Whole genome duplication (WGD) is a major factor in the evolution of multicellular eukaryotes, yet by doubling the number of homologs, WGD severely challenges reliable chromosome segregation [ 1–3 ], a process conserved across kingdoms [ 4 ]. Despite this, numerous genome-duplicated (polyploid) species persist in nature, indicating early problems can be overcome [ 1, 2 ]. Little is known about which genes are involved—only one has been molecularly characterized [ 5 ]. To gain new insights into the molecular basis of adaptation to polyploidy, we investigated genome-wide patterns of differentiation between natural diploids and tetraploids of Arabidopsis arenosa, an outcrossing relative of A. thaliana [ 6, 7 ]. We first show that diploids are not preadapted to polyploid meiosis. We then use a genome scanning approach to show that although polymorphism is extensively shared across ploidy levels, there is strong ploidy-specific differentiation in 39 regions spanning 44 genes. These are discrete, mostly single-gene peaks of sharply elevated differentiation. Among these peaks are eight meiosis genes whose encoded proteins coordinate a specific subset of early meiotic functions, suggesting these genes comprise a polygenic solution to WGD-associated chromosome segregation challenges. Our findings indicate that even conserved meiotic processes can be capable of nimble evolutionary shifts when required.