Source: UNIVERSITY OF TENNESSEE submitted to
QUANTITATIVE GENETICS OF METABOLIC PATHWAYS
Sponsoring Institution
National Institute of Food and Agriculture
Project Status
TERMINATED
Funding Source
Reporting Frequency
Annual
Accession No.
0194475
Grant No.
(N/A)
Project No.
TEN00274
Proposal No.
(N/A)
Multistate No.
(N/A)
Program Code
(N/A)
Project Start Date
Oct 1, 2002
Project End Date
Sep 30, 2007
Grant Year
(N/A)
Project Director
Saxton, A. M.
Recipient Organization
UNIVERSITY OF TENNESSEE
2621 MORGAN CIR
KNOXVILLE,TN 37996-4540
Performing Department
ANIMAL SCIENCE
Non Technical Summary
The genomic revolution is making feasible the routine collection of genotypes for all genes controlling agricultural traits. Use of such detailed information in genetic improvement of farm species requires new methodology. This project will examine new approaches to selection and mating of parents that attempt to maximize benefits from genomic data.
Animal Health Component
(N/A)
Research Effort Categories
Basic
100%
Applied
(N/A)
Developmental
(N/A)
Classification

Knowledge Area (KA)Subject of Investigation (SOI)Field of Science (FOS)Percent
3043910108050%
3043910209050%
Goals / Objectives
1. Implement computer simulation of various informative metabolic pathways using available biochemical pathway software or new SAS programs. 2. Examine response of these pathways to traditional genetic manipulation (e.g. BLUP selection, heritability estimation), and develop new quantitative genetic models as needed. 3. Develop genetic improvement programs that maximize rates of genetic gain for metabolic pathways, including selection and mating systems.
Project Methods
Although several metabolic pathway software packages are available, such as Dbsolve, these are designed for biochemical research. They will be examined for use in this project, but it is expected that new simulation tools will be required to allow integration of quantitative genetic needs. SAS software will be used for this purpose, as its high-level language and pre-packaged statistical analysis will allow more rapid development. With a working simulation package, populations with known genotypes and environmental influence, and resulting traditionally observed phenotypes, will be processed through standard quantitative genetic methods. Observations on how effectively these standard methods capture the genetic information from a realistic biological setting will be made. If weaknesses are found in standard methods, development of more appropriate theory will be undertaken. Of primary interest is how these simulated populations respond to genetic selection. The ability of standard selection methods to produce desired genotypes will be tested. Preliminary studies have already found circumstances where standard genetic selection methods are ineffective, so development of new methods for genetic improvement of populations will be required. In short, this project is theoretical in nature, and will use mathematical models and computer simulation to address the objectives.

Progress 10/01/02 to 09/30/07

Outputs
This project has continued to evolve from its initial objectives, and is thus being terminated. Instead of theoretical methods for improving thousands of genes, the focus has become practical methods for identifying which genes might be of interest for genetic improvement. This will have greater short-term impact. Progress this year has been in the use of microarray data to extract coexpression of genes. Coexpression implies joint regulation, in turn suggesting functional relationships. Methods being studied generate a correlation matrix among all genes from array expression data, then convert the matrix to a graph and use graph algorithms to find "cliques" of highly correlated genes. Statistical problems with these high-dimensional data (eg. 400 million correlations from 30 arrays) and with comparing cliques are of immediate interest.

Impacts
Methods are being developed to extract additional information from microarray experiments, focused on gene coexpression. This information will assist discovery of gene function, particularly how genes work together in networks. Identification of candidate genes for genetic improvement of livestock will then be easier, leading to a safe and plentiful food supply.

Publications

  • Kim HY, Steward TP, Vyas KR, Saxton AM, Nishina PM, Naggert JK, Kim JH. 2005. Functional genomic study of dietary obesity in congenic mice. FASEB Journal 19 (5 Part 2 Suppl. S): A1498.
  • Blouse GE, Peterson CB, Minor KH, Perron MJ, Saxton AM, Anagli JY, Shore JD. 2005. An ordered mechanism for assembly of complexes of vitronectin and plasminogen activator inhibitor-I: pre-steady state kinetic analysis of step-wise binding and conformational changes that trigger assembly. Thrombosis & Haemostasis 93 (4): A29.
  • Peng, X, MA Langston, AM Saxton, N Baldwin, JR Snoddy. 2004. Detecting Network Motifs in Gene Co-expression Networks. Critical Assessment of Microarray Data Analysis V, Duke University, Nov 10-12, 2004.


Progress 01/01/04 to 12/31/04

Outputs
Purpose of the project is to investigate how the extensive genomic data being collected might be used to increase rates of genetic improvement, by selecting on genotypes instead of phenotypes. Possibilities for converting this project from theoretical to practical application were explored this year, including SNP detection, microarray technology and QTL identification in various species (see publications). It is apparent that practical application is many years away. It will take extensive research to identify all genes in metabolic pathways, and estimate functional performance of those genes. Currently it is practical to genetically improve a population for a few genes (marker assisted selection), but the goal of this project is to improve hundreds of genes simultaneously. Theoretical work will continue.

Impacts
Potential impact of this research is to increase the rate of genetic improvement in agriculture. This would greatly assist efforts to produce a plentiful and safe food supply for the world.

Publications

  • Wang, Y., Voy, B.J., Urs, S., Kim, S., Soltlani-Bejnood, M., Quigley, N., Heo, Y.-R., Standridge, M., Andersen, B., Dhar, M., Joshi, R., Wortman, P., Taylor, J.W., Chun, J., Leuze, M., Claycombe, K., Saxton, A.M. and Moustaid-Moussa, N. 2004. The human fatty acid synthase gene and de novo lipogenesis are coordinately regulated in human adipose tissue. J. Nutr. 134: 1032-1038.
  • Urs, S., Smith, C., Campbell, B., Saxton, A.M., Taylor, J., Zhang, B., Snoddy, J.R., Jones Voy, B. and Moustaid-Moussa, N. 2004. Gene Expression Profiling in human preadipocytes and adipocytes by microarray analysis. J. Nutr. 134: 762-770.
  • Panthee, D.R., Pantalone, V.R., Sams, C.E., Saxton, A.M., West, D.R. and Rayford. W.E. 2004. Genomic regions governing soybean seed nitrogen accumulation. J. Amer. Oil Chemists Soc. 81(1): 77-81.
  • Youngerman, S.M., Saxton, A.M., Oliver, S.P. and Pighetti, G.M. 2004. Association of CXCR2 polymorphisms with subclinical and clinical mastitis in dairy cattle. J Dairy Science 87:2442-2448.
  • Hyten, D.L., Pantalone, V.R., Sams, C.E., Saxton, A.M., Landau-Ellis, D., Stefaniak, T.R. and Schmidt, M.E. 2004. Seed quality QTL in a prominent soybean population. Theoretical and Applied Genetics 109(3): 552-561.
  • Smiley, R.D., Saxton, A.M., Jackson, M.J., Hicks, S.N., Stinnett, L.G. and Howell, E.E. 2004. Non-Linear Fitting of Bi-Substrate Enzyme Kinetic Data using SAS: Application to R67 Dihydrofolate Reductase. Analytical Biochemistry 334(1): 204-206.
  • Youngerman, S.M., Saxton, A.M. and Pighetti, G.M. 2004. Novel single nucleotide polymorphisms and haplotypes within the bovine CXCR2 gene. Immunogenetics 56(5): 355-359.


Progress 01/01/03 to 12/31/03

Outputs
A preliminary version of the simulation program has been written using SAS software, which simulates genotypes for a metabolic pathway, and tracks the effect of genetic selection on gene frequencies. Flexibility in genetic selection provided by investigator written software appears to justify the programming effort, as compared to using existing metabolic simulation programs. Ability to specify different metabolic pathways needs to be incorporated in the SAS program.

Impacts
No impacts were expected in the first year of this project.

Publications

  • Saxton, A.M. and Stalder, K.J. 2002. Selection of genotypes. 7th World Congress on Genetics Applied to Livestock Production. August 19-23, Montpelier, France. Paper No. 22-32.