HETEROZYGOSITY MAPPING OF PARTIALLY CONGENIC LINES - MAPPING OF A SEMIDOMINANT NEUROLOGICAL MUTATION, WHEELS (WHL), ON MOUSE CHROMOSOME-4

We identified a semidominant, chemically induced, mouse mutation with a complex array of abnormal behaviors including bidirectional circling and hyperactivity, abnormal circadian rhythmicity and abnormal respon ses to light. In this report, we genetically and phenotypically charac terized the circling/waltzing component of the abnormal behavior. We m apped the locus controlling this trait by heterozygosity mapping of pa rtially congenic lines carrying the mutagenized chromosome outcrossed to different inbred strains for three generations. Analysis of 68 PCR- based markers in 13 affected individuals indicated that the mutant loc us, named Wheels (Whl), resides in the subcentromeric portion of mouse chromosome 4. The statistical evaluation of data obtained by heterozy gosity mapping validates this efficient mapping approach. Further char acterization of the Whl mutation demonstrated that Whl/Whl homozygotes die during embryonic life and that the penetrance of circling behavio r depends on genetic background. Morphological analysis of the inner e ars of Whl/+ mice revealed a variable number of abnormalities in the s ensory and nonsensory portions of their semicircular canals. Abnormali ties ranged from slight atrophy of one or more cristae to complete abs ence of the lateral crista and canal. The molecular characterization o f the gene disrupted in the Whl mutation will provide insight into dev elopmental mechanisms involved in inner ear formation.