Adaptation to hypoxia in experimentally evolved Drosophila melanogaster: convergent and highly polygenic. Aashish R. Jha^1,2, Christopher D. Brown², Dan Zhou³, Gabriel H. Haddad³, Kevin P. White^1,2,4. 1) Human Genetics, The University of Chicago, Chicago, IL; 2) Institute of Genomics and Systems Biology, The University of Chicago, Chicago, IL; 3) Department of Pediatrics, University of California an Diego; 4) Ecology and Evolution, The University of Chicago, Chicago, IL.

   Adaptation to low oxygen (hypoxia) has fascinated biologists from multiple disciplines. Despite years of research the comprehensive genetic architecture of hypoxia tolerance remains elusive. We implemented experimental evolution followed by whole-genome sequencing approach in Drosophila melanogaster to investigate the role of natural variation in adaptation to hypoxia. Significant allele frequency divergence between replicate hypoxia-tolerant populations and normoxic controls were observed at ~3000 polymorphic loci distributed throughout the genome; however, scans for reduction in gene diversity showed selective sweeps were rare. This suggests adaptation to hypoxia occurred almost exclusively from the natural standing variants via soft sweeps and heterozygosity based tests are poorly suited to identify polygenic adaptation occurring from standing variation. The differentiated variants were harbored by ~1400 genes. Filtering these genes based on evolutionary conservation and differential gene expression identified ~600 positively selected genes that are involved in various development processes including respiratory and tracheal systems development, several metabolic processes and neuron generation. Genes in Wnt and Cadherin pathways were significantly enriched and many genes have known functions in Notch and EGFR pathways. Most notable positively selected genes included Drosophila homologs of EPAS1, PPARA, and GCH1, the classic O2-sensing genes under selection in high-altitude Tibetans. Human orthologs of many positively selected genes in our Drosophila populations have known functions in cancer. This suggests that adaptation to hypoxia is convergent and highly polygenic and Drosophila melanogaster can be an excellent model system to understand genetic pathways and networks involved in cancer.