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1. High-Altitude Adaptation: Mechanistic Insights from Integrated Genomics and Physiology

   https://doi.org/10.1093/molbev/msab064  

   Storz, Jay F. (March 2021, Molecular Biology and Evolution)

   Nielsen, Rasmus (Ed.)

   Abstract Population genomic analyses of high-altitude humans and other vertebrates have identified numerous candidate genes for hypoxia adaptation, and the physiological pathways implicated by such analyses suggest testable hypotheses about underlying mechanisms. Studies of highland natives that integrate genomic data with experimental measures of physiological performance capacities and subordinate traits are revealing associations between genotypes (e.g., hypoxia-inducible factor gene variants) and hypoxia-responsive phenotypes. The subsequent search for causal mechanisms is complicated by the fact that observed genotypic associations with hypoxia-induced phenotypes may reflect second-order consequences of selection-mediated changes in other (unmeasured) traits that are coupled with the focal trait via feedback regulation. Manipulative experiments to decipher circuits of feedback control and patterns of phenotypic integration can help identify causal relationships that underlie observed genotype–phenotype associations. Such experiments are critical for correct inferences about phenotypic targets of selection and mechanisms of adaptation. 

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2. Life Ascending: Mechanism and Process in Physiological Adaptation to High-Altitude Hypoxia

   https://doi.org/10.1146/annurev-ecolsys-110218-025014  

   Storz, Jay F.; Scott, Graham R. (November 2019, Annual Review of Ecology, Evolution, and Systematics)

   To cope with the reduced availability of O 2 at high altitude, air-breathing vertebrates have evolved myriad adjustments in the cardiorespiratory system to match tissue O 2 delivery with metabolic O 2 demand. We explain how changes at interacting steps of the O 2 transport pathway contribute to plastic and evolved changes in whole-animal aerobic performance under hypoxia. In vertebrates native to high altitude, enhancements of aerobic performance under hypoxia are attributable to a combination of environmentally induced and evolved changes in multiple steps of the pathway. Additionally, evidence suggests that many high-altitude natives have evolved mechanisms for attenuating maladaptive acclimatization responses to hypoxia, resulting in counter-gradient patterns of altitudinal variation for key physiological phenotypes. For traits that exhibit counteracting environmental and genetic effects, evolved changes in phenotype may be cryptic under field conditions and can only be revealed by rearing representatives of high- and low-altitude populations under standardized environmental conditions to control for plasticity. 

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3. Association of EGLN1 gene with high aerobic capacity of Peruvian Quechua at high altitude

   https://doi.org/10.1073/pnas.1906171116  

   Brutsaert, Tom D.; Kiyamu, Melisa; Elias Revollendo, Gianpietro; Isherwood, Jenna L.; Lee, Frank S.; Rivera-Ch, Maria; Leon-Velarde, Fabiola; Ghosh, Sudipta; Bigham, Abigail W. (November 2019, Proceedings of the National Academy of Sciences)

   Highland native Andeans have resided at altitude for millennia. They display high aerobic capacity (VO 2 max) at altitude, which may be a reflection of genetic adaptation to hypoxia. Previous genomewide (GW) scans for natural selection have nominated Egl-9 homolog 1 gene ( EGLN1 ) as a candidate gene. The encoded protein, EGLN1/PHD2, is an O 2 sensor that controls levels of the Hypoxia Inducible Factor-α (HIF-α), which regulates the cellular response to hypoxia. From GW association and analysis of covariance performed on a total sample of 429 Peruvian Quechua and 94 US lowland referents, we identified 5 EGLN1 SNPs associated with higher VO 2 max (L⋅min −1 and mL⋅min −1 ⋅kg −1 ) in hypoxia (rs1769793, rs2064766, rs2437150, rs2491403, rs479200). For 4 of these SNPs, Quechua had the highest frequency of the advantageous (high VO 2 max) allele compared with 25 diverse lowland comparison populations from the 1000 Genomes Project. Genotype effects were substantial, with high versus low VO 2 max genotype categories differing by ∼11% (e.g., for rs1769793 SNP genotype TT = 34.2 mL⋅min −1 ⋅kg −1 vs. CC = 30.5 mL⋅min −1 ⋅kg −1 ). To guard against spurious association, we controlled for population stratification. Findings were replicated for EGLN1 SNP rs1769793 in an independent Andean sample collected in 2002. These findings contextualize previous reports of natural selection at EGLN1 in Andeans, and support the hypothesis that natural selection has increased the frequency of an EGLN1 causal variant that enhances O 2 delivery or use during exercise at altitude in Peruvian Quechua. 

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4. Coordinated changes across the O ₂ transport pathway underlie adaptive increases in thermogenic capacity in high-altitude deer mice

   https://doi.org/10.1098/rspb.2019.2750  

   Tate, Kevin B.; Wearing, Oliver H.; Ivy, Catherine M.; Cheviron, Zachary A.; Storz, Jay F.; McClelland, Grant B.; Scott, Graham R. (May 2020, Proceedings of the Royal Society B: Biological Sciences)

   null (Ed.)

   Animals native to the hypoxic and cold environment at high altitude provide an excellent opportunity to elucidate the integrative mechanisms underlying the adaptive evolution and plasticity of complex traits. The capacity for aerobic thermogenesis can be a critical determinant of survival for small mammals at high altitude, but the physiological mechanisms underlying the evolution of this performance trait remain unresolved. We examined this issue by comparing high-altitude deer mice ( Peromyscus maniculatus ) with low-altitude deer mice and white-footed mice ( P. leucopus ). Mice were bred in captivity and adults were acclimated to each of four treatments: warm (25°C) normoxia, warm hypoxia (12 kPa O 2 ), cold (5°C) normoxia or cold hypoxia. Acclimation to hypoxia and/or cold increased thermogenic capacity in deer mice, but hypoxia acclimation led to much greater increases in thermogenic capacity in highlanders than in lowlanders. The high thermogenic capacity of highlanders was associated with increases in pulmonary O 2 extraction, arterial O 2 saturation, cardiac output and arterial–venous O 2 difference. Mechanisms underlying the evolution of enhanced thermogenic capacity in highlanders were partially distinct from those underlying the ancestral acclimation responses of lowlanders. Environmental adaptation has thus enhanced phenotypic plasticity and expanded the physiological toolkit for coping with the challenges at high altitude. 

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5. Combining Experimental Evolution and Genomics to Understand How Seed Beetles Adapt to a Marginal Host Plant

   https://doi.org/10.3390/genes11040400  

   Rêgo, Alexandre; Chaturvedi, Samridhi; Springer, Amy; Lish, Alexandra M.; Barton, Caroline L.; Kapheim, Karen M.; Messina, Frank J.; Gompert, Zachariah (April 2020, Genes)

   Genes that affect adaptive traits have been identified, but our knowledge of the genetic basis of adaptation in a more general sense (across multiple traits) remains limited. We combined population-genomic analyses of evolve-and-resequence experiments, genome-wide association mapping of performance traits, and analyses of gene expression to fill this knowledge gap and shed light on the genomics of adaptation to a marginal host (lentil) by the seed beetle Callosobruchus maculatus. Using population-genomic approaches, we detected modest parallelism in allele frequency change across replicate lines during adaptation to lentil. Mapping populations derived from each lentil-adapted line revealed a polygenic basis for two host-specific performance traits (weight and development time), which had low to modest heritabilities. We found less evidence of parallelism in genotype-phenotype associations across these lines than in allele frequency changes during the experiments. Differential gene expression caused by differences in recent evolutionary history exceeded that caused by immediate rearing host. Together, the three genomic datasets suggest that genes affecting traits other than weight and development time are likely to be the main causes of parallel evolution and that detoxification genes (especially cytochrome P450s and beta-glucosidase) could be especially important for colonization of lentil by C. maculatus. 

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