Paul B. Vrana
Ph.D. 1994 Columbia University
University of California, Irvine
Department of Biological Chemistry
Irvine, CA 92697
Office: (949) 824-9464
pvrana@uci.edu
Research Interests:
A significant number of mammalian genes show unequal transcription of the two parental alleles. This effect is known as genomic imprinting. Genomic imprinting presents a genetic conundrum: why should a mechanism that renders an organism hemizygous for ~100 genes arise in evolution? It has been proposed that imprinting is a form of conflict between mothers and fathers in non-mongamous species. Consistent with this theory, many of these genes appear to be involved in embryonic/neonatal growth pathways. Paternally expressed genes tend to promote growth, while maternally expressed genes inhibit growth. It is not clear what mechanism(s) is common to all these loci, save that the silenced alleles tend to have methylated promoters. These genes tend to be clustered, suggesting that higher order control such as chromatin structure may also play a role.
We have been studying the impact of imprinting in two species of deer mice (Peromyscus)that display hybrid dysgenesis. We have shown that imprinting acts at both the genetic and epigenetic level to dramatically affect the growth of Peromyscus hybrids. We propose that imprinting may contribute to the rapid rate of speciation in mammals by increasing the frequency with which recessive incompatibilities arise in populations. It may also explain the variability seen in mammalian growth control and placentas.
The fact that imprinting is perturbed in the hybrids also suggests higher order control of these loci. One goal is to find such a locus. We are also examining candidate loci for two genes that appear to interact in the hybrid growth phenotypes. Chief among these are Pw1/Peg3, a zinc finger transcription factor thought to be involved in growth, apoptosis, and behavior and Esx1, a homeobox gene involved in placental development.
We will examine how these genes interact with each other as well as other (imprinted) growth pathways. Given its deregulation in the hybrids, Pw1/Peg3 will also serve as a model for locus specific imprinting control.
Thus, we are interested in the global role of imprinting, the mechanism(s) of imprinting, and its origins. We utilize strains of house mice to study these questions via transgenic/knockout approaches as well as deer mice. Comparative genomic approaches, population genetics and application to specific human diseases are also of interest.
Genomic Imprinting and Growth Control
Parent-of-Origin effects are cases in which a characteristic follows either a maternal or paternal lineage, rather than following standard Mendelian inheritance patterns. Such effects are commonly seen in interspecies hybrids as well as human disease, and often involve growth phenotypes. Maternal effects, X inactivation, transmission ratiodistortion, and genomic imprinting can account for these effects. Genomic imprinting is defined as the unequal expression of the two parental alleles of a gene.. A number of mammalian imprinted genes have been found in recent years, and many appear to be involved in growth.
The rodent genus Peromyscus ("deer mice") is approximately 20 million years removed from the domestic mouse. Crosses between two closely related species in this genus, P. maniculatus (BW) and P. polionotus (PO) yield interesting parent-of-origin effects which are suggestive of differential genomic imprinting between the two species. The two species are roughly the same size, but a female BW crossed with a male PO yields offspring that are much smaller than either parent. In the reciprocal cross, the offspring are oversized and exhibit lethal phenotypes. Often only an extra-embryonic mass is present. This size effect is particularly pronounced in the placenta, where 6 fold differences in size are observed between the two hybrids.
One predominant theory on the evolutionary rationale for the existence of imprinting has been put forth by David Haig. Haig’s theory predicts that maternal and paternal interests in growth rates of embryos are different in any non-monogamous species, and lead to imprinting of genes involved in growth control. These Peromyscus species are also a model for testing Haig’s theory of imprinting as parental conflict in that one species (PO) is monogamous, while BW is more promiscuous. Thus imprinting might be predicted to be ‘weakened’ or absent in PO. While imprinting is still clearly present in this species, it may not be able to ‘read’ imprints of the other species.
We have tested the parental expression status of known imprinted genes in these hybrids. The over-sized hybrids in particular show imprinting disruptions for a number of genes. Such disruptions are also common in human cancers, and are found in a number of inherited disorders, several involving growth. To understand the sex and parent-of-origin-specific patterns of overgrowth seen for hybrids between two species of Peromyscus, we analyzed reciprocal backcross populations. These studies reveal that hybrid inviability is due to a deleterious genetic interaction between a maternally expressed X-linked locus from PO and an imprinted paternally expressed autosomal locus from BW. In addition, the hybrids display an extreme skewing of X chromosome inactivation in favor of the expression of the BW X chromosome. The most severe overgrowth is accompanied by widespread relaxation of imprinting of primarily paternally expressed genes. Thus both genetic and epigenetic mechanisms underlie hybrid inviability in Peromyscus and hence play a role in the establishment and maintenance of reproductive isolation barriers in mammals. There is also evidence for a maternal effect locus involved in setting up imprints. This locus either does not recognize or is not able to maintain imprints from the other species.
These findings may also suggest the basis of a human syndrome known as hydatidiform moles. This condition is characterized by the presence of only overgrown extra-embryonic tissues, with overexpression of paternally expressed genes. Moreover, a susceptibility locus for this condition maps to the equivalent region in human of thePeromyscus autosomal overgrowth locus.
Links:
- Peromyscus Genetic Stock Center
- Mouse Imprinting Map
- Jirtle Lab's Imprinting Page
- The Catalogue of Imprinted Genes and Parent-of-origin Effects
- Human Imprinting Map
- Skarnes Lab Gene Traps
Selected Publications:
Vrana, P.B., J.A. Fossella, P.G. Matteson, M.J. O'neill, and S. M. Tilghman. 2000. Genetic and Epigenetic Incompatibilities Underlie Hybrid Dysgenesis in Peromyscus. Nature Genetics 25:120-124.
O"neill, M.J., R.S. Ingram, P.B. Vrana, and S.M. Tilghman. 1999. Allelic expression of Igf2 in marsupials and birds. Development, Genes and Evolution, 210:18-20.
Vrana, P.B., X.J. Guan, R.S. Ingram and S.M. Tilghman. 1998. Genomic Imprinting is disrupted in interspecific Peromyscus hybrids. Nature Genetics 20:362-365.
Science Volume 281, Number 5385, Issue of 25 Sep 1998, pp. 1984-1985.
