Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants

We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.     

Chicken welfare is influenced more by housing conditions than by stocking density

Intensive broiler (meat) chicken production now exceeds 800 million birds each year in the United Kingdom and 2 x 10(10) birds worldwide, but it attracts accusations of poor welfare. The European Union is currently adopting standards for broilers aimed at a chief welfare concern--namely, overcrowding--by limiting maximum 'stocking density' (bird weight per unit area). It is not clear, however, whether this will genuinely improve bird welfare because evidence is contradictory. Here we report on broiler welfare in relation to the European Union proposals through a large-scale study (2.7 million birds) with the unprecedented cooperation of ten major broiler producers in an experimental manipulation of stocking density under a range of commercial conditions. Producer companies stocked birds to five different final densities, but otherwise followed company practice, which we recorded in addition to temperature, humidity, litter and air quality. We assessed welfare through mortality, physiology, behaviour and health, with an emphasis on leg health and walking ability. Our results show that differences among producers in the environment that they provide for chickens have more impact on welfare than has stocking density itself.     

The influence of ridge migration on the magmatic segmentation of mid-ocean ridges

The Earth's mid-ocean ridges display systematic changes in depth and shape, which subdivide the ridges into discrete spreading segments bounded by transform faults and smaller non-transform offsets of the axis. These morphological changes have been attributed to spatial variations in the supply of magma from the mantle, although the origin of the variations is poorly understood. Here we show that magmatic segmentation of ridges with fast and intermediate spreading rates is directly related to the migration velocity of the spreading axis over the mantle. For over 9,500 km of mid-ocean ridge examined, leading ridge segments in the 'hotspot' reference frame coincide with the shallow magmatically robust segments across 86 per cent of all transform faults and 73 per cent of all second-order discontinuities. We attribute this relationship to asymmetric mantle upwelling and melt production due to ridge migration, with focusing of melt towards ridge segments across discontinuities. The model is consistent with variations in crustal structure across discontinuities of the East Pacific Rise, and may explain variations in depth of melting and the distribution of enriched lavas.     

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.     

Pneumococcal genome sequencing tracks a vaccine escape variant formed through a multi-fragment recombination event

Streptococcus pneumoniae ('pneumococcus') causes an estimated 14.5 million cases of serious disease and 826,000 deaths annually in children under 5 years of age(1). The highly effective introduction of the PCV7 pneumococcal vaccine in 2000 in the United States(2,3) provided an unprecedented opportunity to investigate the response of an important pathogen to widespread, vaccine-induced selective pressure. Here, we use array-based sequencing of 62 isolates from a US national monitoring program to study five independent instances of vaccine escape recombination(4), showing the simultaneous transfer of multiple and often large (up to at least 44 kb) DNA fragments. We show that one such new strain quickly became established, spreading from east to west across the United States. These observations clarify the roles of recombination and selection in the population genomics of pneumococcus and provide proof of principle of the considerable value of combining genomic and epidemiological information in the surveillance and enhanced understanding of infectious diseases.     

Collagen treated with (+)-catechin becomes resistant to the action of mammalian collagenase

Summary Treatment of radioactively labeled guinea-pig skin soluble collagen or calf skin collagen with the flavonoid (+)-catechin makes the collagen resistant to the action of mammalian collagenase but not to the action of bacterial collagenase. Complete resistance to the action of the mammalian enzyme may be achieved by incubating 0.6 mg of collagen (dry weight) with 0.1 mM (+)-catechin, followed by dialysis to remove the unbound flavonoid. Since incubation of the mammalian enzyme with (+)-catechin does not inhibit its activity, it is postulated that (+)-catechin binds tightly to collagen and modifies its structure sufficiently to make it resistant to enzyme degradation.Acknowledgments. This work was supported by grants from the Easter Seal Research Foundation of the National Easter Seal Society for Crippled Children and Adults (R-7821), and the National Institutes of Health (HL-20447). (+)-Catechin was a generous gift from Zyma SA, CH-1260 Nyon, Switzerland.     

Genome-wide strategies for detecting multiple loci that influence complex diseases

After nearly 10 years of intense academic and commercial research effort, large genome-wide association studies for common complex diseases are now imminent. Although these conditions involve a complex relationship between genotype and phenotype, including interactions between unlinked loci, the prevailing strategies for analysis of such studies focus on the locus-by-locus paradigm. Here we consider analytical methods that explicitly look for statistical interactions between loci. We show first that they are computationally feasible, even for studies of hundreds of thousands of loci, and second that even with a conservative correction for multiple testing, they can be more powerful than traditional analyses under a range of models for interlocus interactions. We also show that plausible variations across populations in allele frequencies among interacting loci can markedly affect the power to detect their marginal effects, which may account in part for the well-known difficulties in replicating association results. These results suggest that searching for interactions among genetic loci can be fruitfully incorporated into analysis strategies for genome-wide association studies.     

Positive and negative effects of widespread badger culling on tuberculosis in cattle

Human and livestock diseases can be difficult to control where infection persists in wildlife populations. For three decades, European badgers (Meles meles) have been culled by the British government in a series of attempts to limit the spread of Mycobacterium bovis, the causative agent of bovine tuberculosis (TB), to cattle. Despite these efforts, the incidence of TB in cattle has risen consistently, re-emerging as a primary concern for Britain's cattle industry. Recently, badger culling has attracted controversy because experimental studies have reached contrasting conclusions (albeit using different protocols), with culled areas showing either markedly reduced or increased incidence of TB in cattle. This has confused attempts to develop a science-based management policy. Here we use data from a large-scale, randomized field experiment to help resolve these apparent differences. We show that, as carried out in this experiment, culling reduces cattle TB incidence in the areas that are culled, but increases incidence in adjoining areas. These findings are biologically consistent with previous studies but will present challenges for policy development.