Abstract
Loss of limbs evolved many times in squamate reptiles. Here we investigated the genomic basis of convergent limb loss in reptiles. We sequenced the genomes of a closely related pair of limbless-limbed gymnophthalmid lizards and performed a comparative genomic analysis including five snakes and the limbless glass lizard. Our analysis of these three independent limbless lineages revealed that signatures of shared sequence or transcription factor binding site divergence in individual limb regulatory elements are generally rare. Instead, shared divergence occurs more often at the level of signaling pathways, involving different regulatory elements associated with the same limb genes (such as Hand2 or Hox) and/or patterning mechanisms (such as Shh signaling). Interestingly, although snakes are known to have mutations in the Shh ZRS limb enhancer, this enhancer lacks relevant mutations in limbless lizards. Thus, different mechanisms could contribute to limb loss, and there are likely multiple evolutionary paths to limblessness in reptiles.
Highlights
Loss of limbs is a drastic but recurrent morphological change in tetrapod evolution
We sequenced the genomes of a closely related pair of limbless-limbed gymnophthalmid lizards and performed a comparative genomic analysis including five snakes and the limbless glass lizard. Our analysis of these three independent limbless lineages revealed that signatures of shared sequence or transcription factor binding site divergence in individual limb regulatory elements are generally rare
A genome-wide analysis of conserved non-coding elements (CNEs), genomic regions that evolve under purifying selection and often overlap cisregulatory elements (Pennacchio et al, 2006; Visel et al, 2008; Wittkopp and Kalay, 2011; Woolfe et al, 2005), showed that CNEs with snake-specific sequence divergence tend to be located near genes involved in limb development and preferentially overlap regulatory elements active in the developing limbs of limbed species (Roscito et al, 2018a)
Summary
Loss of limbs is a drastic but recurrent morphological change in tetrapod evolution. Among the many lineages where limb loss has evolved, modern snakes are a prominent example of a successful, highly diverse group of virtually limbless species. Other studies revealed that expression changes of the morphogen sonic hedgehog (Shh) and the transcription factors Gli and Hand contribute to arrest of limb development, leading to the absence of adult limbs in snakes (Cohn and Tickle, 1999; Leal and Cohn, 2016). Misexpression of Shh in the developing limbs of snakes is due to mutations in the limb-specific enhancer (ZRS) that controls expression of this morphogen in the developing limb, leading to alterations in signaling centers that are required for proper limb patterning and outgrowth (Kvon et al, 2016; Leal and Cohn, 2016). In addition to mutations in the ZRS enhancer, snakes exhibit sequence and transcription factor binding site (TFBS) divergence in numerous other limb regulatory elements. Snake-diverged CNEs overlap the ZRS enhancer and limb regulatory elements near many other key limb genes (Roscito et al, 2018a), indicating a large-scale divergence of the cis-regulatory landscape that is required for proper limb development
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