Dataset Information

No gene is an island: the flip-flop phenomenon.

ABSTRACT: An increasing number of publications are replicating a previously reported disease-marker association but with the risk allele reversed from the previous report. Do such "flip-flop" associations confirm or refute the previous association findings? We hypothesized that these associations may indeed be confirmations but that multilocus effects and variation in interlocus correlations contribute to this flip-flop phenomenon. We used theoretical modeling to demonstrate that flip-flop associations can occur when the investigated variant is correlated, through interactive effects or linkage disequilibrium, with a causal variant at another locus, and we show how these findings could explain previous reports of flip-flop associations.

SUBMITTER: Lin PI

PROVIDER: S-EPMC1821115 | biostudies-literature | 2007 Mar

REPOSITORIES: biostudies-literature

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Publications

No gene is an island: the flip-flop phenomenon.

Lin Ping-I PI Vance Jeffery M JM Pericak-Vance Margaret A MA Martin Eden R ER

American journal of human genetics 20070122 3

An increasing number of publications are replicating a previously reported disease-marker association but with the risk allele reversed from the previous report. Do such "flip-flop" associations confirm or refute the previous association findings? We hypothesized that these associations may indeed be confirmations but that multilocus effects and variation in interlocus correlations contribute to this flip-flop phenomenon. We used theoretical modeling to demonstrate that flip-flop associations ca ...[more]

PMID: 17273975

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Project description:Unlike most transmembrane proteins, phospholipids can migrate from one leaflet of the membrane to the other. Because this spontaneous lipid translocation (flip-flop) tends to be very slow, cells facilitate the process with enzymes that catalyze the transmembrane movement and thereby regulate the transbilayer lipid distribution. Nonenzymatic membrane-spanning proteins with unrelated primary functions have also been found to accelerate lipid flip-flop in a nonspecific manner and by various hypothesized mechanisms. Using deuterated phospholipids, we examined the acceleration of flip-flop by gramicidin channels, which have well-defined structures and known functions, features that make them ideal candidates for probing the protein-membrane interactions underlying lipid flip-flop. To study compositionally and isotopically asymmetric proteoliposomes containing gramicidin, we expanded a recently developed protocol for the preparation and characterization of lipid-only asymmetric vesicles. Channel incorporation, conformation, and function were examined with small angle x-ray scattering, circular dichroism, and a stopped-flow spectrofluorometric assay, respectively. As a measure of lipid scrambling, we used differential scanning calorimetry to monitor the effect of gramicidin on the melting transition temperatures of the two bilayer leaflets. The two calorimetric peaks of the individual leaflets merged into a single peak over time, suggestive of scrambling, and the effect of the channel on the transbilayer lipid distribution in both symmetric 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine and asymmetric 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine/1,2-dimyristoyl-sn-glycero-3-phosphocholine vesicles was quantified from proton NMR measurements. Our results show that gramicidin increases lipid flip-flop in a complex, concentration-dependent manner. To determine the molecular mechanism of the process, we used molecular dynamics simulations and further computational analysis of the trajectories to estimate the extent of membrane deformation. Together, the experimental and computational approaches were found to constitute an effective means for studying the effects of transmembrane proteins on lipid distribution in both symmetric and asymmetric model membranes.

Dataset Information

No gene is an island: the flip-flop phenomenon.

Publications

No gene is an island: the flip-flop phenomenon.

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