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Frequent monoallelic or skewed expression for developmental genes in CNS-derived cells and evidence for balancing selection.

ABSTRACT: Cellular mosaicism due to monoallelic autosomal expression (MAE), with cell selection during development, is becoming increasingly recognized as prevalent in mammals, leading to interest in understanding its extent and mechanism(s). We report here use of clonal cell lines derived from the CNS of adult female [Formula: see text] hybrid (C57BL/6 X JF1) mice to characterize MAE as neural stem cells (nscs) differentiate to astrocyte-like cells (asls). We found that different subsets of genes show MAE in the two populations of cells; in each case, there is strong enrichment for genes specific to the respective developmental state. Genes that exhibit MAE are 22% of nsc-specific genes and 26% of asl-specific genes. Moreover, the promoters of genes with MAE have reduced CpG dinucleotides but increased CpG differences between the two parental mouse strains. Extending the study of variability to wild populations of mice, we found evidence for balancing selection as a contributing force in evolution of those genes showing developmental specificity (i.e., expressed in either nsc or asl), not just for genes showing MAE. Furthermore, we found that genes showing skewed allelic expression (SKE) were similarly enriched among cell type-specific genes and also showed a heightened probability of balancing selection. Thus, developmental stage-specific genes and genes with MAE or SKE seem to make up overlapping classes subject to selection for increased diversity. The implications of these results for development and evolution are discussed in the context of a model with stochastic epigenetic modifications taking place only during a relatively brief developmental window.

SUBMITTER: Branciamore S

PROVIDER: S-EPMC6217436 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Frequent monoallelic or skewed expression for developmental genes in CNS-derived cells and evidence for balancing selection.

Branciamore Sergio S Valo Zuzana Z Li Min M Wang Jinhui J Riggs Arthur D AD Singer-Sam Judith J

Proceedings of the National Academy of Sciences of the United States of America 20181015 44

Cellular mosaicism due to monoallelic autosomal expression (MAE), with cell selection during development, is becoming increasingly recognized as prevalent in mammals, leading to interest in understanding its extent and mechanism(s). We report here use of clonal cell lines derived from the CNS of adult female [Formula: see text] hybrid (C57BL/6 X JF1) mice to characterize MAE as neural stem cells (<i>nsc</i>s) differentiate to astrocyte-like cells (<i>asl</i>s). We found that different subsets of ...[more]

PMID: 30322913

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Project description:BackgroundBalancing selection operating for long evolutionary periods at a locus is characterized by the maintenance of distinct alleles because of a heterozygote or rare-allele advantage. The loci under balancing selection are distinguished by their unusually high polymorphism levels. In this report, we provide statistical and comparative genetic evidence suggesting that the SDHA gene is under long-term balancing selection. SDHA encodes the major catalytical subunit (flavoprotein, Fp) of the succinate dehydrogenase enzyme complex (SDH; mitochondrial complex II). The inhibition of Fp by homozygous SDHA mutations or by 3-nitropropionic acid poisoning causes central nervous system pathologies. In contrast, heterozygous mutations in SDHB, SDHC, and SDHD, the other SDH subunit genes, cause hereditary paraganglioma (PGL) tumors, which show constitutive activation of pathways induced by oxygen deprivation (hypoxia).ResultsWe sequenced the four SDH subunit genes (10.8 kb) in 24 African American and 24 European American samples. We also sequenced the SDHA gene (2.8 kb) in 18 chimpanzees. Increased nucleotide diversity distinguished the human SDHA gene from its chimpanzee ortholog and from the PGL genes. Sequence analysis uncovered two common SDHA missense variants and refuted the previous suggestions that these variants originate from different genetic loci. Two highly dissimilar SDHA haplotype clusters were present in intermediate frequencies in both racial groups. The SDHA variation pattern showed statistically significant deviations from neutrality by the Tajima, Fu and Li, Hudson-Kreitman-Aguadé, and Depaulis haplotype number tests. Empirically, the elevated values of the nucleotide diversity (% pi = 0.231) and the Tajima statistics (D = 1.954) in the SDHA gene were comparable with the most outstanding cases for balancing selection in the African American population.ConclusionThe SDHA gene has a strong signature of balancing selection. The SDHA variants that have increased in frequency during human evolution might, by influencing the regulation of cellular oxygen homeostasis, confer protection against certain environmental toxins or pathogens that are prevalent in Africa.

Dataset Information

Frequent monoallelic or skewed expression for developmental genes in CNS-derived cells and evidence for balancing selection.

Publications

Frequent monoallelic or skewed expression for developmental genes in CNS-derived cells and evidence for balancing selection.

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