Mutations in SUFU predispose to medulloblastoma

Enchondromas are common benign cartilage tumors of bone. They can occur as solitary lesions or as multiple lesions in enchondromatosis (Ollier and Maffucci diseases). Clinical problems caused by enchondromas include skeletal deformity and the potential for malignant change to chondrosarcoma. The extent of skeletal involvement is variable in enchondromatosis and may include dysplasia that is not directly attributable to enchondromas. Enchondromatosis is rare, obvious inheritance of the condition is unusual and no candidate loci have been identified. Enchondromas are usually in close proximity to, or in continuity with, growth-plate cartilage. Consequently, they may result from abnormal regulation of proliferation and terminal differentiation of chondrocytes in the adjoining growth plate. In normal growth plates, differentiation of proliferative chondrocytes to post-mitotic hypertrophic chondrocytes is regulated in part by a tightly coupled signaling relay involving parathyroid hormone related protein (PTHrP) and Indian hedgehog (IHH). PTHrP delays the hypertrophic differentiation of proliferating chondrocytes, whereas IHH promotes chondrocyte proliferation. We identified a mutant PTH/PTHrP type I receptor (PTHR1) in human enchondromatosis that signals abnormally in vitro and causes enchondroma-like lesions in transgenic mice. The mutant receptor constitutively activates Hedgehog signaling, and excessive Hedgehog signaling is sufficient to cause formation of enchondroma-like lesions.     

The origin of geomagnetic jerks

Geomagnetic jerks, which in the second half of the twentieth century occurred in 1969 (refs 1, 2), 1978 (refs 3, 4), 1991 (ref. 5) and 1999 (ref. 6), are abrupt changes in the second time-derivative (secular acceleration) of the Earth's magnetic field. Jerks separate periods of almost steady secular acceleration, so that the first time-derivative (secular variation) appears as a series of straight-line segments separated by geomagnetic jerks. The fact that they represent a reorganization of the secular variation implies that they are of internal origin (as has been established through spherical harmonic analysis), and their short timescale implies that they are due to a change in the fluid flow at the surface of the Earth's core (as has also been established through mapping the time-varying flow at the core surface). However, little is understood of their physical origin. Here we show that geomagnetic jerks can be explained by the combination of a steady flow and a simple time-varying, axisymmetric, equatorially symmetric, toroidal zonal flow. Such a flow is consistent with torsional oscillations in the Earth's core, which are simple oscillatory flows in the core that are expected on theoretical grounds, and observed in both core flow models and numerical dynamo models.     

Microconversion between murine H-2 genes integrated into yeast

Patchwork homology observed between divergent members of polymorphic multigene families is thought to reflect evolution by short-tract gene conversion (nonreciprocal recombination), although this mechanism cannot usually be confirmed in higher organisms. In contrast to meiotic conversions observed in laboratory yeast strains, apparent conversions between polymorphic sequences, such as the class I loci of the major histocompatibility complex (MHC), are short and do not seem to be associated with reciprocal recombination (crossover, exchanges). We have now integrated two nonallelic murine class I genes into yeast to characterize their meiotic recombination. We found no crossovers between the MHC genes, but short-tract 'microconversions' of 1-215 base-pairs were observed in about 6% of all meioses. Strikingly, one of these events was accompanied by a single base-pair mutation. These results underscore both the importance of meiotic gene conversion and sequence heterology in determining conversion patterns between divergent genes.     

A Soft System Framework for the Conservation Management of Material Cultural Heritage

Experience gained from cultural heritage management in Norway and the UK has led to the development of a framework describing the key conservation activities required to sustain a diverse range between material cultural heritage assets. A soft system approach allows the complex interaction between various activities and external factors impacting on cultural heritage management to be examined as a single entity, for example, the contributions made by human interaction, environmental impact and the properties of the material heritage itself, on the preservation or loss of a cultural object. By constructing such a framework it is possible to identify potential indicators that can be used to measure the quality of conservation activities. Arguments are presented for grouping these indicators of impact into social, economic and environmental categories and examples are given of how this approach can be universally applied to real situations.     

Methods of metal incorporation into intracellular granules

Summary The hepatopancreas of the garden snail (Helix aspersa) contains basophil cells which produce intracellular granules of CaMgP₂O₇. A variety of metals are incorporated into these granules either by direct substitution or by the synthesis of new pyrophosphate material.Supported by NERC grant GR3/3063.     

Quality assessment of the human genome sequence

As the final sequencing of the human genome has now been completed, we present the results of the largest examination of the quality of the finished DNA sequence. The completed study covers the major contributing sequencing centres and is based on a rigorous combination of laboratory experiments and computational analysis.     

The DNA sequence and comparative analysis of human chromosome 5

Chromosome 5 is one of the largest human chromosomes and contains numerous intrachromosomal duplications, yet it has one of the lowest gene densities. This is partially explained by numerous gene-poor regions that display a remarkable degree of noncoding conservation with non-mammalian vertebrates, suggesting that they are functionally constrained. In total, we compiled 177.7 million base pairs of highly accurate finished sequence containing 923 manually curated protein-coding genes including the protocadherin and interleukin gene families. We also completely sequenced versions of the large chromosome-5-specific internal duplications. These duplications are very recent evolutionary events and probably have a mechanistic role in human physiological variation, as deletions in these regions are the cause of debilitating disorders including spinal muscular atrophy.