Joseph Nadeau Department Chair/Professor Ph.D. Training Faculty

Department of Genetics School of Medicine Case Western Reserve University Biomedical Research Building 731 2109 Adelbert Road Cleveland, Ohio 44106-4955 Tel: (216) 368-0581 Fax: (216) 368-3432 E-mail: joseph.nadeau@case.edu http://genetics.case.edu/nadeaulab/ http://genomics.case.edu/

About Joseph Nadeau

Joseph Nadeau received his Ph.D. in population biology from Boston University in 1978. He was a postdoctoral fellow with Jan Klein in the Immunogenetics Department, Max Planck Institute for Biology, Tübingen (1978-1980) and with Eva Eicher at the Jackson Laboratory (1980-1981).

He was appointed Associate Staff Scientist (1981-1985), Staff Scientist (1985-1991) and Senior Staff Scientist (1991-1994) at the Jackson Laboratory, and then Professor, Department of Human Genetics, McGill University, and Medical Scientist, Department of Medicine, Montreal General Hospital (1994-1996).

He is currently James H. Jewel Professor and Chair of Genetics Department at Case Western Reserve University School of Medicine.

He was a founding member of the International Mammalian Genome Society and a founding editor of Mammalian Genome. He was founder and director of the Mouse Genome Informatics Project (1989-1994) and founder of the Mouse Gene Expression Database Project (1992-1994). He has served on review panels and advisory groups at the National Institutes of Health, the National Science Foundation and the Human Genome Database.

He has consulted for GlaxoSmithKline, Pharmacia, Celera Genomics, Exelixis, NineSigma and CellTech Chiroscience, and is on the Scientific Advisory Board of Galileo Genomics.

Research

Many common human diseases are complex involving various combinations of genes and environmental factors. Although remarkable progress is being made to characterize the genetic basis of these diseases, studies with laboratory mice are important because they provide experimental models for identifying disease genes, characterizing the physiological and developmental pathways in which these genes function, and defining interactions among these genes and environmental factors, - insights that can be used to guide corresponding studies in humans.
We use a combination of genetic, developmental, molecular, biochemical, physiological, genomic, statistical and analytical methods for studying these problems, with an emphasis on developing new mouse resources and computational methods as well as on applying these innovations to a variety of mouse models of human diseases.

Functional genomics and systems biology in health and disease
Many complex diseases involve diverse anomalies in many aspects of the physiological systems of humans and animal models. We are testing various approaches for using principles of functional genomics and systems biology to characterize normal biological systems, We are focusing on two systems,
(1) the folate and homocysteine pathways in mouse models of neural tube defects using an integrated combination of genes and diets as perturbations (causes) and gene expression and metabolite profiles as responses (consequences), and
(2) metabolic syndrome X the combination of obesity, hypertension, dyslipdemia, and atherosclerosis.
We pioneered the use of single gene mutations as well as multifactorial non-pathological variants to perturb complex biological systems in hard and in subtle ways in mice.
A recent proof-of-concept study showed that a novel computational method correctly predicts certain aspects of cardiovascular functionality as well as ways to use reference networks to interpret the pleiotropic and homeostatic consequences in single gene mutant mice.

Folate and homocysteine metabolism
These pathways are an ideal model system for evaluating methods to study systems biology in mammals and for characterizing the role of these pathways in common birth defects and adult diseases.
Several attributes make these pathways appropriate models:
(1) their basic circuitry and functionality is known;
(2) traits can be measured at several phenotypic levels from the primary action of the genes (expression profiles), intermediate phenotypes (metabolite profiles), to end-phenotypes;
(3) anomalies in these pathways are associated with common diseases in humans, and
(4) mouse models for many of these birth defects and adult diseases are readily identified and outstanding collections of these single gene mutants and multigenic variants are available for study.
We have focused on expression and metabolite profiles in mice with mutations that cause neural tube defects (spina bifida) as well as colon cancer. A key discovery is that mutations in the WNT, disheveled and hedgehog signal transduction pathways adversely affect expression and metabolite profiles in the folate and homocysteine pathways.
We have also recently studied the effect of folic acid (FA) on neural tube defect outcome. An interesting finding was a substantial FA-induced pre-implantation loss of homozygous as well as otherwise healthy and viable heterozygous embryos. Another finding was a functional dependence of neural tube development on the level of Wnt signaling which is in turn affected by FA. For further details refer to the published Thesis: Genetic and Phenotypic Response of Neural tube Defect Mouse Mutants to Folic Acid.For related APPENDIX material click HERE

Metabolic syndrome X
Many individuals show unexpected combinations of obesity, diabetes, hypertension and dyspilidemia, - a combination of conditions and diseases that is known as metabolic syndrome X. Given the considerable genetic and physiological complexities associated with Syndrome X, mouse models are useful providing insights to guide human studies. We are characterizing the genetics and physiology of two strains, one susceptible and the other resistant to diet-induced Syndrome X. These studies are based on Chromosome Substitution and Recombinant Inbred Strains and on linkage testing crosses derived from them. An important discovery is that many chromosomes in the panel of Chromosome Substitution Strains confer resistance to weight gain on a high fat, high sugar diet.

Testicular cancer
Testicular germ cell tumors (TGCTs) are the most common cancer affecting young men. Remarkably, genes that control inherited susceptibility to these cancers have not yet been identified, in contrast to many other cancers where susceptibility genes have been identified and characterized. We are using the 129/Sv strain as a model to identify these genes and to characterize the ways that they lead to these cancers. Susceptibility in 129/Sv is a highly multigenic trait and simple crosses are therefore unlikely to lead to gene identification.
We are therefore using alternative approaches that include
(1) using various single gene mutations that increase or in some cases decrease susceptibility to TGCTs a method called sensitized polygenic trait analysis,
(2) pioneering the use of chromosome substitution strains (also known as consomic strains) to simplify the genetic analysis, and
(3) characterizing gene interaction effects on susceptibility in single- and double-mutant mice.
Recent discoveries include evidence that susceptibility may be strongly influenced by epigenetic control and resistance to TGCTs in TRP53 MGF double-mutant mice.

Disorganization a mouse model for sporadic birth defects
Most birth defects in humans occur sporadically without obvious evidence for genetic or environmental causation. Mice with the Disorganization mutation have a remarkable and unpredictable variety of birth defects. These involve all body parts and derivatives of all three germ layers. No two mice have identical birth defects and penetrance is low and more than 90% of carriers and homozygotes are normal.
Examples of these birth defects include cleft tongue, cyclopia, ectopic limbs, single, missing or fused kidneys, a small intestine that forms a complete circle, gastroschisis, rachischisis, polydactyly, syndactyly, and various kinds of mirror-image duplications. The trait is inherited as a true dominant, - heterozygotes and homozygotes are phenotypically indistinguishable.
In addition, Disorganization is one of the few documented examples of a gain-of-function mutation; trisomic +/+/Ds mice can be affected. Interestingly, these mice are not susceptible to cancers, they have normal behavior, fertility and longevity, and show no toher deficits besides morphological anomalies. We are using positional cloning to identify the Disorganization to learn about the kind of gene that affects development in such profound ways as well as the nature of the mutation that has such unpredictable effects on development.

Computational genomics
We continue to explore ways to incorporate bioinformatics and computational methods to study mouse models of complex diseases. Ongoing projects include pathways databases, modeling pathway dynamics, discovery of functional networks, and studies of pathway organization and evolution. Additional data can be found on the Computational Genomics site.

Novel phenotyping methods
With collaborators in the Department of Electrical Engineering and Computer Science, we are developing, testing, validating and using novel micro- and nano-technologies to assess phenotypes in real-time and in vivo. For further data click here

22 Mouse CSS panel
A complete 22 panel of consomic mice has been derived from the A/J and C57BL/6J progenitor strains. A consomic strain has been created for each of the 19 autosomes, the 2 sex chromosomes, and the mitochondria. These strains and their distinct phenotypic differences, allow for complex trait analysis and modeling of defects and adult diseases in humans. This unique panel of consomic strains are now available for commercial applications. Additional information can be found here here. For more information and licensing inquiries, contact Michael Haag , Case Western Reserve University at (216) 368-6106.

Selected Publications