Genome-wide association study identifies multiple loci influencing human serum metabolite levels

Nuclear magnetic resonance assays allow for measurement of a wide range of metabolic phenotypes. We report here the results of a GWAS on 8,330 Finnish individuals genotyped and imputed at 7.7 million SNPs for a range of 216 serum metabolic phenotypes assessed by NMR of serum samples. We identified significant associations (P < 2.31 × 10(-10)) at 31 loci, including 11 for which there have not been previous reports of associations to a metabolic trait or disorder. Analyses of Finnish twin pairs suggested that the metabolic measures reported here show higher heritability than comparable conventional metabolic phenotypes. In accordance with our expectations, SNPs at the 31 loci associated with individual metabolites account for a greater proportion of the genetic component of trait variance (up to 40%) than is typically observed for conventional serum metabolic phenotypes. The identification of such associations may provide substantial insight into cardiometabolic disorders.     

MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis

The increased burden of chronic kidney and end-stage kidney diseases (ESKD) in populations of African ancestry has been largely unexplained. To identify genetic variants predisposing to idiopathic and HIV-1-associated focal segmental glomerulosclerosis (FSGS), we carried out an admixture-mapping linkage-disequilibrium genome scan on 190 African American individuals with FSGS and 222 controls. We identified a chromosome 22 region with a genome-wide logarithm of the odds (lod) score of 9.2 and a peak lod of 12.4 centered on MYH9, a functional candidate gene expressed in kidney podocytes. Multiple MYH9 SNPs and haplotypes were recessively associated with FSGS, most strongly a haplotype spanning exons 14 through 23 (OR = 5.0, 95% CI = 3.5-7.1; P = 4 x 10(-23), n = 852). This association extended to hypertensive ESKD (OR = 2.2, 95% CI = 1.5-3.4; n = 433), but not type 2 diabetic ESKD (n = 476). Genetic variation at the MYH9 locus substantially explains the increased burden of FSGS and hypertensive ESKD among African Americans.     

Heterogeneity of macrophage cytophilic antibodies in immunized mice

Résumé Des souris immunisés avec des globules rouges de mouton dans l'adjuvant de Freund produisent deux types de facteurs cytophiles pour macrophages. L'un s'attache aux macrophages trypsinisées et se trouve parmi les immunoglobulines. L'autre ne s'attache pas aux macrophages trypsinisées et se rencontre dans une fraction de sérum contenant de l'albumine et de la globuline-₁.

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Supported by grants from the Australian Research Grants Committee, the National Health and Medical Research Council of Australia and the Postgraduate Medical Foundation, University of Sydney.     

Fatty acid profiles of major food sources of howler monkeys (Alouatta palliata) in the neotropics

Wild howler monkeys (Alouatta palliata) get most of their calories from carbohydrates (65%) and fats (18%) of native tropical plants, but little is known about their intake of individual fatty acids. The fatty acid composition of several natural food sources of howler monkeys collected in Panama was determined by gas-liquid chromatography. The predominant fatty acids were palmitic (30%), linoleic (23%), linoleic (23%), -linolenic (16%) and oleic (15%). Fatty acids with less than 16, and more than 18, carbon chains were uncommon (0–7%). Although total saturated fatty acids were high in some specific food sources (22–54% of total fatty acids and 8 energy %), most of the calories from fat in the animals' diets are derived from mono-and polyunsaturated fatty acids (9.75 energy %) All food sources had significant amounts of the -3 fatty acid, -linolenic acid (2.9 energy %). In terms of human diets, the howler monkey's fat consumption would not be considered atherogenic. Unless these animals show a particular adverse susceptibility to dietary fat, it is unlikely that their fat intake is the primary cause of the low, but significant, incidence of atherosclerosis that develops in these animals in the wild state.     

The genomic and epidemiological dynamics of human influenza A virus

The evolutionary interaction between influenza A virus and the human immune system, manifest as 'antigenic drift' of the viral haemagglutinin, is one of the best described patterns in molecular evolution. However, little is known about the genome-scale evolutionary dynamics of this pathogen. Similarly, how genomic processes relate to global influenza epidemiology, in which the A/H3N2 and A/H1N1 subtypes co-circulate, is poorly understood. Here through an analysis of 1,302 complete viral genomes sampled from temperate populations in both hemispheres, we show that the genomic evolution of influenza A virus is characterized by a complex interplay between frequent reassortment and periodic selective sweeps. The A/H3N2 and A/H1N1 subtypes exhibit different evolutionary dynamics, with diverse lineages circulating in A/H1N1, indicative of weaker antigenic drift. These results suggest a sink-source model of viral ecology in which new lineages are seeded from a persistent influenza reservoir, which we hypothesize to be located in the tropics, to sink populations in temperate regions.     

Small-amplitude cycles emerge from stage-structured interactions in Daphnia-algal systems

A long-standing issue in ecology is reconciling the apparent stability of many populations with robust predictions of large-amplitude population cycles from general theory on consumer-resource interactions. Even when consumers are decoupled from dynamic resources, large-amplitude cycles can theoretically emerge from delayed feedback processes found in many consumers. Here we show that resource-dependent mortality and a dynamic developmental delay in consumers produces a new type of small-amplitude cycle that coexists with large-amplitude fluctuations in coupled consumer-resource systems. A distinctive characteristic of the small-amplitude cycles is slow juvenile development for consumers, leading to a developmental delay that is longer than the cycle period. By contrast, the period exceeds the delay in large-amplitude cycles. These theoretical predictions may explain previous empirical results on coexisting attractors found in Daphnia-algal systems. To test this, we used bioassay experiments that measure the growth rates of individuals in populations exhibiting each type of cycle. The results were consistent with predictions. Together, the new theory and experiments establish that two very general features of consumers--a resource-dependent juvenile stage duration and resource-dependent mortality--combine to produce small-amplitude resource-consumer cycles. This phenomenon may contribute to the prevalence of small-amplitude fluctuations in many other consumer-resource populations.     

Single ionic channels observed in tissue-cultured muscle

The extracellular patch clamp technique developed by Neher et al. to record the responses of single channels in skeletal muscle has provided firm evidence for the two-state nature of the conductance event in nicotinic endplate channels. We report here the use of the extracellular patch technique to record single-channel responses from tissue-cultured chick skeletal muscle cells. The temperature dependence of channel conductance and gating kinetics shows no evidence of discontinuous behaviour between 17 and 37 degrees C.