Abstract
In recent years, high-throughput genomic technologies and computational advancements have invigorated efforts to identify the molecular mechanisms regulating human adaptation to high altitude. Although exceptional progress regarding the identification of genomic regions showing evidence of recent positive selection has been made, many of the key “hypoxia tolerant” phenotypes of highland populations have not yet been linked to putative adaptive genetic variants. As a result, fundamental questions regarding the biological processes by which such adaptations are acquired remain unanswered. This Mini Review discusses the hypothesis that the epigenome works in coordination with underlying genomic sequence to govern adaptation to the chronic hypoxia of high altitude by influencing adaptive capacity and phenotypic variation under conditions of environmental hypoxia. Efforts to unravel the complex interactions between the genome, epigenome, and environmental exposures are essential to more fully appreciate the mechanisms underlying human adaptation to hypoxia.
Highlights
Promising investigations are poised to begin unraveling the molecular mechanisms by which genomic signals showing evidence of natural selection confer purportedly advantageous phenotypes of highland populations within the context of the high-altitude environment
The adaptive variants identified by single nucleotide polymorphism (SNP) array or case-control comparisons do not explain the full range of hypoxia-tolerant features characteristic to highland populations, emphasizing the need for whole-genome sequencing and a fuller understanding of the degree to which non-sequence based features of the genome contribute to the adaptive physiological features observed
In recent years, sequencing technologies and analytical capabilities have vastly expanded knowledge regarding the mechanisms governing human variation and disease and provide the opportunity to gain a deeper understanding of the genome-epigenome interaction and its relevance for human adaptation and adaptive potential
Summary
“Each living organism has two histories that determine its biology: an evolutionary history whose duration is in the hundreds of thousands of years, and a developmental history that starts at the time of conception.”. An Aptitude for Altitude which most often are the product of gene-gene interaction, gene-environment interaction and non-sequence-based features of the genome (e.g., epigenetic marks) that are critical for transcriptional regulation in response to environmental and developmental triggers This complexity underscores the need to emphasize more dynamic models of human adaptation than have traditionally been appreciated (Box 1). Non-sequence based changes to chromatin conformation enable phenotypic flexibility about a given genotype This Mini Review considers that epigenomic mechanisms may contribute to human adaptation to the high altitude environment in a least four interconnected ways including (1) the modification of transcriptional or phenotypic flexibility under conditions of limited oxygen availability, (2) enhancing (or limiting) phenotypic variation and thereby influencing the heritability of traits, (3) underlying genetic variation affecting local or distant methylation state, and (4) epigenetic silencing to mask deleterious dominant mutations or reveal recessive mutations. While still speculative and theoretical, the concept that epigenomic processes contribute to heritable phenotypic variation is gathering momentum
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