Arthrospira are multicellular cyanobacteria that typically reside in alkaline lakes of (sub)tropical regions and are mass cultivated around the globe in a variety of outdoor facilities and photobioreactors for their high nutritional, pharmaceutical and clinical value. Arthrospira sp. strain PCC 8005 was selected by the European Space Agency as an oxygen producer and nutritional end-product in a bioregenerative life support system for long-haul missions. Being highly resistant to ionizing radiation, it is also an ideal candidate for other space applications such as in situ resource utilization and terraformation. During long-term strain maintenance involving continuous subculturing we noted an irreversible morphological change in PCC 8005 subcultures i.e. from only helical to only straight trichomes. These morphotypes displayed differences in growth rate, buoyancy and resistance to gamma radiation. We also found marked differences in antioxidant capacity, pigment content and trehalose concentration, while whole-genome comparison revealed a difference of 168 SNPs, 48 indels and four large insertions affecting, in total, 41 coding regions across both genomes. Although nine of these regions encoded proteins with a known function, no conclusive genotype-phenotype associations could be determined. Nonetheless, genomic changes within the gvpC gene (encoding a gas vesicle protein) and within the regulatory region of the psbD gene (encoding the D2 protein of PSII) provided some clues for the observed differences in buoyancy and growth.