Involvement of the Modifier Gene of a Human Mendelian Disorder in a Negative Selection Process

BACKGROUND:Identification of modifier genes and characterization of their effects represent major challenges in human genetics. SAA1 is one of the few modifiers identified in humans: this gene influences the risk of renal amyloidosis (RA) in patients with familial Mediterranean fever (FMF), a Mendelian autoinflammatory disorder associated with mutations in MEFV. Indeed, the SAA1 alpha homozygous genotype and the p.Met694Val homozygous genotype at the MEFV locus are two main risk factors for RA. METHODOLOGY/PRINCIPAL FINDINGS:HERE, WE INVESTIGATED ARMENIAN FMF PATIENTS AND CONTROLS FROM TWO NEIGHBORING COUNTRIES: Armenia, where RA is frequent (24%), and Karabakh, where RA is rare (2.5%). Sequencing of MEFV revealed similar frequencies of p.Met694Val homozygotes in the two groups of patients. However, a major deficit of SAA1 alpha homozygotes was found among Karabakhian patients (4%) as compared to Armenian patients (24%) (p = 5.10(-5)). Most importantly, we observed deviations from Hardy-Weinberg equilibrium (HWE) in the two groups of patients, and unexpectedly, in opposite directions, whereas, in the two control populations, genotype distributions at this locus were similar and complied with (HWE). CONCLUSIONS/SIGNIFICANCE:The excess of SAA1alpha homozygotes among Armenian patients could be explained by the recruitment of patients with severe phenotypes. In contrast, a population-based study revealed that the deficit of alpha/alpha among Karabakhian patients would result from a negative selection against carriers of this genotype. This study, which provides new insights into the role of SAA1 in the pathophysiology of FMF, represents the first example of deviations from HWE and selection involving the modifier gene of a Mendelian disorder

Ultrafast hot-carrier-dominated photocurrent in graphene

The combination of its high electron mobility, broadband absorption and ultrafast luminescence make graphene attractive for optoelectronic and photonic applications, including transparent electrodes, mode-locked lasers and high-speed optical modulators. Photo-excited carriers that have not cooled to the temperature of the graphene lattice are known as hot carriers, and may limit device speed and energy efficiency. However, their roles in charge and energy transport are not fully understood. Here, we use time-resolved scanning photocurrent microscopy to demonstrate that hot carriers, rather than phonons, dominate energy transport across a tunable graphene p-n junction excited by ultrafast laser pulses. The photocurrent response time varies from 1.5 ps at room temperature to 4 ps at 20 K, implying a fundamental bandwidth of approximately 500 GHz (refs 12, 13, 21). Gate-dependent pump-probe measurements demonstrate that both thermoelectric and built-in electric field effects contribute to the photocurrent, with the contribution from each depending on the junction configuration. The photocurrent produced by a single pulsed laser also displays multiple polarity reversals as a function of carrier density, which is a possible signature of impact ionization.link_to_subscribed_fulltex