is nearly 5-fold higher than that expected when there is complete congruence between the gene and species trees (n Ϫ 1 ϭ 8).…”

Section: Primate Dqa1 Promoter Haplotypes Exhibit Widespread Trans-spmentioning

confidence: 99%

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Ancient polymorphism and functional variation in the primate MHC-DQA15′ cis-regulatory region

Loisel

Rockman

Wray

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Precise regulation of MHC gene expression is critical to vertebrate immune surveillance and response. Polymorphisms in the 5 proximal promoter region of the human class II gene HLA-DQA1 have been shown to influence its transcriptional regulation and may contribute to the pathogenesis of autoimmune diseases. We investigated the evolutionary history of this cis-regulatory region by sequencing the DQA1 5 proximal promoter region in eight nonhuman primate species. We observed unexpectedly high levels of sequence variation and multiple strong signatures of balancing selection in this region. Specifically, the considerable DQA1 promoter region diversity was characterized by abundant shared (or trans-species) polymorphism and a pronounced lack of fixed differences between species. The majority of transcription factor binding sites in the DQA1 promoter region were polymorphic within species, and these binding site polymorphisms were commonly shared among multiple species despite evidence for negative selection eliminating a significant fraction of binding site mutations. We assessed the functional consequences of intraspecific promoter region diversity using a cell line-based reporter assay and detected significant differences among baboon DQA1 promoter haplotypes in their ability to drive transcription in vitro. The functional differentiation of baboon promoter haplotypes, together with the significant deviations from neutral sequence evolution, suggests a role for balancing selection in the evolution of DQA1 transcriptional regulation in primates.balancing selection ͉ cis-regulatory evolution ͉ major histocompatibility complex ͉ primate molecular evolution

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“…This signature can include intermediate frequency polymorphisms and a peak of increased nucleotide diversity. 4 Molecular evidence for balanced polymorphisms has been obtained for several genes and/or genomic regions, e.g., the human class I and II MHC genes, 5 Drosophila Adh, 6,7 Arabidopsis thaliana MAM 8 and disease resistance loci. [9][10][11][12] Genomic scans based on nucleotide sequences are used to identify genes targeted by selection.…”

Section: Introductionmentioning

confidence: 99%

Bimodal expression level polymorphisms inArabidopsis thaliana

Nagano

Tsuchimatsu

Okuyama

et al. 2012

Plant Signaling & Behavior

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Differences in gene expression are termed expression level polymorphisms (ELPs). Here, we propose a new ELP class, bimodal ELPs (bELPs), as a criterion to screen for genes that are responsible for natural phenotypic variation and/or that are targeted by balancing selection. bELP genes are characterized by two expression level modes. Genomic scans based on nucleotide sequences are not ideal for identifying genes targeted for selection. A critical concern is that several genes can be present in the selection-targeted regions identified by such scans. This situation indicates the importance of integrating genomic sequence data and other information, such as gene expression data. Comparative transcriptomics is useful for determining evolutionarily and ecologically important polymorphisms. In a genome-wide expression screen of 34 accessions, we identified 344 Arabidopsis thaliana genes exhibiting bELPs. Population genetic analysis revealed that bELP genes had high nucleotide diversities and long linkage disequilibriums. The highest nucleotide diversity (11-fold greater than the genomic mean) was found in the At1g23780 gene, which encodes a putative F-box protein. We observed a clear association between the expression mode and sequence type of the At1g23780 gene. Our results suggest that bELPs will be useful for the screening and functional analysis of genes responsible for phenotypic polymorphisms. Such a "multi-omics" approach has the potential to facilitate the scanning of genes relevant to balanced polymorphisms not only in A. thaliana, but also in other model and non-model organisms.

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Perspective: Detecting Adaptive Molecular Polymorphism: Lessons From the MHC

Cited by 417 publications

References 107 publications

High MHC diversity maintained by balancing selection in an otherwise genetically monomorphic mammal

High MHC diversity maintained by balancing selection in an otherwise genetically monomorphic mammal

Ancient polymorphism and functional variation in the primate MHC-DQA15′ cis-regulatory region

Bimodal expression level polymorphisms inArabidopsis thaliana

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