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Borrelia) burgdorferi is a spirochete bacterium that causes tick-borne Lyme disease. Along its lifecycle B. burgdorferi develops several pleomorphic forms with unclear biological and medical relevance. Surprisingly, these morphotypes have never been compared at the global transcriptome level. To fill this void, we grew B. burgdorferi spirochete, round body, bleb, and biofilm-dominated cultures and recovered their transcriptomes by RNAseq profiling. We found that round bodies share similar expression profiles with spirochetes, despite their morphological differences. This sharply contrasts to blebs and biofilms that showed unique transcriptomes, profoundly distinct from spirochetes and round bodies. To better characterize differentially expressed genes in non-spirochete morphotypes, we performed functional, positional, and evolutionary enrichment analyses. Our results suggest that spirochete to round body transition relies on the delicate regulation of a relatively small number of highly conserved genes, which are located on the main chromosome and involved in translation. In contrast, spirochete to bleb or biofilm transition includes substantial reshaping of transcription profiles towards plasmids-residing and evolutionary young genes, which originated in the ancestor of Borreliaceae. Despite their abundance the function of these Borreliaceae-specific genes is largely unknown. However, many known Lyme disease virulence genes implicated in immune evasion and tissue adhesion originated in this evolutionary period. Taken together, these regularities point to the possibility that bleb and biofilm morphotypes might be important in the dissemination and persistence of B. burgdorferi inside the mammalian host. On the other hand, they prioritize the large pool of unstudied Borreliaceae-specific genes for functional characterization because this subset likely contains undiscovered Lyme disease pathogenesis genes.<\/jats:p>","DOI":"10.3390\/ijms24065594","type":"journal-article","created":{"date-parts":[[2023,3,15]],"date-time":"2023-03-15T05:53:44Z","timestamp":1678859624000},"page":"5594","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Pleomorphic Variants of Borreliella (syn. Borrelia) burgdorferi Express Evolutionary Distinct Transcriptomes"],"prefix":"10.3390","volume":"24","author":[{"given":"Nina","family":"\u010corak","sequence":"first","affiliation":[{"name":"Laboratory of Evolutionary Genetics, Division of Molecular Biology, Ru\u0111er Bo\u0161kovi\u0107 Institute, Bijeni\u010dka Cesta 54, HR-10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sirli","family":"Anniko","sequence":"additional","affiliation":[{"name":"BCA-Research, BCA-Clinic Betriebs GmbH & Co. KG, D-86159 Augsburg, Germany"},{"name":"Institute of Cancer Therapeutics, Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Daschkin-Steinborn","sequence":"additional","affiliation":[{"name":"BCA-Research, BCA-Clinic Betriebs GmbH & Co. KG, D-86159 Augsburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viktoria","family":"Krey","sequence":"additional","affiliation":[{"name":"BCA-Research, BCA-Clinic Betriebs GmbH & Co. KG, D-86159 Augsburg, Germany"},{"name":"Physics of Synthetic Biological Systems-E14, Physics Department and ZNN, Technische Universit\u00e4t M\u00fcnchen, D-85748 Garching, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Koska","sequence":"additional","affiliation":[{"name":"Laboratory of Evolutionary Genetics, Division of Molecular Biology, Ru\u0111er Bo\u0161kovi\u0107 Institute, Bijeni\u010dka Cesta 54, HR-10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Momir","family":"Futo","sequence":"additional","affiliation":[{"name":"Laboratory of Evolutionary Genetics, Division of Molecular Biology, Ru\u0111er Bo\u0161kovi\u0107 Institute, Bijeni\u010dka Cesta 54, HR-10000 Zagreb, Croatia"},{"name":"Faculty of Electrical Engineering and Computing, University of Zagreb, Unska 3, HR-10000 Zagreb, Croatia"},{"name":"School of Medicine, Catholic University of Croatia, Ilica 242, HR-10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tin","family":"\u0160iroki","sequence":"additional","affiliation":[{"name":"Faculty of Electrical Engineering and Computing, University of Zagreb, Unska 3, HR-10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Innokenty","family":"Woichansky","sequence":"additional","affiliation":[{"name":"BCA-Research, BCA-Clinic Betriebs GmbH & Co. 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