BSc, MSc (Windsor), PhD (British Columbia) Professor Departments of Medical Genetics; Biochemistry & Molecular Biology Adjunct Professor, Department of Biological Sciences University of Calgary Tel: (403) 220-5273 or 220-4473 Fax: (403) 210-8119 Email: fgbiddle -at- ucalgary.ca
Research Interests and Philosophy
I study the genetic and functional analysis of complex traits of development and disease processes using mouse model systems. Many heritable traits appear complex because they have phenotypic variation that arises from the inherent noise in the dynamics of their underlying biology. The challenge for genetic analysis is to use, rather than ignore, the information in noisy phenotypes to identify the heritable character states which can be attached to the genome. If there was a simple formula for this analysis, I certainly wouldn't call it research.
Understanding complex traits is facilitated by visualizing them as the expression of gene-regulatory networks and, then interrogating the biology that generates variation when it transforms environment into phenotype. We are beginning to understand that information, leading to phenotypic complexity, lies in the interaction between genetic and environmental variation and we are developing simple methods to visualize this interaction.
The mouse is the key mammalian genetic model system. Through its rich resource of genetic tools, it provides a context to assess genes and their transcriptional control in both individuals and populations of individuals. We can functionally interrogate the interactions among specified genes and sets of genes in different environments. I believe that a selective evolutionary advantage is provided to individuals when they maintain genetic variation in their populations causing noisy phenotypes. What is this selective advantage is the real challenge to understanding complex traits of development and disease processes. Opportunity for discovery lies in this challenge.
Primary Research Focus and Selected PublicationsLearning and memory determines asymmetry of hand usage
I am characterizing the genetics of hand-preference behavior of mice, which is a regulated process of learning and memory. From mathematical analysis of replicable quantitative measures, we are able to dynamically model the phenotypic variation of different genotypes. Learning and memory emerged as a property of the system, rather than from a specific gene or gene product. We can fully reconstruct phenotypic differences in behavior among different strains from identified genetic components and we are cloning causative genes by molecular map location. We are developing testable theories of cause of the behavior and the maintenance of its variation in populations.
A. S. Ribeiro, B. A. Eales and F. G. Biddle, (2011) Learning of paw preference in mice is strain dependent, gradual and based on short-term memory of previous reaches, Animal Behavior, 81(1), 249-257.
Ribeiro, A.S., Lloyd-Price, J., Eales, B.A., Biddle, F.G. (2009) A model of hand-preference behavior in mice, Adaptive Behavior (in press).
. Biddle, F.G., and Eales, B.A. (2006) Hand-preference training in the mouse reveals key elements of its learning and memory process and resolves the phenotypic complexity in the behaviour. Genome, 49: 666-677. (pdf) (link to journal)
. Biddle, F.G., Jones, D.A., and Eales, B.A. (2001) A two-locus model for experience-conditioned paw usage in the mouse is suggested by dominant and recessive paw usage behaviours. Genome, 44: 872-882. (pdf) (link to journal)
. Biddle, F.G., and Eales, B.A. (2001) Lateral asymmetry of paw usage: phenotypic survey of constitutive and experience-conditioned paw-usage behaviours among common strains of the mouse. Genome, 44: 539-548. (pdf) (link to journal)
. Biddle, F.G., and Eales, B.A. (1996) The degree of lateralization of paw usage (handedness) in the mouse is defined by three major phenotypes. Behavior Genetics, 26: 391-406. (pdf) (link to journal)
Secondary Research Focus and Selected References
1. Genetic determinants of mammalian lifespan
We described a model of increased longevity in the POSCH-2/Bid strain of wild-derived Mus musculus domesticus. Its pre-reproductive life span is increased from 6 - 10 weeks, expected for most laboratory strains and wild-derived Mus species, to almost one year of age; total life span is doubled. This model provides an opportunity to assess the relationship between age of onset of reproduction and life span and a framework to assess the underlying biology in age-dependent degenerative disease, including the concept of longevity assurance genes.
In a collaborative study provided, we provided a comprehensive assessment of age-related loss of monoaminergic neuronal cell populations in brain and retina of C57BL/6JBid mice from 8 to 104 weeks. We discovered that the kinetics of cell death, over the two-year period, is exponential with different rates in different neuronal cell populations. This means that cell loss in different neuronal cell populations is random and the remaining fraction of cells is lost at a constant (uniform) rate. Therefore, any functional and behavioral consequences from the interactions between mutant genes and environment will need to be assessed relative to this constant exponential rate of cell loss. Our results rejected the model that neuronal cell death is caused by cumulative cellular damage, which predicts the probability of neuronal cell death increases with age rather than occurs at a constant (exponential) rate. Others have rediscovered this phenomenon in the form of "mutant steady state" models of neuronal cell death.
. Tatton, W.G., Greenwood, C.E., Verrier, M.C., Holland, D.P., Kwan, M.M., and Biddle, F.G. (1991) Different rates of age-related loss for four murine monoaminergic neuronal populations. Neurobiology of Aging, 12: 543-556. (pdf) (link to journal)
. Greenwood, C.E., Tatton, W.G., Seniuk, N.A., and Biddle, F.G. (1991) Increased dopamine synthesis in aging substantia nigra neurons. Neurobiology of Aging, 12: 557-565. (pdf) (pdf2) (link to journal)
2. Genetics of mammalian sex determination
. Eales, B.A., Nahas, M., and Biddle, F.G. (1996) Directional dominance and a developmental model for the expression of the Tda testis-determining autosomal trait of the mouse. Genome, 39: 520-527. (pdf) (link to journal)
. Eisner, J.R., Eales, B.A., and Biddle, F.G. (1996) Segregation analysis of the testis-determining autosomal trait, Tda, that differs between C57BL/6J and DBA/2J mouse strains suggests a multigenic threshold model. Genome, 39: 322-335. (pdf) (link to journal)
. Biddle, F.G., Eisner, J.R., and Eales, B.A. (1994) The testis-determining autosomal trait, Tda-1, of C57BL/6J is determined by more than a single autosomal gene when compared with DBA/2J mice. Genome, 37: 296-304. (pdf) (link to journal)
. Biddle, F.G., Eales, B.A., and Nishioka, Y. (1991) A DNA polymorphism from five inbred strains of the mouse identifies a functional class of domesticus-type Y chromosome that produces the same phenotypic distribution of gonadal hermaphrodites. Genome, 34: 96-104. (pdf) (link to journal)
3. Interspecific hybrids
4. Genetics of developmental asymmetries
. Biddle, F.G., Mulholland, L.R., and Eales, B.A. (1993) Penetrance and expressivity of acetazolamide-ectrodactyly provide a method to define a right-left teratogenic gradient that differs between the C57BL/6J and WB/ReJ mouse strains. Teratology, 47: 603-612. (pdf) (pdf2) (link to journal)
. Layton, W.M., Layton, M.W., Binder, M., Kurnit, D.M., Hanzlik, A.J., Van Keuren, M., and Biddle, F.G. (1993) Expression of the IV (reversed and/or heterotaxic) phenotype in SWV mice. Teratology, 47: 595-602. (pdf) (pdf2) (link to journal)
. Biddle, F.G., Mulholland, L.R., and Eales, B.A. (1991) Time-response and dose-response to acetazolamide in the WB/ReJ and C57BL/6J mouse strains: genetic interaction in the ectrodactyly response. Teratology, 44: 107-120. (pdf) (link to journal). Biddle, F.G. (1990) Genetically-determined transient edema in the WB/ReJ mouse strain in a teratogenic survey with acetazolamide. Teratology, 42: 659-670. (pdf) (link to journal)
A. Hakkinen, F.G. Biddle, O-P. Smolander, O. Yli-Harja, and A. S. Ribeiro (2011) Evolutionary Dynamics of a Population of Cells with a Toxin Suppressor Gene, Lecture Notes in Computer Science, Vol. 6575, subseries Transactions on Computational Systems Biology. 193 p., ISBN: 978-3-642-19747-5
Andre S. Ribeiro, PhD (Assistant Prof., Laboratory of Biosystem Dynamics, Computational Systems Biology Research Group, Tampere University of Technology, Tampere, Finland) (http://www.cs.tut.fi/~sanchesr/)
Dr. N. Torben Bech-Hansen (University of Calgary, Medical Genetics, Calgary, Canada)