SCIENTIFIC APPROACH

Studies of mouse mutations and their phenotypic consequences have provided insights into the functions of thousands of genes. Yet, as many as a third of mammalian genes have not begun to be functionally characterized by any means, and the genetic bases of neural function and complex behaviors are still poorly understood. A powerful approach to bridge this gap is to combine random genome-wide chemical mutagenesis with screens to detect phenotypic alterations in progeny of mutagen-treated mice. Altered phenotypes lead to the identification of mutants, hence this is characterized as a phenotype-driven, or forward genetic, approach. This strategy requires no a priori assumptions of the nature of underlying genes or pathways.

The mutagen N-Ethyl-N-Nitrosourea (ENU) has been demonstrated to produce a high forward mutation rate in the mouse, and has become the mutagen of choice for such studies. ENU typically leads to intragenic point mutations rather than chromosomal rearrangements, and thus can provide more subtle, distinct changes in gene function than either radiation or traditional "knock-out" gene targetting.

All three Neuromice.org sites are using ENU mutagenesis and high-throughput phenotyping protocols to screen mice, thus identifying mutations affecting a broad array of neural and behavioral domains.