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Molecular Mission Unveils New Genetic Link To Common Birth Defect

t artificial chromosomes) that can package extraordinarily large amounts of DNA--containing not only the gene of interest but also thousands of base pairs that "flank," or surround, the gene in its usual environment within the chromosomes inside the mouse cell's nucleus. With the help of YACs, Dr. Engel and his group hoped to replace not only the missing GATA-2 gene in mouse embryos lacking it, but also all of the gene's "control elements"--the coded information specifying where, when, and how much of a particular gene is made into RNA, and then into protein, in all of the tissues where it is needed.

In fact, the team was lucky in the sense that despite the large amount of DNA inserted into the YACs along with the GATA-2 gene--which did contain the elements specifying GATA-2 production in blood-forming tissues and "rescued" the mice from death--the DNA sequences accounting for expression of the gene in the kidneys, ureters, and bladder were still missing, thus unveiling the protein's new role in genitourinary development.

Scientists generally assume that a gene's control elements reside near the gene itself, usually within a few hundred base pairs from a gene's beginning or end. Thus, Dr. Engel and his colleagues at Northwestern University, Harvard Medical School, and Tsukuba University School of Medicine in Tsukuba, Japan, were particularly surprised to discover that some of GATA-2's control elements--specifically, those governing the expression of the gene in tissues such as the genitourinary system--must reside hundreds of thousands of base pairs away from the gene itself.

Notwithstanding the power of the new method, Dr. Engel was quick to note that it does not preclude the need for other, more routine genetic probing strategies. Rather, he said, using large DNA vectors such as YACs offers genetic researchers a second chance, as it were, to peer into later developmental windows, thereby exposing previously unknown functions of a variety of genes.

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Contact: Alison Davis
davisa@nigms.nih.gov
301-496-7301
NIH/National Institute of General Medical Sciences
16-Nov-1998


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