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Gene Approach (gene + approach)
Kinds of Gene Approach Selected AbstractsXenopus Wnt11b is identified as a potential pronephric inducerDEVELOPMENTAL DYNAMICS, Issue 1 2010Stéphanie Tételin Abstract In this study, we aimed to establish if known wnt signaling molecules could be responsible for inducing early pronephros specification, using a novel and effective in vitro bioassay in Xenopus embryos. Anterior somites have the unique biological activity to signal to unspecified intermediate mesoderm to induce pronephros formation in Xenopus embryos. We have used a molecular candidate gene approach to analyze both canonical and noncanonical wnt expression in isolated anterior and posterior somites and dissected presumptive pronephros, pronephric anlagen, and pronephros from stage 12.5,35 embryos. We have identified potential candidate wnt genes expressed in the right time and place to specify pronephric development. These candidates were then directly tested in an in vitro pronephrogenesis assay based on Holtfreter sandwich cultures. Results revealed that noncanonical wnt11b and wnt11 can induce pronephros formation in vitro. Loss-of-function experiments confirmed that these genes are necessary for normal pronephros development. Developmental Dynamics 239:148,159, 2010. © 2009 Wiley-Liss, Inc. [source] Reverse dissimilatory sulfite reductase as phylogenetic marker for a subgroup of sulfur-oxidizing prokaryotesENVIRONMENTAL MICROBIOLOGY, Issue 2 2009Alexander Loy Summary Sulfur-oxidizing prokaryotes (SOP) catalyse a central step in the global S-cycle and are of major functional importance for a variety of natural and engineered systems, but our knowledge on their actual diversity and environmental distribution patterns is still rather limited. In this study we developed a specific PCR assay for the detection of dsrAB that encode the reversely operating sirohaem dissimilatory sulfite reductase (rDSR) and are present in many but not all published genomes of SOP. The PCR assay was used to screen 42 strains of SOP (most without published genome sequence) representing the recognized diversity of this guild. For 13 of these strains dsrAB was detected and the respective PCR product was sequenced. Interestingly, most dsrAB -encoding SOP are capable of forming sulfur storage compounds. Phylogenetic analysis demonstrated largely congruent rDSR and 16S rRNA consensus tree topologies, indicating that lateral transfer events did not play an important role in the evolutionary history of known rDSR. Thus, this enzyme represents a suitable phylogenetic marker for diversity analyses of sulfur storage compound-exploiting SOP in the environment. The potential of this new functional gene approach was demonstrated by comparative sequence analyses of all dsrAB present in published metagenomes and by applying it for a SOP census in selected marine worms and an alkaline lake sediment. [source] Candidate gene studies in the 21st century: meta-analysis, mediation, moderationGENES, BRAIN AND BEHAVIOR, Issue S1 2006M. R. Munafò The results of a large body of candidate gene studies of behavioural and psychiatric phenotypes have been largely inconclusive, with most findings failing to replicate reliably. A variety of approaches that augment the ,traditional' candidate gene approach are discussed, including the use of meta-analysis to combine findings from existing published reports, the investigation of mediating variables (including the use of intermediate phenotypes or endophenotypes) and the awareness of possible moderating influences (such as sex or ethnicity) and gene,environment interactions on genetic associations, possibly via epigenetic mechanisms. Advances in genotyping technology will also allow the routine use of haplotype analysis and linkage disequilibrium mapping. Examples of how these approaches may improve our understanding of how genetic associations with behavioural and psychiatric phenotypes obtain are given. [source] A BCR,JAK2 fusion gene as the result of a t(9;22)(p24;q11.2) translocation in a patient with a clinically typical chronic myeloid leukemiaGENES, CHROMOSOMES AND CANCER, Issue 3 2005Frank Griesinger Chronic myeloid leukemia (CML) is characterized by the presence of a t(9;22)(q34;q11.2), which leads to the well-known BCR,ABL1 fusion protein. We describe a patient who was diagnosed clinically with a typical CML but on cytogenetic analysis was found to have a t(9;22)(p24;q11.2). Chromosomal fluorescence in situ hybridization showed that the BCR gene locus spanned the breakpoint at band 22q11.2 but that the ABL1 gene was not rearranged. By means of a candidate gene approach, the JAK2 gene, at 9p24, was identified as the fusion partner of BCR in this case. The BCR,JAK2 fusion protein contains the coiled-coil dimerization domain of BCR and the protein tyrosine kinase domain (JH1) of JAK2. The patient's disease did not respond to Imatinib, and this unresponsiveness was most likely a result of the BCR,JAK2 fusion protein. © 2005 Wiley-Liss, Inc. [source] Genome-wide amplification and allelotyping of sporadic pituitary adenomas identify novel regions of genetic lossGENES, CHROMOSOMES AND CANCER, Issue 3 2003D. J. Simpson Through the use of a candidate gene approach, several previous studies have identified loss of heterozygosity (LOH) at putative tumor-suppressor gene (TSG) loci in sporadic pituitary tumors. This study reports a genome-wide allelotyping by use of 122 microsatellite markers in a large cohort of tumors, consisting of somatotrophinomas and non-functioning adenomas. Samples were first subject to prior whole genome amplification by primer extension pre-amplification (PEP) to circumvent limitations imposed by insufficient DNA for whole-genome analysis with this number of microsatellite markers. The overall mean frequency of loss in invasive tumors was significantly higher than that in their non-invasive counterparts (7 vs. 3% somatotrophinomas; 6 vs. 3% non-functioning adenomas, respectively). Analysis of the mean frequency of LOH, across all markers to individual chromosomal arms, identified 13 chromosomal arms in somatotrophinomas and 10 in non-functioning tumors, with LOH greater than the 99% upper confidence interval calculated for the rate of overall random allelic loss. In the majority of cases, these losses were more frequent in invasive tumors than in their non-invasive counterparts, suggesting these to be markers of tumor progression. Other regions showed similar frequencies of LOH in both invasive and non-invasive tumors, implying these to be early changes in pituitary tumorigenesis. This genome-wide study also revealed chromosomal regions where losses were frequently associated with an individual marker, for example, chromosome arm 1q (LOH > 30%). In some cases, these losses were subtype-specific and were found at a higher frequency in invasive tumors than in their non-invasive counterparts. Identification of these regions of loss provides the first preliminary evidence for the location of novel putative TSGs involved in pituitary tumorigenesis that are, in some cases, subtype-specific. This investigation provides an unbiased estimate of global aberrations in sporadic pituitary tumors as assessed by LOH analysis. The identification of multiple "hotspots" throughout the genome may be a reflection of an unstable chromatin structure that is susceptible to a deletion or epigenetic-mediated gene-silencing events. © 2003 Wiley-Liss, Inc. [source] Broad-Complex, E74, and E75 early genes control DNA puff BhC4-1 expression in prepupal salivary glandsGENESIS: THE JOURNAL OF GENETICS AND DEVELOPMENT, Issue 11 2006L.R. Basso Jr. Abstract The DNA puff BhC4-1 gene of the sciarid Bradysia hygida is induced in salivary glands prior to the pupal molt as a secondary response to the increase in ecdysone titers. Previous studies demonstrated that the BhC4-1 promoter is activated in transgenic Drosophila melanogaster salivary glands as a late response to the ecdysone peak that triggers metamorphosis, revealing that this aspect of BhC4-1 transcriptional regulation is conserved in the Drosophila background. To identify regulators of BhC4-1 expression, we utilized a candidate gene approach and tested the roles of the ecdysone-induced genes BR-C, E74, and E75. Our results reveal that the BR-C Z3 isoform is essential for BhC4-1-lacZ induction in prepupal salivary glands and constitute the first demonstration of the participation of early genes products on DNA puff genes regulation. genesis 44:505,514, 2006. © 2006 Wiley-Liss, Inc. [source] Identification of novel DNA methylation markers in cervical cancer,INTERNATIONAL JOURNAL OF CANCER, Issue 1 2008Hung-Cheng Lai Abstract Testing for DNA methylation has potential in cancer screening. Most previous studies of DNA methylation in cervical cancer used a candidate gene approach. The aim our study was to identify novel genes that are methylated in cervical cancers and to test their potential in clinical applications. We did a differential methylation hybridization using a CpG island (CGI) microarray containing 8640 CGI tags to uncover methylated genes in squamous cell carcinomas (SCC) of the uterine cervix. Pooled DNA from cancer tissues and normal cervical swabs were used for comparison. Methylation-specific polymerase chain reaction, bisulfite sequencing and reverse transcription polymerase chain reaction were used to confirm the methylation status in cell lines, normal cervices (n = 45), low-grade lesions (n = 45), high-grade lesions (HSIL; n = 58) and invasive squamous cell carcinomas (SCC; n = 22 from swabs and n = 109 from tissues). Human papillomavirus (HPV) was detected using reverse line blots. We reported 6 genes (SOX1, PAX1, LMX1A, NKX6-1, WT1 and ONECUT1) more frequently methylated in SCC tissues (81.5, 94.4, 89.9, 80.4, 77.8 and 20.4%, respectively) than in their normal controls (2.2, 0, 6.7, 11.9, 11.1 and 0%, respectively; p < 0.0001). Parallel testing of HPV and PAX1 methylation in cervical swabs confers an improved sensitivity than HPV testing alone (80% vs. 66%) without compromising specificity (63% vs. 64%) for HSIL/SCC. Testing PAX1 methylation marker alone, the specificity for HSIL/SCC is 99%. The analysis of these novel DNA methylations may be a promising approach for the screening of cervical cancers. © 2008 Wiley-Liss, Inc. [source] Searching for genes in diabetes and the metabolic syndromeINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 2004G. A. Hitman Summary Evidence for a genetic basis for type 2 diabetes and the metabolic syndrome has been derived from studies of families, twins and populations with genetic admixture. Identification of genes associated with disease pathogenesis is now underway using techniques such as genome scanning by positional cloning and the candidate gene approach. Genome scanning in several different ethnic groups has identified chromosome regions harbouring type 2 diabetes susceptibility genes such as the novel gene, calpain 10 (CAPN10). The hepatic nuclear factor 4, (HNF4,) gene partly explains the linkage peak on chromosome 20, while the upstream transcription factor (USF1) is associated with familial combined hyperlipidaemia (FCHL) and maps close to the type 2 diabetes associated 1q peak. Peroxisome proliferator-activated receptor gamma (PPAR,) was identified as a candidate gene based on its biology. A Pro12Ala variant of this gene has been associated with an increased risk of type 2 diabetes. Many genes accounting for monogenic forms of diabetes have been identified , such as maturity onset diabetes of the young (MODY); glucokinase (GCK) and HNF1, mutations being the most common causes of MODY. GCK variants result in ,mild' diabetes or impaired glucose tolerance (IGT) and relatively few cardiovascular complications, while HNF1,- associated MODY is more typical of type 2 diabetes, frequently being treated with sulphonylureas or insulin and resulting in microvascular complications. Testing for single gene disorders associated with type 2 diabetes and obesity may determine cause, prognosis and appropriate treatment; however, for the more common polygenic diseases this is not the case. In type 2 diabetes, molecular genetics has the potential to enhance understanding of disease pathogenesis, and help formulate preventative and treatment strategies. [source] CADISP-genetics: an International project searching for genetic risk factors of cervical artery dissectionsINTERNATIONAL JOURNAL OF STROKE, Issue 3 2009S. Debette Background Cervical artery dissection (CAD) is a frequent cause of ischemic stroke, and occasionally death, in young adults. Several lines of evidence suggest a genetic predisposition to CAD. However, previous genetic studies have been inconclusive mainly due to insufficient numbers of patients. Our hypothesis is that CAD is a multifactorial disease caused by yet largely unidentified genetic variants and environmental factors, which may interact. Our aim is to identify genetic variants associated with an increased risk of CAD and possibly gene,environment interactions. Methods We organized a multinational European network, Cervical Artery Dissection and Ischemic Stroke Patients (CADISP), which aims at increasing our knowledge of the pathophysiological mechanisms of this disease in a large group of patients. Within this network, we are aiming to perform a de novo genetic association analysis using both a genome-wide and a candidate gene approach. For this purpose, DNA from approximately 1100 patients with CAD, and 2000 healthy controls is being collected. In addition, detailed clinical, laboratory, diagnostic, therapeutic, and outcome data are being collected from all participants applying predefined criteria and definitions in a standardized way. We are expecting to reach the above numbers of subjects by early 2009. Conclusions We present the strategy of a collaborative project searching for the genetic risk factors of CAD. The CADISP network will provide detailed and novel data on environmental risk factors and genetic susceptibility to CAD. [source] Multiple molecular approaches yield no evidence for sex-determining genes in lake sturgeon (Acipenser fulvescens)JOURNAL OF APPLIED ICHTHYOLOGY, Issue 6 2008C. R. McCormick Summary Common DNA-based sexing assays have been widely used for the conservation and management of mammals and birds. However, many fishes do not have genetic sex determination and in those that do, the plasticity of the genes involved means that species-specific assays are normally required. Such DNA-sexing markers would be especially valuable in lake sturgeon (Acipenser fulvescens) because of their sexual monomorphism, delayed sexual maturity, and conservation status. We tried to identify genetic differences between male and female lake sturgeon using several different molecular genetic methods, including randomly amplified polymorphic DNA, representational difference analyses, subtractive hybridization, and a candidate gene approach. Ultimately, a number of genes were identified but none was sex-specific. Although the ultimate mechanism of sex determination is yet unknown, it is possible that sex determination is environmental in lake sturgeon, especially since recent studies have also failed to identify sex determination genes in other sturgeon species. [source] AKT1 leader gene and downstream targets are involved in a rat model of kidney allograft tolerance,JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 3 2010Vojislav Jovanovic Abstract Tolerance is the so-called "Holy Grail" of transplantation but achieving this state is proving a major challenge, particularly in the clinical settings. This tolerance state can be induced in rodent models using a variety of maneuvers. This phenomenon is classically characterized by donor specificity (recipients accept a secondary donor-specific allograft but reject third-party allograft) as well as by the absence of chronic rejection lesion. We previously showed that administration and anti-donor anti-class II serum on the day of transplantation induce tolerance to a kidney allograft in the LEW-1W to LEW-1A strain combination. In this study, we used DNA microarrays to compare gene patterns involved in anti-donor anti-class II tolerated or untreated syngeneic kidney transplants in this strain combination. Statistical and non-statistical analyses were combined with ab initio analysis, using the recently developed leader gene approach, to shed new light on this phenomenon. Theoretical and experimental results suggest that tolerance and rejection outcome may be in large part determined by low expression variations of some genes, which can form a core gene network around specific genes such as Rac1, NFKB1, RelA, AKT1, IKBKB, BCL2, BCLX, and CHUK. Through this model, we showed that AKT1 gene, WNT pathway and NO synthesis are strictly connected to each other and may play an important role in kidney tolerance and rejection processes, with AKT1 gene being the center of this complex network of interactions. J. Cell. Biochem. 111: 709,719, 2010. © 2010 Wiley-Liss, Inc. [source] Methodological and statistical issues in pharmacogenomicsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 2 2010Bas J. M. Peters Abstract Pharmacogenomics strives to explain the interindividual variability in response to drugs due to genetic variation. Although technological advances have provided us with relatively easy and cheap methods for genotyping, promises about personalised medicine have not yet met our high expectations. Successful results that have been achieved within the field of pharmacogenomics so far are, to name a few, HLA-B*5701 screening to avoid hypersensitivity to the antiretroviral abacavir, thiopurine S-methyltransferase (TPMT) genotyping to avoid thiopurine toxicity, and CYP2C9 and VKORC1 genotyping for better dosing of the anticoagulant warfarin. However, few pharmacogenetic examples have made it into clinical practice in the treatment of complex diseases. Unfortunately, lack of reproducibility of results from observational studies involving many genes and diseases seems to be a common pattern in pharmacogenomic studies. In this article we address some of the methodological and statistical issues within study design, gene and single nucleotide polymorphism (SNP) selection and data analysis that should be considered in future pharmacogenomic research. First, we discuss some of the issues related to the design of epidemiological studies, specific to pharmacogenomic research. Second, we describe some of the pros and cons of a candidate gene approach (including gene and SNP selection) and a genome-wide scan approach. Finally, conventional as well as several innovative approaches to the analysis of large pharmacogenomic datasets are proposed that deal with the issues of multiple testing and systems biology in different ways. [source] Candidate Gene Association Study for Noise-induced Hearing Loss in Two Independent Noise-exposed PopulationsANNALS OF HUMAN GENETICS, Issue 2 2009A. Konings Summary Millions of people are daily exposed to high levels of noise. Consequently, noise-induced hearing loss (NIHL) is one of the most important occupational health hazards worldwide. In this study, we performed an association study for NIHL based on a candidate gene approach. 644 Single Nucleotide Polymorphisms (SNPs) in 53 candidate genes were analyzed in two independent NIHL sample sets, a Swedish set and part of a Polish set. Eight SNPs with promising results were selected and analysed in the remaining part of the Polish samples. One SNP in PCDH15 (rs7095441), resulted in significant associations in both sample sets while two SNPs in MYH14 (rs667907 and rs588035), resulted in significant associations in the Polish sample set and significant interactions with noise exposure level in the Swedish sample set. Calculation of odds ratios revealed a significant association of rs588035 with NIHL in the Swedish high noise exposure level group. Our studies suggest that PCDH15 and MYH14 may be NIHL susceptibility genes, but further replication in independent sample sets is mandatory. [source] Disrupted SOX10 regulation of GJC2 transcription causes Pelizaeus-Merzbacher-like diseaseANNALS OF NEUROLOGY, Issue 2 2010Hitoshi Osaka MD Mutations in the gap junction protein gamma-2 gene, GJC2, cause a central hypomyelinating disorder; Pelizaeus-Merzbacher-like disease (PMLD; MIM311601). Using a homozygosity mapping and positional candidate gene approach, we identified a homozygous mutation (c.-167A>G) within the GJC2 promoter at a potent SOX10 binding site in a patient with mild PMLD. Functionally, this mutation completely abolished the SOX10 binding and attenuated GJC2 promoter activity. These findings suggest not only that the SOX10 -to- GJC2 transcriptional dysregulation is a cause of PMLD, but also that GJC2 may be in part responsible for the central hypomyelination caused by SOX10 mutations. ANN NEUROL 2010;68:250,254 [source] Molecular cloning, characterization and nutritional regulation of key enzymes required for the effective utilization of marine wax esters by Atlantic salmon (Salmo salar L.)AQUACULTURE NUTRITION, Issue 5 2010M. MINGHETTI Abstract Previous studies had shown that wax ester-rich lipid extracted from calanoid copepods could be a useful alternative to fish oil as a provider of long-chain n-3 polyunsaturated fatty acids in diets for use in salmon aquaculture. Effective utilization of wax ester requires digestion and metabolism in the intestine with the fatty alcohol component being oxidized to fatty acid in intestinal cells through the combined activities of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). We studied wax ester utilization in Atlantic salmon using a candidate gene approach, focusing on ADH and ALDH as sequence information was available for these genes, including fish sequences, facilitating isolation of the cDNAs. Here, we report on the isolation and cloning of full-length cDNAs for ADH3 and ALDH3a2 genes from salmon intestinal tissue. Functional characterization by heterologous expression in the yeast, Saccharomyces cerevisiae, showed the products of these cDNAs had long-chain ADH and ALDH enzyme activities. Thus, ADH3 was capable of oxidizing long-chain fatty alcohol, and ALDH3a2 was capable of oxidizing long-chain fatty aldehyde to the corresponding fatty acid. The genes were highly expressed in intestinal tissue, particularly pyloric caeca, but their expression was not increased in salmon fed dietary copepod oil in comparison to fish fed fish oil. [source] Replication of the tumor necrosis factor receptor,associated factor 1/complement component 5 region as a susceptibility locus for rheumatoid arthritis in a European family-based studyARTHRITIS & RHEUMATISM, Issue 9 2008F. A. S. Kurreeman Objective We recently showed, using a candidate gene approach in a case,control association study, that a 65-kb block encompassing tumor necrosis factor receptor,associated factor 1 (TRAF1) and C5 is strongly associated with rheumatoid arthritis (RA). Compared with case,control association studies, family-based studies have the added advantage of controlling potential differences in population structure and are not likely to be hampered by variation in population allele frequencies, as is seen for many genetic polymorphisms, including the TRAF1/C5 locus. The aim of this study was to confirm this association in populations of European origin by using a family-based approach. Methods A total of 1,356 western European white individuals from 452 "trio" families were genotyped for the rs10818488 polymorphism, using the TaqMan allelic discrimination assay. Results We observed evidence for association, demonstrating departure from Mendel's law, with an overtransmission of the rs10818488 A allele (A = 55%; P = 0.036). By taking into consideration parental phenotypes, we also observed an increased A allele frequency in affected versus unaffected parents (A = 64%; combined P = 0.015). Individuals carrying the A allele had a 1.2-fold increased risk of developing RA (allelic odds ratio 1.24, 95% confidence interval 1.04,1.50). Conclusion Using a family-based study that is robust against population stratification, we provide evidence for the association of the TRAF1/C5 rs10818488 A allele and RA in populations of European descent, further substantiating our previous findings. Future functional studies should yield insight into the biologic relevance of this locus to the pathways involved in RA. [source] Novel genetic markers in the 5,-flanking region of ANKH are associated with ankylosing spondylitisARTHRITIS & RHEUMATISM, Issue 3 2003Florence W. L. Tsui Objective To use a candidate gene approach for the identification of genetic markers that are significantly linked to and associated with ankylosing spondylitis (AS). Methods We searched for novel polymorphisms in the ANKH gene (human homolog of the murine progressive ankylosis gene) and genotyped 2 polymorphic sites, one in the 5,-noncoding region and the other in the promoter region of ANKH, using DNA from affected (n = 273) and unaffected (n = 112) individuals from 124 AS families. We used these ANKH and other nearby polymorphisms to perform linkage and family-based association analyses. Results We identified 2 novel polymorphic sites: one in the 5,-noncoding region of ANKH involving 1,2 copies of an 8-bp repeat (denoted as ANKH-OR), and the other in the promoter region involving different copy numbers of a triplet repeat (denoted as ANKH-TR). ANKH-OR and ANKH-TR were in complete linkage disequilibrium. Five markers (D5S1953, ANKH-TR, ANKH-OR, D5S1954, and D5S1963) were used for both the linkage and association analyses. Multipoint linkage analysis of 124 AS families showed a modest level of significance (nonparametric linkage score 2.15; P = 0.015) at the ANKH region. The contribution of ANKH to AS susceptibility (,s) was 1.9. A family-based association study on the same AS families revealed that both ANKH-OR allele 1 and ANKH-TR allele 7 were significantly associated with disease, assuming an additive model (for ANKH-OR allele 1, P = 0.03; for ANKH-TR allele 7, P = 0.04). Conclusion Our results indicate that ANKH-OR and ANKH-TR are novel genetic markers that are significantly associated with AS. [source] Suggestive linkage of familial primary cutaneous amyloidosis to a locus on chromosome 1q23BRITISH JOURNAL OF DERMATOLOGY, Issue 1 2005M-W. Lin Summary Background, There is a high incidence of primary cutaneous amyloidosis (PCA) in South America, South-east Asia and Taiwan. To date, the aetiology of PCA remains unknown, but it is believed to be multifactorial. Although most cases are sporadic, some patients have a family history. Familial aggregation and different susceptibility to PCA among ethnic groups suggest that genetic factors may play an important role in its pathogenesis. However, no genetic loci for familial PCA (FPCA) have been identified so far. Objectives, In order to identify the susceptibility gene of FPCA, we took a candidate gene approach and performed linkage analysis on chromosome 1q21.3,24.2, including the 1q23.2 region where the gene encoding serum amyloid P component (APCS) is located. Patients and methods, Nine FPCA families including 29 individuals affected with PCA were recruited for this linkage study. Initially, 11 highly polymorphic microsatellite markers spanning the region from 1q21.3 to 1q24.2 were genotyped and revealed a suggestive linkage region. This region was further fine-mapped with seven additional markers. We also re-sequenced the 2·5-kb genomic region of the APCS gene in 29 affected and 42 control individuals. Two-point and multipoint linkage analyses were performed using the LINKAGE program. Nonparametric linkage (NPL) analysis and reconstruction of haplotypes were performed with the GENEHUNTER program. Results, Both two-point and multipoint linkage analysis for all 11 markers generated negative or small positive total lod scores for all nine families. However, when we considered only three families, a maximum two-point total lod score of 2·09 was obtained for the marker D1S2844 at , = 0·01. A plateau of multipoint total lod score between D1S2768 and D1S2878 with a maximum of 2·48 at the marker D1S2844 was observed. A maximum NPL score of 3·11 (P = 0·008) was also obtained for the marker D1S2878. However, re-sequencing of the APCS gene identified no functional mutation. Conclusions, Both parametric and nonparametric linkage evidence suggested that a possible susceptibility locus for a subset of FPCA might exist on chromosome 1q23. This is the first report demonstrating suggestive evidence of linkage of FPCA to a locus in this candidate region. No functional sequence variations of the APCS gene were found to be associated with this disease among the study families. Our data imply the existence of at least one additional locus responsible for FPCA in these families, confirming genetic heterogeneity of this skin disorder. [source] The University of California, San Francisco Family Alcoholism Study.ALCOHOLISM, Issue 10 2004Background: The University of California, San Francisco (UCSF) Family Alcoholism Study is a project designed to identify genetic loci that influence susceptibility to alcohol dependence and related phenotypes. Evidence supports a substantial genetic contribution to alcoholism susceptibility. However, the genetic epidemiology of alcoholism is complex, and its clinical manifestation is heterogeneous, making phenotype definition and demonstration of linkage difficult. Despite these challenges, some progress has been made toward identifying genes. Methods: The UCSF Family Alcoholism Study used a small family design, focusing primarily on sibling pairs and parent-child trios for linkage and association studies. Alcoholism-related phenotypes were assessed through interview and self-report questionnaires, with a focus on unidimensional and subphenotypical traits. Data-driven approaches to determining the most promising phenotypes for genetic analysis are being used. Both genome-wide scan and candidate gene approaches were used. Results: The study enrolled 2154 individuals from 970 families from December 1995 through January 2003. Test-retest and interrater reliability for clinical data are very good, and power estimates suggest that this study will have adequate power by linkage analysis to detect loci with moderate effects. Design, methods, and sample demographics of the UCSF Family Study are presented, along with intrafamilial correlations for primary diagnostic phenotypes. Conclusions: Plans for genetic analysis, novel approaches to phenotype refinement, and the implications of ascertainment bias for heritability estimates are discussed. [source] Molecular ecology of global changeMOLECULAR ECOLOGY, Issue 19 2007THORSTEN B. H. REUSCH Abstract Global environmental change is altering the selection regime for all biota. The key selective factors are altered mean, variance and seasonality of climatic variables and increase in CO2 concentration itself. We review recent studies that document rapid evolution to global climate change at the phenotypic and genetic level, as a response to shifts in these factors. Among the traits that have changed are photoperiod responses, stress tolerance and traits associated with enhanced dispersal. The genetic basis of two traits with a critical role under climate change, stress tolerance and photoperiod behaviour, is beginning to be understood for model organisms, providing a starting point for candidate gene approaches in targeted nonmodel species. Most studies that have documented evolutionary change are correlative, while selection experiments that manipulate relevant variables are rare. The latter are particularly valuable for prediction because they provide insight into heritable change to simulated future conditions. An important gap is that experimental selection regimes have mostly been testing one variable at a time, while synergistic interactions are likely under global change. The expanding toolbox available to molecular ecologists holds great promise for identifying the genetic basis of many more traits relevant to fitness under global change. Such knowledge, in turn, will significantly advance predictions on global change effects because presence and polymorphism of critical genes can be directly assessed. Moreover, knowledge of the genetic architecture of trait correlations will provide the necessary framework for understanding limits to phenotypic evolution; in particular as lack of critical gene polymorphism or entire pathways, metabolic costs of tolerance and linkage or pleiotropy causing negative trait correlations. Synergism among stressor impacts on organismal function may be causally related to conflict among transcriptomic syndromes specific to stressor types. Because adaptation to changing environment is always contingent upon the spatial distribution of genetic variation, high-resolution estimates of gene flow and hybridization should be used to inform predictions of evolutionary rates. [source] | ||||||||||||||||||||||||||||