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

D20 Prediction of Regulatory Regions: Sequence and Computational Analysis of the Murine Tbx4 Locus

Amy Horton, Naiche Adler, Jeremy Gibson-Brown, Virginia Papaioannou, and Lee Silver. Princeton University, Princeton, New Jersey

We are interested in the manner by which duplicated genes have been maintained in the genome and have evolved new functions. During the evolution of the vertebrate lineage, numerous genes appear to have undergone two duplication events, which are thought to have allowed novel morphologies such as jaws and differentiated fore- and hind-limbs. The divergence in expression patterns, rather than in coding sequences, of some of these genes following duplication may have driven the evolution of such features. The T-box gene family, many members of which appear to have arisen from such duplications, encodes at least 14 transcription factors that participate in organogenesis of these and other structures. Two closely related duplicates, Tbx4 and Tbx5, are involved early in the development of hind- and fore-limbs, respectively. Studies of the expression patterns of these two genes in mammals show regions of both overlapping and exclusive activity. As a result, isolation of the regulatory regions of these genes is very important for the molecular study of macroevolution. Large scale mutagenic screens in mice are unreasonable for saturating an entire locus and examining the effects on gene expression of small site deletions or alterations. Currently, several available algorithms based on sequence conservation between orthologous genes can, in conjunction with transcription factor binding site search programs, predict gene regulatory regions for further study using targeted mutagenesis. We present here the genomic sequence of the murine Tbx4 gene, as well as computational work using such programs to identify regulatory regions on the basis of similarity to the human ortholog. Additionally, we discuss patterns of conservation of these predicted regulatory regions among paralogs and their evolutionary implications.


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