International Mammalian Genome Society

The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

E44 New Murine Hippocampus-Specific QTL Maps to Distal Chr 1

Lu Lu, David C. Airey, Emmanuel Gilissen, Guomin Zhou, Robert W. Williams. Center for Neuroscience and Department of Anatomy and Neurobiology, Memphis TN 38163

Our goal is to map and characterize genes responsible for quantitative anatomical differences in functional mammalian brain systems. We are primarily interested in understanding the control of cell number.

The hippocampus is a well studied, anatomically discrete brain area that is an important model for learning and memory. The hippocampus is also functionally important in spatial memory intensive behaviors, both in rodents and humans. The hippocampus exhibits an interesting developmental profile of cell proliferation, with new neurons incorporated during adulthood. The kinetics of cell proliferation also differs greatly among common inbred strains of mice, including C57BL/6J and DBA/2J.

Using a set of BXD recombinant inbred mice and a reciprocal F2 intercross between C57BL/6J and DBA/2J, we discovered a quantitative trait locus (Hipp1) for adult hippocampus weight linked to distal Chr 1. Right and left hippocampi from an average of 9 mice belonging to each of 34 BXD strains were dissected from fixed brains and weighed at room temperature. Mean bilateral hippocampal weight was 26.1 +/- 3.3 mg across strains, while strain means ranged from 21.2 mg to 34.6 mg. Hippocampal variance asssociated with brain weight, body weight, dissector (LL or EG), sex, and age was removed by regression analysis. The standard deviation of the hippocampal residual weight was 2.51 mg across strains, while means ranged from +4.70 mg to -4.56 mg. Heritability for hippocampal and residual hippocampal weights were estimated at ~35% and ~34%, respectively.

Strain means for hippocampal weight and residual weight were mapped with Map Manager QT. The strongest linkage was detected on distal Chr 1 between D1Mit200 (73 cM) and D1Mit145 (87 cM) with a peak LRS of 12.7 (genome-wide P ~ 0.10). Analysis of 178 F2 progeny confirms linkage to distal Chr 1 with an LRS of 10.2 for raw data and an LRS of 17. 5 and genome-wide P < 0.05 for residuals. The effect size for Hipp1 is 0.5-0.6 mg in the F2 and 1.1 mg in the BXD strains with B alleles increasing hippocampal weight. Possible candidate genes located between 70 and 90 cM on Chr 1 include: Lhx4, Lamc1, Rxrg.

We are currently investigating the relation between allelic differences at Hipp1 and cell number in the hippocampus. We are also refining the location of this QTL using an advanced intercross that should provide sufficient positional precision for more refined analysis of the candidate genes.


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