News & Views in 2001

Many bacteria in nature and in persistent infections grow in communities on biofilms. A new study demonstrates that this adaptation is accompanied by a suprisingly modest change in the transcriptional profile of Pseudomonas aeruginosa.

Translation initiation is a tightly regulated process, central to cell function, and proteins involved in this process and its regulation are highly conserved throughout evolution. New results show that mutations in genes encoding subunits of the ubiquitously expressed eIF2B translation initiation factor are responsible for a rare neurological disorder in humans—leukoencephalopathy with vanishing white matter (VWM). The eIF2/eIF2B complex has a key role in the response to a variety of stress conditions. Notably, mutations affecting other proteins of this complex or regulatory kinases cause distinct disorders.

In a typical microarray study, experimental RNA samples are compared to a reference sample and expression ratios are clustered. A new study of the effects of sex, aging and genotype on gene expression in Drosophila melanogaster departs from this paradigm. Highly replicated comparisons generate measures of expression that are analyzed using classical analysis of variance (ANOVA) techniques, revealing substantial differences in gene expression between the two sexes as well as smaller effects of age and strain. Moreover, this study demonstrates that replication and experimental design are essential to detecting small but biologically important differences in expression patterns.

Arabidopsis thaliana isolates from the wild vary enormously in their morphology and physiological responses to standard conditions, indicating that substantial genetic variation is accessible in this species. Natural variant alleles encoding two Arabidopsis photoreceptors, phytochrome A and cryptochrome 2, have now been identified by different experimental methods. The amino-acid substitutions suggest new features of phytochrome and cryptochrome function that regulate plant growth and flowering time.

It is well known that the efficacy of certain drugs varies from individual to individual, depending in part on variation in the genes that encode drug metabolizing enzymes. Whereas ethnic and geographic differences are commonly used to classify drug response, new results show that more accurate and robust genetic clusters—identified by genotyping a modest number of neutral markers—can be inferred with no prior knowledge of ethnicity. Such an approach may eventually become a part of drug evaluation and clinical practice.

Human geneticists withhold judgment on any report of linkage or allelic association until it is independently replicated. But the independent replication criterion has become harder to meet. Does this signal the demise of the reverse genetics paradigm or a problem with the replication requirement itself?

The Oct4 transcription factor has a critical role in the maintenance of pluripotent stem cells in an undifferentiated state and in the formation of mammalian germ cells. Recent work demonstrates that a specific nuclear receptor is involved in regulating the expression of Oct4 itself. This finding has important implications for understanding pluripotent stem-cell biology and nuclear reprogramming.

The pyrin domain was first noted in the familial Mediterranean fever protein from which it takes its name. It belongs to a structural superfamily that includes death domains, death effector domains and caspase activation and recruitment domains. Several genes underlying autoinflammatory diseases have at least one of these four death domain–fold motifs. Mutations in CIAS1, encoding cryopyrin, a leukocyte-specific member of this growing superfamily, have now been shown to cause both familial cold autoinflammatory syndrome and Muckle-Wells syndrome. These new findings add to the growing body of evidence that the dysregulation of leukocyte apoptosis may be a common molecular pathway leading to inflammatory disease.

Among apparently healthy men who nonetheless produce few or no sperm, about ten percent have microdeletions on their Y chromosome. Most of these de novo mutations occur in the AZFc region on the long arm of the chromosome. The high frequency of deletion is explained by the extraordinary structure of the region, which consists almost entirely of very long repeat units.

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.

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.

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.

The scientific process, and scientific progress, require a critical examination of all published reports. Recent publications detailing errors in the draft human genome sequence are an integral part of our quest to better understand nature and demonstrate the value of free access to scientific data.

Biogenesis of eukaryotic mRNA requires several post-transcriptional processing steps that must be completed accurately before it can be exported. Several processing factors are known to associate with RNA polymerase II during elongation, thereby positioning them to mediate efficient RNA processing. mRNAs are exported as complexes containing several RNA-binding proteins and other proteins. A recent study indicates that some of these packaging proteins also associate with RNA polymerase II during transcription. This suggests close coordination and mechanistic coupling of the events required to produce and export functional mRNAs.

Regeneration of rod visual pigments after photobleaching requires a protein called Rpe65. Several studies clarify its role in visual physiology and pathology, including a new one that shows it is required pigment regeneration in cone cells.