Evidence of oligogenic inheritance in nephronophthisis

Nephronophthisis is a recessive cystic renal disease that leads to end-stage renal failure in the first two decades of life. Twenty-five percent of nephronophthisis cases are caused by large homozygous deletions of NPHP1, but six genes responsible for nephronophthisis have been identified. Because oligogenic inheritance has been described for the related Bardet-Biedl syndrome, we evaluated whether mutations in more than one gene may also be detected in cases of nephronophthisis. Because the nephrocystins 1 to 4 are known to interact, we examined patients with nephronophthisis from 94 different families and sequenced all exons of the NPHP1, NPHP2, NPHP3, and NPHP4 genes. In our previous studies involving 44 families, we detected two mutations in one of the NPHP1-4 genes. Here, we detected in six families two mutations in either NPHP1, NPHP3, or NPHP4, and identified a third mutation in one of the other NPHP genes. Furthermore, we found possible digenic disease by detecting one individual who carried one mutation in NPHP2 and a second mutation in NPHP3. Finally, we detected the presence of a single mutation in nine families, suggesting that the second recessive mutation may be in another as yet unidentified NPHP gene. Our findings suggest that oligogenicity may occur in cases of nephronophthisis.

Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes

BACKGROUND: Duplications and deletions in the human genome can cause disease or predispose persons to disease. Advances in technologies to detect these changes allow for the routine identification of submicroscopic imbalances in large numbers of patients. METHODS: We tested for the presence of microdeletions and microduplications at a specific region of chromosome 1q21.1 in two groups of patients with unexplained mental retardation, autism, or congenital anomalies and in unaffected persons. RESULTS: We identified 25 persons with a recurrent 1.35-Mb deletion within 1q21.1 from screening 5218 patients. The microdeletions had arisen de novo in eight patients, were inherited from a mildly affected parent in three patients, were inherited from an apparently unaffected parent in six patients, and were of unknown inheritance in eight patients. The deletion was absent in a series of 4737 control persons (P=1.1x10(-7)). We found considerable variability in the level of phenotypic expression of the microdeletion; phenotypes included mild-to-moderate mental retardation, microcephaly, cardiac abnormalities, and cataracts. The reciprocal duplication was enriched in nine children with mental retardation or autism spectrum disorder and other variable features (P=0.02). We identified three deletions and three duplications of the 1q21.1 region in an independent sample of 788 patients with mental retardation and congenital anomalies. CONCLUSIONS: We have identified recurrent molecular lesions that elude syndromic classification and whose disease manifestations must be considered in a broader context of development as opposed to being assigned to a specific disease. Clinical diagnosis in patients with these lesions may be most readily achieved on the basis of genotype rather than phenotype.

Patch selection by wintering white-tailed deer : consequences for eastern hemlock regeneration at local and landscape scales

Tsuga canadensis (eastern hemlock) is a highly shade-tolerant, late-successional, and long-lived conifer species found throughout eastern North America. It is most often found in pure or nearly pure stands, because highly acidic and nutrient poor forest floor conditions are thought to favor T. canadensis regeneration while simultaneously limiting the establishment of some hardwood species with greater nutrient requirements. Once a common species, T. canadensis is currently experiencing widescale declines across its range. The hemlock woolly adelgid (Adelges tsugae) is decimating the population across its eastern distribution. Across the Upper Great Lakes region, where the adelgid is currently being held at bay by cold winter temperatures, T. canadensis has been experiencing failures in regeneration attributed, in part, to herbivory by white-tailed deer (Odocoileus virginianus). Deer utilize T. canadensis stands as winter habitat in areas of high snow depth. Tsuga canadensis, once a major component of these forests, currently exists at just a fraction of its pre-settlement abundance due to historic logging and contemporary forest management practices, and what remains is found in small remnant patches surrounded by second- and third-growth deciduous forests. The deer population across the region, however, is likely double that of pre-European settlement times. In this dissertation I explore the relationship between white-tailed deer use of T. canadensis as winter habitat and the effect this use is having on regeneration and forest succession. For this research I quantified stand composition and structure and abiotic variables of elevation and snow depth in 39 randomly selected T. canadensis stands from across the western Upper Peninsula of Michigan. I also quantified composition and the configuration of the landscapes surrounding these stands. I measured relative deer use of T. canadensis stands as pellet group piles deposited in each stand during each of three consecutive winters, 2005-06, 2006-07, and 2007-08. The results of this research suggest that deer use of T. canadensis stands as winter habitat is influenced primarily by snow depth, elevation, and the composition and configuration of the greater landscapes surrounding these stands. Specifically, stands with more heterogeneous landscapes surrounding them (i.e., a patchy mosaic of conifer, deciduous, and open cover) had higher relative deer use than stands surrounded by homogenous deciduous forest cover. Additionally, the intensity of use and the number of stands used was greater in years with higher average snow depth. Tsuga canadensis regeneration in these stands was negatively associated with deer use and Acer saccharum (sugar maple) basal area. Of the 39 stands, 17 and 22 stands had no T. canadensis regeneration in small and large sapling categories, respectively. Acer saccharum was the most common understory tree species, and the importance of A. saccharum in the understory (stems < 10 cm dbh) of the stands was positively associated with overstory A. saccharum dominance. Tsuga canadensis establishment was associated with high-decay coarse woody debris and moss, and deciduous leaf litter inputs in these stands may be limiting access to these important microsites. Furthermore, A. saccharum is more tolerant to the effects of deer herbivory than T. canadensis, giving A. saccharum a competitive advantage in stands being utilized as winter habitat by deer. My research suggests that limited microsite availability, in conjunction with deer herbivory, may be leading to an erosion in T. canadensis patch stability and an altered successional trajectory toward one of A. saccharum dominance, an alternately stable climax species.

Genetic association studies under the population stratification, family pedigree and application to genome-wide association studies

This dissertation has three separate parts: the first part deals with the general pedigree association testing incorporating continuous covariates; the second part deals with the association tests under population stratification using the conditional likelihood tests; the third part deals with the genome-wide association studies based on the real rheumatoid arthritis (RA) disease data sets from Genetic Analysis Workshop 16 (GAW16) problem 1. Many statistical tests are developed to test the linkage and association using either case-control status or phenotype covariates for family data structure, separately. Those univariate analyses might not use all the information coming from the family members in practical studies. On the other hand, the human complex disease do not have a clear inheritance pattern, there might exist the gene interactions or act independently. In part I, the new proposed approach MPDT is focused on how to use both the case control information as well as the phenotype covariates. This approach can be applied to detect multiple marker effects. Based on the two existing popular statistics in family studies for case-control and quantitative traits respectively, the new approach could be used in the simple family structure data set as well as general pedigree structure. The combined statistics are calculated using the two statistics; A permutation procedure is applied for assessing the p-value with adjustment from the Bonferroni for the multiple markers. We use simulation studies to evaluate the type I error rates and the powers of the proposed approach. Our results show that the combined test using both case-control information and phenotype covariates not only has the correct type I error rates but also is more powerful than the other existing methods. For multiple marker interactions, our proposed method is also very powerful. Selective genotyping is an economical strategy in detecting and mapping quantitative trait loci in the genetic dissection of complex disease. When the samples arise from different ethnic groups or an admixture population, all the existing selective genotyping methods may result in spurious association due to different ancestry distributions. The problem can be more serious when the sample size is large, a general requirement to obtain sufficient power to detect modest genetic effects for most complex traits. In part II, I describe a useful strategy in selective genotyping while population stratification is present. Our procedure used a principal component based approach to eliminate any effect of population stratification. The paper evaluates the performance of our procedure using both simulated data from an early study data sets and also the HapMap data sets in a variety of population admixture models generated from empirical data. There are one binary trait and two continuous traits in the rheumatoid arthritis dataset of Problem 1 in the Genetic Analysis Workshop 16 (GAW16): RA status, AntiCCP and IgM. To allow multiple traits, we suggest a set of SNP-level F statistics by the concept of multiple-correlation to measure the genetic association between multiple trait values and SNP-specific genotypic scores and obtain their null distributions. Hereby, we perform 6 genome-wide association analyses using the novel one- and two-stage approaches which are based on single, double and triple traits. Incorporating all these 6 analyses, we successfully validate the SNPs which have been identified to be responsible for rheumatoid arthritis in the literature and detect more disease susceptibility SNPs for follow-up studies in the future. Except for chromosome 13 and 18, each of the others is found to harbour susceptible genetic regions for rheumatoid arthritis or related diseases, i.e., lupus erythematosus. This topic is discussed in part III.

Identification of novel mutations in X-linked retinitis pigmentosa families and implications for diagnostic testing

PURPOSE: The goal of this study was to identify mutations in X-chromosomal genes associated with retinitis pigmentosa (RP) in patients from Germany, The Netherlands, Denmark, and Switzerland. METHODS: In addition to all coding exons of RP2, exons 1 through 15, 9a, ORF15, 15a and 15b of RPGR were screened for mutations. PCR products were amplified from genomic DNA extracted from blood samples and analyzed by direct sequencing. In one family with apparently dominant inheritance of RP, linkage analysis identified an interval on the X chromosome containing RPGR, and mutation screening revealed a pathogenic variant in this gene. Patients of this family were examined clinically and by X-inactivation studies. RESULTS: This study included 141 RP families with possible X-chromosomal inheritance. In total, we identified 46 families with pathogenic sequence alterations in RPGR and RP2, of which 17 mutations have not been described previously. Two of the novel mutations represent the most 3'-terminal pathogenic sequence variants in RPGR and RP2 reported to date. In exon ORF15 of RPGR, we found eight novel and 14 known mutations. All lead to a disruption of open reading frame. Of the families with suggested X-chromosomal inheritance, 35% showed mutations in ORF15. In addition, we found five novel mutations in other exons of RPGR and four in RP2. Deletions in ORF15 of RPGR were identified in three families in which female carriers showed variable manifestation of the phenotype. Furthermore, an ORF15 mutation was found in an RP patient who additionally carries a 6.4 kbp deletion downstream of the coding region of exon ORF15. We did not identify mutations in 39 sporadic male cases from Switzerland. CONCLUSIONS: RPGR mutations were confirmed to be the most frequent cause of RP in families with an X-chromosomal inheritance pattern. We propose a screening strategy to provide molecular diagnostics in these families.

Ankyloglossia: facts and myths in diagnosis and treatment

BACKGROUND: The objective of this study was to systematically review the diagnostic criteria, indications, and need for treatment of ankyloglossia (tongue-tie), as well as the various treatment options for patients in different age groups. METHODS: The MEDLINE databases and the Cochrane Library were searched according to well-defined criteria, resulting in 64 included articles. The evidence regarding the classifications of tongue-tie, epidemiologic data, inheritance, breastfeeding problems, impaired tongue mobility, speech disorders, malocclusion, gingival recessions, therapy, and complications due to surgery was analyzed in detail. RESULTS: Different classifications for ankyloglossia have been proposed but not uniformly accepted. Breastfeeding problems in neonates could be associated with a tongue-tie, but not enough controlled trials have been performed to identify an ideal treatment option. In children and adults with ankyloglossia, limitations in tongue mobility are present, but the individual degree of discomfort, as well as the severity of an associated speech problem, are subjective and difficult to categorize. There is no evidence supporting the development of gingival recessions because of ankyloglossia. Frenotomy, frenectomy, and frenuloplasty are the main surgical treatment options to release/remove an ankyloglossia. Because of the limited evidence available, no specific surgical method can be favored. CONCLUSIONS: The lack of an accepted definition and classification of ankyloglossia makes comparisons between studies almost impossible. Because almost no controlled prospective trials for surgical interventions in patients with tongue-ties are present in the literature, no conclusive suggestions regarding the method of choice can be made. It also remains controversial which tongue-ties need to be surgically removed and which can be left to observation.

Education and Ideologies of the Knowledge Economy: Europe and the Politics of Emulation

The Austrian philosopher Ludwig Wittgenstein famously proposed a style of philosophy that was directed against certain pictures [bild] that tacitly direct our language and forms of life. His aim was to show the fly the way out of the fly bottle and to fight against the bewitchment of our intelligence by means of language: “A picture held us captive. And we could not get outside it, for it lay in our language and language seemed to repeat it to us inexorably” (Wittgenstein 1953, 115). In this context Wittgenstein is talking of philosophical pictures, deep metaphors that have structured our language but he does also use the term picture in other contexts (see Owen 2003, 83). I want to appeal to Wittgenstein in my use of the term ideology to refer to the way in which powerful underlying metaphors in neoclassical economics have a strong rhetorical and constitutive force at the level of public policy. Indeed, I am specifically speaking of the notion of ‘the performative’ in Wittgenstein and Austin. The notion of the knowledge economy has a prehistory in Hayek (1937; 1945) who founded the economics of knowledge in the 1930s, in Machlup (1962; 1970), who mapped the emerging employment shift to the US service economy in the early 1960s, and to sociologists Bell (1973) and Touraine (1974) who began to tease out the consequences of these changes for social structure in the post-industrial society in the early 1970s. The term has been taken up since by economists, sociologists, futurists and policy experts recently to explain the transition to the so-called ‘new economy’. It is not just a matter of noting these discursive strands in the genealogy of the ‘knowledge economy’ and related or cognate terms. We can also make a number of observations on the basis of this brief analysis. First, there has been a succession of terms like ‘postindustrial economy’, ‘information economy’, ‘knowledge economy’, ‘learning economy’, each with a set of related concepts emphasising its social, political, management or educational aspects. Often these literatures are not cross-threading and tend to focus on only one aspect of phenomena leading to classic dichotomies such as that between economy and society, knowledge and information. Second, these terms and their family concepts are discursive, historical and ideological products in the sense that they create their own meanings and often lead to constitutive effects at the level of policy. Third, while there is some empirical evidence to support claims concerning these terms, at the level of public policy these claims are empirically underdetermined and contain an integrating, visionary or futures component, which necessarily remains untested and is, perhaps, in principle untestable.

Endangering of Businesses by the German Inheritance Tax? – An Empirical Analysis

This contribution addresses the substantial tax privilege for businesses introduced by the German Inheritance Tax Act 2009. Advocates of the vast or even entire tax exemption for businesses stress the potential damage of the inheritance tax on businesses, as those often lack liquidity to meet tax liability. This submission tackles this issue empirically based on data of the German Inheritance Tax Statistics and the SOEP. The results indicate that former German inheritance tax law has not endangered transferred businesses. Hence, there is no need for the tremendous tax privilege for businesses in current German inheritance tax law. An alternative flat inheritance tax without tax privileges, which meets revenue neutrality per tax class according to current tax law, provokes in some cases relative high tax loads which might trouble businesses.

Mixed inheritance of equine recurrent airway obstruction

BACKGROUND: Mode of inheritance of equine recurrent airway obstruction (RAO) is unknown. HYPOTHESIS: Major genes are responsible for RAO. ANIMALS: Direct offspring of 2 RAO-affected Warmblood stallions (n = 197; n = 163) and a representative sample of Swiss Warmbloods (n = 401). METHODS: One environmental and 4 genetic models (general, mixed inheritance, major gene, and polygene) were tested for Horse Owner Assessed Respiratory Signs Index (1-4, unaffected to severely affected) by segregation analyses of the 2 half-sib sire families, both combined and separately, using prevalences estimated in a representative sample. RESULTS: In all data sets the mixed inheritance model was most likely to explain the pattern of inheritance. In all 3 datasets the mixed inheritance model did not differ significantly from the general model (P= .62, P= 1.00, and P= .27) but was always better than the major gene model (P < .01) and the polygene model (P < .01). The frequency of the deleterious allele differed considerably between the 2 sire families (P= .23 and P= .06). In both sire families the displacement was large (t= 17.52 and t= 12.24) and the heritability extremely large (h(2)= 1). CONCLUSIONS AND CLINICAL RELEVANCE: Segregation analyses clearly reveal the presence of a major gene playing a role in RAO. In 1 family, the mode of inheritance was autosomal dominant, whereas in the other family it was autosomal recessive. Although the expression of RAO is influenced by exposure to hay, these findings suggest a strong, complex genetic background for RAO.

Hanging Together, Together Hung? Career Implications of Interpersonal Ties Between CEOs and Top Managers

Is it good or bad for senior executives to have strong interpersonal ties to the CEO? We argue that a strong relationship with the CEO raises the likelihood that a top manager stays in office or makes an upward career move when the CEO leaves office voluntarily. At the same time, such interpersonal ties also reinforce the negative spillover effects of a dismissal of the CEO on the career prospects of the manager concerned. Our empirical analysis lends support to both arguments. We contribute to managerial succession research by underlining the ambivalence of interpersonal ties within top management teams.

Old captains at the helm: chairman age and firm performance

This paper examines whether the chairmen of the boards (COBs) impose their life cycles on the firms over which they preside. Using a large sample of unlisted firms, we find a robust negative relation between COB age and firm performance. COBs age much like ‘ordinary’ people. Their cognitive abilities deteriorate, and they experience significant shifts in motivation. Deteriorating cognitive abilities are the main driver of the performance effect that we observe. The results imply that succession planning problems in unlisted firms are real. Mandatory retirement age clauses cannot solve these problems.

Petrology and geochronology of "muscovite age standard" B4M

Muscovite B4M, distributed in 1961 as an age standard, was ground under ethanol. Five grain size fractions were obtained and characterized by X-ray diffraction. They display a mixing trend between a phengitic (enriched in the fraction <0.2 µm) and a muscovitic component (predominant in the fraction >20 µm). High-pressure phengite is preserved as a relict in retrograde muscovite. Electron microprobe analyses of the distributed mineral separate reveal at least four white mica populations based on Si, Al, Mg, Na, Fe and F. Rb/K ratios vary by one order of magnitude. Rb–Sr analyses link the mineralogical heterogeneity to variable Rb/Sr and 87Sr/86Sr ratios. The grain size fractions define no internal isochron. Relict fine-grained phengite gives older ages than coarse-grained retrograde greenschist facies muscovite. The inverse grain size–age relationship also characterizes 39Ar/40Ar analyses. Cl/K anticorrelates with step ages: Cl-rich coarse muscovite is younger than Cl-poor fine relict phengite. Sr and Ar preserve a similar isotopic inheritance despite peak metamorphism reaching 635±20 °C. A suitable mineral standard requires that its petrological equilibrium first be demonstrated. Relicts and retrograde reaction textures are a guarantee of isotopic disequilibrium and heterogeneous ages within single crystal at the micrometre scale.

Relations between the attentional blink and aspects of psychometric intelligence: A fixed-links modeling approach

The attentional blink phenomenon (AB) represents impaired identification of the second of two targets presented in rapid succession within a stream of stimuli. Despite the well-known association between attentional processes and psychometric intelligence (PI), evidence for a relationship between AB and PI is highly inconsistent. Theory and empirical findings suggest AB to be multifaceted. Hence, relations between AB and PI may be blurred when AB is measured as a single process. Furthermore, different aspects of PI might be differentially related to AB. The present study explored the relationship between processes underlying AB and general PI as well as specific aspects of PI (Reasoning, Speed, Memory, and Creativity) in 201 female students. Fixed-links modeling revealed three processes underlying AB: (1) a U-shaped process positively related to Speed and negatively related to Memory but unrelated to Reasoning, Creativity, and general PI, (2) an increasing process positively related to Reasoning, Speed, Memory, and general PI but not to Creativity, and (3) a decreasing process positively related to general PI and Memory but not to other aspects of PI. Our findings demonstrate that dissociating processes underlying AB and considering specific aspects of PI is required to understand the relationship between AB and PI.

Inheritance of ectopic ureters in Entlebucher Mountain Dogs

To test the hypothesis of a heritable base of ectopic ureters (EU) in Entlebucher Mountain Dogs (EMD) and to elucidate associated risk factors and mode of inheritance of the disease, 565 EMD were clinically investigated and population genetic analyses performed. Based on the location of the most caudal termination of the ureteral openings, 552 EMD were classified into three phenotype groups trigone, intravesically and extravesically ectopic based on results of abdominal sonography, urethra-cystoscopy and/or contrast-enhanced computed tomography. One-third (32.9%) of the phenotyped animals had normal terminations of both ureters in the bladder trigone, 47.3% had at least one intravesicular ectopic termination and 19.8% had at least one extravesicular ectopic termination. Multivariate mixed logistic regression revealed gender as a risk factor associated with EU as males were more often affected than females. Complex segregation analysis indicated a hereditary basis for EU in EMD and the involvement of a major gene in the occurrence of the extravesicular EU phenotype.

Modeling the heterogeneous ice and gas coma of Comet 103P/Hartley 2

The spectacular images of Comet 103P/Hartley 2 recorded by the Medium Resolution Instrument (MRI) and High Resolution Instrument (HRI) on board of the Extrasolar Planet Observation and Deep Impact Extended Investigation (EPOXI) spacecraft, as the Deep Impact extended mission, revealed that its bi-lobed very active nucleus outgasses volatiles heterogeneously. Indeed, CO2 is the primary driver of activity by dragging out chunks of pure ice out of the nucleus from the sub-solar lobe that appear to be the main source of water in Hartley 2's coma by sublimating slowly as they go away from the nucleus. However, water vapor is released by direct sublimation of the nucleus at the waist without any significant amount of either CO2 or icy grains. The coma structure for a comet with such areas of diverse chemistry differs from the usual models where gases are produced in a homogeneous way from the surface. We use the fully kinetic Direct Simulation Monte Carlo model of Tenishev et al. (Tenishev, V.M., Combi, M.R., Davidsson, B. [2008]. Astrophys. J. 685, 659-677; Tenishev, V.M., Combi, M.R., Rubin, M. [2011]. Astrophys. J. 732, 104-120) applied to Comet 103P/Hartley 2 including sublimating icy grains to reproduce the observations made by EPOXI and ground-based measurements. A realistic bi-lobed nucleus with a succession of active areas with different chemistry was included in the model enabling us to study in details the coma of Hartley 2. The different gas production rates from each area were found by fitting the spectra computed using a line-by-line non-LTE radiative transfer model to the HRI observations. The presence of icy grains with long lifetimes, which are pushed anti-sunward by radiation pressure, explains the observed OH asymmetry with enhancement on the night side of the coma.