Mathematical Models Reveal How Organisms Transcend The Sum Of Their Genes

February 9, 2009 at 11:00 am Leave a comment

Molecular and cellular biologists have made tremendous scientific advances
by dissecting apart the functions of individual genes, proteins, and
pathways. Researchers at the University of Wisconsin-Madison College of
Engineering are looking to expand that understanding by putting the pieces
back together, mathematically.

John Yin, a professor of chemical and biological engineering, developed
computer models of a relatively simple virus to show that genes alone do
not make an organism. With mathematical representations of the virus’s
known biology, he and former graduate student Kwang-il Lim demonstrate how
genomic organization and regulation can have a large impact on biological
outcomes. As shown in a new paper, simply shuffling the order of the five
genes in the virus’s genome has a huge impact on how well the virus grows
and how it interacts with its simulated host cell.

Their new results are reported today (Feb. 6) in the journal PLoS
Computational Biology at

The eventual goal is to understand the full picture of how an organism’s
genome guides its growth and development, Yin says. “How does the biology
of individual genes come together in genetic interactions to ultimately
give rise to behavior?”

He and Lim, now a postdoctoral fellow at the University of
California-Berkeley, computationally modeled the lifecycle of the
vesicular stomatitis virus (VSV), a well-studied virus with only five
genes and years of background research on its growth and function.

Virologists have previously created strains with 11 of the possible gene
arrangements, but with their computational models, the Wisconsin
researchers were able to simulate all 120 possible gene-order variants.
Comparisons of the simulated strains revealed that the positions of the
first and last genes are key to viral success.

The work has many potential applications. Understanding how to control the
virus’s growth and infectivity will help guide efforts to develop VSV as a
cancer-targeting agent and create vaccines against more problematic
viruses such as HIV-1 and influenza.

The models can also be used to investigate the genetic basis of other
viral characteristics. For example, Yin is currently working to simulate
drug effects on a virus to look for ways the virus can evolve drug

Ultimately he hopes his approach will scale up to more complex organisms
with more complex genomes. For example, the completion of the Human Genome
Project has inspired hopes of understanding how a person’s genome
determines their biology.

The era of such “predictive biology” is a long way off yet, Yin says, but
the ability to identify key elements of genetic organization and
regulation are a critical early step. “This establishes a foundation for
linking a genome to developmental processes and ultimately to phenotypes
or behavior of biological systems,” he says.

University of Wisconsin-Madison College of


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