Nature Genetics pp 179 - 183, pp 141 - 142 and pp 107 - 109

The genetic causes of some forms of cleft lip and palate are described in two reports in the October issue of Nature Genetics. The discoveries offer important insights into human development and the mechanisms involved in a class of common birth defects about which surprisingly little is known. Cleft lip and/or palate forms when structures around the mouth fail to come together properly during early human development. Such defects are seen, often in combination with other abnormalities, in about 0.4 to 2 babies out of 1,000 who are born. While some cases of cleft lip and/or palate are inherited, most occur in individuals with no family history of disease (sporadic cases), and are believed to be a result of both genetic and environmental factors.

In the first report, Philip Stanier and colleagues at Imperial College, London, identified a gene (TBX22) important for the proper growth of structures in the face, which, when mutated, causes a type of cleft palate defect that is inherited through the X chromosome. The same mutation was detected in several families from different ethnic backgrounds who were affected by the disease. In the second paper, Richard Spritz and colleagues at the University of Colorado, in collaboration with scientists in Venezuela, identified a variant of another gene (PVRL1) that predisposes individuals from a population in northern Venezuela to a sporadic cleft lip and palate defect. Previously, the scientists had found that mutations in the same gene, which is important for cell fusion during development, causes an inherited cleft lip and palate syndrome in another small population in Venezuela. Thus, the same gene can contribute to both inherited and sporadic forms of the disease. Together the two reports provide clues to the causes underlying human developmental defects.

The significance of the findings are summarized in an accompanying News & Views article by Jeffrey Murray of the University of Iowa, in which the author points out that research into birth defects has been slow since these diseases are not "attractive candidates for study by the large corporate enterprises that increasingly serve as the engines of gene mapping and product development".

Nature Genetics pp 153 - 159 and pp 105 - 106

A detailed road map of the interactions between factors that regulate gene expression in yeast reveals that surprisingly few factors acting in different combinations are central to the control of transcription, according to researchers in Boston.

The expression of genetic information in organisms from yeast to humans is regulated by complex interactions between different regulators of gene transcription, each of which recognizes specific DNA sequences or motifs within a gene. Taking advantage of the fact that the entire yeast genome has been sequenced, George Church and colleagues at Harvard Medical School identified yeast genes that contain different regulatory sequence motifs and then looked at the expression profiles of these genes under different conditions using gene chip technology. If the expression of a gene containing two different motifs was greater than that of genes containing either motif alone, the motifs were considered to interact to control the transcription of similar pathways. By tallying the results, the researchers were able to build a global map of yeast transcription pathways. The map contains a few 'hubs' of interactions indicative of a few motifs interacting with many others. The finding suggests that, at least in yeast, a small number of transcription factors are sufficient to control gene expression in diverse conditions by interacting in different combinations with other factors.

The availability of similar road maps of gene expression for various organisms may allow scientists to predict the expression profile of any gene depending on the motifs it contains.

Nature Genetics pp 143 - 152

The ability of a cancer to spread to other parts of the body and form metastases is typically a telltale sign of poor prognosis. US researchers have identified a genetic signature for metastatic medulloblastoma, a childhood cancer of the brain, and possible molecular targets for therapies that would selectively thwart the cancer's ability to spread.

Up until now there was no sure way of predicting whether a medulloblastoma will spread. Dietrich Stephan and colleagues at the Children's National Medical Center in Washington DC used gene chip expression profiling, a technique to look a the expression of thousands of genes in a sample at once, to identify a set of 85 genes that are expressed differently depending on whether a medulloblastoma will go on to form metastases or not. This set of genes was used to correctly predict the behavior of four of five medulloblastomas. Many of the 'predictor genes' belong to a specific signaling cascade inside cells. By blocking the cascade with a drug, the scientists were able to make metastatic medulloblastoma cells behave less aggressively--at least in a petri dish.

Several inhibitors of the pathway pinpointed in this study are currently available, and include the powerful leukemia drug Gleevec. The results suggest that such agents should be considered as possible treatments against medulloblastoma.