New concepts for distinguishing the hidden patterns of linkage disequilibrium which underlie association between genotypes and complex phenotypes

A disappointing feature of conventional methods for detecting association between DNA variation and a phenotype of interest is that they tell us little about the hidden pattern of linkage disequilibrium (LD) with the functional variant that is actually responsible for the association. This limitation applies to case-control studies and also to the transmission/disequilibrium test (TDT) and other family-based association methods. Here we present a fresh perspective on genetic association based on two novel concepts called 'LD squares' and 'equi-risk alleles'. These describe and characterize the different patterns of gametic LD which underlie genetic association. These concepts lead to a general principle - the Equi-Risk Allele Segregation Principle - which captures the way in which underlying LD patterns affect the transmission patterns of genetic variants associated with a phenotype. This provides a basis for distinguishing the hidden LD patterns and might help to locate the functional variants responsible for the association.

The value of a small microkernel for dreamy memory and the RAMpage memory hierarchy

This paper explores potential for the RAMpage memory hierarchy to use a microkernel with a small memory footprint, in a specialized cache-speed static RAM (tightly-coupled memory, TCM). Dreamy memory is DRAM kept in low-power mode, unless referenced. Simulations show that a small microkernel suits RAMpage well, in that it achieves significantly better speed and energy gains than a standard hierarchy from adding TCM. RAMpage, in its best 128KB L2 case, gained 11% speed using TCM, and reduced energy 14%. Equivalent conventional hierarchy gains were under 1%. While 1MB L2 was significantly faster against lower-energy cases for the smaller L2, the larger SRAM's energy does not justify the speed gain. Using a 128KB L2 cache in a conventional architecture resulted in a best-case overall run time of 2.58s, compared with the best dreamy mode run time (RAMpage without context switches on misses) of 3.34s, a speed penalty of 29%. Energy in the fastest 128KB L2 case was 2.18J vs. 1.50J, a reduction of 31%. The same RAMpage configuration without dreamy mode took 2.83s as simulated, and used 2.39J, an acceptable trade-off (penalty under 10%) for being able to switch easily to a lower-energy mode.

Pax9 and Jagged1 act downstream of Gli3 in vertabrate limb development

From early in limb development the transcription factor Gli3 acts to define boundaries of gene expression along the anterior-posterior (AP) axis, establishing asymmetric patterns required to provide positional information. As limb development proceeds, posterior mesenchyme expression of Sonic hedgehog (Shh) regulates Gli3 transcription and post-translational processing to specify digit number and identity. The molecular cascades dependent on Gli3 at later stages of limb development, which link early patterning events with final digit morphogenesis, remain poorly characterised. By analysing the transcriptional consequences of loss of Gli3 in the anterior margin of the E11.5 and E12.5 limb bud in the polydactylous mouse mutant extra-toes (Gli3(Xt/Xt)), we have identified a number of known and novel transcripts dependent on Gli3 in the limb. In particular, we demonstrated that the genes encoding the paired box transcription factor Pax9, the Notch ligand Jagged1 and the cell surface receptor Cdo are dependent on Gli3 for correct expression in the anterior limb mesenchyme. Analysis of expression in compound Shh;Gli3 mutant mouse embryos and in both in vitro and in vivo Shh signaling assays, further defined the importance of Shh regulated processing of Gli3 in controlling gene expression. In particular Pax9 regulation by Shh and Gli3 was shown to be context dependent, with major differences between the limb and somite revealed by Shh bead implantation experiments in the chick. Jagged1 was shown to be induced by Shh in the chick limb and in a C3H10T1/2 cell based signaling assay, with Shh;Gli3 mutant analysis indicating that expression is dependent on Gli3 derepression. Our data have also revealed that perturbation of early patterning events within the Gli3(Xt/Xt), limb culminates in a specific delay of anterior chondrogenesis which is subsequently realised as extra digits. (c) 2005 Elsevier Ireland Ltd. All rights reserved.

Intervention Trial to Assess Arsenic Exposure from Food Crops in Bangladesh

The authors assessed the contribution of food irrigated with arsenic-contaminated water to human exposure to arsenic in Bangladesh. An intervention trial was conducted in a village in the Jessore District of Bangladesh, where irrigation water had been field-tested in March 2000 and was found to contain arsenic with concentrations ranging from 100 to 500 mu g/l. In May 2000, a random sample of 63 households was selected from the village, and I eligible person from each household was recruited to the study and randomized to an intervention or control group. The intervention group received food purchased from a village where irrigation water was found to contain 100 mu g/l arsenic. Pre- and postintervention urine samples were collected for urinary arsenic speciation assays. Preintervention, the mean urinary total arsenic concentrations were 139.25 mu g/l and 129.15 mu g/l for the intervention and control groups, respectively. These concentrations did not change significantly following intervention. Arsenic concentrations in samples of selected raw and cooked foods from the low-contamination area did not contain less arsenic than samples from the high-contamination area. Further studies to investigate the arsenic content of food grown in areas with high and low arsenic contamination of irrigation water are recommended.