Request for Information (RFI): Functional Validation of Environmentally-Responsive Genetic Variants

Notice Number: NOT-ES-07-006

Key Dates
Release Date: February 12, 2007
Expiration Date:  April 20, 2007

Issued by
National Institute of Environmental Health Sciences (NIEHS)  (

The identification of candidate genes and genetic association studies has progressed in recent years through an increased understanding of biological pathways and broad-scale “omics” applications.  As the performance of whole genome-wide association studies for numerous complex diseases becomes realistic, it is becoming increasingly apparent that there is a need for better resources and tools to test the functional significance of environmentally-relevant SNPs and genetic variants in order to move these discoveries to final prediction of disease risk and therapeutic interventions.   


The National Institute of Environmental Health Sciences (NIEHS) has developed numerous programs and resources for the scientific community relevant to the discovery and analysis of environmentally-relevant genes.  The Environmental Genome Project (EGP) was established in 1997 to improve the understanding of human genetic susceptibility to environmental exposures.  NIEHS initiated a systematic effort to identify sequence variation in the human genome in over 600 prioritized candidate genes considered to play important roles in environmentally associated diseases.  Most of these environmentally-responsive genes are relevant to cell cycle, DNA repair, cell division, cell signaling, cell structure, gene expression, apoptosis, and metabolism, and are thought to play a role in susceptibility to environmental exposure.  The GeneSNPs database is the Environmental Genome Project’s web resource that integrates gene, sequence, and polymorphism data into individually annotated gene models for human and mouse environmental responsive genes.  The NIEHS Comparative Mouse Genomics Centers Consortium (CMGCC) was established with the goal of developing knockout and transgenic mouse models that harbor human single nucleotide polymorphisms (SNPs) and/or mutations in DNA repair and cell cycle control genes that could alter sensitivity to environmental agents.  These models are being used to enhance our understanding of the biological significance of human DNA polymorphisms and their role in combination with environmental stressors resulting in disease outcomes such as multiple cancers, aging-related diseases (including Werner’s Syndrome), diabetes, and obesity.  NIEHS has also recently issued a comparative biology RFA to further develop and utilize the power of comparative studies in key model organisms to further advance our understanding of biological pathways relevant to environmentally-sensitive diseases.  The Toxicogenomics Research Consortium has utilized comparative transcriptomics to study mechanisms relevant to environmentally-influenced disease.  NIEHS has also solicited applications in both proteomics and metabolomics. 

Information Requested

NIEHS is soliciting information and comments from the extramural community regarding how polymorphisms or genetic variants identified through genetic association studies, candidate gene studies, or  epidemiological studies for environmentally-relevant diseases can best be validated in functional prescreens and studies. What are currently the best available resources and tools to study functional significance of these genetic variants for each of the general categories of environmentally-responsive genes (DNA repair, cell signaling, cell cycle, metabolism, etc.) and what further resources or tools are needed for testing the functional significance of these genetic variants? What short-term resources or services could NIEHS provide to facilitate in the advancement of functional tests for genetic variants in any of the general categories of environmentally-responsive genes? What services or resources would allow some of these resources and tools to be more useful to the broader scientific community?  Please feel free to respond to any of the questions below at the Environmental Genome Project Request for Information webpage by April 20, 2007.
High-Throughput Assays and Screens:
What currently available functional screens and high-throughput assays are most useful for tracking phenotypic changes due to functionally-significant SNP or polymorphism alterations?  What are the advantages/ disadvantages for high throughput screening approaches in specific model organism systems and for specific categories of environmentally-relevant genes?

Cell-Based Assays:

What cell-based assays and cell line resources are available for isolating mutants with phenotypes (for example, relevant to repair of DNA damage, apoptosis, reporter gene outcomes, changes in expression levels, etc.) demonstrating sensitivity to environmental agents or for testing the functional significance of variants? What are their relative strengths and weaknesses?

Computational and Bioinformatics Needs:

How can one best use the predictive power of computational modeling and analysis of biological networks (gene-regulatory networks, protein interaction maps, etc.) to prioritize functional studies of disease risk polymorphisms for any of the broad classifications of environmentally-responsive genes?  What are the bioinformatics or computational gaps or needs?

High-Data Content Technologies:

How can current “omics” technologies be better integrated to help identify and test functional variants relevant to human disease risk?  How can the increased use of nanotechnology, proteomics, and metabolomics applications and systems biology approaches best be implemented and applied for functional studies of gene variants?

RNAi and siRNA silencing approaches:

What RNAi and siRNA resources (in both cell culture and whole organisms) are most relevant to testing genetic variants and identifying functional SNPs?

Environmental Challenges:

What strategies might be used to develop short-term environmental stressor or exposure challenges in model organism systems for environmentally-responsive genes related to DNA repair, cell cycle and division, signaling, etc.?


This request for information is for planning purposes only and shall not be construed as a solicitation for applications or as an obligation on the part of the Government.  The Government will not pay for the preparation of any information submitted or for the Government’s use of that information.  Acknowledgement of receipt of responses will not be made, nor will respondents be notified of the Government’s assessment of the information received.  No basis for claims against the Government shall arise as a result of response to this request for information, or in the Government’s use of such information as either part of our evaluation process or in developing specifications for any subsequent announcement.  Responses will be held in a confidential manner, but the general content of responses may be shared anonymously with National Advisory Environmental Health Sciences Council.  Any proprietary information should be so marked.


Direct inquiries regarding this notice to:

Kimberly A. McAllister, Ph.D.
Program Administrator
Susceptibility and Population Health Branch
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233 (MD EC-21)
Research Triangle Park, NC  27709
Phone:  (919) 541-4528
Fax:  (919) 316-4606

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