Developmental hourglass and heterochronic shifts in fin and limb development

Elife. 2021 Feb 9:10:e62865. doi: 10.7554/eLife.62865.


How genetic changes are linked to morphological novelties and developmental constraints remains elusive. Here, we investigate genetic apparatuses that distinguish fish fins from tetrapod limbs by analyzing transcriptomes and open-chromatin regions (OCRs). Specifically, we compared mouse forelimb buds with the pectoral fin buds of an elasmobranch, the brown-banded bamboo shark (Chiloscyllium punctatum). A transcriptomic comparison with an accurate orthology map revealed both a mass heterochrony and hourglass-shaped conservation of gene expression between fins and limbs. Furthermore, open-chromatin analysis suggested that access to conserved regulatory sequences is transiently increased during mid-stage limb development. During this stage, stage-specific and tissue-specific OCRs were also enriched. Together, early and late stages of fin/limb development are more permissive to mutations than middle stages, which may have contributed to major morphological changes during the fin-to-limb evolution. We hypothesize that the middle stages are constrained by regulatory complexity that results from dynamic and tissue-specific transcriptional controls.

Keywords: ATAC-seq; brown-banded bamboo shark; developmental biology; evolutionary biology; fin development; limb development; morphological evolution; mouse; transcriptome.

Plain language summary

Animals come in all shapes and sizes. This diversity arose through genetic mutations during evolution, but it is unclear exactly how these variations led to the formation of new shapes. There is increasing evidence to suggest that not all shapes are possible and that variability between animals is limited by a phenomenon known as “developmental constraint”. These limitations direct parts of the body towards a specific shape as they develop in the embryo. Therefore, understanding the mechanisms underlying these developmental constraints could help explain how different body shapes evolved. The limbs of humans and other mammals evolved from the fins of fish, and this transition is often used to study the role developmental constraints play in evolution. This is an ideal model as there is already a detailed fossil record mapping this evolutionary event, and data pinpointing some of the genes involved in the development of limbs and fins. But this data is incomplete, and a full comparison between the genes activated in the fin and the limb during embryonic development had not been achieved. This is because most fish used for research have undergone recent genetic changes, making it hard to spot which genetic differences are linked to the evolution of the limb. To overcome this barrier, Onimaru et al. compared genetic data from the developing limbs of mice to the developing fins of the brown-banded bamboo shark, which evolves much slower than other fish. This revealed that although many genes commonly played a role in the development of the fin and the limb in the embryo, the activity of these shared genes was not the same. For example, genes that switched on in the late stages of limb development, switched off in the late stages of fin development. But in the middle of development, those differences were relatively small and both species activated very similar sets of genes. Many of these genes were pleiotropic, which means they have important roles in other tissues and therefore mutate less often. This suggests that the mid-stage of limb development is under the strongest level of constraint. Darwin’s theory of natural selection explains that mutations drive evolution. But the theory cannot predict what kinds of new body shapes new mutations will produce. Understanding how the activity levels of different genes affect development could help to fill this knowledge gap. This has potential medical applications, for example, understanding why some genetic changes cause more serious problems than others. This work suggests that mutations in genes that are active during the mid-stage of limb development may have the most serious impact.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animal Fins / embryology*
  • Animals
  • Biological Evolution*
  • Embryo, Mammalian / embryology*
  • Embryo, Nonmammalian / embryology*
  • Extremities / embryology
  • Limb Buds / embryology*
  • Mice
  • Phylogeny
  • Sharks / embryology*

Associated data

  • GEO/GSE136445

Grants and funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.