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| Physiological Profiling | |
| | Overview | Authors | Extended Abstract | Description of Physiological Profiling | Maps & Data | Contact | |
This resource is linked to the manuscript titled A Genomic-Systems Biology Map for Cardiovascular Function for Science
Monika Stoll(1), Allen W. Cowley Jr.(1), Peter J. Tonellato(1,2), Andrew S. Greene(1), Mary L. Kaldunski(1), Richard J. Roman(1), Pierre Dumas(1,3), Nicholas J. Schork(4,5,6), Zhitao Wang(1,2), Howard J. Jacob(1,3).
1. Medical College of Wisconsin, Department of Physiology, Milwaukee, WI
2. Bioinformatics Research Center, Medical College of Wisconsin, Milwaukee, WI
3. Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI
4. Case Western Reserve University, Cleveland, OH
5. The Jackson Laboratory, Bar Harbor, ME
6. Harvard School of Public Health, Boston, MA
With the draft sequence of the human genome available there is a need to define gene function and to place this function in the context of systems biology. We have measured 239 cardiovascular and renal phenotypes in 113 male rats derived from an F2 intercross, during normal and stressed conditions. Genomic regions accounting for a large degree of the variability of 81 of the traits were identified, allowing us to map these cardiovascular traits onto the genome. Aggregates of traits were identified on chromosomes 1,2,3,7, and 18 suggesting that multiple genes within a genomic region may be contributing to cardiovascular and renal biology and disease etiology. Systems biology was assessed by examining patterns of correlations ('physiological profiles'). The utility of this approach is demonstrated in an example where we identify a new relationship between alleles of the nitric oxide synthase (NOS) enzymes and arterial pressure responses. The relationships between the allelic subtypes and complex functional responses are often difficult to detect because of the difficulty in assessing patterns in such a large volume of generated data (over 5 million data points). The discovery of such relationships can be uniquely facilitated by the tools of physiological profiling. This QTL map, together with physiological profiling, can be used for gene hunting, for mechanism-based physiological studies, and, with comparative genomics, for translating these data to the human genome.
To assess systems biology of these mapped cardiovascular and renal traits, a novel analytical approach has been developed to determine the relationships among the physiological hierarchies under genetic control. The analytical concept, referred to as "physiological profiling", is based on ordering the phenotypes following traditional genetic mapping. The 81 mapped phenotypes (parametric LOD > 2.8; non-parametric LOD > 3.5) were incorporated into a physiological profile that visually demonstrates correlation structures. An additional 18 phenotypes with evidence of linkage
(parametric LOD 2.5-2.8), and 26 phenotypes with demonstrated functional relationships to blood pressure were also included in 125 profiled traits. The phenotypes were grouped into functionally related clusters (vascular, heart, renal, endocrine, and morphometric) that impact on the control of blood pressure, and ordered within the clusters by known physiological relationships. A color scale for values from +1 to -1 was developed to graphically depict correlation coefficients between traits. The large-scale genetic mapping of many cardiovascular and renal phenotypes, combined with physiological profiling, enables one to examine both genetic (first order) and physiological (second order) linkages. The first order linkage is dependent on direct influences of genes contributing to the mechanisms measured by the mapped traits. The second order relationships likely reflect mechanistic relationships among pathways involved in the control of blood pressure. Combining genetic linkage analysis (QTL aggregates) and the physiological profiles, provides a way to relate genetic information with functional pathways. The present manuscript and associated Website (http://brc.mcw.edu/phyprf) enables the reader to access: 1) all of the results of the linkage analyses; and 2) phenotypic physiological profiles for each microsatellite marker on the linkage map sorted by genotype.
White blocks within the profile grid indicate the absence of phenotyping data at that marker for rats used for the generation of the profile. Not all rats are genotyped at every marker.
To view the completed BN/SS map with QTLs, you can select to view the clickable
maps with the primary link below.
NOTE: Files are large and may take some time to download.
F2 BN/SS Genomic Map with 97 QTLs:
| Chr 1 | Chr 2 | Chr 3 | Chr 4 | Chr 5 | Chr 6 | Chr 7 |
| Chr 8 | Chr 9 | Chr 10 | Chr 11 | Chr 12 | Chr 13 | Chr 14 |
| Chr 15 | Chr 16 | Chr 17 | Chr 18 | Chr 19 | Chr 20 |
Description of the 81 mapped phenotypes:
Click to see details.
Description of the 125 phenotypes used in the physiological profile:
Click to see details.
BN, SS and F2 Rat physiological profiles:
NOTE: Files are large and may take some time to download.
| BN | F2 | SS |
Address for correspondence:
Howard J. Jacob, Ph.D.
Medical College of Wisconsin
Laboratory for Genetic Research
8701 Watertown Plank Road
Milwaukee, WI 53226-0509
Phone: (414) 456 4887
Fax: (414) 456 6516
e-mail: jacob@mcw.edu
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