Linkage disequilibrium and age estimates of a deletion polymorphism (1597ΔC) in HLA-G suggest non-neutral evolution

Aldrich, Carrie; Wambebe, Charles; Odama, L. E.; Rienzo, Anna Di; Ober, Carole

doi:10.1016/s0198-8859(02)00377-4

Cited by 58 publications

(44 citation statements)

References 42 publications

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“…The deletion of nucleotide 1597 in exon 3 does not cause a total failure of the protein to perform its function, rather it changes its morphology to resemble a class II MHC molecule rather than a class I molecule, to which it is evolutionarily related. Aldrich et al (2002) hypothesize that the 1597⌬C is a recent mutation and has achieved a high frequency due to the action of positive selection. If the mutation is recent, one expects that it would be in strong disequilibrium with flanking markers, whereas no such association would exist with older mutations that occur at the same frequency.…”

Section: Linkage Disequilibriummentioning

confidence: 99%

Perspective: Detecting Adaptive Molecular Polymorphism: Lessons From the MHC

2003

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Abstract. In the 1960s, when population geneticists first began to collect data on the amount of genetic variation in natural populations, balancing selection was invoked as a possible explanation for how such high levels of molecular variation are maintained. However, the predictions of the neutral theory of molecular evolution have since become the standard by which cases of balancing selection may be inferred. Here we review the evidence for balancing selection acting on the major histocompatibility complex (MHC) of vertebrates, a genetic system that defies many of the predictions of neutrality. We apply many widely used tests of neutrality to MHC data as a benchmark for assessing the power of these tests. These tests can be categorized as detecting selection in the current generation, over the history of populations, or over the histories of species. We find that selection is not detectable in MHC datasets in every generation, population, or every evolutionary lineage. This suggests either that selection on the MHC is heterogeneous or that many of the current neutrality tests lack sufficient power to detect the selection consistently. Additionally, we identify a potential inference problem associated with several tests of neutrality. We demonstrate that the signals of selection may be generated in a relatively short period of microevolutionary time, yet these signals may take exceptionally long periods of time to be erased in the absence of selection. This is especially true for the neutrality test based on the ratio of nonsynonymous to synonymous substitutions. Inference of the nature of the selection events that create such signals should be approached with caution. However, a combination of tests on different time scales may overcome such problems.

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Section: Linkage Disequilibriummentioning

confidence: 99%

Perspective: Detecting Adaptive Molecular Polymorphism: Lessons From the MHC

2003

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“…First, assuming neutrality and an infinite allele model, mean allele age and an MLE of allele age and its approximate confidence interval were estimated from the observed allele frequencies in the sample following Griffiths (2003) and Slatkin and Rannala (2000). Allele age estimates were also obtained using the approach outlined in Aldrich et al (2002) and Toomajian et al (2003). The basic idea is to estimate an allele's age by the decay of ancestral haplotype sharing (DHS, McPeek and Strahs, 1999).…”

Section: Dna Sequence Analysismentioning

confidence: 99%

Recent degeneration of an old duplicated flowering time gene in Brassica nigra

et al. 2007

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Gene and genome duplications play a major role in the evolution of plant species. The Brassica nigra genome is highly replicated as a result of ancient polyploidization events. Two copies of the flowering time gene CONSTANS (COa and COb) have been identified in B. nigra, and previous studies showed that COa is functional. In the present study, the polymorphism of 92 COb alleles sampled in seven populations was analyzed. Both polymorphism and recombination levels were elevated and varied strongly among populations and 8% of COb alleles exhibit apparently disabling mutations. Sequence data, however, do not provide unambiguous support for the presence of relaxed selective constraint on COb as compared to known functional CO genes. On the one hand, some of the disabling mutations reached high-frequency arguing for a loss of function but, on the other hand, the ratio of nonsynonymous to synonymous nucleotide polymorphism and diversity is low and similar to that observed in other B. nigra CO and CO-like genes, supporting the conservation of some function. We also showed that COb is still transcribed. Finally, the flowering time of Arabidopsis thaliana co mutant plants transformed with COb alleles with and without apparent disabling mutations was similar. We propose that COb was retained for a long period after duplication, but a recent fixation of a detrimental mutation, possibly as an effect of a bottleneck, resulted in its nonfunctionalization. We also speculate as to the presence of subsequent selection for rapid degeneration of the gene.

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“…Given the putative role of HLA-G in placental development, it has been proposed that the G*0105N allele is maintained in high frequency in some populations by non-neutral evolutionary forces [10]. The highest frequencies of G*0105N in geographic areas with a historically high pathogen load suggest that intrauterine pathogens may act as selective agents, increasing survival of heterozygous fetuses carrying the G*0105N allele in infected pregnancies (balancing selection).…”

Section: Introductionmentioning

confidence: 99%

“…The highest frequencies of G*0105N in geographic areas with a historically high pathogen load suggest that intrauterine pathogens may act as selective agents, increasing survival of heterozygous fetuses carrying the G*0105N allele in infected pregnancies (balancing selection). In this case, the reduced HLA-G1 expression in G*0105N heterozygous placentas may result in an overall increase in the number of T cells available in the uterus and reverse the inhibition of NK cells, improving the intrauterine defense against infections [10,18]. The survival of healthy individuals homozygous for the G*0105N allele [7,18,19] that do not express the G1, G4, and G5 soluble isoforms suggest that such isoforms are not essential for fetal survival in uncomplicated pregnancies [10,20].…”

Section: Introductionmentioning

confidence: 99%

“…In this case, the reduced HLA-G1 expression in G*0105N heterozygous placentas may result in an overall increase in the number of T cells available in the uterus and reverse the inhibition of NK cells, improving the intrauterine defense against infections [10,18]. The survival of healthy individuals homozygous for the G*0105N allele [7,18,19] that do not express the G1, G4, and G5 soluble isoforms suggest that such isoforms are not essential for fetal survival in uncomplicated pregnancies [10,20]. Given that G*0113N transcripts do not result in any functional protein isoforms, the observation of a healthy homozygous individual for the G*0113N allele would be unexpected.…”

Section: Introductionmentioning

confidence: 99%

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