Abstract
The molecular events leading to the development of the bat wing remain largely unknown, and are thought to be caused, in part, by changes in gene expression during limb development. These expression changes could be instigated by variations in gene regulatory enhancers. Here, we used a comparative genomics approach to identify regions that evolved rapidly in the bat ancestor, but are highly conserved in other vertebrates. We discovered 166 bat accelerated regions (BARs) that overlap H3K27ac and p300 ChIP-seq peaks in developing mouse limbs. Using a mouse enhancer assay, we show that five Myotis lucifugus BARs drive gene expression in the developing mouse limb, with the majority showing differential enhancer activity compared to the mouse orthologous BAR sequences. These include BAR116, which is located telomeric to the HoxD cluster and had robust forelimb expression for the M. lucifugus sequence and no activity for the mouse sequence at embryonic day 12.5. Developing limb expression analysis of Hoxd10-Hoxd13 in Miniopterus natalensis bats showed a high-forelimb weak-hindlimb expression for Hoxd10-Hoxd11, similar to the expression trend observed for M. lucifugus BAR116 in mice, suggesting that it could be involved in the regulation of the bat HoxD complex. Combined, our results highlight novel regulatory regions that could be instrumental for the morphological differences leading to the development of the bat wing.
Highlights
Vertebrate limbs show a wide range of morphological variety ranging from fins to limbs
To identify elements that may contribute to bat wing development, we characterized sequences that are conserved between vertebrates, but changed significantly in the bat lineage
We overlapped these sequences with predicted developing limb enhancers as determined by ChIP-seq, finding 166 bat accelerated sequences (BARs)
Summary
Vertebrate limbs show a wide range of morphological variety ranging from fins to limbs. To form a wing, bat forelimbs have gone through three major changes: elongation of digits II-V, retention of membranous tissue forming the inter-digital patagia (chiropatagium) and a relative reduction in the diameter of the ulna [3,4,5]. These morphological innovations are clearly apparent in bat fossils from 52.5 million years ago [6,7]. The genetic changes that led to the development of these specialized limb structures and mammalian flight are likely to have occurred prior to the radiation of the Chiroptera, one of the most diverse mammalian orders
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