Germline mutations in RAD51D confer susceptibility to ovarian cancer

Recently, RAD51C mutations were identified in families with breast and ovarian cancer. This observation prompted us to investigate the role of RAD51D in cancer susceptibility. We identified eight inactivating RAD51D mutations in unrelated individuals from 911 breast-ovarian cancer families compared with one inactivating mutation identified in 1,060 controls (P = 0.01). The association found here was principally with ovarian cancer, with three mutations identified in the 59 pedigrees with three or more individuals with ovarian cancer (P = 0.0005). The relative risk of ovarian cancer for RAD51D mutation carriers was estimated to be 6.30 (95% CI 2.86-13.85, P = 4.8 × 10(-6)). By contrast, we estimated the relative risk of breast cancer to be 1.32 (95% CI 0.59-2.96, P = 0.50). These data indicate that RAD51D mutation testing may have clinical utility in individuals with ovarian cancer and their families. Moreover, we show that cells deficient in RAD51D are sensitive to treatment with a PARP inhibitor, suggesting a possible therapeutic approach for cancers arising in RAD51D mutation carriers.     

Variation in genome-wide mutation rates within and between human families

J.B.S. Haldane proposed in 1947 that the male germline may be more mutagenic than the female germline. Diverse studies have supported Haldane's contention of a higher average mutation rate in the male germline in a variety of mammals, including humans. Here we present, to our knowledge, the first direct comparative analysis of male and female germline mutation rates from the complete genome sequences of two parent-offspring trios. Through extensive validation, we identified 49 and 35 germline de novo mutations (DNMs) in two trio offspring, as well as 1,586 non-germline DNMs arising either somatically or in the cell lines from which the DNA was derived. Most strikingly, in one family, we observed that 92% of germline DNMs were from the paternal germline, whereas, in contrast, in the other family, 64% of DNMs were from the maternal germline. These observations suggest considerable variation in mutation rates within and between families.     

Using wavelets to obtain a consistent ordinary least squares estimator of the long‐memory parameter

We develop an ordinary least squares estimator of the long‐memory parameter from a fractionally integrated process that is an alternative to the Geweke and Porter‐Hudak (1983) estimator. Using the wavelet transform from a fractionally integrated process, we establish a log‐linear relationship between the wavelet coefficients' variance and the scaling parameter equal to the log‐memory parameter. This log‐linear relationship yields a consistent ordinary least squares estimator of the long‐memory parameter when the wavelet coefficients' population variance is replaced by their sample variance. We derive the small sample bias and variance of the ordinary least squares estimator and test it against the GPH estimator and the McCoy–Walden maximum likelihood wavelet estimator by conducting a number of Monte Carlo experiments. Based upon the criterion of choosing the estimator which minimizes the mean squared error, the wavelet OLS approach was superior to the GPH estimator, but inferior to the McCoy–Walden wavelet estimator for the processes simulated. However, given the simplicity of programming and running the wavelet OLS estimator and its statistical inference of the long‐memory parameter we feel the general practitioner will be attracted to the wavelet OLS estimator. Copyright © 1999 John Wiley & Sons, Ltd.     

Forecasting US GNP growth: The role of uncertainty

A large number of models have been developed in the literature to analyze and forecast changes in output dynamics. The objective of this paper was to compare the predictive ability of univariate and bivariate models, in terms of forecasting US gross national product (GNP) growth at different forecasting horizons, with the bivariate models containing information on a measure of economic uncertainty. Based on point and density forecast accuracy measures, as well as on equal predictive ability (EPA) and superior predictive ability (SPA) tests, we evaluate the relative forecasting performance of different model specifications over the quarterly period of 1919:Q2 until 2014:Q4. We find that the economic policy uncertainty (EPU) index should improve the accuracy of US GNP growth forecasts in bivariate models. We also find that the EPU exhibits similar forecasting ability to the term spread and outperforms other uncertainty measures such as the volatility index and geopolitical risk in predicting US recessions. While the Markov switching time‐varying parameter vector autoregressive model yields the lowest values for the root mean squared error in most cases, we observe relatively low values for the log predictive density score, when using the Bayesian vector regression model with stochastic volatility. More importantly, our results highlight the importance of uncertainty in forecasting US GNP growth rates.     

Structural variations in wheat HKT1;5 underpin differences in Na<Superscript>+</Superscript> transport capacity

An important trait associated with the salt tolerance of wheat is the exclusion of sodium ions (Na⁺) from the shoot. We have previously shown that the sodium transporters TmHKT1;5-A and TaHKT1;5-D, from Triticum monoccocum (Tm) and Triticum aestivum (Ta), are encoded by genes underlying the major shoot Na⁺-exclusion loci Nax1 and Kna1, respectively. Here, using heterologous expression, we show that the affinity (K _m) for the Na⁺ transport of TmHKT1;5-A, at 2.66 mM, is higher than that of TaHKT1;5-D at 7.50 mM. Through 3D structural modelling, we identify residues D⁴⁷¹/a gap and D⁴⁷⁴/G⁴⁷³ that contribute to this property. We identify four additional mutations in amino acid residues that inhibit the transport activity of TmHKT1;5-A, which are predicted to be the result of an occlusion of the pore. We propose that the underlying transport properties of TmHKT1;5-A and TaHKT1;5-D contribute to their unique ability to improve Na⁺ exclusion in wheat that leads to an improved salinity tolerance in the field.     

Estimating coverage and power for genetic association studies using near-complete variation data

Although studies suggest that SNPs derived from HapMap provide promising coverage and power for association studies, the lack of alternative variation datasets limits independent analysis. Using near-complete variation data for 76 genes resequenced in HapMap samples, we find that coverage of common variation by commercial genotyping arrays is substantially lower compared to the HapMap-based estimates. We quantify the power offered by these arrays for a range of disease models.     

A mutation of human cytochrome c enhances the intrinsic apoptotic pathway but causes only thrombocytopenia

We report the first identified mutation in the gene encoding human cytochrome c (CYCS). Glycine 41, invariant throughout eukaryotes, is substituted by serine in a family with autosomal dominant thrombocytopenia caused by dysregulated platelet formation. The mutation yields a cytochrome c variant with enhanced apoptotic activity in vitro. Notably, the family has no other phenotypic indication of abnormal apoptosis, implying that cytochrome c activity is not a critical regulator of most physiological apoptosis.     

Roadside foraging by kangaroo rats in a grazed short-grass prairie landscape

We used live-trapping and foraging experiments to describe use of roadside vegetation by kangaroo rats ( Dipodomys ordii ) in short-grass prairie in Colorado, and to determine whether this species' perception of predation risk differed between roadside habitats, where predators were expected to be most active, and locations 120 m into adjacent grazed pastures. Giving-up densities (GUDs) were measured in paired seed trays placed beneath saltbush ( Atriplex canescens ) shrubs and in the open, 3 m from shrubs along transects in roadside and pasture locations. Trials were conducted on nights with a partial (1st-quarter), full, and new moon to assess how intensity of risk affected microhabitat use. Kangaroo rats were much more abundant in areas with saltbush cover than in grazed prairie, and were 4–6 times more numerous along roadsides in saltbush areas than in other locations. On dark nights and in pasture locations, foraging rates of kangaroo rats were similar in shrub trays and open trays. The fewest seeds were removed (i.e., GUDs were highest), however, in open trays along roads on moonlit nights, suggesting that kangaroo rats recognized potential risks associated with roadsides on bright nights. The high numbers of kangaroo rats along roads suggest that benefits associated with these habitats (ease of digging, dust bathing, higher soil seed banks) exceed the costs associated with higher risk of mortality from predators and vehicles. Our results demonstrate how foraging decisions differ depending on the spatial and temporal contexts in which behaviors are measured, and underscore the potential value of less common habitats such as road margins for increasing landscape-scale diversity and wildlife habitat in grazed grasslands.     

A new feathered maniraptoran dinosaur fossil that fills a morphological gap in avian origin

Recent fossil discoveries have substantially reduced the morphological gap between non-avian and avian dinosaurs, yet avians including Archaeopteryx differ from non-avian theropods in their limb proportions. In particular, avians have proportionally longer and more robust forelimbs that are capable of supporting a large aerodynamic surface. Here we report on a new maniraptoran dinosaur, Anchiornis huxleyi gen. et sp. nov., based on a specimen collected from lacustrine deposits of uncertain age in western Liaoning, China. With an estimated mass of 110 grams, Anchiornis is the smallest known non-avian theropod dinosaur. It exhibits some wrist features indicative of high mobility, presaging the wing-folding mechanisms seen in more derived birds and suggesting rapid evolution of the carpus. Otherwise, Anchiornis is intermediate in general morphology between non-avian and avian dinosaurs, particularly with regard to relative forelimb length and thickness, and represents a transitional step toward the avian condition. In contrast with some recent comprehensive phylogenetic analyses, our phylogenetic analysis incorporates subtle morphological variations and recovers a conventional result supporting the monophyly of Avialae. Supported by Hundred Talents Project of the Chinese Academy of Sciences, National Natural Science Foundation of China (Grant Nos. 40125006, 40472018), and National Basic Research Program of China (Grant No. 2006CB806400)