Extended Data Fig. 9: Expanded hox clusters preserve regulatory landscape architecture.

a, In spite of a dramatic expansion of the lungfish Hox clusters whereby the Lepidosiren paradoxa clusters are approximately 20-fold enlarged compared to mouse, which is lower than the proportional difference in genome size. Consistent with this observation is that all four clusters preserve a conserved core subcluster (indicated in red) that has expanded relatively little and is low in repeat content. These regions are hoxa4-a11, hoxb2-b9, hoxc4-c11 and hoxd8-d11 indicating topological constraints on the expansion of these regions. In addition, hoxa3 and hoxd3 (purple) show expansion of their intronic region, which is similar to the expansion of the hoxa3 intron in the expanded axolotl Hoxa cluster⁷. An interesting difference is that the hoxa11-hoxa13 intergenic shows a tendency for expansion in lungfishes but not in axolotl, potentially related to additional constraints induced by the fin to limb transition. Furthermore, signatures of repeat insertion in the anterior Hoxc and posterior Hoxb clusters mirror those observed in anolis lizards⁴¹. b, HiC analysis for Midas cichlid, human and Protopterus annectens Hoxa and Hoxd clusters. Despite the approximate 70 times size difference between these species there is a remarkable conservation of the flanking regulatory landscapes whereby both clusters are present on the intersection of a 3’ and 5’ TAD. Known fin and limb enhancers (blue ovals) are conserved in an expected fashion (open ovals for Lepidosirenidae mm406 and e10 indicate secondary loss), altogether suggesting that long range regulatory landscapes remain preserved under conditions of genome expansion. Synteny regions shown encompass the following sizes: HoxA; Pan 3.2 Mb, Hsa 3.1 Mb Aci 0.31 Mb, Hoxd; Pan 28 Mb, Hsa 2.8 Mb, Aci 0.41 Mb. Species name abbreviations are the same as in the other figures.