Regulatory divergence modifies limb length between mammals

Abstract

Natural selection acts on variation within populations, resulting in modified organ morphology, physiology, and ultimately the formation of new species. Although variation in orthologous proteins can contribute to these modifications, differences in DNA sequences regulating gene expression may be a primary source of variation. We replaced a limb-specific transcriptional enhancer of the mouse Prx1 locus with the orthologous sequence from a bat. Prx1 expression directed by the bat enhancer results in elevated transcript levels in developing forelimb bones and forelimbs that are significantly longer than controls because of endochondral bone formation alterations. Surprisingly, deletion of the mouse Prx1 limb enhancer results in normal forelimb length and Prx1 expression, revealing regulatory redundancy. These findings suggest that mutations accumulating in pre-existing noncoding regulatory sequences within a population are a source of variation for the evolution of morphological differences between species and that cis-regulatory redundancy may facilitate accumulation of such mutations.[Keywords: Chiroptera; Carollia perspicillata; Prx1; Prrx1; limb development; evolution] Supplemental material is available at http://www.genesdev.org.

Dual hindlimb control elements in theTbx4gene and region-specific control of bone size in vertebrate limbs

“…Fine-scale changes in the size of hindlimb skeletal elements can thus arise from quantitative changes in Tbx4 expression, and these expression levels are themselves controlled by at least two different hindlimb enhancer regions. Recent studies suggest that regulatory alterations in key developmental control genes, such as Shh, Pitx1 and Prx1 (Prrx1), play an important role in limb modifications in naturally occurring species (Sagai et al, 2004;Shapiro et al, 2004;Cretekos et al, 2008). In each case, null mutations in the corresponding gene are lethal, whereas regulatory mutations are viable and fertile.…”

The developmental basis of bat wing muscle

“…However, the fossil record of bats is currently quite poor 9 , so there is still a possibility that transitional fossils may be discovered in the future. In that case, the evolution of the unique body plan of bats might be better explained by means of gradual processes, such as the divergence of many regulatory elements for several developmental control genes 10 . In any case, molecular and cellular mechanisms underlying the evolution of the bat wing remain poorly understood.…”

Unique expression patterns of multiple key genes associated with the evolution of mammalian flight

“…However, so far, targeted candidate gene approaches have identified only seven genes with differences in expression in bat forelimb compared with hindlimb and mouse limbs during development. Only two of these are transcription factors that may play an upstream and regulatory role for bat wing development [4][5][6][7][8][9]. Thus, the full complexity of the mechanism of bat wing evolution remains to be shown, and the key differentially expressed genes contributing to this unique morphology remain to be identified.…”