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Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disease causing cell death of motor neurons and progressive muscle weakness. The disease is familial in ten percent of cases, of which one-fifth are due to mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Two papers in this issue of Nature Genetics describe homozygous mutations in a new gene on chromosome 2q33 in 4 families of Arabian origin with a rare form of juvenile onset ALS (ALS2). The predicted protein structure has domains homologous to GTPase regulatory proteins, and both the types of mutation and the pattern of inheritance suggest that motor neuron degeneration is the result of a loss of function. Further work will determine the relevance of this breakthrough to other, more common forms of ALS.
The availability of the complete genomic sequence of yeast now enables elucidation of molecular mechanisms governing gene expression patterns. New results from the yeast genome and recent advances in predicting and finding human promoters support the use of similar combinatorial approaches to study genome-wide transcriptional regulation in humans.
Comparative studies of nematode development provide a powerful framework for investigating the evolution of developmental mechanisms. A recent report also demonstrates how comparative work can inform our understanding of basic developmental signaling pathways. In particular, investigation of the differences in vulva development between Caenorhabditis elegans and Pristionchus pacificus has clarified the molecular relationship between an epidermal growth factor–Ras–MAP kinase signaling pathway and downstream Hox transcription factor activity.
Genetic defects responsible for cleft lip and cleft palate are only now beginning to be uncovered. Mutations in the gene encoding a T-box transcription factor have been identified as the cause of the rare X-linked syndrome cleft palate with tongue-tie. And in another study, heterozygotes for a defective allele for a cell adhesion molecule, which is responsible for a rare clefting syndrome when homozygous, have been found at higher than expected incidence in sporadic forms of clefting.
A detailed knowledge of patterns of linkage disequilibrium in human populations is widely seen as a prerequisite for effective population-based disease gene mapping. New data suggest that linkage disequilibrium is highly structured into discrete blocks of sequence separated by hot spots of recombination.
