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Experimental Validation of Evolutionarily Conserved Genes Regulating Hypoxia Adaption in Drosophila and Humans
Author(s) -
Zhou Dan,
Jha Aashish R,
Xue Jin,
White Kevin P,
Haddad Gabriel G
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.lb703
Subject(s) - biology , gene , genetics , gene knockdown , hypoxia (environmental) , genome , model organism , candidate gene , snp , rna interference , single nucleotide polymorphism , genotype , rna , chemistry , organic chemistry , oxygen
Hypoxia tolerance is regulated by polygenic mechanisms in metazoan organisms. The following study was performed to determine whether such polygenic mechanisms are shared evolutionarily between organisms like Drosophila and humans. Using a generalized linear mixed model we identified significant allele frequency differences between three independently evolved hypoxia‐tolerant populations and normoxic control populations of Drosophila. Around 50% of the ~3,800 SNP variants are clustered in 66 distinct genomic regions that contain genes that are differentially expressed when hypoxia‐tolerant and normoxic populations were compared. In addition, using genome‐wide SNP data from four high‐altitude human populations (i.e., Sherpas, Tibetans, Ethiopians, and Andeans), we found that several human orthologs of the genes under selection in flies are also likely under positive selection in all four high‐altitude human populations, suggesting that these conserved genes and pathways may regulate hypoxia tolerance in both flies and humans. Currently we have experimentally evaluated the role of these candidate genes in hypoxia tolerance in flies using RNAi‐mediated knockdown. We found that down‐regulation of several candidate genes’ expression, such as pyd , significantly enhanced survival in severe hypoxia in flies. Our results demonstrated that fundamental genetic mechanisms regulating hypoxia tolerance have indeed remained conserved throughout evolution. Such mechanisms may help us to develop novel therapeutic strategies to treat hypoxia‐related diseases in humans. Support or Funding Information This work was supported by the following grants from National Institute of Health: Training in Oxygen in Health and Disease Grant T32HL094282 to ARJ; 5P01HD32573 to GGH; and P50 GM081892 to KPW.