Speciation by host switch in brood parasitic indigobirds

A growing body of empirical and theoretical work supports the plausibility of sympatric speciation, but there remain few examples in which all the essential components of the process are well understood. The African indigobirds Vidua spp. are host-specific brood parasites. Indigobird nestlings are reared along with host young, and mimic the mouth markings of their respective hosts. As adults, male indigobirds mimic host song, whereas females use these songs to choose both their mates and the nests they parasitize. These behavioural mechanisms promote the cohesion of indigobird populations associated with a given host species, and provide a mechanism for reproductive isolation after a new host is colonized. Here we show that all indigobird species are similar genetically, but are significantly differentiated in both mitochondrial haplotype and nuclear allele frequencies. These data support a model of recent sympatric speciation. In contrast to the cuckoo Cuculus canorus, in which only female lineages are faithful to specific hosts, host switches have led to speciation in indigobirds because both males and females imprint on their hosts.     

Massive gene decay in the leprosy bacillus

Leprosy, a chronic human neurological disease, results from infection with the obligate intracellular pathogen Mycobacterium leprae, a close relative of the tubercle bacillus. Mycobacterium leprae has the longest doubling time of all known bacteria and has thwarted every effort at culture in the laboratory. Comparing the 3.27-megabase (Mb) genome sequence of an armadillo-derived Indian isolate of the leprosy bacillus with that of Mycobacterium tuberculosis (4.41 Mb) provides clear explanations for these properties and reveals an extreme case of reductive evolution. Less than half of the genome contains functional genes but pseudogenes, with intact counterparts in M. tuberculosis, abound. Genome downsizing and the current mosaic arrangement appear to have resulted from extensive recombination events between dispersed repetitive sequences. Gene deletion and decay have eliminated many important metabolic activities including siderophore production, part of the oxidative and most of the microaerophilic and anaerobic respiratory chains, and numerous catabolic systems and their regulatory circuits.     

Identification of ALK as a major familial neuroblastoma predisposition gene

Neuroblastoma is a childhood cancer that can be inherited, but the genetic aetiology is largely unknown. Here we show that germline mutations in the anaplastic lymphoma kinase (ALK) gene explain most hereditary neuroblastomas, and that activating mutations can also be somatically acquired. We first identified a significant linkage signal at chromosome bands 2p23-24 using a whole-genome scan in neuroblastoma pedigrees. Resequencing of regional candidate genes identified three separate germline missense mutations in the tyrosine kinase domain of ALK that segregated with the disease in eight separate families. Resequencing in 194 high-risk neuroblastoma samples showed somatically acquired mutations in the tyrosine kinase domain in 12.4% of samples. Nine of the ten mutations map to critical regions of the kinase domain and were predicted, with high probability, to be oncogenic drivers. Mutations resulted in constitutive phosphorylation, and targeted knockdown of ALK messenger RNA resulted in profound inhibition of growth in all cell lines harbouring mutant or amplified ALK, as well as in two out of six wild-type cell lines for ALK. Our results demonstrate that heritable mutations of ALK are the main cause of familial neuroblastoma, and that germline or acquired activation of this cell-surface kinase is a tractable therapeutic target for this lethal paediatric malignancy.     

A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder of skeletal malformations and progressive extraskeletal ossification. We mapped FOP to chromosome 2q23-24 by linkage analysis and identified an identical heterozygous mutation (617G --> A; R206H) in the glycine-serine (GS) activation domain of ACVR1, a BMP type I receptor, in all affected individuals examined. Protein modeling predicts destabilization of the GS domain, consistent with constitutive activation of ACVR1 as the underlying cause of the ectopic chondrogenesis, osteogenesis and joint fusions seen in FOP.     

Using artificial systems to explore the ecology and evolution of symbioses

The web of life is weaved from diverse symbiotic interactions between species. Symbioses vary from antagonistic interactions such as competition and predation to beneficial interactions such as mutualism. What are the bases for the origin and persistence of symbiosis? What affects the ecology and evolution of symbioses? How do symbiotic interactions generate ecological patterns? How do symbiotic partners evolve and coevolve? Many of these questions are difficult to address in natural systems. Artificial systems, from abstract to living, have been constructed to capture essential features of natural symbioses and to address these key questions. With reduced complexity and increased controllability, artificial systems can serve as useful models for natural systems. We review how artificial systems have contributed to our understanding of symbioses.     

Multiple ADH genes are associated with upper aerodigestive cancers

Alcohol is an important risk factor for upper aerodigestive cancers and is principally metabolized by alcohol dehydrogenase (ADH) enzymes. We have investigated six ADH genetic variants in over 3,800 aerodigestive cancer cases and 5,200 controls from three individual studies. Gene variants rs1229984 (ADH1B) and rs1573496 (ADH7) were significantly protective against aerodigestive cancer in each individual study and overall (P = 10(-10) and 10(-9), respectively). These effects became more apparent with increasing alcohol consumption (P for trend = 0.0002 and 0.065, respectively). Both gene effects were independent of each other, implying that multiple ADH genes may be involved in upper aerodigestive cancer etiology.     

A robust neural network filter for electricity demand prediction

This paper is concerned with one-day-ahead hourly predictions of electricity demand for Puget Power, a local electricity utility for the Seattle area. Standard modelling techniques, including neural networks, will fail when the assumptions of the model are violated. It is demonstrated that typical modelling assumptions such as no outliers or level shifts are incorrect for electric power demand time series. A filter which removes or lessens the significance of outliers and level shifts is demonstrated. This filter produces ‘clean data’ which is used as the basis for future robust predictions. The robust predictions are shown to be better than non-robust counterparts on electricity load data. The outliers identified by the filter are shown to correspond with suspicious data. Finally, the estimated level shifts are in agreement with the belief that load growth is taking place year to year.     

Genetic variegation of clonal architecture and propagating cells in leukaemia

Little is known of the genetic architecture of cancer at the subclonal and single-cell level or in the cells responsible for cancer clone maintenance and propagation. Here we have examined this issue in childhood acute lymphoblastic leukaemia in which the ETV6-RUNX1 gene fusion is an early or initiating genetic lesion followed by a modest number of recurrent or 'driver' copy number alterations. By multiplexing fluorescence in situ hybridization probes for these mutations, up to eight genetic abnormalities can be detected in single cells, a genetic signature of subclones identified and a composite picture of subclonal architecture and putative ancestral trees assembled. Subclones in acute lymphoblastic leukaemia have variegated genetics and complex, nonlinear or branching evolutionary histories. Copy number alterations are independently and reiteratively acquired in subclones of individual patients, and in no preferential order. Clonal architecture is dynamic and is subject to change in the lead-up to a diagnosis and in relapse. Leukaemia propagating cells, assayed by serial transplantation in NOD/SCID IL2Rγ(null) mice, are also genetically variegated, mirroring subclonal patterns, and vary in competitive regenerative capacity in vivo. These data have implications for cancer genomics and for the targeted therapy of cancer.