The Huntington's disease candidate region exhibits many different haplotypes.

Analysis of 78 Huntington's disease (HD) chromosomes with multi-allele markers revealed 26 different haplotypes, suggesting a variety of independent HD mutations. The most frequent haplotype, accounting for about one third of disease chromosomes, suggests that the disease gene is between D4S182 and D4S180. However, the paucity of an expected class of chromosomes that can be related to this major haplotype by assuming single crossovers may reflect the operation of other mechanisms in creating haplotype diversity. Some of these mechanisms sustain alternative scenarios that do not require a multiple mutational origin for HD and/or its positioning between D4S182 and D4S180.     

Acquired immunity and epidemiology of Schistosoma haematobium

Human immune responses to schistosome infection have been characterized in detail. But there has been controversy over the relative importance of ecological factors (variation in exposure to infection) and immunological factors (acquired immunity) in determining the relationships between levels of infection and age typically found in areas where infection is endemic. Independent effects of exposure and age on the rates of reinfection with Schistosoma haematobium after chemotherapy have been demonstrated in the Gambia and Zimbabwe. This age effect could be the result of acquired immunity to infection. Indeed, allowing for variation in exposure and age, low rates of reinfection in the Gambia are correlated with high amounts of specific IgE antibodies--human IgE can kill S. mansoni schistosomulae in vitro. Further, animals can acquire immunologically mediated resistance to S. mansoni infection, although nonimmunological factors could also be involved. Acquisition of this immunity seems to be related to the cumulative effects of repeated infection and provides only partial protection. These characteristics are consistent with immuno-epidemiological data for both S. mansoni and S. haematobium infections of humans. We have now analysed age-prevalence data for human infection with S. haematobium, and find patterns of variation that are indeed consistent with the epidemiological effects of acquired immunity predicted by mathematical models.     

Cadmium is a mutagen that acts by inhibiting mismatch repair

Most errors that arise during DNA replication can be corrected by DNA polymerase proofreading or by post-replication mismatch repair (MMR). Inactivation of both mutation-avoidance systems results in extremely high mutability that can lead to error catastrophe. High mutability and the likelihood of cancer can be caused by mutations and epigenetic changes that reduce MMR. Hypermutability can also be caused by external factors that directly inhibit MMR. Identifying such factors has important implications for understanding the role of the environment in genome stability. We found that chronic exposure of yeast to environmentally relevant concentrations of cadmium, a known human carcinogen, can result in extreme hypermutability. The mutation specificity along with responses in proofreading-deficient and MMR-deficient mutants indicate that cadmium reduces the capacity for MMR of small misalignments and base-base mismatches. In extracts of human cells, cadmium inhibited at least one step leading to mismatch removal. Together, our data show that a high level of genetic instability can result from environmental impediment of a mutation-avoidance system.     

Minimum information about a microarray experiment (MIAME)-toward standards for microarray data.

Microarray analysis has become a widely used tool for the generation of gene expression data on a genomic scale. Although many significant results have been derived from microarray studies, one limitation has been the lack of standards for presenting and exchanging such data. Here we present a proposal, the Minimum Information About a Microarray Experiment (MIAME), that describes the minimum information required to ensure that microarray data can be easily interpreted and that results derived from its analysis can be independently verified. The ultimate goal of this work is to establish a standard for recording and reporting microarray-based gene expression data, which will in turn facilitate the establishment of databases and public repositories and enable the development of data analysis tools. With respect to MIAME, we concentrate on defining the content and structure of the necessary information rather than the technical format for capturing it.     

Extraction of a weak climatic signal by an ecosystem

The complexity of ecosystems can cause subtle and chaotic responses to changes in external forcing. Although ecosystems may not normally behave chaotically, sensitivity to external influences associated with nonlinearity can lead to amplification of climatic signals. Strong correlations between an El Ni?o index and rainfall and maize yield in Zimbabwe have been demonstrated; the correlation with maize yield was stronger than that with rainfall. A second example is the 100,000-year ice-age cycle, which may arise from a weak cycle in radiation through its influence on the concentration of atmospheric CO2 (ref. 5). Such integration of a weak climatic signal has yet to be demonstrated in a realistic theoretical system. Here we use a particular climatic phenomenon-the observed association between plankton populations around the UK and the position of the Gulf Stream-as a probe to demonstrate how a detailed marine ecosystem model extracts a weak signal that is spread across different meteorological variables. Biological systems may therefore respond to climatic signals other than those that dominate the driving variables.     

A PPARγ-FGF1 axis is required for adaptive adipose remodelling and metabolic homeostasis

Although feast and famine cycles illustrate that remodelling of adipose tissue in response to fluctuations in nutrient availability is essential for maintaining metabolic homeostasis, the underlying mechanisms remain poorly understood. Here we identify fibroblast growth factor 1 (FGF1) as a critical transducer in this process in mice, and link its regulation to the nuclear receptor PPARγ (peroxisome proliferator activated receptor γ), which is the adipocyte master regulator and the target of the thiazolidinedione class of insulin sensitizing drugs. FGF1 is the prototype of the 22-member FGF family of proteins and has been implicated in a range of physiological processes, including development, wound healing and cardiovascular changes. Surprisingly, FGF1 knockout mice display no significant phenotype under standard laboratory conditions. We show that FGF1 is highly induced in adipose tissue in response to a high-fat diet and that mice lacking FGF1 develop an aggressive diabetic phenotype coupled to aberrant adipose expansion when challenged with a high-fat diet. Further analysis of adipose depots in FGF1-deficient mice revealed multiple histopathologies in the vasculature network, an accentuated inflammatory response, aberrant adipocyte size distribution and ectopic expression of pancreatic lipases. On withdrawal of the high-fat diet, this inflamed adipose tissue fails to properly resolve, resulting in extensive fat necrosis. In terms of mechanisms, we show that adipose induction of FGF1 in the fed state is regulated by PPARγ acting through an evolutionarily conserved promoter proximal PPAR response element within the FGF1 gene. The discovery of a phenotype for the FGF1 knockout mouse establishes the PPARγ–FGF1 axis as critical for maintaining metabolic homeostasis and insulin sensitization.     

Assortative mating in insects: sexual selection vs. sampling artifact

In this report we analyze patterns of size-assortative mating in an insect genus by (1) describing the consistency and strength of assortative mating among populations of a species and among species of a genus, and (2) determining the role of sampling artifacts in generating this nonrandom pattern of mating. Our data consist of 18 samples of soldier beetles (8 species of the genus Chauliognathus ) from 17 sites within the southwestern United States. Of the 18 samples, just 6 exhibited significant correlations between elytron lengths of mating pairs. We show how these and other significant correlations are generated by 3 kinds of sampling artifacts: mixed-species samples, mixed-population samples, and mixed-microsite samples.     

Survivorship and cause-specific mortality in five populations of mule deer

We used retrospective analyses to investigate cause-specific mortality and survivorship among 5 populations of mule deer ( N = 168 telemetered animals) wintering in the western Great Basin during 1986-1994. These populations existed under similar environmental conditions, but survivorship functions differed among them. Monthly survival ranged from 0.964 to 0.990, and annual survival ranged from 0.643 to 0.884. The proportion of deaths attributed to predation and malnutrition or anthropogenic causes did not differ among the 5 populations. Predation was the leading cause of mortality; mountain lions were responsible for approximately 90% of the deer killed by predators. No difference existed among these populations in the proportion of telemetered deer that were killed by mountain lions, but proportionally more females than males were killed by these large fields. Predation by mountain lions is the primary source of mortality and a widespread phenomenon among the populations of mule deer we investigated.