Molecular mechanisms of genome size scaling

Across the tree of life, genome size varies by at least six orders of magnitude. Yet, all genomes perform the same essential functions required for cell survival: transcription, chromosome segregation and replication. In this Review, we apply the logic of biological scaling at the organismal scale to the study of genome structure and function at the molecular scale. How do genomes become so large, and what possible evolutionary advantages could large genomes offer? Genomes are dynamically organized by molecular machines that mark and segregate the genome into distinct functional compartments within a three-dimensional (3D) nucleus. As genomes expand, how are these molecular marks and compartments redistributed within a larger nucleus with a lower surface-area-to-volume ratio? We combine historic and modern literature to uncover patterns of genome size scaling across biological systems and hypothesize on molecular-scale adaptations that may accompany changes in genome size. Finally, we propose that the African clawed frog (Xenopus) is an ideal system for dissecting key mechanisms of genome size scaling, due to its enormous dynamic range in genome size and biochemical tractability.