News & Views in 2000

Telomere maintenance is required for chromosome stability. Telomeres are maintained principally by the action of the reverse transcriptase telomerase. In cells that lack telomerase, telomere length is preserved by an alternate mechanism termed ALT. A new study reports that recombination between telomeres is responsible for ALT in human cells. As telomerase is a potential target for cancer therapy, these findings indicate that an assault on telomere maintenance may have to contend with two pathways.

Mitochondrial uncoupling proteins (UCPs) have long been suspected to have a role in obesity. A study¹ of mice ablated of Ucp2 reveals an unexpected role for the protein in macrophage-mediated immunity. It also supports the notion that the UCP proteins, which uncouple respiration from energy production, might also control the production of reactive oxygen species (ROS).

Women with breast cancer suffer a high constant risk of a cancer in the opposite breast. A new hypothesis to explain this observation is that a woman's risk of breast cancer starts from a genetically determined age.

Whereas p73 is closely related to the tumour-suppressor protein p53, its contribution to tumour suppression and the spatial and temporal regulation of its isoforms is unclear. It has now been established that p73 is a transcriptional target of E2F1. Its ability to induce apoptosis in TP53^−/− cells indicates a tumour-control mechanism that runs parallel to but independent of that mediated by p53. The new results illustrate a complex cross-talk between p53, E2F1 and p73.

Giant axonal neuropathy (GAN) is a recessive motor and sensory neuropathy of the central and peripheral nervous system. People with GAN show a distortion of nerve fibres due to axonal swellings caused by the accumulation of neurofilaments. A new study reports the cloning of the gene underlying GAN, whose protein product, gigaxonin, is a novel protein of the cytoskeleton and a member of the kelch-repeat superfamily.

Nucleotide excision repair (NER) is a highly conserved multi-step process. Congenital NER defects are clinically complex, at least in part because components of the NER machinery also function in the basal transcription factor, TFIIH. A new study demonstrates that reduction in the amount, rather than the inherent activity, of TFIIH is the underlying cause of one such congenital NER defect, underscoring the link between transcription and NER-associated disease.

The recognition of new Y-chromosome markers represents a major leap in the investigation of human genetic diversity (in male lineages, complementing the information from female lineages derived from mitochondrial DNA). The resulting phylogeny supports the out-of-Africa origins of our species and opens the way to further insights into prehistoric demography and world prehistory.

The Mep ammonium transporters of Saccharomyces cerevisiae share amino acid sequence identity with the Rh blood group antigen proteins. A new study shows that the Rhg glycoproteins transport ammonium when heterologously expressed in mep mutant yeast cells, indicating a role for the Rh antigen complex.

Apart from resistance to infectious disease, there are few examples of adaptive molecular evolution in humans. A new study indicates that olfactory receptors are exceptions, with natural selection maintaining considerable allelic diversity in this multigene family.

Pair-wise genome comparisons offer new sources of information about the patterns and processes that influence genomic designs. Replication-dependent rearrangements, as indicated by the symmetric gene organization pattern in the genomes of Chlamydia pneumoniae and Chlamydia trachomatis, may provide a missing link in the reconstruction of historical events from modern genomes.

The inability to construct animal models of human diseases caused by mutated mitochondrial DNA (mtDNA) has been a major obstacle to investigating pathogenetic mechanisms associated with specific mtDNA mutations. Mice carrying a large-scale deletion in mtDNA have now been produced. They display some of the key features of the human disorder, but there are surprising differences.

Positional cloning of common disease genes is a central but elusive goal of human geneticists. Progress is now reported by Bell and colleagues in their study of NIDDM1, a locus implicated in type 2 diabetes. The complex nature of the reported association illustrates the challenge of implicating a specific gene and mutation in the causation of polygenic disease.

Usher syndrome is a major cause of combined deafness and blindness. One form of the disease, termed USH1C, is now found to be caused by mutations in the gene encoding a PDZ-containing protein, harmonin. As interactions between PDZ proteins and their targets are known to mediate protein localization, signalling and maintenance of membrane characteristics, this discovery should accelerate our understanding of Usher syndrome and other auditory disorders.

Microarray analysis greatly assists in defining functions of genes and elucidating important biological pathways. To enhance this power, a database or compendium of hundreds of gene-expression profiles was constructed using gene-deletion mutants of yeast. Statistical tools could then sift through the compendium to identify matching fingerprints of expression and thereby unearth, for example, therapeutic targets.

Defective TFG-β signalling through the bone morphogen receptor type II is implicated in autosomal dominant and sporadic primary pulmonary hypertension. This fatal disorder is characterized by vascular remodelling, often triggered by the use of appetite-suppressant drugs which were, until recently, used to treat obesity.

The phenotypes of mice lacking melanocortin-3 (Mcr3) and melanocortin-4 receptors (Mc4r) demonstrate that these isoforms reduce body weight through distinct and complementary mechanisms. Mc4r regulates food intake and possibly energy expenditure, whereas Mc3r influences feed efficiency and the partitioning of fuel stores into fat.