Paul B. Vrana
Biological Chemistry, School of Medicine
Phone: (949) 824-9464
Email: pvrana@uci.edu
http://www.ucihs.uci.edu/biochem/faculty/vrana.html
http://www.faculty.uci.edu/profile.cfm?faculty_id=4709
Paul Vrana
Dr. Vrana’s research is centered on development of a mammalian system for studying the effects of natural genetic and epigenetic variation on disease phenotypes. This is important for at least two reasons: 1. ablating gene function via transgenic technology reveals processes requiring gene function and downstream targets, it does not predict the effects of coding-region or regulatory variants. 2. Common alleles underlie predisposition to many human diseases.
Dr. Vrana uses deer mice (Peromyscus), the most common native North American mammals, as an experimental system. Despite superficial resemblances, these animals are ~ 30 million years diverged from both lab mice and rats. Physiological, morphological, pathogen resistance and behavioral differences are present in interfertile populations. A unique feature of this system is that lab stocks derived from natural populations are available.
They primarily use two species which produce asymmetric developmental and epigenetic defects when crossed. Crosses between two species, P. maniculatus (BW), and P. polionotus ( PO), produce asymmetric effects on growth and development. BW females mated to PO males (bw x po) produce growth-retarded offspring which are viable and fertile. In contrast, PO females mated to BW males ( PO x BW) produce overgrown and severely dysmorphic conceptuses. Roughly half of all PO x BW breedings end in complete death of the litter by mid-gestation. Those which survive to late gestation display numerous developmental defects, many reminiscent of human syndromes.
The placenta is particularly affected in both crosses. The bw x po placentas average half the weight of those from the parental strains; those of the PO x BW cross are ~ three times that of parental strains and are very disorganized. A portion of PO x BW conceptuses lack embryonic structures, analogous to human gestational trophoblast disease. Approximately 20% of the latter develop into choriocarcinomas (trophoblastic tumors).
Dr. Vrana’s hypothesis is that the genetic incompatibilities involve genes responsible for aspects of epigenetic control. Supporting this hypothesis, they have found altered DNA methylation as well as perturbed expression of imprinted and stem-cell loci. Such perturbations are common in several cancer types.
Genetic studies have shown that a maternal effect locus regulating epigenetic gene expression and interactions between an imprinted and X-linked locus are involved in the hybrid defects. Their studies have shown also shown imbalances in proliferation vs. differentiation, and misexpression of a number of genes whose products regulate the cell-cycle (primarily G1 – S-phase transition).
Other research involves 1. genetic differences between the males of the two species in stress response mediated blood glucose regulation 2. epigenetic regulation and behavior.
Selected Publications:
Duselis, A. R., Obergfell, C., Mack, J. A., O'Neill, M. J., Nguyen, Q. K., O'Neill, R. J., and Vrana, P. B. (2007). Changes in cell cycle and extracellular matrix gene expression during placental development in deer mouse (Peromyscus) hybrids. Reprod Fertil Dev 19(5), 695-708.
Duselis, A. R., and Vrana, P. B. (2007). Assessment and disease comparisons of hybrid developmental defects. Hum Mol Genet 16(7), 808-19.
Loschiavo, M., Nguyen, Q. K., Duselis, A. R., and Vrana, P. B. (2007). Mapping and identification of candidate loci responsible for Peromyscus hybrid overgrowth. Mamm Genome 18(1), 75-85. |
