Bone loss diseases, including osteoporosis, are a significant and increasing threat for America's aging population. Degenerative osteopenia is a complex trait with environmental and genetic components, and may have arisen from a reduction in the strength of natural selection to maintain robust bone production in post- reproductive individuals. Natural variation for this complex trait exists in certain vertebrate lineages leading to the adaptive evolution of secondary osteopenia. We apply the innovative strategy of evolutionary mutant models for human disease to the skeletons of osteopenic Antarctic fish, whose ancestors possessed robust skeletons. As natural selection for dense bones diminished in certain lineages of Antarctic fish, the skeleton became osteopenic, allowing animals to inhabit the water column and exploit its abundant resources. Related lineages that retain dense skeletons continue to forage on the ocean floor. The goal of the proposed work is to characterize the genetic and phenotypic differences between species with osteopenic and normal skeletons, and thereby identify new candidate genes and mechanisms for human bone degeneration diseases. Our hypothesis is that mutations that either down-regulate the activity of genes that positively regulate osteogenesis or up-regulate the activity of genes that negatively affect osteogenesis account for evolved differences in related species with osteopenic versus robust skeletons.
Aim 1 will identify the stages at which skeletal development diverges between the osteopenic species Chaenocephalus aceratus (blackfin icefish) and the related robustly ossified species Notothenia coriiceps (yellowbelly rockcod) using stains for cartilage, bone, and extracellular matrix molecules, and the expression of skeletal marker genes.
Aim 2 will use high- throughput cDNA sequencing to compare gene expression profiles of skeletogenic tissues from densely and poorly ossified species as a means to identify regulatory differences between the two species.
Aim 3 will define the functional roles of skeletal regulatory genes in the development of the ossified skeleton using loss- of-function and gain-of-function experiments in three-spine stickleback. Stickleback, a model species related to our Antarctic fish, has a completely sequenced genome, and is amenable to gene knockdown and transgenesis in the laboratory. Significance. These experiments will reveal the identities and functions of genes whose activities have changed, under the force of natural selection, to reduce skeletal ossification in Antarctic fish. Because the reduction of bone mineralization over evolutionary time mimics human bone loss diseases over developmental time, these studies have the potential to identify new genes, and provide new insights into mechanisms for osteopenia, osteoporosis, and other bone wasting disorders that can be exploited to develop novel therapies for human disease. Project Narrative The proposed experiments will reveal the identities and functions of genes whose activities have changed, under the force of natural selection, leading to loss of bone mineral density in certain lineages of Antarctic fish. Because the reduction of bone mineralization over evolutionary time in Antarctic fish mimics the reduction of bone density in humans as they age over developmental time, the proposed studies have the potential to identify new genes, and provide new insights into mechanisms for low bone mineral density, osteoporosis, and other bone wasting disorders that can be exploited to develop novel therapies for human disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG031922-05
Application #
8278561
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Williams, John
Project Start
2008-05-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2012
Total Cost
$471,383
Indirect Cost
$74,700
Name
University of Oregon
Department
Other Basic Sciences
Type
Organized Research Units
DUNS #
948117312
City
Eugene
State
OR
Country
United States
Zip Code
97403
Desvignes, Thomas; Detrich 3rd, H William; Postlethwait, John H (2016) Genomic conservation of erythropoietic microRNAs (erythromiRs) in white-blooded Antarctic icefish. Mar Genomics 30:27-34
Postlethwait, John H; Yan, Yi-Lin; Desvignes, Thomas et al. (2016) Embryogenesis and early skeletogenesis in the antarctic bullhead notothen, Notothenia coriiceps. Dev Dyn 245:1066-1080
Braasch, Ingo; Peterson, Samuel M; Desvignes, Thomas et al. (2015) A new model army: Emerging fish models to study the genomics of vertebrate Evo-Devo. J Exp Zool B Mol Dev Evol 324:316-41
Shin, Seung Chul; Ahn, Do Hwan; Kim, Su Jin et al. (2014) The genome sequence of the Antarctic bullhead notothen reveals evolutionary adaptations to a cold environment. Genome Biol 15:468
Jacobs, Nicole L; Albertson, R Craig; Wiles, Jason R (2011) Using whole mount in situ hybridization to link molecular and organismal biology. J Vis Exp :
Detrich 3rd, H W; Amemiya, Chris T (2010) Antarctic notothenioid fishes: genomic resources and strategies for analyzing an adaptive radiation. Integr Comp Biol 50:1009-17
Cooper, W James; Parsons, Kevin; McIntyre, Alyssa et al. (2010) Bentho-pelagic divergence of cichlid feeding architecture was prodigious and consistent during multiple adaptive radiations within African rift-lakes. PLoS One 5:e9551
Albertson, R Craig; Yan, Yi-Lin; Titus, Tom A et al. (2010) Molecular pedomorphism underlies craniofacial skeletal evolution in Antarctic notothenioid fishes. BMC Evol Biol 10:4
Detrich, H William; Stuart, Andrew; Schoenborn, Michael et al. (2010) Genome enablement of the notothenioidei: genome size estimates from 11 species and BAC libraries from 2 representative taxa. J Exp Zool B Mol Dev Evol 314:369-81
Parsons, Kevin J; Albertson, R Craig (2009) Roles for Bmp4 and CaM1 in shaping the jaw: evo-devo and beyond. Annu Rev Genet 43:369-88

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