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PubMedDate not supplied

Early adoption of BRCA1/2 testing: who and why.

PURPOSE: Relatively little is known about the characteristics of women who chose to undergo BRCA1/2 testing soon after testing became available, including how they became aware of and chose to pursue testing. Diffusion of innovation theory states that acceptance of an innovation is a function of the potential adopter's value for innovation and perceptions of the compatibility, complexity, and relative advantage of the innovation. These factors may contribute to early uptake of BRCA1/2 testing. The purpose of this study was to describe the characteristics of women who were "early adopters" of clinical BRCA1/2 testing and to determine whether diffusion theory explains variation in uptake of testing after participation in genetic counseling for BRCA1/2 testing. METHODS: A retrospective cohort study of participants in genetic counseling for BRCA1/2 testing was conducted at a clinical program in a large academic health system. Measures included components of diffusion of innovation theory (participant's value for innovation, i.e., "innovativeness," and perceptions of the compatibility, complexity, and relative advantage of BRCA1/2 testing), characteristics of how the participant became aware of and sought BRCA1/2 testing, and decisions about testing after counseling. RESULTS: From the 229 respondents, 71 (31%) had undergone testing at the time of the survey. Fifty-seven women (25%) had sought BRCA1/2 testing because a family member had breast or ovarian cancer and 37 (16%) because they had breast or ovarian cancer. Only 15 women (7%) reported seeking testing because of a physician's recommendation. After multivariate adjustment, higher innovativeness and higher ratings of the compatibility of BRCA1/2 testing were associated with undergoing testing after counseling [relative risk (RR) 1.76, 95% confidence interval (CI) 1.2-2.6]. However, ratings of the complexity or relative advantage of testing were not associated with testing decisions. Higher innovativeness was associated with being the first in the family to undergo testing (RR 4.85, 95% CI 1.6-14.9), becoming aware of BRCA1/2 testing through the media (RR 1.50, 95% CI 1.0-2.4), and being aware of BRCA1/2 testing prior to counseling (RR 1.25, 95% CI 1.1-1.4). CONCLUSIONS: The uptake of BRCA1/2 testing among women undergoing genetic counseling was associated with innovative characteristics of the participant and the perceived compatibility of the test with existing values and needs, but not with the complexity or relative advantage of the test. Most "early adopters" had heard of BRCA1/2 testing from a source other than their physician and had sought testing because of a personal or family member's cancer diagnosis. These findings can inform predictions surrounding the introduction of future genetic susceptibility tests and strategies for guiding the further diffusion of BRCA1/2 testing.

Decision Making↗
PubMed2026

Integrating multi-ancestry common and rare variant mapping accelerates therapeutic target discovery.

Integrating human genetics into therapeutic discovery accelerates drug development. However, ancestral biases in historical cohorts have left critical functional variation largely uncharted. Here, we leverage the diverse NIH All of Us Research Program to conduct comprehensive common- and rare-variant association analyses for 624 quantitative traits across 369,655 ancestrally diverse individuals. We identified 6,181 genome-wide significant locus-trait associations (526 novel) and 416 gene-trait associations (105 novel) via rare-variant burden testing. By integrating fine-mapping with computational variant-effect predictors, we systematically prioritized rare, likely causal variants driving these signals. Jointly modeling common and rare variation with protein-class annotations significantly improved the identification of known drug targets compared to common-variant analysis alone. Notably, we identified NRG4 as a high-confidence candidate therapeutic target for preserving kidney function. Our findings demonstrate that characterization of rare and common variation across diverse populations enhances causal gene discovery and identifies novel, actionable therapeutic targets.

Journal Article↗
PubMed2005

Genetic variations in maternal transfer and immune responsiveness to infectious bursal disease virus.

The immune responsiveness to infectious bursal disease virus (IBDV) in four native and crossbred chicken lines was compared. ELISA IBDV antibody titers in hen serum samples, yolk from matched eggs and sera from matched 1-day-old chicks from each chicken line with an identical vaccination program were measured, and plotted. There was considerable variation between lines in the measured IBDV specific antibodies, in vaccinated parent hens and in the amounts of inherited maternally derived antibodies in both yolk and progeny chicks. Differences in ratios of the inherited antibody level from hen to 1-day-old chicks were also found among different chicken lines. Breed differences in regressions of IBDV antibody levels in yolk to that of hen or progeny chicks' sera were also found, so prediction of serum titer of hen and/or progeny chicks from yolk are varied among chicken lines.

Animals↗
PubMed2002

Quantitative trait loci controlling vegetative growth rate in the edible basidiomycete Pleurotus ostreatus.

Mycelium growth rate is a quantitative characteristic that exhibits continuous variation. This trait has applied interest, as growth rate is correlated with production yield and increased advantage against competitors. In this work, we studied growth rate variation in the edible basidiomycete Pleurotus ostreatus growing as monokaryotic or dikaryotic mycelium on Eger medium or on wheat straw. Our analysis resulted in identification of several genomic regions (quantitative trait loci [QTLs]) involved in the control of growth rate that can be mapped on the genetic linkage map of this fungus. In some cases monokaryotic and dikaryotic QTLs clustered at the same map position, indicating that there are principal genomic areas responsible for growth rate control. The availability of this linkage map of growth rate QTLs can help in the design of rational strain breeding programs based on genomic information.

Chromosome Mapping↗
PubMed2006

Identification of a new leucine haplotype (ALQ) at codon 154 in the ovine prion protein gene in Spanish sheep.

Genetic susceptibility to scrapie is closely linked to variations at codons 136, 154, and 171 of the prion protein (PRNP) gene. This association between the PRNP genotype and susceptibility to scrapie is the basis of breeding programs for scrapie resistance in different countries. In this paper, we describe the method used with 2 Spanish dairy sheep breeds (Churra and Castellana) to ascertain the initial status of protection against scrapie as a first step toward adapting their breeding schemes to include resistance as a complementary selection criterion. The procedure for genotype identification is based on multiplex minisequencing methodology and has been shown to be accurate, easy to interpret, and to have a medium throughput. The frequency of the ARQ allele was similar in the 2 populations at nearly 70%. The ARR allele, associated with resistance in the homozygous state, reaches around 23% in Churras and nearly 20% in Castellanas. The high-risk VRQ allele appeared at a relatively low frequency in both breeds. No other haplotypes were found in these 2 breeds. Furthermore, in this screening we found a new allele carrying leucine at codon 154. This new genetic variant might play a role in susceptibility to scrapie because codon 154 belongs to a region considered to have an important role in conformational conversion of the cellular to the pathogenic protein.

Alleles↗
PubMed2000

Neurochemical individuality: genetic diversity among human dopamine and serotonin receptors and transporters.

Behavioral variation in human beings encompasses wide differences in personality and susceptibility to psychiatric illness arising from both genotype and experience. Long-lasting behavioral differences generally have heritabilities of 30% or more, and such inheritance is ultimately attributable to functional variants of genes programming brain development and function. The sequencing of the human genome is revealing a pattern of gene sequence variation. The ability of sequence variants to affect neural function either alone or in concert may reveal effects of behavioral selection on the human genome over evolutionary time frames. Dopamine and serotonin are phylogenetically ancient neurotransmitters intrinsic to brain function and behavior. Dopamine and serotonin receptor and transporter genes have been an early focus for efforts to identify and functionally characterize sequence variation. The purpose of this article is to present a preview of a developing new perspective in human behavior: the genetic variation of the brain or neurochemical individuality. Arch Gen Psychiatry. 2000;57:1105-1114.

Brain↗
PubMed2006

Estimation of genetic parameters for quantitative trait loci for dairy traits in the French Holstein population.

A marker-assisted selection program (MAS) has been implemented in dairy cattle in France. The efficiency of such a selection program depends on the use of correct genetic parameters for the marked quantitative trait loci (QTL). Therefore, the objective of this study was to estimate the proportion of genetic variance explained by 4 QTL described in previous studies (these QTL are segregating on chromosomes 6, 14, 20, and 26). Genotypes for 11 markers were available for 3,974 bulls grouped within 54 sire families of the French Holstein population undergoing MAS. The parameters were estimated for 4 QTL and 5 dairy traits: milk, fat and protein yields, and fat and protein percentages. The proportion of genetic variance explained by the QTL ranged from as low as 0.03 to 0.36%. Both lack of marker informativity and poor monitoring of QTL transmission might limit the accuracy of estimation. The QTL explained a larger proportion of genetic variance for milk composition traits. The QTL on chromosome 14 and chromosomes 6 and 20 have their largest influence on fat and protein percentages, respectively. The overall proportions of genetic variance explained by the QTL were 27.0, 30.7, 24.1, 48.2, and 33.6% for milk, fat and protein yields, and fat and protein percentages, respectively. These results clearly indicated that a large part of the genetic variance is explained by a small number of QTL and that their use in MAS might be beneficial for dairy cattle breeding programs.

Animals↗
PubMed2001

Intracellular signaling from the endoplasmic reticulum to the nucleus: the unfolded protein response in yeast and mammals.

Cellular survival of endoplasmic reticulum stress requires the unfolded protein response (UPR), a stress response first elucidated genetically in yeast. While we continue to refine our knowledge of the yeast system, especially the breadth and significance of the transcriptional response, conservation of the system's elements has allowed identification of corresponding and additional components of the mammalian UPR. Recent results reveal that the output of the mammalian UPR reaches beyond transcriptional regulation of secretory pathway components to control of general translation, the cell cycle and programmed cell death.

Animals↗
PubMed2002

Calcium intake, calcium bioavailability and bone health.

Calcium accounts for 1-2 % of adult human body weight. Over 99 % of total body Ca is found in the teeth and bones. Therefore, in addition to the obvious structural role of the skeleton, it also serves as a reservoir for Ca. Dietary Ca intake has an important impact on bone metabolism and bone health. Chronic Ca deficiency resulting from inadequate intake or poor intestinal absorption is one of several important causes of reduced bone mass and osteoporosis. It is vital, therefore, that adequate dietary Ca is consumed at all stages of life - in early life so that the genetically programmed peak bone mass can be reached and in later adulthood so that the skeletal mass can be maintained and age-related bone loss minimised. Unfortunately, there is wide variation in the estimates of daily Ca requirements made by different expert authorities. Furthermore, there is evidence that many individuals are not consuming these recommended levels. The consequence of this for bone health will be discussed in the present review. Besides the amount of Ca in the diet, the absorption of dietary Ca in foods is also a critical factor in determining the availability of Ca for bone development and maintenance. Thus, there is a need to identify food components and/or functional food ingredients that may positively influence Ca absorption in order to ensure that Ca bioavailability from foods can be optimised. This approach may be of particular value in individuals who fail to achieve the dietary recommended level of Ca.

Age Factors↗
PubMed2005

A powerful and robust method for mapping quantitative trait loci in general pedigrees.

The variance-components model is the method of choice for mapping quantitative trait loci in general human pedigrees. This model assumes normally distributed trait values and includes a major gene effect, random polygenic and environmental effects, and covariate effects. Violation of the normality assumption has detrimental effects on the type I error and power. One possible way of achieving normality is to transform trait values. The true transformation is unknown in practice, and different transformations may yield conflicting results. In addition, the commonly used transformations are ineffective in dealing with outlying trait values. We propose a novel extension of the variance-components model that allows the true transformation function to be completely unspecified. We present efficient likelihood-based procedures to estimate variance components and to test for genetic linkage. Simulation studies demonstrated that the new method is as powerful as the existing variance-components methods when the normality assumption holds; when the normality assumption fails, the new method still provides accurate control of type I error and is substantially more powerful than the existing methods. We performed a genomewide scan of monoamine oxidase B for the Collaborative Study on the Genetics of Alcoholism. In that study, the results that are based on the existing variance-components method changed dramatically when three outlying trait values were excluded from the analysis, whereas our method yielded essentially the same answers with or without those three outliers. The computer program that implements the new method is freely available.

Chromosome Mapping↗
PubMed1995

PdbAlign, PdbDist and DistAlign: tools to aid in relating sequence variability to structure.

Many sequence analysis problems involve consideration of a multiple sequence alignment where the 3-dimensional structure of one (or more) of the aligned sequences is known. In such cases, it is useful to map the sequence variability onto the atomic co-ordinates of known structure. If the structure also includes a bound ligand (or the location of the active site is known), each column position in the multiple sequence alignment may be annotated with its 'distance' from the binding site. These annotations, together with a measure of sequence variability, provide additional insights into drug specificity, for example among viral mutants. This paper describes several useful programs that automate this analysis.

Amino Acid Sequence↗
PubMed2003

The evolution of transcriptional regulation in eukaryotes.

Gene expression is central to the genotype-phenotype relationship in all organisms, and it is an important component of the genetic basis for evolutionary change in diverse aspects of phenotype. However, the evolution of transcriptional regulation remains understudied and poorly understood. Here we review the evolutionary dynamics of promoter, or cis-regulatory, sequences and the evolutionary mechanisms that shape them. Existing evidence indicates that populations harbor extensive genetic variation in promoter sequences, that a substantial fraction of this variation has consequences for both biochemical and organismal phenotype, and that some of this functional variation is sorted by selection. As with protein-coding sequences, rates and patterns of promoter sequence evolution differ considerably among loci and among clades for reasons that are not well understood. Studying the evolution of transcriptional regulation poses empirical and conceptual challenges beyond those typically encountered in analyses of coding sequence evolution: promoter organization is much less regular than that of coding sequences, and sequences required for the transcription of each locus reside at multiple other loci in the genome. Because of the strong context-dependence of transcriptional regulation, sequence inspection alone provides limited information about promoter function. Understanding the functional consequences of sequence differences among promoters generally requires biochemical and in vivo functional assays. Despite these challenges, important insights have already been gained into the evolution of transcriptional regulation, and the pace of discovery is accelerating.

Animals↗
PubMed2005

Genetic diversity and differentiation of central European freshwater pearl mussel (Margaritifera margaritifera L.) populations: implications for conservation and management.

Despite the fact that mollusc species play an important role in many aquatic ecosystems, little is known about their biodiversity and conservation genetics. Freshwater pearl mussel (Margaritifera margaritifera L.) populations are seriously declining all over Europe and a variety of conservation programs are being established to support the remaining endangered central European populations. In order to provide guidelines for conservation strategies and management programs, we investigated the genetic structure of 24 freshwater pearl mussel populations originating from five major central European drainages including Elbe, Danube, Rhine, Maas and Weser, representing the last and most important populations in this area. We present a nondestructive sampling method of haemolymph for DNA analyses, which is applicable for endangered bivalves. The analyses of nine microsatellite loci with different levels of polymorphism revealed a high degree of fragmented population structure and very different levels of genetic diversity within populations. These patterns can be explained by historical and demographic effects and have been enforced by anthropogenic activities. Even within drainages, distinct conservation units were detected, as revealed from high F(ST) values, private alleles and genetic distance measures. Populations sampled close to contact zones between main drainage systems showed lowest levels of correct assignment to present-day drainage systems. Populations with high priority for conservation should not only be selected by means of census population size and geographical distance to other populations. Instead, detailed genetic analyses are mandatory for revealing differentiation and diversity parameters, which should be combined with ecological criteria for sustainable conservation and recovery programs.

Animals↗
PubMed2004

Survey of hepatitis B surface variant infection in children 15 years after a nationwide vaccination programme in Taiwan.

BACKGROUND: It is not known whether hepatitis B virus (HBV) with mutations in the a determinant (amino acids (aa) 121-149) of the hepatitis B surface antigen (HBsAg) affect vaccination efficacy. AIM: To investigate the prevalence and clinical significance of these mutants in children, 15 years after universal vaccination in Taiwan. METHODS: Nucleotide sequences encoding the a determinant region (aa 110-160) of HBsAg were analysed in all HBV-DNA positive sera from 1357 children and 219 adolescents serosurveyed in 1999. We then compared the prevalence and changes in the mutants in these children with our previous surveys in the same area conducted in 1984 (just before vaccination), 1989, and 1994. RESULTS: The prevalence of a determinant mutants in HBV-DNA positive children was 7.8% (8/103) in 1984, which significantly increased to 19.6% (10/51) in 1989, peaked at 28.1% (9/32) in 1994, and remained at 23.1% ((3/13) (T131I, G145R, G145R)) in 1999; it was higher in those fully vaccinated compared with those not vaccinated (15/46 v 15/153; p<0.001). However, the number of mutant infected children in each survey was stable in the first 5-10 year period but decreased 10-15 years post vaccination. Increased amino acid variation in the a determinant region occurred in carrier children in the post vaccination survey. Mutated residues tended to occur more frequently in the region with greater local hydrophilicity (residues 140-149) in those vaccinated than in unvaccinated children with variant infection (12/15 v 6/15; p = 0.062). More HBsAg positive a determinant mutants emerged in children fully vaccinated with plasma derived vaccine than those given recombinant vaccine (10/2399 (0.46%) v 0/503; p = 0.122). CONCLUSION: We found that a determinant variants have an advantage in infecting immunised children but do not threaten current HBV vaccination strategies in Taiwan.

Adolescent↗
PubMed2004

Multi-species sequence comparison reveals dynamic evolution of the elastin gene that has involved purifying selection and lineage-specific insertions/deletions.

BACKGROUND: The elastin gene (ELN) is implicated as a factor in both supravalvular aortic stenosis (SVAS) and Williams Beuren Syndrome (WBS), two diseases involving pronounced complications in mental or physical development. Although the complete spectrum of functional roles of the processed gene product remains to be established, these roles are inferred to be analogous in human and mouse. This view is supported by genomic sequence comparison, in which there are no large-scale differences in the ~1.8 Mb sequence block encompassing the common region deleted in WBS, with the exception of an overall reversed physical orientation between human and mouse. RESULTS: Conserved synteny around ELN does not translate to a high level of conservation in the gene itself. In fact, ELN orthologs in mammals show more sequence divergence than expected for a gene with a critical role in development. The pattern of divergence is non-conventional due to an unusually high ratio of gaps to substitutions. Specifically, multi-sequence alignments of eight mammalian sequences reveal numerous non-aligning regions caused by species-specific insertions and deletions, in spite of the fact that the vast majority of aligning sites appear to be conserved and undergoing purifying selection. CONCLUSIONS: The pattern of lineage-specific, in-frame insertions/deletions in the coding exons of ELN orthologous genes is unusual and has led to unique features of the gene in each lineage. These differences may indicate that the gene has a slightly different functional mechanism in mammalian lineages, or that the corresponding regions are functionally inert. Identified regions that undergo purifying selection reflect a functional importance associated with evolutionary pressure to retain those features.

Animals↗
PubMed2002

Variagenics, inc.

Variagenics, Inc. develops molecular diagnostic tests by identifying genetic markers associated with response to cancer therapies, with the goal of optimizing patient care. Toward this end, the company analyzes genetic variations in both normal and tumor cells, including SNPs, haplotypes, loss of heterozygosity, and gene expression levels. The company's approach of analyzing multiple types of genetic variations increases the likelihood of finding significant associations with drug response and successfully developing diagnostics. Variagenics is pursuing marker identification and diagnostic development through both biopharmaceutical collaborations and internal research programs.

Antineoplastic Agents↗
PubMed2004

[Global situation of leprosy and recent progress in molecular epidemiology of the disease].

Recent discovery of genetic diversity of Mycobacterium leprae such as variable number of tandem repeats opened a new era in molecular epidemiology of leprosy infection. It was revealed that the leprosy bacillus in residential environment of endemic villages is an important source of infection. The global elimination strategy will be revised taking new molecular epidemiological knowledge into account. Responsibility of leprosy specialist is to propose feasible control program to local administration based on the epidemiological analysis on transmission of the disease.

Genetic Variation↗