"This is a very powerful strategy to identify the more subtle genetic abnormalities that lead to disease," said Dr. Engel.
The task of assigning genes to functions is indeed a daunting one that is currently limited by the fact that researchers are stuck in a virtual "Catch-22:" they must work backwards from an outwardly expressed trait or defect (called a phenotype) to its root genetic cause. But in doing so, only the earliest activity of a specific developmental gene can be identified, since deleting it often has fatal consequences, ruling out further studies. If the same protein is required in a different tissue later in development, the activities of these so-called intermediary genes--as Dr. Engel describes them, "things that signal other things"--get lost in the shuffle, and thereby are extremely difficult to study via standard mammalian genetic experiments.
According to Dr. Engel, his team's new results stemmed from the fact that such standard--and usually effective--genetic strategies, in which relatively small stretches of DNA containing a gene of interest are studied, were not answering basic questions the team kept asking about the GATA-2 gene, such as why the protein is so plentiful in tissues all over the body if its only role is in blood formation, a process that takes place in the fetal liver and spleen.
Indeed, Dr. Engel recalled, "We were going about dissecting this problem the wrong way."
Changing tack, the team began a series of experiments using molecules called
Contact: Alison Davis
NIH/National Institute of General Medical Sciences