PgmNr P2139: A genetic parallel between flightlessness evolution in the Galapagos cormorant (Phalacrocorax harrisi) and human skeletal ciliopathies.

Authors:
A. BURGA 1,2 ; W. WANG 3 ; P. C. WOLF 4 ; A. M. RAMNEY 5 ; C. VERDUGO 6 ; K. LYONS 3 ; P. C. PARKER 7,8 ; L. KRUGLYAK 1,2

Institutes
1) Departments of Human Genetics and Biological Chemistry, UCLA, Los Angeles, USA; 2) Howard Hughes Medical Institute (HHMI); 3) Departments of Molecular, Cell and Developmental Biology and Orthopaedic Surgery, UCLA and Orthopaedic Institute for Children, Los Angeles, USA; 4) United States Department of Agriculture/Wildlife Services; 5) U.S. Geological Survey Alaska Science Center, Alaska, USA; 6) Instituto de Patología Animal, Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia, Chile; 7) Department of Biology and Whitney Harris World Ecology Center, University of Missouri-St. Louis, USA; 8) WildCare Institute, Saint Louis Zoo, Saint Louis, USA.

Abstract:

Changes in the morphology and size of limbs have played a key role in the adaptive evolution of species. Our own ancestors experienced such changes as they transitioned towards a bipedal, manually dexterous primate. However, despite the evolutionary importance of these modifications, we have a very limited idea of how these changes  occur on a genetic and molecular level, especially in vertebrates. In order to fill this gap, we studied a recent case of extreme wing size reduction leading to flightlessness in the Galapagos Cormorant (Phalacrocorax harrisi). The Galapagos cormorant is unique in that is the only cormorant that lost the ability to fly among approximately 40 extant species. Their entire population is distributed along the coastline of the Isabela and Fernandina Islands in the Galapagos archipelago. P. harrisi  has a pair of stubby wings, which are smaller than those of any other cormorant in spite of having the largest body mass, resulting in a significant deviation from the allometric relationship between wing length and body mass among flighted birds. We applied a joint predictive and comparative genomics approach to identify deleterious variants that affected the Galapagos Cormorant but were absent in three flighted close relatives. Among these variants, we found a significant enrichment for genes that cause skeletal ciliopathies when mutated in humans.  Individuals affected by ciliopathies have small limbs and rib cages, mirroring the phenotype of P. harrisi. We show that CUX1, a highly conserved transcription factor, has a four amino acid deletion in P. harrisi that affects its regulatory domain.  Moreover, we demonstrate that CUX1 controls the expression of cilia related genes and can promote the differentiation of chondrocytes. Our results suggest that the combined effect of deleterious variants in genes affecting chondrogenic differentiation led to the highly reduced wings of P. harrisi.  .