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Genetic susceptibility to severe childhood asthma and rhinovirus-C maintained by balancing selection in humans for 150 000 years.

ABSTRACT: Selective pressures imposed by pathogens have varied among human populations throughout their evolution, leading to marked inter-population differences at some genes mediating susceptibility to infectious and immune-related diseases. Here, we investigated the evolutionary history of a common polymorphism resulting in a Y529 versus C529 change in the cadherin related family member 3 (CDHR3) receptor which underlies variable susceptibility to rhinovirus-C infection and is associated with severe childhood asthma. The protective variant is the derived allele and is found at high frequency worldwide (69-95%). We detected genome-wide significant signatures of natural selection consistent with a rapid increase of the haplotypes carrying the allele, suggesting that non-neutral processes have acted on this locus across all human populations. However, the allele has not fixed in any population despite multiple lines of evidence suggesting that the mutation predates human migrations out of Africa. Using an approximate Bayesian computation method, we estimate the age of the mutation while explicitly accounting for past demography and positive or frequency-dependent balancing selection. Our analyses indicate a single emergence of the mutation in anatomically modern humans ~150 000 years ago and indicate that balancing selection has maintained the beneficial allele at high equilibrium frequencies worldwide. Apart from the well-known cases of the MHC and ABO genes, this study provides the first evidence that negative frequency-dependent selection plausibly acted on a human disease susceptibility locus, a form of balancing selection compatible with typical transmission dynamics of communicable respiratory viruses that might exploit CDHR3.

SUBMITTER: O'Neill MB

PROVIDER: S-EPMC7104676 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundYoung children with rhinovirus (RV) infection-particularly bronchiolitis-are at high risk for developing childhood asthma. Emerging evidence suggests clinical heterogeneity within RV bronchiolitis. However, little is known about these biologically distinct subgroups (endotypes) and their relations with asthma risk.ObjectiveWe aimed to identify RV bronchiolitis endotypes and examine their longitudinal relations with asthma risk.MethodsAs part of a multicenter prospective cohort study of infants (age <12 months) hospitalized for bronchiolitis, we integrated clinical, RV species (RV-A, RV-B, and RV-C), nasopharyngeal microbiome (16S rRNA gene sequencing), cytokine, and metabolome (liquid chromatography tandem mass spectrometry) data collected at hospitalization. We then applied network and clustering approaches to identify bronchiolitis endotypes. We also examined their longitudinal association with risks of developing recurrent wheeze by age 3 years and asthma by age 5 years.ResultsOf 122 infants hospitalized for RV bronchiolitis (median age, 4 months), we identified 4 distinct endotypes-mainly characterized by RV species, microbiome, and type 2 cytokine (T2) response: endotype A, virusRV-CmicrobiomemixedT2low; endotype B, virusRV-AmicrobiomeHaemophilusT2low; endotype C, virusRSV/RVmicrobiomeStreptococcusT2low; and endotype D, virusRV-CmicrobiomeMoraxellaT2high. Compared with endotype A infants, endotype D infants had a significantly higher rate of recurrent wheeze (33% vs 64%; hazard ratio, 2.23; 95% CI, 1.00-4.96; P = .049) and a higher risk for developing asthma (28% vs 59%; odds ratio, 3.74: 95% CI, 1.21-12.6; P = .03).ConclusionsIntegrated-omics analysis identified biologically meaningful RV bronchiolitis endotypes in infants, such as one characterized by RV-C infection, Moraxella-dominant microbiota, and high T2 cytokine response, at higher risk for developing recurrent wheeze and asthma. This study should facilitate further research toward validating our inferences.

Project description:Balancing selection, an evolutionary force that retains genetic diversity, has been detected in multiple genes and organisms, such as the sexual mating loci in fungi. However, to quantify the strength of balancing selection and define the mating-related genes require a large number of strains. In tetrapolar basidiomycete fungi, sexual type is determined by two unlinked loci, MATA and MATB. Genes in both loci define mating type identity, control successful mating and completion of the life cycle. These loci are usually highly diverse. Previous studies have speculated, based on culture crosses, that species of the non-model genus Trichaptum (Hymenochaetales, Basidiomycota) possess a tetrapolar mating system, with multiple alleles. Here, we sequenced a hundred and eighty strains of three Trichaptum species. We characterized the chromosomal location of MATA and MATB, the molecular structure of MAT regions and their allelic richness. The sequencing effort was sufficient to molecularly characterize multiple MAT alleles segregating before the speciation event of Trichaptum species. Analyses suggested that long-term balancing selection has generated trans-species polymorphisms. Mating sequences were classified in different allelic classes based on an amino acid identity (AAI) threshold supported by phylogenetics. 17,550 mating types were predicted based on the allelic classes. In vitro crosses allowed us to support the degree of allelic divergence needed for successful mating. Even with the high amount of divergence, key amino acids in functional domains are conserved. We conclude that the genetic diversity of mating loci in Trichaptum is due to long-term balancing selection, with limited recombination and duplication activity. The large number of sequenced strains highlighted the importance of sequencing multiple individuals from different species to detect the mating-related genes, the mechanisms generating diversity and the evolutionary forces maintaining them.

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Genetic susceptibility to severe childhood asthma and rhinovirus-C maintained by balancing selection in humans for 150 000 years.

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