SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout

Uric acid is the end product of purine metabolism in humans and great apes, which have lost hepatic uricase activity, leading to uniquely high serum uric acid concentrations (200-500 microM) compared with other mammals (3-120 microM). About 70% of daily urate disposal occurs via the kidneys, and in 5-25% of the human population, impaired renal excretion leads to hyperuricemia. About 10% of people with hyperuricemia develop gout, an inflammatory arthritis that results from deposition of monosodium urate crystals in the joint. We have identified genetic variants within a transporter gene, SLC2A9, that explain 1.7-5.3% of the variance in serum uric acid concentrations, following a genome-wide association scan in a Croatian population sample. SLC2A9 variants were also associated with low fractional excretion of uric acid and/or gout in UK, Croatian and German population samples. SLC2A9 is a known fructose transporter, and we now show that it has strong uric acid transport activity in Xenopus laevis oocytes.     

MYH9 is associated with nondiabetic end-stage renal disease in African Americans

As end-stage renal disease (ESRD) has a four times higher incidence in African Americans compared to European Americans, we hypothesized that susceptibility alleles for ESRD have a higher frequency in the West African than the European gene pool. We carried out a genome-wide admixture scan in 1,372 ESRD cases and 806 controls and found a highly significant association between excess African ancestry and nondiabetic ESRD (lod score = 5.70) but not diabetic ESRD (lod = 0.47) on chromosome 22q12. Each copy of the European ancestral allele conferred a relative risk of 0.50 (95% CI = 0.39-0.63) compared to African ancestry. Multiple common SNPs (allele frequencies ranging from 0.2 to 0.6) in the gene encoding nonmuscle myosin heavy chain type II isoform A (MYH9) were associated with two to four times greater risk of nondiabetic ESRD and accounted for a large proportion of the excess risk of ESRD observed in African compared to European Americans.     

Genome-wide genetic association of complex traits in heterogeneous stock mice

Difficulties in fine-mapping quantitative trait loci (QTLs) are a major impediment to progress in the molecular dissection of complex traits in mice. Here we show that genome-wide high-resolution mapping of multiple phenotypes can be achieved using a stock of genetically heterogeneous mice. We developed a conservative and robust bootstrap analysis to map 843 QTLs with an average 95% confidence interval of 2.8 Mb. The QTLs contribute to variation in 97 traits, including models of human disease (asthma, type 2 diabetes mellitus, obesity and anxiety) as well as immunological, biochemical and hematological phenotypes. The genetic architecture of almost all phenotypes was complex, with many loci each contributing a small proportion to the total variance. Our data set, freely available at http://gscan.well.ox.ac.uk, provides an entry point to the functional characterization of genes involved in many complex traits.     

Influence of prey movement on the aim of predatory strikes of the western rattlesnake ( Crotalus Viridis )

The purpose of this study was to determine whether the western rattlesnake ( Crotalus viridis ) aims its predatory strike at the head/thorax region of mice primarily on the basis of cues related to the direction of prey movement. We hypothesized that when rattlesnakes strike at anesthetized, backward-moving mice, most strikes would be aimed at the forward-most-moving region, i.e., the posterior (abdomen/tail) region of prey. However, most mice were struck in the anterior (head/thorax) region, implying that the visual-infrared image of mice, rather than directional movement, guides the aim of predatory strikes.     

Desert rodents reduce seedling recruitment of Salsola paulsenii

Heteromyid rodents in the deserts of North America have been shown to harvest large quantities of seeds of both native and introduced plants from soil seed banks, but rarely has the impact of this seed removal been demonstrated experimentally. I used a series of fenced plots (some of which excluded rodents) to demonstrate that heteromyids at a western Nevada study site can measurably reduce seed banks and subsequent seedling establishment of Salsola paulsenii , an introduced invasive weed that has become a significant problem over much of the desert Southwest. The frequency of S. paulsenii seedlings in both 2004 and 2005 was significantly greater around the interior perimeters of plots that permitted access by rodents than in plots that excluded rodents. Density of S. paulsenii seedlings was significantly greater inside than outside rodent exclusion plots, but there was no such difference in seedling density inside versus outside plots that permitted rodent access. Salsola paulsenii has such a conspicuous presence in many desert environments that the effect of rodents in reducing its abundance may not be visually apparent; however, rodents may still ameliorate competitive effects of this weed on coexisting plants. Heteromyid rodents disperse seeds through caching, and they also consume them. Caching may enhance establishment of native plant seedlings, but is unlikely to benefit exotics such as S. paulsenii .     

Catastrophic wildfire and number of populations as factors influencing risk of extinction for Gila trout ( Oncorhynchus gilae )

We used the computer program RAMAS to explore the sensitivity of an extinction-risk model for the Gila trout ( Oncorhynchus gilae ) to management of wildfires and number of populations of the species. The Gila trout is an endangered salmonid presently restricted to very few headwaters of the Gila and San Francisco river tributaries in southwestern New Mexico. Life history data for 10 extant populations were used to examine sensitivity of the species viability to changes in a variety of factors including population size, fecundity, life stage structure, number of populations, severity and probability of forest fires, and a regulated fishery. The probability and severity of forest fires and number of populations had the greatest effect on viability. Results indicate that successful conservation of Gila trout requires establishment of additional populations and reduction of the severity of forest fires through a program incorporating more frequent, but less severe, fires.     

Size selection of food by cutthroat trout, Salmo clarki, in an Idaho stream

The mean size of food and amount of food consumed by cutthroat trout from Palisades Creek in southeastern Idaho increased with trout length. Number of organisms of terrestrial origin, number of aquatic larvae, number of ants, and number of berries from redstem dogwood were related to trout length. The size range and number of taxa consumed increased with trout size, indicating that as trout get larger, they broaden their feeding menu. The minimum size of food consumed was relatively constant for all trout, but larger trout appeared to feed more from the stream bottom. Trout may have a minimum length of food, below which items cannot be detected as food. Other possible factors affecting the feeding of cutthroat trout are mentioned.         

Mutations of the BRAF gene in human cancer

Cancers arise owing to the accumulation of mutations in critical genes that alter normal programmes of cell proliferation, differentiation and death. As the first stage of a systematic genome-wide screen for these genes, we have prioritized for analysis signalling pathways in which at least one gene is mutated in human cancer. The RAS RAF MEK ERK MAP kinase pathway mediates cellular responses to growth signals. RAS is mutated to an oncogenic form in about 15% of human cancer. The three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS. Here we report BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers. All mutations are within the kinase domain, with a single substitution (V599E) accounting for 80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH3T3 cells. Furthermore, RAS function is not required for the growth of cancer cell lines with the V599E mutation. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation in human cancer, it may provide new therapeutic opportunities in malignant melanoma.