bluuebunny/crossref_metadata_2025 huggingface dataset:
Ranks of Genuine Associations in Whole-Genome Scans
Authors: Zaykin Dmitri V , Zhivotovsky Lev A
Published: July 2005

With the recent advances in high-throughput genotyping techniques, it is now possible to perform whole-genome association studies to fine map causal polymorphisms underlying important traits that influence susceptibility to human diseases and efficacy of drugs. Once a genome scan is completed the results can be sorted by the association statistic value. What is the probability that true positives will be encountered among the first most associated markers? When a particular polymorphism is found associated with the trait, there is a chance that it represents either a “true” or a “false” association (TA vs. FA). Setting appropriate significance thresholds has been considered to provide assurance of sufficient odds that the associations found to be significant are genuine. However, the problem with genome scans involving thousands of markers is that the statistic values of FAs can reach quite extreme magnitudes. In such situations, the distributions corresponding to TAs and the most extreme FAs become comparable and significance thresholds tend to penalize TAs and FAs in a similar fashion. When sorting between true and false associations, the “typical” place (i.e., rank) of TAs among the most significant outcomes becomes important, ordered by the association statistic value. The distribution of ranks that we study here allows calculation of several useful quantities. In particular, it gives the number of most significant markers needed for a follow-up study to guarantee that a true association is included with certain probability. This can be calculated conditionally on having applied a multiple-testing correction. Effects of multilocus (e.g., haplotype association) tests and impact of linkage disequilibrium on the distribution of ranks associated with TAs are evaluated and can be taken into account.
The RuvAB Branch Migration Translocase and RecU Holliday Junction Resolvase Are Required for Double-Stranded DNA Break Repair in Bacillus subtilis
Authors: Sanchez Humberto , Kidane Dawit , Reed Patricia , Curtis Fiona A , Cozar M Castillo , Graumann Peter L , Sharples Gary J , Alonso Juan C
Published: July 2005

In models of Escherichia coli recombination and DNA repair, the RuvABC complex directs the branch migration and resolution of Holliday junction DNA. To probe the validity of the E. coli paradigm, we examined the impact of mutations in ΔruvAB and ΔrecU (a ruvC functional analog) on DNA repair. Under standard transformation conditions we failed to construct ΔruvAB ΔrecG, ΔrecU ΔruvAB, ΔrecU ΔrecG, or ΔrecU ΔrecJ strains. However, ΔruvAB could be combined with addAB (recBCD), recF, recH, ΔrecS, ΔrecQ, and ΔrecJ mutations. The ΔruvAB and ΔrecU mutations rendered cells extremely sensitive to DNA-damaging agents, although less sensitive than a ΔrecA strain. When damaged cells were analyzed, we found that RecU was recruited to defined double-stranded DNA breaks (DSBs) and colocalized with RecN. RecU localized to these centers at a later time point during DSB repair, and formation was dependent on RuvAB. In addition, expression of RecU in an E. coli ruvC mutant restored full resistance to UV light only when the ruvAB genes were present. The results demonstrate that, as with E. coli RuvABC, RuvAB targets RecU to recombination intermediates and that all three proteins are required for repair of DSBs arising from lesions in chromosomal DNA.
Ultraviolet Radiation, Vitamin D and Risk of Prostate Cancer and Other Diseases
Authors: Moon Samuel J. , Fryer Anthony A. , Strange Richard C.
Published: July 2005

Most common diseases appear to result from complex, poorly understood interactions between genetic and environmental factors. Relatively few factors have been unequivocally linked with disease risk or outcome. Evidence from various studies using different experimental approaches has been interpreted as showing that, apart from its harmful effects on the pathogenesis of the common skin cancers, ultraviolet radiation (UVR) may exert a beneficial effect on development of various internal cancers and other pathologies. This concept is supported by parallel studies showing that hypovitaminosis D is linked with increased risk of various diseases including insulin resistance and multiple sclerosis. These findings suggest that, first, host factors such as skin pigmentation that affect UVR‐induced synthesis of vitamin D and, second, polymorphism in genes that mediate the effectiveness of vitamin D action are susceptibility candidates for a variety of diseases. Collectively, these data suggest the hypothesis that, via effects on vitamin D synthesis, UVR exposure has beneficial effects on susceptibility and outcome to a variety of complex diseases. We describe evidence from studies in various diseases, but mainly from prostate cancer patients, that supports this hypothesis, but we emphasize that, although supportive data are available, the concept is unproven. Indeed, other explanations are possible. However, given the potentially important public health implications of the hypothesis and the potential for the development of novel therapeutic modalities, we believe the concept is worthy of further investigation.
Effect of electron‐beam treatment of zinc sulfide on electroluminescent phosphor properties
Authors: Sychov M. M. , Bakhmetiev V. V. , Komarov E. V. , Mjakin S. V. , Vasilieva I. V. , Nakanishi Y. , Korobko V. N. , Kuznetsov A. I.
Published: July 2005

Abstract— Electron‐beam processing of starting‐material ZnS increased the luminance derived from electroluminescent phosphors. As is shown in the paper, irradiation caused the formation of defects in ZnS that resulted in increased copper content in the phosphor due to the promotion of diffusion and the formation of additional “green” luminescence centers. A change in surface properties was also investigated, and it was found that processing resulted in increased the amount of both surface zinc and sulfur vacancies as well as the amount of surface centers related to copper.
Genetic Variations in the Human Gelatinase A (Matrix Metalloproteinase‐2) Promoter Are Not Associated With Susceptibility to, and Severity of, Chronic Periodontitis
Authors: Holla Lydie Izakovicova , Fassmann Antonin , Vasku Anna , Goldbergova Monika , Beranek Michal , Znojil Vladimír , Vanek Jiri , Vacha Jiri
Published: July 2005

Background: Gelatinase A (matrix metalloproteinase‐2 [MMP‐2]) has been shown to play an important role in the pathogenesis of several disorders, including periodontal diseases. In this study, we test the hypothesis that variations in this gene influence the development and severity of chronic periodontitis.

Methods: Four promoter polymorphisms (‐1575G/A, ‐1306C/T, ‐790T/G, and ‐735C/T) were analyzed by polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) methods in 149 patients with mild to severe chronic periodontitis and 127 age‐matched controls in the Czech population.

Results: No significant differences in distribution of the ‐1575G/A, ‐1306C/T, and ‐735C/T variants between periodontitis and control groups were detected in our study. However, a trend to decreased frequency of the ‐790 GG homozygotes was observed in patients with chronic periodontitis compared to healthy controls (P = 0.036, P corr >0.05). Haplotype analysis of four single nucleotide polymorphisms (SNP) in the MMP‐2 gene showed no significant association of any haplotype with chronic periodontitis.

Conclusion: Our findings suggest that polymorphisms in the MMP‐2 gene promoter do not contribute significantly to the interindividual periodontitis susceptibility and/or severity in European Caucasians, and they are not regulatory variants in this disease. J Periodontol 2005;76:1056‐1060.
Resonance Frequency Analysis of One‐ Stage Dental Implant Stability During the Osseointegration Period
Authors: Ersanli S. , Karabuda C. , Beck F. , Leblebicioglu B.
Published: July 2005

Background: Currently, there is no available clinical tool to evaluate the amount of osseointegration and stability around dental implants. It has been recently suggested that changes in the stiffness of an implant in bone during healing may be monitored by using resonance frequency analysis (RFA). The aim of this study was to determine whether RFA can be integrated into the routine clinical evaluation of initial healing of dental implants.

Methods: Thirty‐one patients (18 female and 13 male; mean age of 51.7 years) were included into this study. A total of 122 implants and three different, but comparable, implant designs were evaluated by using RFA. The specific transducer for each implant system was used. ISQ (implant stability quotient) readings were obtained for each implant at the time of surgery, 3 and 6 weeks postoperatively, and at the time of loading (3 or 6 months following surgery). Data were analyzed for different healing times, various anatomical locations, implant length, and type. Average time in function was 12 months.

Results: Two implants failed during healing. Implant stability was higher on the mandible compared to the maxilla for each implant system studied (Mann‐Whitney test, P <0.01). ISQ readings decreased significantly at 3 and 6 weeks post‐surgery compared to readings obtained at surgery (Wilcoxon matched pairs sign‐rank tests, P <0.01). A recovery to the initial ISQ levels was noted at the time of implant loading. The possible effects of different types and lengths of implants to ISQ readings were examined.

Conclusions: Results of this study support the need for a clinical tool to evaluate dental implant stability prior to loading, especially for implants placed in the maxilla. It appears that implant stability is weakest at 3 to 6 weeks in one‐stage non‐loaded dental implants. ISQ readings can be used to determine different healing phases and the stability of dental implants. However, it is difficult to define a general standardized range of ISQ readings for successful implant integration for various implant systems. Thus, RFA values/ISQ levels should be calibrated for each implant system separately. Further studies are needed to compare the early changes seen in immediately loaded dental implants and to determine whether there is any time in which the total recovery in ISQ levels may occur. J Periodontol 2005;76:1066‐1071.
Periodontal Disease and the Incidence of Tooth Loss in Postmenopausal Women
Authors: Tezal Mine , Wactawski‐Wende Jean , Grossi Sara G. , Dmochowski Jacek , Genco Robert J.
Published: July 2005

Background: The role of periodontal disease as a predictor of incident tooth loss in postmenopausal women has not been determined. The aim of this cohort study was to determine the extent of the association between baseline periodontal status and incident tooth loss in a population of postmenopausal women.

Methods: The study population included 106 dentate white postmenopausal women who participated in a cross‐sectional study between 1989 and 1991 who were willing and eligible to have a repeat examination after 10 to 13 years. At baseline, full‐mouth assessment of periodontal status was performed clinically and radiographically. Assessment of tooth loss during follow‐ up was assessed clinically by a periodontist. Odds ratio (OR) and its 95% confidence interval (CI) for each periodontal variable was obtained from separate multiple logistic regression analyses adjusting for the effect of age, household income, smoking, hormone therapy, snack consumption, and number of decayed teeth.

Results: Sixty‐one (57.5%) subjects lost at least one tooth during follow‐up. Mean tooth loss per person was 1.81 ± 2.77. After adjusting for confounders, each millimeter of alveolar bone loss at baseline increased the risk of tooth loss 3‐fold (OR = 3.26; 95% CI: 1.60 to 6.64). The risk of tooth loss also increased 2.5 times for each millimeter of clinical attachment loss (OR = 2.50; 95% CI: 1.24 to 5.07). Probing depth (OR = 2.53; 95% CI: 0.98 to 6.53), gingival bleeding (OR = 1.99; 95% CI: 0.21 to 18.94), calculus (OR = 2.05; 95% CI: 0.91 to 4.61), and plaque (OR = 0.70; 95% CI: 0.13 to 3.34) were not significantly associated with incident tooth loss.

Conclusion: Periodontal disease, especially measured by alveolar bone loss, is a strong and independent predictor for incident tooth loss in postmenopausal women. J Periodontol 2005;76:1123‐1128.
Integrated Management of Cogongrass [Imperata cylindrica (L.) Rauesch.] in Corn Using Tillage, Glyphosate, Row Spacing, Cultivar, and Cover Cropping
Authors: Chikoye David , Udensi Udensi E. , Ogunyemi Shola
Published: July 2005

Cogongrass [Imperata cylindrica (L.) Raeusch.] is a major weed in the tropics where land is intensively cultivated and fallow duration is less than 5 yr. Field studies were conducted in 1999 and 2000 in Nigeria to evaluate cogongrass response to combinations of five weed control options. Treatment combinations were tillage (hoe tillage and no‐tillage), corn (Zea mays L.), row spacing (50 and 75 cm), corn cultivar [open‐pollinated (OP) and hybrid], herbicide (glyphosate and no glyphosate), and cover crop {velvetbean [Mucuna cochinchinensis (Lour) A. Chev] and no velvetbean}. The treatment combinations were arranged in a randomized complete block design with three replications. Integrating tillage, herbicide, and cover cropping with velvetbean gave optimal control of cogongrass. Corn height and leaf area were negatively correlated with cogongrass shoot, rhizome, and total biomass. Corn grain yield was negatively correlated with cogongrass shoot biomass and total cogongrass biomass (shoot + rhizome). Good control of other weeds was achieved through the use of narrow corn row spacing and cover cropping with velvetbean. Tillage, narrow corn row spacing, and the use of herbicide had a positive effect on corn grain yield. The use of competitive cultivars, narrow row spacing, cover crop, and herbicide may be sustainable approaches to the control of cogongrass and other weeds in corn.
Initiation Date and Nitrogen Rate for Stockpiling Smooth Bromegrass in the North‐Central USA
Authors: Cuomo Gregory J. , Rudstrom Margot V. , Peterson Paul R. , Johnson Dennis G. , Singh Av , Sheaffer Craig C.
Published: July 2005

Increasing costs associated with winter feeding have renewed interest in extending the grazing season in the North‐Central USA. A factorial design with three N treatments was applied to existing smooth bromegrass (Bromus inermis Leyss.) pastures to evaluate initiation dates and N fertilization rates for stockpiling forage. Stockpile initiation dates were 1 June, 15 June, 1 July, 15 July, 1 August, and 15 August. Nitrogen fertilization treatments were 0, 56, or 112 kg ha−1. Data collected included forage mass in October, residual forage mass the subsequent April, leaf concentration, and forage nutritive value. October forage availability was generally greater from earlier stockpile initiation dates (2.58, 2.44, 1.98, 1.28, 0.78, and 0.65 Mg dry matter ha−1 for 1 June, 15 June, 1 July, 15 July, 1 August, and 15 August stockpile initiation dates, respectively; LSD at 0.05 = 0.19). Leaf mass available in October was similar through the 15 July stockpile initiation date. October forage mass was greater with 56 kg N ha−1 than with 0 N fertilization, averaging 1.26, 1.75, and 1.85 Mg ha−1 (LSD at 0.05 = 0.14) for 0, 56, and 112 kg N ha−1, respectively, when averaged across stockpile initiation dates and years. Trends in April forage mass for stockpile initiation date and N fertilization tended to be similar to October. Crude protein tended to increase and acid detergent fiber and neutral detergent fiber tended to decrease as stockpile initiation was later in the season. These results indicate that initiating stockpiling of smooth bromegrass–dominated pastures about 1 July with 56 kg N ha−1 optimizes stockpiled smooth bromegrass in the North‐Central region.
Agronomic Response of Cool‐Season Grasses to Low‐Intensity Harvest Management and Low Potassium Fertility
Authors: Cherney J. H. , Cherney D. J. R.
Published: July 2005

Species selection, fertilization, and harvest management can have a major impact on forage K concentration, and low K is critical for nonlactating dairy cow forage. Our objective was to determine if selection of grass species, along with appropriate fertilization and harvest management, will result in minimizing forage K concentration for nonlactating dairy cows while maintaining stand persistence. Three K fertilizer treatments were applied to reed canarygrass (Phalaris arundinaceaeL.), timothy (Phleum pratenseL.), orchardgrass (Dactylis glomerataL.), smooth bromegrass (Bromus inermisLeyss.), and tall fescue (Festuca arundinaceaSchreb.) for 6 yr on a Williamson silt loam (coarse‐silty, mixed, active, mesic Typic Fragiudepts) soil type in Ithaca, NY. All grass species persisted through the completion of the experiment, without visible K deficiency symptoms. Yield of dry matter (DM) was 5.6% higher (P< 0.05) under split applications of K fertilizer compared with the 0 K fertilizer treatment. Annual K uptake was increased 17.2% with split application of K fertilizer although apparent recovery of K averaged less than 20%. Forage quality was not greatly impacted by K fertilization although the K concentration of forage increased by 12% due to K fertilization. Fertilization with K tended to reduce the forage concentration of P, Ca, Mg, B, and Na. Application of K fertilizer to 0 K fertilizer plots at the conclusion of the experiment overcame any negative effects on DM yield due to prolonged absence of K fertilization. It was possible to achieve sufficiently low forage K concentrations for nonlactating dairy cow forage in all five cool‐season grasses and maintain stand persistence, with lowest forage K concentrations in timothy.
Corn Response to Nitrogen Fertilization in a Soil with High Residual Nitrogen
Authors: Halvorson Ardell D. , Schweissing Frank C. , Bartolo Michael E. , Reule Curtis A.
Published: July 2005

High levels of residual NO3–N are present in the soils of the Arkansas River Valley in Colorado where alfalfa (Medicago sativa L.), grains, fruits, and vegetable crops are produced. This study evaluated the use of continuous corn (Zea mays L.) to reduce residual N levels in a furrow‐irrigated, silty clay soil. Fertilizer N needed to maintain optimum corn yields following watermelon [Citrullus lanatus (Thunb.) Matsum. and Nakai], and its impacts on NO3–N leaching potential were also evaluated. Treatments evaluated from 2000 through 2003 included two N sources (urea and Polyon) and six fertilizer N rates. Corn grain yields were not significantly increased by N fertilization the first year following watermelon but increased with increasing residual soil NO3–N levels the second year without additional N fertilization and increased by N fertilization in the third and fourth years. Nitrogen source did not significantly affect corn grain yields, residual soil NO3–N, or N fertilizer use efficiency (NFUE). Nitrogen use efficiency generally decreased with increasing level of available N. Average NFUE based on grain N removal over 4 yr was 55% at the lowest fertilizer N rate and 30% at the highest N rate. Excluding the first corn crop, grain yields and gross economic returns less N costs were maximized with about 265 and 258 kg ha−1 of available N (soil plus fertilizer N), respectively. Soil residual NO3–N levels declined following the second, third, and fourth corn crops. Reducing N application rates (based on credits for residual soil NO3–N and previous crop) to the first corn crop produced in rotation with fruit or vegetable crops in the Arkansas River Valley will improve profitability and reduce root zone residual soil NO3–N levels and NO3–N leaching potential. Continuous corn production for 2 to 3 yr with conservative N fertilization rates can reduce residual soil NO3–N levels in the Arkansas River Valley.
Corn Yield Response to Nitrogen Rate and Timing in Sandy Irrigated Soils
Authors: Gehl Ronald J. , Schmidt John P. , Maddux Larry D. , Gordon W. Barney
Published: July 2005

Efficient use of N fertilizer for corn (Zea mays L.) production is important for maximizing economic return and minimizing NO3 leaching to groundwater. The objective of this study was to evaluate grain yield response to irrigation rate and N rate and timing for irrigated corn in the sandy soils along major Kansas waterways. Nitrogen treatments included 300 and 250 kg N ha−1 applied at planting; 250 kg N ha−1 applied at planting (one‐half) and sidedress (one‐half); 185 kg N ha−1 applied at planting (one‐third) and sidedress (two‐thirds); 125 kg N ha−1 applied at planting (one‐fifth) and sidedress (two‐fifths, two‐fifths); and 0 kg N ha−1. Nitrogen treatments were duplicated at one site for each of two irrigation treatments (IS): 1.0× (optimal) and 1.25× (25% > optimal). A split application of 185 kg N ha−1 was sufficient to achieve maximum corn yield at every location, and in most instances 125 kg N ha−1 was sufficient. These rates were on average 88 kg N ha−1 less than the current N recommendation for corn in Kansas, indicating that N rates could be reduced for these soils by an average of about 40% of the current N recommendation when N is split applied. The environmental risk associated with irrigated corn production on these sandy‐textured soils, specifically, NO3 leaching to groundwater, will be minimized only when N fertilizer and irrigation inputs do not exceed crop requirements and N fertilizer is applied to more closely match crop demand (e.g., in‐season applications).
Potassium Fertilization Effects on Cotton Lint Yield, Yield Components, and Reniform Nematode Populations
Authors: Pettigrew W. T. , Meredith W. R. , Young L. D.
Published: July 2005

Cotton (Gossypium hirsutum L.) lint yields have not changed appreciably during the last decade. Because more and higher infestations of reniform nematodes (Rotylenchulus reniformis) have been identified in mid‐southern USA fields, this nematode might be a mitigating factor in the cotton yield stagnation. The objectives were to determine how varying rates of K fertilization interacted with different cotton genotypes to influence dry matter partitioning, lint yield, fiber quality, and reniform nematode populations. Nine cotton genotypes were grown in the field under two levels of K fertilization (0 and 112 kg K ha−1) and two levels of aldicarb [2‐methyl‐2‐(methylthio)propionaldehyde 0‐methylcarbamoyloxime] application (0 and 1.68 kg a.i. ha−1) from 1999 through 2001. Reniform nematode numbers and aboveground dry matter partitioning were determined at various times in the growing season. Lint yield, yield components, and fiber quality were determined at the end of the season. Cotton grown with K fertilization hosted a 12% larger post‐harvest population of reniform nematode than the unfertilized control plants. Plants grown without K fertilization averaged a 10% greater specific leaf weight than the K fertilized plants. Of the 9 genotypes grown, only PayMaster 1218BR increased lint yield (10%) in response to K fertilization. An interaction between aldicarb application and K fertilization for lint yield during the 2000 growing season indicated that both reniform nematode parasitism and insufficient K fertilization may impose limitations to lint yield production. Large reinform nematode populations may be suppressing the yield response to K fertilization. Production practices that encourage robust plant growth may enhance proliferation of existing reniform nematode populations.
Determining the Feasibility of Early Seeding Canola in the Northern Great Plains
Authors: Chen Chengci , Jackson Grant , Neill Karnes , Wichman David , Johnson Gregory , Johnson Duane
Published: July 2005

Canola (Brassica napus L.) yield is often limited by heat and water stress. Early seeding may avoid the heat and water stress at critical growth stages but will encounter low soil temperatures and frequent frosts. Three experiments were performed at two locations in Montana from 2002 to 2004 to determine (i) early spring seeding effect on seed yield and oil content and optimum seeding rates for early seeding, (ii) base temperature (Tb) for germination and heat requirement for emergence, and (iii) suitable cultivars for early spring seeding. Late‐March‐seeded canola yielded 0 to 5% greater than mid‐April seeding. Delaying seeding from mid‐April to mid‐May resulted in 43 to 63% yield reduction. Oil content was 12 to 22 g kg−1 greater for mid‐May seeding than mid‐April seeding in 3 out of 5 site‐year combinations. A seeding rate of 32 to 65 seeds m−2 was found sufficient to produce optimum yields. Oil content tended to decrease 10 to 20 g kg−1 when seeding rate increased from 11 to 97 seeds m−2. The Tb for germination was less than 4°C, and the growing degree days for 50% emergence (GDD50) were 42 to 81. Yield was negatively correlated (r = −0.46 to −0.65) to the days to 50% flowering, and biomass measured at 60 d after planting was negatively correlated to the chlorophyll fluorescence ratio (Fv/Fm) after cold stress (r = −0.58). The optimal seeding period for the region is between late March and mid‐April. Several genotypes were found to have favorable characteristics for early seeding.
Cover Crop Effects on Corn Yield Response to Nitrogen on an Irrigated Sandy Soil
Authors: Andraski Todd W. , Bundy Larry G.
Published: July 2005

Nonlegume winter cover crops are extensively grown to control wind erosion in the Central Sands region of Wisconsin. Subsequent corn (Zea mays L.) yield benefits following winter cover crops can occur on these coarse‐textured soils even though cover crop biomass and residual N recovery are minimal due to the limited time period for cover crop growth. A 3‐yr study was conducted to determine cover crop species and management effects on subsequent corn grain yield responses to N fertilizer. Cover crops were planted in late summer following sweet corn harvest and included oat (Avena sativa L.), winter triticale (×Triticosecale), winter rye (Secale cereale L.) with and without the top growth removed, and fallow. Cover crop treatments were plowed in the spring, and corn was grown with six N fertilizer rates (0 to 280 kg ha−1). In 2 of 3 yr, economic optimum N rates (EONR) for corn were lower (32 ± 8 kg N ha−1), and corn grain yields at the EONR were higher (1.4 ± 0.3 Mg ha−1) where cover crops were grown compared with fallow. These results were similar following all cover crops, including winter‐killed oat and rye with top growth removed, indicating that beneficial cover crop effects were primarily the result of a rotation effect rather than direct N contributions from the cover crop. The yield enhancement provided by cover crops probably offers the greatest practical benefit to growers since lowering N rates on these soils may increase the risk of N deficiency in years with high leaching potential.
Measuring variation in natural populations: a primer
Authors: Harpending Henry
Published: July 2005

In this brief primer, I will first discuss common kinds of data sources appropriate for measuring variation and then describe statistical computations appropriate to each. With one exception all the methods I discuss are equivalent in the sense that they estimate average coalescence times of pairs of marker loci chosen from a population.
The visualization of chromosomes
Authors: Schwartz Stuart
Published: July 2005

Chromosomes have been studied for over 100 years, and our methods of visualization have changed and improved over that time. These studies initially involved squash preparations of meiotic chromosomes and have evolved to the eloquent study of high‐resolution G‐banded chromosomes and most recently to the analysis of BAC arrays to detect small chromosomal changes. During this time, we have learned the true chromosome number in humans as well as a large variety of both aneuploidies and small deletion/duplication syndromes. In this overview, I will review the process underlying the increased visualization of chromosomes, the methodologies leading to the advances and the findings resulting from our increased resolution.
Preimplantation genetic diagnosis for chromosome abnormalities
Authors: Munné Santiago
Published: July 2005

Preimplantation genetic diagnosis (PGD) is the earliest form of prenatal diagnosis and has been used in over 5000 infertile patient procedures to improve pregnancy outcome for in vitro fertilization (IVF). PGD has also been used to limit spontaneous abortions and chromosomally unbalanced or aneuploid offspring in patients of advanced maternal age or carriers of translocations or other chromosome abnormalities.
The histone code and epigenetic inheritance
Authors: Hoffman Andrew R. , Vu Thanh H.
Published: July 2005

The role of histones as active participants in gene regulation has only recently been appreciated. Previously, these proteins, which are assembled into nucleosomes, forming beads around which the DNA is wrapped, were considered to be relatively inert scaffolding for packaging the genetic material. However, the histones' amino‐terminal tails extend away from the central core, and are thus available for posttranslational, reversible acetylation, methylation, phosphorylation, ADP‐ribosylation, and ubiquitination. Amino acids in the histone cores may also be modified in a similar way. The enzymes responsible for these modifications are often specific for particular histones and for restricted amino acid residues. The array and combination of these specific attachments to the various histones have been postulated to constitute a code that may entail thousands of histone isoforms and that may make it possible to determine how these proteins will interact with their nearby DNA sequences. Histone modifications interact with DNA methylation to mark genes for silencing or transcription. In conjunction with DNA methylation, the histone code constitutes a heritable epigenetic signature that is faithfully replicated in daughter cells after cell division. The mechanism for transmitting the histone code to subsequent generations of cells remains to be fully elucidated. The study of the histone code is examined through the prism of the regulation of genomic imprinting. By reading the combinatorial and/or sequential histone modifications that constitute the histone code, it may be possible to predict which gene products will be transcribed and thus determine a cell's RNA repertoire and ultimately its proteome, just as reading the DNA code allows us to predict the encoded protein sequence.
Imprinting at the

GNAS

locus and endocrine disease
Authors: Weinstein Lee S. , Chen Min , Sakamoto Akio , Liu Jie
Published: July 2005

The ubiquitously expressed G protein α‐subunit G
s
α couples receptors to adenylyl cyclase and is required for the intracellular cyclic AMP response to hormones and other extracellular signals. G
s
α is one of several gene products of the
GNAS
locus at 20q13. G
s
α is imprinted in a tissue‐specific manner, being expressed primarily from the maternal allele in hormone‐target tissues such as renal proximal tubules, thyroid, ovary, and pituitary but biallelically expressed in most other tissues. Heterozygous G
s
α null mutations result in Albright hereditary osteodystrophy (AHO), which is characterized by obesity, short stature, and skeletal defects, and is likely the result of G
s
α haploinsufficiency in many tissues. Because of tissue‐specific G
s
α imprinting, patients who inherit their mutations maternally also develop resistance to multiple hormones (parathyroid hormone, thyrotropin) whose receptors activate G
s
α (a condition referred to as pseudohypoparathyroidism type 1A), while patients who inherit their mutations paternally only develop AHO. Pseudohypoparathyroidism type 1B (PHPIB), in which patients develop parathyroid hormone (and sometimes thyrotropin) resistance in the absence of AHO, is caused by
GNAS
imprinting defects in which a paternal epigenotype is present on both parental alleles. This presumably leads to G
s
α deficiency only in tissues where G
s
α is normally imprinted. Familial PHPIB is usually associated with a deletion of a region within the closely linked
STX16
gene that appears to be required for normal
GNAS
imprinting. Most likely, tissue‐specific G
s
α imprinting results from an indirect mechanism involving a closely linked differentially methylated region (DMR) whose imprinting is lost in PHPIB.
Initiation of
X
‐chromosome inactivation
Authors: Pereira Lygia V. , Stabellini Raquel
Published: July 2005

Dosage compensation is the process by which the amount of X‐linked gene products between individuals with one and two X chromosomes is equalized. In mammals, dosage compensation is achieved by the transcriptional silencing of one X chromosome in female cells. Inactivation is attained by the establishment of several sequential epigenetic modifications in the future inactive X triggered by expression of the
Xist
gene in cis, and including different histone modifications and methylation of CpG islands. These transformations occur during early embryonic development and require that the cell counts the X chromosomes and chooses one to be active per diploid genome, inactivating the others. Here, we will review what is currently known about the early events of X‐chromosome inactivation, and discuss the mechanisms by which a cell counts and chooses X chromosomes.
Parametric versus nonparametric and two‐point versus multipoint: controversies in gene mapping
Authors: Bailey‐Wilson Joan E.
Published: July 2005

In parametric or model‐based linkage analysis (often called LOD score linkage analysis), one assumes that models describing both the trait and marker loci are known without error. This means that one assumes that the allele frequencies, dominance relationships among the alleles, and relationships between genotypes and phenotypes are known without error at both the trait and marker loci. Nonparametric (or model‐free or weakly parametric) linkage methods make fewer assumptions about the trait model, although the assumption that the marker locus model(s) is known without error is still in force. These methods of analysis have different strengths and weaknesses that should be taken into account by the analyst when choosing how to analyze linkage data. Parametric linkage analysis is more powerful than nonparametric linkage methods if the genetic model for both trait and marker loci are correctly specified but for complex traits where such correct model specification is difficult, nonparametric methods may be more powerful. Both parametric and nonparametric analyses may be performed between a trait locus and a single marker locus (two‐point linkage) or between a trait locus and a map of multiple markers (multipoint linkage). Again, these methods have different strengths and weaknesses that should be understood before embarking upon their use. Multipoint methods give more power to detect linkage than two‐point methods as long as the marker order and intermarker distances are correctly specified and assumptions about the trait and marker models are correct, but failures of these assumptions may strongly decrease the power of multipoint methods.
Gene mapping and the transition from
STRPs
to
SNPs
Authors: Wijsman Ellen M.
Published: July 2005

Linkage analysis based on DNA markers is a major activity in human genetics. Time, cost, and inability to extract complete mapping information are important considerations. While multiallelic single tandem repeat polymorphisms (STRPs) have dominated for 15 years, single‐nucleotide polymorphisms (SNPs) are an alternative that may have some advantages. In considering a transition to SNPs, it is important to highlight the assumptions that may need to be reconsidered and additional analytical and computational challenges that are posed by the use of densely spaced diallelic markers. These are the issues that will affect the analysis and interpretation of results obtained with SNPs, and the modifications to the analytical techniques needed to make full use of this new type of data.
Algorithmic improvements in gene mapping
Authors: Abecasis Gonçalo R. , Zhao Yu
Published: July 2005

The analysis of human gene mapping data presents daunting computational challenges. Improvements in laboratory technology have motivated the development and refinement of increasingly sophisticated algorithms for the analysis of human pedigrees. We review and summarize some of the more important developments, and present a short history of the software packages that are now in widespread use in human gene mapping studies.
Choices in gene mapping: populations and family structures
Authors: Pollin Toni I. , O'Connell Jeffrey R.
Published: July 2005

There are many choices of population for gene mapping of complex diseases. Recent technological advances for genotyping single‐nucleotide polymorphisms have shifted our focus from family‐based gene mapping to large case‐control genome‐wide linkage disequilibrium mapping. However, genetic isolates remain an important resource for mapping complex diseases, as these populations have greater genetic and environmental homogeneity. In addition, emerging single‐molecule genotyping technologies will eliminate the current computational barriers of both linkage and association mapping in the rich extended pedigrees found in genetic isolates. These technologies will reaffirm the importance of genetic isolates for mapping susceptibility genes for complex diseases.
Polymorphic inversions, deletions, and duplications in gene mapping
Authors: Christian Susan L.
Published: July 2005

The underlying architecture of the human genome contains segmental duplications that predispose to the formation of inversions, deletions, and duplications. The effects of these chromosomal aberrations on gene mapping are multifold. Inversions may disrupt disease genes, while deletions and duplications produce genomic imbalances that may affect dosage of disease genes. These anomalies are not readily detected using standard linkage and association analyses. Current studies are ongoing to develop methods to detect gene dosage using high‐density SNP genotyping, while other studies are cataloging the copy number polymorphisms present in the genome. Determining whether these polymorphisms are benign or provide susceptibility to complex diseases will be an important question for future studies.
Allergy and asthma
Authors: Moffatt Miriam F. , Cookson William O.C.
Published: July 2005

Asthma and eczema (atopic dermatitis, AD) are the most common chronic diseases of childhood. These diseases are characterized by the production of high levels of immunoglobulin E in response to common allergens. Their development depends on both genetic and environmental factors. Genes and genetic loci that are associated with increased susceptibility to asthma and AD have been described. A surprising number of these are expressed in the mucosa and epidermis, suggesting that events at epithelial surfaces may be driving disease processes.
Complexity of cancer as a genetic disease
Authors: Vallenius Tea , Mäkelä Tomi P.
Published: July 2005

Our understanding of cancer as a genetic disease is increasingly growing using information from genome‐scale experimental approaches, and the focus is turning from analyzing single genes to analyzing signaling networks. Together with the first targeted therapy successes, this has resulted in an excitement and optimism in the field, while at the same time improved classification and diagnostics are identifying at increasing accuracy the patients who will benefit from a given therapy.
Genetics of cognitive disorders
Authors: Abrahams Brett S. , Geschwind Daniel H.
Published: July 2005

Disorders of cognition impair mental processes mediating awareness, perception, reasoning, or judgment, and consequently interfere with thought. Although interindividual differences in human cognition are easily observed, little is known about the genetic factors underlying such phenotypic variation, or the relationship of such variation to disease. Global measures of intelligence, such as Spearman's “g”, are heritable and thus likely to engender new links between genes and cognition. However, the breadth of these measures may limit the extent to which mechanistic insights are obtained. Finding readily measurable and heritable components of disease (endophenotypes) represents one of the most promising avenues for a precise understanding of how individual genes come to modulate brain function. The high heritability of interindividual differences in brain morphology suggests that a more thorough understanding of disease‐associated structural variation may clarify the relationship between individual genes and disorders of cognition. Identification and study of endophenotypes for autism and disorders of spoken and written language will facilitate a deeper understanding of how genetic variation comes to modulate the structure and function of particular neural systems and in turn contributes to specific cognitive deficits.
Hypertension genetics: under pressure
Authors: Charchar Fadi J. , Tomaszewski Maciej , Dominiczak Anna F.
Published: July 2005

Hypertension genetics is now at a critical juncture. The molecular methods used so far have not revealed the numerous genes causing the common familial forms of hypertension. Here we present a brief review of the future directions of hypertension genetics research and what its implication and challenges are.
Current approaches to prenatal screening and diagnosis
Authors: Cosper Paula C.
Published: July 2005

Prenatal screening and diagnosis has advanced tremendously since its inception in 1966. We now have various means for screening in the first and second trimesters of pregnancy using noninvasive techniques such as ultrasound and maternal serum screening. For diagnostic testing, invasive procedures are required. The most frequently used procedures are chorionic villus sampling and amniocentesis. The types of testing on these fetal cells and number of abnormalities detectable are changing rapidly. Techniques allowing defects to be detected before pregnancy are also becoming more readily available. The current methods and technologies for prenatal screening and diagnosis are discussed.
Mechanisms of inheritance
Authors: Aylsworth Arthur S.
Published: July 2005

Inheritance patterns depend on genetic factors that can be monogenic or multigenic and deterministic or nondeterministic. Environment, epistasis, and chance are the factors that affect phenotypic expression. Variations on the basic themes of monogenic inheritance commonly involve issues of penetrance and expression. Mendel's concepts of dominance and recessiveness are now blurred by our recognition of phenomena such as heterozygote expression, incomplete penetrance, gene–gene interaction, and gene–environment interaction. While pedigrees with only distant relatives affected are frequently interpreted as representing examples of complex or multifactorial inheritance, it is clear that the same patterns of inheritance can be caused by chromosome rearrangements and mutations in single genes with major effects. The causes of complex phenotypes are heterogeneous and include stochastic combinations of genetic and environmental factors, where the genetic contribution may be determined by one or more genes.
Genetic counseling process
Authors: Schneider Gretchen H.
Published: July 2005

Genetic counseling is a process whose aim is to communicate information about genetic disease to patients or families. This process involves multiple steps that may include, but not be limited to, gathering and assessment of information, establishment of a diagnosis or risk of disease, and discussion of the implications as well as available options to address risk for family members. Support and counseling is also a very important component of this process, which focuses on promoting informed decision‐making for patients who are often in very difficult situations.
Gene therapy I: principles and clinical applications
Authors: Ulm J. Wesley
Published: July 2005

Gene therapy encompasses a recently developed group of pharmaceuticals in which the therapeutic agent consists of nucleic acid sequences – DNA, RNA, or some modification thereof – rather than a small molecule. The field arose in the 1980s in the wake of improvements in recombinant DNA technology, and in the midst of better comprehension of gene regulation and modulation processes that could be exploited to construct practical gene therapy systems. Most gene therapy vectors are viral in nature, with retroviruses, adenoviruses, and AAVs (adeno‐associated viruses) dominating most protocols, and they have been applied to treat a wide variety of disease subtypes: inherited genetic disorders, cancer, protein aggregation diseases, cardiovascular diseases, and infectious diseases have all been considered in proposed modalities. Gene therapy offers the potential to treat disease with an unprecedented selectivity and therapeutic index, and to allow the flexible design of new pharmaceutical agents on a much more rapid scale than in most traditional schemes. However, technical obstacles related to vector delivery, adequate expression levels, and persistence of viral transgenic sequences continue to pose difficult challenges for clinical application. This article reviews the basic gene therapy principles, common vectors and disease targets, and clinical approaches to convey the current state of the field and its future directions.
Adeno‐associated viral vectors: depend(o)ble stability
Authors: Snyder Richard O.
Published: July 2005

Recombinant adeno‐associated viral (rAAV) vectors can mediate the safe and long‐term correction of genetic diseases in animal models following a single administration, and have been shown to persist and are safe in humans following delivery to lung, sinus, skeletal muscle, brain, and liver. The physiochemical properties of rAAV vector virions are amenable to industry‐accepted manufacturing methodologies, long‐term storage, and direct in vivo administration.
Gene transfer to skeletal muscle
Authors: Chamberlain Jeffrey S.
Published: July 2005

Muscle tissue is an important target for gene therapy applications due to the large number of disorders of skeletal and cardiac muscle. These include inherited disorders such as Duchenne muscular dystrophy (DMD) and acquired disorders such as heart failure and age‐associated muscle weakness (sarcopenia). A potentially powerful approach to treating these various conditions involves delivery of a gene or genes to the affected muscles. In the case of a genetic disorder, the goal may be to deliver a normal version of the defective gene. In other cases, benefit might result from delivery of a gene that could augment normal muscle function, such as a growth factor gene. Other applications include delivery of DNA fragments that could modulate gene expression or lead to correction of a genetic mutation. Since muscle tissue represents nearly 40% of the total body mass, gene transfer to muscle is an enormously challenging proposition. Consequently, numerous types of gene or DNA vectors and delivery strategies are being explored for gene therapy of muscle disorders. No single gene vector or delivery method is likely to be universally applicable for all conditions, but some have been developed to greater degrees than others. This article briefly reviews the major vectors and delivery methods currently being developed for gene therapy of muscle diseases.