A Practical Genome Scan for Population-Specific Strong Selective Sweeps That Have Reached Fixation

Phenotypic divergences between modern human populations have developed as a result of genetic adaptation to local environments over the past 100,000 years. To identify genes involved in population-specific phenotypes, it is necessary to detect signatures of recent positive selection in the human genome. Although detection of elongated linkage disequilibrium (LD) has been a powerful tool in the field of evolutionary genetics, current LD-based approaches are not applicable to already fixed loci. Here, we report a method of scanning for population-specific strong selective sweeps that have reached fixation. In this method, genome-wide SNP data is used to analyze differences in the haplotype frequency, nucleotide diversity, and LD between populations, using the ratio of haplotype homozygosity between populations. To estimate the detection power of the statistics used in this study, we performed computer simulations and found that these tests are relatively robust against the density of typed SNPs and demographic parameters if the advantageous allele has reached fixation. Therefore, we could determine the threshold for maintaining high detection power, regardless of SNP density and demographic history. When this method was applied to the HapMap data, it was able to identify the candidates of population-specific strong selective sweeps more efficiently than the outlier approach that depends on the empirical distribution. This study, confirming strong positive selection on genes previously reported to be associated with specific phenotypes, also identifies other candidates that are likely to contribute to phenotypic differences between human populations

Fanconi Anemia Complementation Group D2 (FANCD2) Functions Independently of BRCA2- and RAD51-Associated Homologous Recombination in Response to DNA Damage

The BRCA2 breast cancer tumor suppressor is involved in the repair of double strand breaks and broken replication forks by homologous recombination through its interaction with DNA repair protein Rad51. Cells defective in BRCA2-FANCD1 are extremely sensitive to mitomycin C (MMC) similarly to cells deficient in any of the Fanconi anemia (FA) complementation group proteins (FANC). These observations suggest that the FA pathway and the BRCA2 and Rad51 repair pathway may be linked, although a functional connection between these pathways in DNA damage signaling remains to be determined. Here, we systematically investigated the interaction between these pathways. We show that in response to DNA damage, BRCA2-dependent Rad51 nuclear focus formation was normal in the absence of FANCD2 and that FANCD2 nuclear focus formation and mono-ubiquitination appeared normal in BRCA2-deficient cells. We report that the absence of BRCA2 substantially reduced homologous recombination repair of DNA breaks, whereas the absence of FANCD2 had little effect. Furthermore, we established that depletion of BRCA2 or Rad51 had a greater effect on cell survival in response to MMC than depletion of FANCD2 and that depletion of BRCA2 in FANCD2 mutant cells further sensitized these cells to MMC. Our results suggest that FANCD2 mediates double strand DNA break repair independently of Rad51-associated homologous recombination

Detectability of the Warm/Hot Intergalactic Medium Through Emission Lines of OVII and OVIII

Most of cosmic baryons predicted by the big-bang nucleosynthesis has evaded the direct detection. Recent numerical simulations indicate that approximately 30 to 50 percent of the total baryons in the present universe is supposed to take a form of warm/hot intergalactic medium (WHIM) whose X-ray continuum emission is very weak. To identify those missing baryons, we consider in detail the detectability of WHIM directly through emission lines of OVII (561, 568, 574, 665eV) and OVIII (653eV). For this purpose, we create mock spectra of the emission lines of WHIM using a light-cone output of the cosmological hydrodynamic simulations. Since the predicted fluxes are generally below the current detection limit, the unambiguous detection requires a dedicated X-ray satellite mission that we also discuss in detail. We find that our proposed mission is sensitive to the WHIM with gas temperature $T=10^{6-7}$K and overdensity $\delta=10-100$ up to a redshift of 0.3 without being significantly contaminated by the cosmic X-ray background and the Galactic emissions. Thus such a mission provides a unique and important tool to identify a large fraction of otherwise elusive baryons in the universe.Comment: 22 pages, 10 figures. To appear in PASJ, v55, Oct. 25 (2003) issu

A pathway of neuregulin-induced activation of cofilin-phosphatase Slingshot and cofilin in lamellipodia

Cofilin mediates lamellipodium extension and polarized cell migration by stimulating actin filament dynamics at the leading edge of migrating cells. Cofilin is inactivated by phosphorylation at Ser-3 and reactivated by cofilin-phosphatase Slingshot-1L (SSH1L). Little is known of signaling mechanisms of cofilin activation and how this activation is spatially regulated. Here, we show that cofilin-phosphatase activity of SSH1L increases ∼10-fold by association with actin filaments, which indicates that actin assembly at the leading edge per se triggers local activation of SSH1L and thereby stimulates cofilin-mediated actin turnover in lamellipodia. We also provide evidence that 14-3-3 proteins inhibit SSH1L activity, dependent on the phosphorylation of Ser-937 and Ser-978 of SSH1L. Stimulation of cells with neuregulin-1β induced Ser-978 dephosphorylation, translocation of SSH1L onto F-actin–rich lamellipodia, and cofilin dephosphorylation. These findings suggest that SSH1L is locally activated by translocation to and association with F-actin in lamellipodia in response to neuregulin-1β and 14-3-3 proteins negatively regulate SSH1L activity by sequestering it in the cytoplasm

Towards high-resolution ptychographic x-ray diffraction microscopy

Ptychographic x-ray diffraction microscopy is a lensless imaging technique with a large field of view and high spatial resolution, which is also useful for characterizing the wavefront of an x-ray probe. The performance of this technique is degraded by positioning errors due to the drift between the sample and illumination optics. We propose an experimental approach for correcting the positioning errors and demonstrate success by two-dimensionally reconstructing both the wavefront of the focused x-ray beam and the complex transmissivity of the weakly scattering objects at the pixel resolution of better than 10 nm in the field of view larger than 5 μm. This method is applicable to not only the observation of organelles inside cells or nano-mesoscale structures buried within bulk materials but also the characterization of probe for single-shot imaging with x-ray free electron lasers. © 2011 American Physical Society.Yukio Takahashi, Akihiro Suzuki, Nobuyuki Zettsu, Yoshiki Kohmura, Yasunori Senba, Haruhiko Ohashi, Kazuto Yamauchi, and Tetsuya Ishikawa. Phys. Rev. B 83(21), 214109 (2011)

A replication study confirmed the EDAR gene to be a major contributor to population differentiation regarding head hair thickness in Asia

Hair morphology is a highly divergent phenotype among human populations. We recently reported that a nonsynonymous SNP in the ectodysplasin A receptor (EDAR 1540T/C) is associated with head hair fiber thickness in an ethnic group in Thailand (Thai-Mai) and an Indonesian population. However, these Southeast Asian populations are genetically and geographically close, and thus the genetic contribution of EDAR to hair morphological variation in the other Asian populations has remained unclear. In this study, we examined the association of 1540T/C with hair morphology in a Japanese population (Northeast Asian). As observed in our previous study, 1540T/C showed a significant association with hair cross-sectional area (P = 2.7 × 10−6) in Japanese. When all populations (Thai-Mai, Indonesian, and Japanese) were combined, the association of 1540T/C was stronger (P = 3.8 × 10−10) than those of age, sex, and population. These results indicate that EDAR is the genetic determinant of hair thickness as well as a strong contributor to hair fiber thickness variation among Asian populations

Handheld magnetic probe with permanent magnet and Hall sensor for identifying sentinel lymph nodes in breast cancer patients

Abstract The newly developed radioisotope-free technique based on magnetic nanoparticle detection using a magnetic probe is a promising method for sentinel lymph node biopsy. In this study, a novel handheld magnetic probe with a permanent magnet and magnetic sensor is developed to detect the sentinel lymph nodes in breast cancer patients. An outstanding feature of the probe is the precise positioning of the sensor at the magnetic null point of the magnet, leading to highly sensitive measurements unaffected by the strong ambient magnetic fields of the magnet. Numerical and experimental results show that the longitudinal detection length is approximately 10 mm, for 140 μg of iron. Clinical tests were performed, for the first time, using magnetic and blue dye tracers—without radioisotopes—in breast cancer patients to demonstrate the performance of the probe. The nodes were identified through transcutaneous and ex-vivo measurements, and the iron accumulation in the nodes was quantitatively revealed. These results show that the handheld magnetic probe is useful in sentinel lymph node biopsy and that magnetic techniques are widely being accepted as future standard methods in medical institutions lacking nuclear medicine facilities