International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


Oral Presentation

WEDNESDAY 20 November

09:00 - 09:15 HRS

ISOLATION AND IDENTIFICATION OF RECESSIVE MUTATIONS AFFECTING MURINE HEMATOPOIESIS USING A BALANCER CHROMOSOME.

BT Kile
Baylor College of Medicine

Co-Authors: 1) Ross M, 1) Mason-Garrison CL, 1) Salinger AP, 1) Bradley A, 2) Behringer RR, 1) Justice MJ
Institutions: 1) Baylor College of Medicine, 2) MD Anderson Cancer Centre

As part of an ongoing screen, we are isolating pedigrees harboring N-ethyl-N-nitrosourea (ENU)-induced recessive mutations causing hematopoietic and immunological abnormalities. Thus far, we have isolated mutations causing anemias, neutrophilias, thrombocytopenias and inflammatory disorders. To facilitate the rapid mapping of these lesions, we are employing a three-generation breeding scheme that utilizes an engineered mouse balancer chromosome. The balancer chromosome contains a 24 cM inversion between the Trp53 and Wnt3 loci on chromosome 11, the effect of which is to completely suppress recombination across this gene-rich interval. Inclusion of the balancer in the breeding scheme enables selection for mutations that localize to, or are closely linked to, the Trp53 Wnt3 interval, and almost half the mutations isolated to date fall into this category. The first hemopoietic mutation identified in this screen, Fitness1, manifests as a severe anemia, with 80-90% of pups dying within 1 week of birth. Immediate localization of the mutation to chromosome 11 allowed a candidate gene, Ae1, which encodes an integral erythrocyte membrane anion transporter, to be identified. Complementation tests with an Ae1 knockout mouse suggested Fitness1 is indeed an allele of Ae1, and subsequent genomic DNA and mRNA sequencing confirmed a single A to T transition in the Ae1 coding region of Fitness1 animals. The resulting missense mutation appears to recapitulate the deletion phenotype in its entirety. This mutation represents the first example of an ENU-induced lesion isolated using a balancer chromosome in the mouse, and provides a valuable tool for further exploration of Ae1 function in vivo.


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