Elsevier

Genomics

Volume 78, Issue 3, December 2001, Pages 197-205
Genomics

Regular Article
A High-Resolution Genetic, Physical, and Comparative Gene Map of the Doublefoot (Dbf) Region of Mouse Chromosome 1 and the Region of Conserved Synteny on Human Chromosome 2q35

https://doi.org/10.1006/geno.2001.6657Get rights and content

Abstract

The mouse doublefoot (Dbf) mutant exhibits preaxial polydactyly in association with craniofacial defects. This mutation has previously been mapped to mouse chromosome 1. We have used a positional cloning strategy, coupled with a comparative sequencing approach using available human draft sequence, to identify putative candidates for the Dbf gene in the mouse and in homologous human region. We have constructed a high-resolution genetic map of the region, localizing the mutation to a 0. 4-cM (±0.0061) interval on mouse chromosome 1. Furthermore, we have constructed contiguous BAC/PAC clone maps across the mouse and human Dbf region. Using existing markers and additional sequence tagged sites, which we have generated, we have anchored the physical map to the genetic map. Through the comparative sequencing of these clones we have identified 35 genes within this interval, indicating that the region is gene-rich. From this we have identified several genes that are known to be differentially expressed in the developing mid-gestation mouse embryo, some in the developing embryonic limb buds. These genes include those encoding known developmental signaling molecules such as WNT proteins and IHH, and we provide evidence that these genes are candidates for the Dbf mutation.

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      This suggests that perhaps the role of one of the endogenous Shh regulatory elements is to act as repressor segregating the activity of Shh from Ihh (de la Fuente and Helms, 2005). Direct misregulation of Ihh itself has been implicated in the Doublefoot mutant that shows PPD and craniofacial abnormalities (Hayes et al., 2001; Yang et al., 1998). In a small but growing number of cases the observed phenotypes cannot easily be explained by hypothesizing the involvement of a single gene, but are more likely to be the result of a combination of effects on two or more genes, either neighboring genes under common control or artificially juxtaposed by a translocation.

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    *

    Present address: Department of Molecular Biology, Neuroscience Research Centre, Merck, Sharp and Dohme, Terlings Park, Eastwick Road, Harlow, Essex, CM20 2QR, UK

    §

    These authors contributed equally to this work.

    #

    To whom correspondence and reprint requests should be addressed. Fax: +44 (0) 1279 440390. E-mail: [email protected].

    Present address: MetaGen Pharmaceuticals, Ihnestrasse 63, 14195 Berlin, Germany

    Present address: Department of Zoology, University of Oxford, South Parks Road, Oxford, OX1 3PS, UK

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