Request for Information (RFI): Community Input for the Nomination and Prioritization of Environmentally Responsive Genes to be Targeted in the Knockout Mouse Project (KOMP)

Notice Number: NOT-DA-07-011

Key Dates
Release Date: February 1, 2007

Issued by
National Institute on Drug Abuse (NIDA), (http://www.nida.nih.gov)

We request community input for the nomination and prioritization of candidate environmentally-responsive genes to be targeted in the Knockout Mouse Project (KOMP).

THE GENE ENVIRONMENT INITIATIVE (GEI) AND KOMP

GEI is a DHHS initiative through the NIH institutes to investigate the environmental and genetic bases of common diseases (http://www.gei.nih.gov/ ).  Genetic differences between individuals can determine the relative sensitivity of the individual to particular environmental exposures such as diet, chemical toxins, psychosocial stress, or drugs of abuse.  For many complex human disease phenotypes (such as asthma, atherosclerosis, addictions, diabetes, and certain types of cancer), the genetic blueprint of each individual does not in and of itself cause disease; instead disease is the outcome of a complex interplay between multiple genetic and environmental factors. 

The Knockout Mouse Project (KOMP) is accepting nominations for genes for targeted knockout (see below and http://www.nih.gov/science/models/mouse/knockout/). Environmental exposure is an important factor in the etiology of many common human diseases.  Therefore, pending availability, GEI intends to provide funds for the knockout of environmentally-responsive genes through the KOMP initiative.  These environmentally-responsive candidates for targeted knockout will be referred to as eKOMP.  It is hoped that knockouts in the eKOMP genes will facilitate functional validation and characterization of genes implicated in complex human diseases in which the role of the environment is significant. 

What are environmentally-responsive genes?  The biological components that influence the outcome of environmental exposures (toxins, pesticides, addictive drugs, radiation, life stressors, etc)  include but are not limited to the following: cellular receptors for environmental exposures, enzymes that modify or activate chemical toxins or illicit drugs, genes involved in dietary or oxidative stress responses, regulators of the HPA axis for psychosocial stress response, enzymes that repair DNA damage, inflammation factors, and genes that regulate cell division and death. Thus, many environmentally-responsive genes fall into the following general categories: cell cycle, cell division, DNA repair, cell signaling, cell structure, gene expression, apoptosis, plasma membrane and nuclear receptors, metabolism, factors involved in chromatin remodeling, and factors involved in neuronal plasticity.  In addition to these, candidate genes for human disease susceptibility identified through GEI funded genome-wide association scans may also be nominated for eKOMP. 

THE KNOCKOUT MOUSE PROJECT

Recently the NIH Knockout Mouse Project (KOMP), a trans-NIH initiative, funded by 19 Institutes and Centers, was funded to produce a comprehensive resource of mouse mutant ES cells. The mission of KOMP is to ensure that every gene in the mouse genome has been knocked out, marked with a reporter system of high utility (RFA-HG-05-007) and made publicly available through a KOMP repository (http://www.nih.gov/science/models/mouse/knockout/).  The preferred resource would be one in which all of the mutations are carried on a uniform background in strain C57BL/6 because of its broad experimental utility; KOMP aims to produce the majority of the knockouts in this strain (RFA-DA-06-009).

The KOMP working group, in conjunction with NIH Staff, the Welcome Trust Sanger Institute staff, grantees of KOMP and the KOMP Data Coordinating Center (DCC) (RFA-05-008) (http://knockoutmouse.org/), has compiled and will continue to update a gene list to be used by KOMP in selecting targets for this project (http://knockoutmouse.org/data.shtml). The initial master list is based on the mouse consensus coding sequence (CCDS) list, for which there is agreement between the National Center for Biotechnology Information (NCBI), NIH and Ensemble genome annotation pipelines. The master list will be expanded beyond the consensus coding sequence (CCDS) list to contain additional protein coding genes that are highly annotated.

Subsequently, genes are subtracted in order to produce a set of genes for targeting (the “target” list). Genes that are subtracted from this list include those that have been previously knocked out, those for which there are gene trap cell lines, and those that are being knocked out by European and North American Conditional Mouse Mutagenesis Projects. This notice is soliciting input from the scientific community to assist in prioritizing and nominating genes in this program. There will be two different mechanisms in this process described below, which is coordinated by the KOMP DCC (http://knockoutmouse.org/): (1) Prioritization of the KOMP Target List and (2) Nomination of a Gene or Multiple Genes to the Target List.  Each is described below.

Prioritization of the KOMP Target List

Members of the scientific community may vote for genes of interest by visiting the web site (www.knockoutmouse.org) to view the list of genes that have been targeted for knockout. All knockouts are intended to produce null mutations but KOMP employs two complimentary methods, a deletion of the entire gene or a conditional targeted trapping approach. 
The desired approach can also be voted for by the investigator (more information will be provided on the website (http://knockoutmouse.org/).  Highly specific requirements that are outside of the stated goals of KOMP cannot be considered (e.g. creating point mutations, knock-in alleles or changing reporters).

Individuals may vote for as many genes as desired but they should not vote for the same gene more than once.  All votes will be tabulated and weighted equally.  The results will be used to guide the scientific steering committee in the prioritization process.

This process also allows investigators to write a brief justification for a gene or genes on the KOMP target list to receive higher prioritization. For example, an investigator that is interested in a pathway or gene family may justify prioritization of a group of targets. The areas that will be given highest priority in the evaluation process are disease related genes, relevant impact on human health, size of the research community, gene families and pathways.

In the case of eKOMP, justifications should also include a brief description of how the gene is environmentally-responsive and specific cellular, biochemical, and/or behavioral assays that test responsiveness.  Genes that respond to multiple environmental stimuli are of particular interest. 

Nomination of a Gene or Multiple Genes to the Target List

Members of the scientific community may also request that genes be added to the KOMP target list. In its current form, the subtracted set represents a fairly conservative selection. In addition, genes not on the mouse CCDS may be nominated.  Because previously published targeted knockouts or gene trap lines may not have a reporter, may be hard to obtain, may not be conditional alleles, may not be a complete null or may be in a less desirable strain, proposals to “re-make” knockouts will be evaluated.The web site will provide the ability to enter various relevant data fields, such as gene name, symbol, and accession IDs, and to submit a written justification that may include additional information such as phenotype data, publications, mutant construction, and comments to justify re-making the KO.

In the case of eKOMP nominations, justifications should also include a brief description of how the gene is environmentally-responsive and specific cellular, biochemical, and/or behavioral assays that test responsiveness.  Genes that respond to multiple environmental stimuli are of particular interest. 

Requests for Prioritization and Nominations will be accepted on a continuing basis and reviewed monthly. KOMP will provide these targeted ES cells to the community but their production to mice will require additional investigator initiated efforts.
 
Responses

Genes for Prioritization and Nominations must be submitted electronically through: http://knockoutmouse.org/
For eKOMP nominations, please be certain to click on GEI at the bottom of the webpage, in addition to identifying the institute(s) which normally fund your research. 

Inquiries

Direct inquiries regarding this Notice to:  

John Satterlee, Ph.D.
Program Director, Division of Basic Neuroscience and Behavioral Research
National Institute on Drug Abuse
National Institutes of Health
Rm.4264, MSC 9555
6001 Executive Boulevard
Bethesda, Maryland 20892
Phone: 301-435-1020
Email: satterleej@nida.nih.gov


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