A novel ubiquitin ligase is deficient in Fanconi anemia

Fanconi anemia is a recessively inherited disease characterized by congenital defects, bone marrow failure and cancer susceptibility. Cells from individuals with Fanconi anemia are highly sensitive to DNA-crosslinking drugs, such as mitomycin C (MMC). Fanconi anemia proteins function in a DNA damage response pathway involving breast cancer susceptibility gene products, BRCA1 and BRCA2 (refs. 1,2). A key step in this pathway is monoubiquitination of FANCD2, resulting in the redistribution of FANCD2 to nuclear foci containing BRCA1 (ref. 3). The underlying mechanism is unclear because the five Fanconi anemia proteins known to be required for this ubiquitination have no recognizable ubiquitin ligase motifs. Here we report a new component of a Fanconi anemia protein complex, called PHF9, which possesses E3 ubiquitin ligase activity in vitro and is essential for FANCD2 monoubiquitination in vivo. Because PHF9 is defective in a cell line derived from an individual with Fanconi anemia, we conclude that PHF9 (also called FANCL) represents a novel Fanconi anemia complementation group (FA-L). Our data suggest that PHF9 has a crucial role in the Fanconi anemia pathway as the likely catalytic subunit required for monoubiquitination of FANCD2.     

Ecological and genetic spatial structuring in the Canadian lynx

The Canadian lynx, distributed all across the northern part of North America, is well known for its regular population cycles-cycles that have different underlying structures in different parts of Canada. Using both nuclear and mitochondrial DNA markers, we report here a close resemblance between the earlier observed spatial ecological structuring of the Canadian lynx and its spatial genetic structuring. Specifically, we demonstrate that the Rocky Mountains represent a barrier to gene flow in western Canada, and, somewhat surprisingly, we detect the presence of a geographically invisible barrier south of Hudson Bay (coinciding with the separation between the ecological Continental and Atlantic regions). No evidence for isolation in different glacial refugia within North America was found. We suggest that ecological factors underlying the spatial dynamic structuring also strongly influence the genetic structuring of the Canadian lynx.     

Detecting recent positive selection in the human genome from haplotype structure

The ability to detect recent natural selection in the human population would have profound implications for the study of human history and for medicine. Here, we introduce a framework for detecting the genetic imprint of recent positive selection by analysing long-range haplotypes in human populations. We first identify haplotypes at a locus of interest (core haplotypes). We then assess the age of each core haplotype by the decay of its association to alleles at various distances from the locus, as measured by extended haplotype homozygosity (EHH). Core haplotypes that have unusually high EHH and a high population frequency indicate the presence of a mutation that rose to prominence in the human gene pool faster than expected under neutral evolution. We applied this approach to investigate selection at two genes carrying common variants implicated in resistance to malaria: G6PD and CD40 ligand. At both loci, the core haplotypes carrying the proposed protective mutation stand out and show significant evidence of selection. More generally, the method could be used to scan the entire genome for evidence of recent positive selection.     

State Modelling and Simultaneous Control of Discrete Part Manufacturing Product Transformation Processes and Resource Allocation

As competition in the market for discrete part prod uc ts gets harder and harder the requirements for extreme manufacturing operati on efficiencies get increasingly accentuated. Therefore requirements for well behaved manufacturing operation control get more and more significant. The purpose of the paper is to establish a framework for development of formal m ethods for design of systems for simultaneous control of continuous manufacturin g task processes and resource allocation of discrete part manu...     

Permian tetrapods from the Sahara show climate-controlled endemism in Pangaea

New fossils from the Upper Permian Moradi Formation of northern Niger provide an insight into the faunas that inhabited low-latitude, xeric environments near the end of the Palaeozoic era (approximately 251 million years ago). We describe here two new temnospondyl amphibians, the cochleosaurid Nigerpeton ricqlesi gen. et sp. nov. and the stem edopoid Saharastega moradiensis gen. et sp. nov., as relicts of Carboniferous lineages that diverged 40-90 million years earlier. Coupled with a scarcity of therapsids, the new finds suggest that faunas from the poorly sampled xeric belt that straddled the Equator during the Permian period differed markedly from well-sampled faunas that dominated tropical-to-temperate zones to the north and south. Our results show that long-standing theories of Late Permian faunal homogeneity are probably oversimplified as the result of uneven latitudinal sampling.     

Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder

The large conductance calcium-sensitive potassium (BK) channel is widely expressed in many organs and tissues, but its in vivo physiological functions have not been fully defined. Here we report a genetic locus associated with a human syndrome of coexistent generalized epilepsy and paroxysmal dyskinesia on chromosome 10q22 and show that a mutation of the alpha subunit of the BK channel causes this syndrome. The mutant BK channel had a markedly greater macroscopic current. Single-channel recordings showed an increase in open-channel probability due to a three- to fivefold increase in Ca(2+) sensitivity. We propose that enhancement of BK channels in vivo leads to increased excitability by inducing rapid repolarization of action potentials, resulting in generalized epilepsy and paroxysmal dyskinesia by allowing neurons to fire at a faster rate. These results identify a gene that is mutated in generalized epilepsy and paroxysmal dyskinesia and have implications for the pathogenesis of human epilepsy, the neurophysiology of paroxysmal movement disorders and the role of BK channels in neurological disease.