The long-term objective of my research program is to understand the molecular genetic mechanisms and driving forces of phenotypic variation and evolution, where the phenotype may be at molecular, cellular, tissue, organ, organismal or other levels. Gene expression is a phenotypic trait at the molecular level that is critical to all forms of life. This proposal centers on one aspect of gene expression known as position effect, which refers to the influence of the chromosomal location of a gene on its activity. Position effect has been implicated in a number of genetic diseases such as sex reversal, aniridia (absence of iris), and holoprosencephaly (a brain developmental disorder that typically leads to embryonic death). Any genetic disease caused by a chromosomal rearrangement that does not disrupt gene structure may be regarded as a result of position effect. Position effect has been observed many times in transgenic organisms, revealing the significance of the location at which the transgene is placed in a genome on its expression. Position effect has also been invoked in the explanations of multiple nonrandom features of genome organization. Despite its importance, our knowledge about the pattern and mechanism of position effect is limited and many hypotheses regarding position effect remain untested. Past studies of position effect focused on the role of heterochromatin, largely ignoring euchromatin where the vast majority of genes are located (and translocated in mutants and in evolution). A genomic study of position effects on mean protein expression and expression noise in the budding yeast Saccharomyces cerevisiae is proposed. The generated data will be used to probe the general patterns of position effects, to study the underlying genetic and epigenetic mechanisms of position effects, and to test the role of position effects in the formation of nonrandom features of genome organization. Furthermore, a series of manipulative experiments will be conducted in yeast to test a previously unrecognized role of position effect on expression noise in the origin of chromosomal clustering of functionally related genes. Overall, this project is expected to (i) provide unprecedented genome-wide information of position effect on gene expression and expression noise in yeast, (ii) uncover the molecular and mechanistic basis of position effects, and (iii) deepen our understanding of the role of position effect in the evolution of eukaryotic genome organization.

Public Health Relevance

Because position effect has been implicated in a number of diseases such as aniridia, X-Linked deafness, and sex reversal, there is an urgent need to understand the extent of position effect at the genomic scale and the underlying molecular basis of position effect. Investigating the genomic landscape of position effects on gene expression and expression noise using yeast as a model system will greatly accelerate the understanding of position effect, which will shed light on the mechanisms of position-effect-related diseases in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM120093-04
Application #
9694099
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Adkins, Ronald
Project Start
2016-09-01
Project End
2020-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Arts and Sciences
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Moyers, Bryan A; Zhang, Jianzhi (2018) Toward Reducing Phylostratigraphic Errors and Biases. Genome Biol Evol 10:2037-2048
Liu, Zhen; Zhang, Jianzhi (2018) Human C-to-U Coding RNA Editing Is Largely Nonadaptive. Mol Biol Evol 35:963-969
Wei, Xinzhu; Zhang, Jianzhi (2018) The optimal mating distance resulting from heterosis and genetic incompatibility. Sci Adv 4:eaau5518
Wei, Xinzhu; Zhang, Jianzhi (2018) On the Origin of Compositional Features of Ribosomes. Genome Biol Evol 10:2010-2016
Zhang, Jianzhi (2018) Neutral Theory and Phenotypic Evolution. Mol Biol Evol 35:1327-1331
Vijay, Nagarjun; Park, Chungoo; Oh, Jooseong et al. (2018) Population Genomic Analysis Reveals Contrasting Demographic Changes of Two Closely Related Dolphin Species in the Last Glacial. Mol Biol Evol 35:2026-2033
Moyers, Bryan A; Zhang, Jianzhi (2017) Further Simulations and Analyses Demonstrate Open Problems of Phylostratigraphy. Genome Biol Evol 9:1519-1527
Liu, Zhen; Zhang, Jianzhi (2017) Most m6A RNA modifications in protein-coding regions are evolutionarily unconserved and likely nonfunctional. Mol Biol Evol :
Zhang, Jianzhi (2017) Epistasis Analysis Goes Genome-Wide. PLoS Genet 13:e1006558
Chen, Xiaoshu; Zhang, Jianzhi (2016) The Genomic Landscape of Position Effects on Protein Expression Level and Noise in Yeast. Cell Syst 2:347-54