Read, Write, Adapt: Challenges and Opportunities during Kinetoplastid Genome Replication.

The genomes of all organisms are read throughout their growth and development, generating new copies during cell division and encoding the cellular activities dictated by the genome's content. However, genomes are not invariant information stores but are purposefully altered in minor and major ways, adapting cellular behaviour and driving evolution. Kinetoplastids are eukaryotic microbes that display a wide range of such read–write genome activities, in many cases affecting critical aspects of their biology, such as host adaptation. Here we discuss the range of read–write genome changes found in two well-studied kinetoplastid parasites, Trypanosoma brucei and Leishmania , focusing on recent work that suggests such adaptive genome variation is linked to novel strategies the parasites use to replicate their unconventional genomes. Polycistronic transcription dominates and shapes kinetoplastid genomes, inevitably leading to clashes with DNA replication. By harnessing the resultant DNA damage for adaptation, kinetoplastids have huge potential for dynamic read–write genome variation. Major origins of DNA replication are confined to the boundaries of polycistronic transcription units in the Trypanosoma brucei and Leishmania genomes, putatively limiting DNA damage. Subtelomeres may lack this arrangement, generating read–write hotspots. In T. brucei , early replication of the highly transcribed subtelomeric variant surface glycoprotein (VSG) expression site may ensure replication-transcription clashes within this site to trigger DNA recombination, an event critical for antigenic variation. Leishmania genomes show extensive aneuploidy and copy number variation. Notably, DNA replication requires recombination factors and relies on post-S phase replication of subtelomeres. Evolution of compartmentalised DNA replication programmes underpin important aspects of genome biology in kinetoplastids, illustrating the consolidation of genome maintenance strategies to promote genome plasticity. [ABSTRACT FROM AUTHOR]