International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)


E3. Sifting Sequence for Function: Exploiting the Mouse

Eddy Rubin
Department of Genome Sciences, Life Sciences Division, Lawrence Berkeley National Laboratory, University of California, Berkeley

A near contiguous 1.2 megabase region of human 5q31 and the orthologous region from mouse chromosome 11 containing the interleukin growth factor gene cluster were sequenced and annotated both for the function of the genes and the conserved noncoding sequences (CNSs) present in the interval.

Ninety noncoding conserved sequences (CNS) (>/= 100 base pairs in length and >/= 70% identity) were identified in analysis of the orthologous mouse human DNA. Functional properties of the largest element (401 bp) conserved both with regard to sequence (80% identity in mice, humans, dogs, rabbits) and location (in the IL4 IL13 intergenic region in mice, humans, baboon, dogs) were assessed in a series of YAC transgenic mouse studies. These studies showed this conserved noncoding element to be a potent regulator of the expression in Th2 cells of IL-4, IL-13 and IL-5 expression - genes that are spread over 120 kb.

Of the 23 genes identified in the orthologous interval functional information was available for less than a third of the uncharacterized genes in the interval using the Cre Lox system to generate large targeted deletions including multiple genes. The most progress has been made on the analysis of a 450 Kb region where sequence annotation had identified nine genes, none of which whose function is known. Mice containing a deletion of this 450Kb region were created using Cre-Lox. A noticeable phenotype of these animals was a 10-fold increase in plasma triglycerides and a two-fold increase in liver weight primarily the result of hepatic triglyceride accumulation. In order to identify which gene was responsible for the trigylceride abnormalities a panel of BAC and YAC transgenic mice each containing different segments of the deletion were tested for complementation. By this approach an organic cation transporter, OCTN2, was shown to be responsible for the triglyceride abnormalities.

 


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