Assistant Professor
Publications | Research | Faculty
Background:
Daniel Barbash is an Assistant Professor in the Department of Molecular Biology and Genetics. He received a B.S. degree in Biology from the Massachusetts Institute of Technology in 1989 and a Ph.D. in Genetics from the University of California, Berkeley in 1995. He did postdoctoral research in the Department of Genetics at the University of Cambridge with support from a NSF / Sloan Foundation Fellowship in Molecular Evolution, and in the Section of Evolution and Ecology at the University of California, Davis with support from the NSF. He joined the Cornell faculty in 2004.
Our laboratory is interested in understanding the relationship between genomic change and the creation and divergence of species. Much of our current research investigates the evolutionary origins and developmental mechanisms of reproductive isolating mechanisms between species, such as hybrid sterility and lethality. We are currently using diverse approaches including developmental genetics, biochemistry, molecular evolution and population genetics, and comparative genomics to investigate interspecific hybrid lethality in the fruitfly Drosophila.
Crosses between D. melanogaster and any one of its three sibling species D. simulans, D. mauritiana and D. sechellia produce no F1 hybrid males and severely defective F1 hybrid females.
Fig. 1 An F1 D. melanogaster / D. simulans female hybrid.
Mutations in the gene Hybrid male rescue (Hmr) have the remarkable property of suppressing these anomalies in both male and female F1 hybrids. We recently cloned the Hmr gene in order to understand its role in causing hybrid lethality and to investigate its molecular evolution in D. melanogaster and the sibling species.
We discovered that Hmr encodes a protein related to the Myb family of DNA binding proteins. Myb and related proteins are involved in diverse aspects of gene regulation in many eukaryotes, including the human Myb proto-oncogene. This finding led us to propose that Hmr causes hybrid incompatibility due to gene misregulation, and we are currently taking multiple approaches to test this hypothesis. These include biochemical studies to determine whether Hmr is a sequence-specific DNA binding protein and to identify which genes are regulated by Hmr. A second approach is to use whole-genome transcriptional profiling with DNA microarrays to identify genes that are misexpressed in interspecific hybrids and in Hmr mutant backgrounds.
Our molecular evolutionary analyses have shown that Hmr is one of the most highly diverged proteins known between D. melanogaster and its sibling species, and that Hmr has especially high divergence compared to other putative transcriptional regulators. Population genetic analyses strongly suggest that this divergence of Hmr is not due to a relaxation of selection but rather has occurred under the force of positive selection. We are pursuing several areas of research to understand what forces are driving the divergence of Hmr and how this divergence relates to its role in causing hybrid lethality. One approach is to use developmental genetic techniques to investigate the biological role of Hmr within D. melanogaster and its sibling species, in order to identify what phenotype or biological process is under such strong selection. A second question follows from our observation that patterns of divergence across Hmr are not homogenous, and that some regions show particularly strong evidence of positive selection. We are using interspecific chimeric genes and transgenic technologies to identify the diverged regions of Hmr that are critical for causing interspecific incompatibility.
Fig. 2 A sliding window analysis of the ratios of polymorphism (?N/?S) and divergence (DN /DS) at replacement and silent sites across the Hmr gene for D. melanogaster and D. simulans.
We are also interested in identifying and characterizing the network of genes which Hmr interacts with to cause hybrid lethality. The Lethal hybrid rescue (Lhr) gene from D. simulans is one such candidate gene. Our genetic studies support a model where Hmr and Lhr interact to misregulate additional downstream genes, which in turn leads to hybrid lethality. The molecular identification of Lhr will allow us to perform definitive molecular genetic tests of whether Hmr and Lhr form a pair of hybrid lethality genes which conforms to the predictions of the classic Dobzhansky-Muller model formulated over 60 years ago. Identifying Lhr and other interacting genes will also allow us to ask whether hybrid lethality genes in general are part of a subset of the genome that is diverging rapidly between species under the force of positive selection.
In addition to these studies of hybrid incompatibilities we are also developing experiments to examine the evolution of new cis-regulatory DNA modules, to assess the frequency and importance during evolution of changes in the DNA binding preferences of transcriptional regulators, and to understand the relationship between molecular evolution and morphological diversity in animals.
Recent publications:
N. J. Brideau*, H. A. Flores*, J. Wang*, S. Maheshwari, X. Wang and D. A. Barbash. Two Dobzhansky-Muller genes interact to cause hybrid lethality in Drosophila. Science, 314: 1292 - 1295 (2006). (*These authors contributed equally).
D.A. Barbash and J.G. Lorigan. Lethality in Drosophila melanogaster / Drosophila simulans species hybrids is not associated with substantial transcriptional misregulation. JEZ Part B: Molecular and Developmental Evolution. Published online Oct. 30, 2006.
D.A. Barbash*, P. Awadalla*, and A.M. Tarone. Functional divergence caused by ancient positive selection of a Drosophila hybrid incompatibility locus. PLoS Biology, 2: 839-848 (2004). (*These authors contributed equally).
D.A. Barbash, J. Roote, G. Johnson and M. Ashburner. A new hybrid rescue allele in Drosophila melanogaster. Genetica, 120: 261-266 (2004).
D.A. Barbash, D.F. Siino, A.M. Tarone, and J. Roote. A rapidly evolving MYB-related protein causes species isolation in Drosophila. Proc. Natl. Acad. Sci. USA 100: 5302-5307 (2003).
D.A. Barbash and M. Ashburner. A novel system of fertility rescue in Drosophila hybrids reveals a link between hybrid lethality and female sterility. Genetics 163: 217-226 (2003).
D.A. Barbash, J. Roote, and M. Ashburner. The Drosophila melanogaster Hybrid male rescue gene causes lethality in both male and female species hybrids. Genetics 154: 1747-1771 (2000).