The identification of common variants that contribute to the genesis of human inherited disorders remains a significant challenge. Hirschsprung disease (HSCR) is a multifactorial, non-mendelian disorder in which rare high-penetrance coding sequence mutations in the receptor tyrosine kinase RET contribute to risk in combination with mutations at other genes. We have used family-based association studies to identify a disease interval, and integrated this with comparative and functional genomic analysis to prioritize conserved and functional elements within which mutations can be sought. We now show that a common non-coding RET variant within a conserved enhancer-like sequence in intron 1 is significantly associated with HSCR susceptibility and makes a 20-fold greater contribution to risk than rare alleles do. This mutation reduces in vitro enhancer activity markedly, has low penetrance, has different genetic effects in males and females, and explains several features of the complex inheritance pattern of HSCR. Thus, common low-penetrance variants, identified by association studies, can underlie both common and rare diseases.

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This study describes the sorption of As(V) and As(III) to schwertmannite as a function of pH and arsenic loading. In general, sorption of As(V) was greatest at low pH, whereas high pH favored the sorption of As(III). The actual pH of equivalent As(V) and As(III) sorption was strongly loading dependent, decreasing from pH approximately 8.0 at loadings <120 mmol(As) mol(Fe)(-1) to pH approximately 4.6 at a loading of 380 mmol(As) mol(Fe)(-1). Sorption isotherms for As(V) were characterized by strong partitioning to the schwertmannite solid-phase at low loadings and sorption capacities of 225-330 mmol(As(V)) mol(Fe)(-1) at high loadings. In contrast, the As(III) isotherms revealed a weak affinity for sorption of As(III) versus As(V) at low loadings yet a greater affinity for As(III) sorption compared with As(V) at high loadings (when pH > 4.6). Sorption of As(V) and As(III) caused significant release of SO(4)(2-) from within the schwertmannite solid-phase, without major degradation of the schwertmannite structure (as evident by X-ray diffraction and Raman spectroscopy). This can be interpreted as arsenic sorption via incorporation into the schwertmannite structure, rather than merely surface complexation at the mineral-water interface. The results of this study have important implications for arsenic mobility in the presence of schwertmannite, such as in areas affected by acid-mine drainage and acid-sulfate soils. In particular, arsenic speciation, arsenic loading, and pH should be considered when predicting and managing arsenic mobility in schwertmannite-rich systems.

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Iron-monosulfide oxidation and associated S transformations in a natural sediment were examined by combining selective extractions, electron microscopy and S K-edge X-ray absorption near-edge structure (XANES) spectroscopy, The sediment examined in this study was collected from a waterway receiving acid-sulfate soil drainage. It contained a high acid-volatile sulfide content (1031 micromol g(-1)), reflecting an abundance of iron-monosulfide. The iron-monosulfide speciation in the initial sediment sample was dominated by nanocrystalline mackinawite (tetragonal FeS). At near-neutral pH and an 02 partial pressure of approximately 0.2 atm, the mackinawite was found to oxidize rapidly, with a half-time of 29 +/- 2 min. This oxidation rate did not differ significantly (P < 0.05) between abiotic versus biotic conditions, demonstrating that oxidation of nanocrystalline mackinawite was not microbially mediated. The extraction results suggested that elemental S (S8(0)) was a key intermediate S oxidation product Transmission electron microscopy showed the S8(0) to be amorphous nanoglobules, 100-200 nm in diameter. The quantitative importance of S8(0) was confirmed by linear combination XANES spectroscopy, after accounting for the inherent effect of the nanoscale S8(0) particle-size on the corresponding XANES spectrum. Both the selective extraction and XANES data showed that oxidation of S8(0) to SO4(2-) was mediated by microbial activity. In addition to directly revealing important S transformations, the XANES results support the accuracy of the selective extraction scheme employed here.