Myosin gene mutation correlates with anatomical changes in the human lineage

Powerful masticatory muscles are found in most primates, including chimpanzees and gorillas, and were part of a prominent adaptation of Australopithecus and Paranthropus, extinct genera of the family Hominidae. In contrast, masticatory muscles are considerably smaller in both modern and fossil members of Homo. The evolving hominid masticatory apparatus--traceable to a Late Miocene, chimpanzee-like morphology--shifted towards a pattern of gracilization nearly simultaneously with accelerated encephalization in early Homo. Here, we show that the gene encoding the predominant myosin heavy chain (MYH) expressed in these muscles was inactivated by a frameshifting mutation after the lineages leading to humans and chimpanzees diverged. Loss of this protein isoform is associated with marked size reductions in individual muscle fibres and entire masticatory muscles. Using the coding sequence for the myosin rod domains as a molecular clock, we estimate that this mutation appeared approximately 2.4 million years ago, predating the appearance of modern human body size and emigration of Homo from Africa. This represents the first proteomic distinction between humans and chimpanzees that can be correlated with a traceable anatomic imprint in the fossil record.     

Assessing the forecasting accuracy of alternative nominal exchange rate models: the case of long memory

This paper presents an autoregressive fractionally integrated moving‐average (ARFIMA) model of nominal exchange rates and compares its forecasting capability with the monetary structural models and the random walk model. Monthly observations are used for Canada, France, Germany, Italy, Japan and the United Kingdom for the period of April 1973 through December 1998. The estimation method is Sowell's (1992) exact maximum likelihood estimation. The forecasting accuracy of the long‐memory model is formally compared to the random walk and the monetary models, using the recently developed Harvey, Leybourne and Newbold (1997) test statistics. The results show that the long‐memory model is more efficient than the random walk model in steps‐ahead forecasts beyond 1 month for most currencies and more efficient than the monetary models in multi‐step‐ahead forecasts. This new finding strongly suggests that the long‐memory model of nominal exchange rates be studied as a viable alternative to the conventional models. Copyright © 2006 John Wiley & Sons, Ltd.     

Regulation of HP1-chromatin binding by histone H3 methylation and phosphorylation

Tri-methylation of histone H3 lysine 9 is important for recruiting heterochromatin protein 1 (HP1) to discrete regions of the genome, thereby regulating gene expression, chromatin packaging and heterochromatin formation. Here we show that HP1alpha, -beta, and -gamma are released from chromatin during the M phase of the cell cycle, even though tri-methylation levels of histone H3 lysine 9 remain unchanged. However, the additional, transient modification of histone H3 by phosphorylation of serine 10 next to the more stable methyl-lysine 9 mark is sufficient to eject HP1 proteins from their binding sites. Inhibition or depletion of the mitotic kinase Aurora B, which phosphorylates serine 10 on histone H3, causes retention of HP1 proteins on mitotic chromosomes, suggesting that H3 serine 10 phosphorylation is necessary for the dissociation of HP1 from chromatin in M phase. These findings establish a regulatory mechanism of protein-protein interactions, through a combinatorial readout of two adjacent post-translational modifications: a stable methylation and a dynamic phosphorylation mark.     

Mutations in SEPT9 cause hereditary neuralgic amyotrophy

Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant recurrent neuropathy affecting the brachial plexus. HNA is triggered by environmental factors such as infection or parturition. We report three mutations in the gene septin 9 (SEPT9) in six families with HNA linked to chromosome 17q25. HNA is the first monogenetic disease caused by mutations in a gene of the septin family. Septins are implicated in formation of the cytoskeleton, cell division and tumorigenesis.     

Acoustics: the vocal tract and the sound of a didgeridoo

The Australian didgeridoo (or yidaki in the Yolngu language of northern Australia) is a simple musical instrument that, at the lips of an experienced player, is capable of a spectacular variety of timbres--considerably greater than those that can be coaxed from orchestral instruments, for example. To understand this phenomenon, we simultaneously measured the sound produced by the didgeridoo and the acoustic impedance of the player's vocal tract. We find that the maxima in the envelope of the sound spectrum are associated with minima in the impedance of the vocal tract, as measured just inside the lips. This acoustic effect is similar to the production of vowel sounds made during human speech or singing, although the mechanism is different, and leads to the surprising conclusion that experienced players are subconsciously using their glottis to accentuate the instrument's tonal variation.     

A broadband superconducting detector suitable for use in large arrays

Cryogenic detectors are extremely sensitive and have a wide variety of applications (particularly in astronomy), but are difficult to integrate into large arrays like a modern CCD (charge-coupled device) camera. As current detectors of the cosmic microwave background (CMB) already have sensitivities comparable to the noise arising from the random arrival of CMB photons, the further gains in sensitivity needed to probe the very early Universe will have to arise from large arrays. A similar situation is encountered at other wavelengths. Single-pixel X-ray detectors now have a resolving power of DeltaE < 5 eV for single 6-keV photons, and future X-ray astronomy missions anticipate the need for 1,000-pixel arrays. Here we report the demonstration of a superconducting detector that is easily fabricated and can readily be incorporated into such an array. Its sensitivity is already within an order of magnitude of that needed for CMB observations, and its energy resolution is similarly close to the targets required for future X-ray astronomy missions.     

Functional genetic analysis of mouse chromosome 11

Now that the mouse and human genome sequences are complete, biologists need systematic approaches to determine the function of each gene. A powerful way to discover gene function is to determine the consequence of mutations in living organisms. Large-scale production of mouse mutations with the point mutagen N-ethyl-N-nitrosourea (ENU) is a key strategy for analysing the human genome because mouse mutants will reveal functions unique to mammals, and many may model human diseases. To examine genes conserved between human and mouse, we performed a recessive ENU mutagenesis screen that uses a balancer chromosome, inversion chromosome 11 (refs 4, 5). Initially identified in the fruitfly, balancer chromosomes are valuable genetic tools that allow the easy isolation of mutations on selected chromosomes. Here we show the isolation of 230 new recessive mouse mutations, 88 of which are on chromosome 11. This genetic strategy efficiently generates and maps mutations on a single chromosome, even as mutations throughout the genome are discovered. The mutations reveal new defects in haematopoiesis, craniofacial and cardiovascular development, and fertility.     

Probing the free-energy surface for protein folding with single-molecule fluorescence spectroscopy

Protein folding is inherently a heterogeneous process because of the very large number of microscopic pathways that connect the myriad unfolded conformations to the unique conformation of the native structure. In a first step towards the long-range goal of describing the distribution of pathways experimentally, F?rster resonance energy transfer (FRET) has been measured on single, freely diffusing molecules. Here we use this method to determine properties of the free-energy surface for folding that have not been obtained from ensemble experiments. We show that single-molecule FRET measurements of a small cold-shock protein expose equilibrium collapse of the unfolded polypeptide and allow us to calculate limits on the polypeptide reconfiguration time. From these results, limits on the height of the free-energy barrier to folding are obtained that are consistent with a simple statistical mechanical model, but not with the barriers derived from simulations using molecular dynamics. Unlike the activation energy, the free-energy barrier includes the activation entropy and thus has been elusive to experimental determination for any kinetic process in solution.     

Neurodegenerative disease: amyloid pores from pathogenic mutations

Alzheimer's and Parkinson's diseases are associated with the formation in the brain of amyloid fibrils from beta-amyloid and alpha-synuclein proteins, respectively. It is likely that oligomeric fibrillization intermediates (protofibrils), rather than the fibrils themselves, are pathogenic, but the mechanism by which they cause neuronal death remains a mystery. We show here that mutant amyloid proteins associated with familial Alzheimer's and Parkinson's diseases form morphologically indistinguishable annular protofibrils that resemble a class of pore-forming bacterial toxins, suggesting that inappropriate membrane permeabilization might be the cause of cell dysfunction and even cell death in amyloid diseases.