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Fine Mapping (fine + mapping)

Distribution by Scientific Domains

Life Sciences	61%
Medical Sciences	35%

Distribution within Life Sciences

Human Genetics	32%
Plant Science	8%

Selected Abstracts

Fine Mapping of Polymorphic Alcohol-Related Quantitative Trait Loci Candidate Genes Using Interval-Specific Congenic Recombinant Mice

ALCOHOLISM, Issue 11 2002
Marissa A. Ehringer
Background The inbred long-sleep (ILS) and inbred short-sleep (ISS) strains of mice are widely studied as a model of initial sensitivity to alcohol. Recently, a large comparative DNA sequencing study of candidate genes located within the four Lore quantitative trait loci (QTLs) associated with the ethanol-induced loss of righting reflex in ILS and ISS mice has identified eight genes that contain coding region differences corresponding to amino acid changes. Here, recently developed interval-specific congenic recombinant mice (ISCRs) have been used to map these genes in relationship to newly narrowed QTL regions. Methods Regions of candidate genes containing DNA differences corresponding to previously identified amino acid changes between ISS and ILS mice were amplified from either genomic DNA or complementary DNA from ISCR mice using polymerase chain reaction. The products were purified and directly sequenced to determine the genotypes for each polymorphism. On the basis of these genotypic data, each candidate gene was determined to be located either within or outside of recently narrowed Lore QTL intervals. Results Of these eight candidates with protein-coding differences, five are now excluded from their respective Lore intervals. The other three (Znf142, Ptprn, and Znf133) have been localized to the narrowed QTL intervals. Conclusions These three central nervous system genes (Znf142, Ptprn, and Znf133) represent promising candidates for involvement in the differential sensitivity to alcohol exhibited between ILS and ISS mice. This study also demonstrates how the combination of high-throughput comparative gene sequencing and concomitant genetic fine mapping of QTL regions with ISCRs can be an effective tool for accelerating the process of moving from QTL to gene. [source]

A narrow deletion of 7q is common to HCL, and SMZL, but not CLL

EUROPEAN JOURNAL OF HAEMATOLOGY, Issue 6 2004
Claus Lindbjerg Andersen
Abstract: To further characterise the genetic background of the two closely related B-lymphocytic malignancies hairy cell leukaemia (HCL), and splenic marginal zone lymphoma (SMZL) we have identified characteristic copy number imbalances by comparative genomic hybridisation (CGH). Based on these findings, areas of special interest were fine mapped, and relevant probes constructed for use in interphase-fluorescence in situ hybridisation (FISH) investigations. Thus, using the CGH data from 52 HCL and 61 SMZL patients, we identified the characteristic profiles of copy number imbalances for both diseases. These were a gain of 5q13-31 (19%) and loss of 7q22-q35 (6%) for HCL, and gain of 3q25 (28%), loss of 7q31 (16%), and gain of 12q15 (16%) for SMZL. A partial loss of 7q unsual for low-malignant B-cell diseases was found to be common to the two diseases. This loss was therefore fine mapped with BAC/PAC clones. Fine mapping revealed that in SMZL the minimal lost region covers 11.4 Mb spanning from 7q31.33 to 7q33 located between sequence tagged site (STS)-markers SHGC-3275 and D7S725. This area was distinct from the commonly deleted 7q region of myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML). A FISH probe specific for the 7q region was constructed. Using this probe in an interphase-FISH investigation we showed the minimal lost 7q-region of HCL and SMZL to be one and the same. In one HCL case, this investigation furthermore showed the extent of the deleted region to be below the detection limit of CGH, whereas interphase-FISH screening of 36 chronic lymphocytic leukaemia (CLL) cases showed no deletion of the 7q area. In conclusion, we have identified characteristic profiles of copy number imbalances in HCL and SMZL and fine mapped the minimal extent of a commonly lost 7q area of special interest. We hypothesise that this region may contain (a) gene(s) important for the pathology of HCL and SMZL. [source]

Fine mapping of a sedative-hypnotic drug withdrawal locus on mouse chromosome 11

GENES, BRAIN AND BEHAVIOR, Issue 1 2006
H. M. Hood
We have established that there is a considerable amount of common genetic influence on physiological dependence and associated withdrawal from sedative-hypnotic drugs including alcohol, benzodiazepines, barbiturates and inhalants. We previously mapped two loci responsible for 12 and 9% of the genetic variance in acute alcohol and pentobarbital withdrawal convulsion liability in mice, respectively, to an approximately 28-cM interval of proximal chromosome 11. Here, we narrow the position of these two loci to a 3-cM interval (8.8 Mb, containing 34 known and predicted genes) using haplotype analysis. These include genes encoding four subunits of the GABAA receptor, which is implicated as a pivotal component in sedative-hypnotic dependence and withdrawal. We report that the DBA/2J mouse strain, which exhibits severe withdrawal from sedative-hypnotic drugs, encodes a unique GABAA receptor ,2 subunit variant compared with other standard inbred strains including the genetically similar DBA/1J strain. We also demonstrate that withdrawal from zolpidem, a benzodiazepine receptor agonist selective for ,1 subunit containing GABAA receptors, is influenced by a chromosome 11 locus, suggesting that the same locus (gene) influences risk of alcohol, benzodiazepine and barbiturate withdrawal. Our results, together with recent knockout studies, point to the GABAA receptor ,2 subunit gene (Gabrg2) as a promising candidate gene to underlie phenotypic differences in sedative-hypnotic physiological dependence and associated withdrawal episodes. [source]

Genome-wide analysis of allelic imbalances reveals 4q deletions as a poor prognostic factor and MDM4 amplification at 1q32.1 in hepatoblastoma

GENES, CHROMOSOMES AND CANCER, Issue 7 2010
Yasuhito Arai
In a single-nucleotide polymorphism array-based analysis of 56 hepatoblastoma (HB) tumors, allelic imbalances were detected in 37 tumors (66%). Chromosome gains were found in 1q (28 tumors), 2q (24), 6p (8), 8q (8), 17q (6), and 20pq (10), and losses in 1p (6), 4q (9), and 16q (4). Fine mapping delineated the shortest overlapping region (SOR) of gains at 1q32.1 (1.3 Mb) and 2q24.2-q24.3 (4.8 Mb), and losses at 4q34.3-q35.2 (8.7 Mb) and 4q32.3 (1.6 Mb). Uniparental disomy of 11pter-11p15.4 (IGF2) and loss of 11pter-p14.1 were found in 11 and 2 tumors, respectively. Expression of HTATIP2 (11p15.1) was absent in 9 of 20 tumors. Amplification was identified in four tumors at 1q32.1, where the candidate oncogene MDM4 is located. In the 4q32.3-SRO, ANXA10S, a variant of the candidate tumor suppressor ANXA10, showed no expression in 19 of 24 tumors. Sequence analysis of ANXA10S identified a missense mutation (E36K, c.106G>A) in a HB cell line. Multivariate analysis revealed that both 4q deletion and RASSF1A methylation (relative risks: 4.21 and 7.55, respectively) are independent prognostic factors. Our results indicate that allelic imbalances and gene expression patterns provide possible diagnostic and prognostic markers, as well as therapeutic targets in a subset of HB. © 2010 Wiley-Liss, Inc. [source]

Fine mapping and detection of the causative mutation underlying Quantitative Trait Loci

JOURNAL OF ANIMAL BREEDING AND GENETICS, Issue 5 2010
E. Uleberg
Summary The effect on power and precision of including the causative SNP amongst the investigated markers in Quantitative Trait Loci (QTL) mapping experiments was investigated. Three fine mapping methods were tested to see which was most efficient in finding the causative mutation: combined linkage and linkage disequilibrium mapping (LLD); association mapping (MARK); a combination of LLD and association mapping (LLDMARK). Two simulated data sets were analysed: in one set, the causative SNP was included amongst the markers, while in the other set the causative SNP was masked between markers. Including the causative SNP amongst the markers increased both precision and power in the analyses. For the LLD method the number of correctly positioned QTL increased from 17 for the analysis without the causative SNP to 77 for the analysis including the causative SNP. The likelihood of the data analysis increased from 3.4 to 13.3 likelihood units for the MARK method when the causative SNP was included. When the causative SNP was masked between the analysed markers, the LLD method was most efficient in detecting the correct QTL position, while the MARK method was most efficient when the causative SNP was included as a marker in the analysis. The LLDMARK method, combining association mapping and LLD, assumes a QTL as the null hypothesis (using LLD method) and tests whether the ,putative causative SNP' explains significantly more variance than a QTL in the region. Thus, if the putative causative SNP does not only give an Identical-By-Descent (IBD) signal, but also an Alike-In-State (AIS) signal, LLDMARK gives a positive likelihood ratio. LLDMARK detected less than half as many causative SNPs as the other methods, and also had a relatively high false discovery rate when the QTL effect was large. LLDMARK may however be more robust against spurious associations, because the regional IBD is largely corrected for by fitting a QTL effect in the null hypothesis model. [source]

Fine mapping of a quantitative trait locus on chromosome 9 affecting non-return rate in Swedish dairy cattle

JOURNAL OF ANIMAL BREEDING AND GENETICS, Issue 5 2007
M. Holmberg
Summary We previously mapped a quantitative trait locus (QTL) affecting the trait non-return rate at 56 days in heifers to bovine chromosome 9. The purpose of this study was to confirm and refine the position of the QTL by using a denser marker map and fine mapping methods. Five families that previously showed segregation for the QTL were included in the study. The mapping population consisted of 139 bulls in a granddaughter design. All bulls were genotyped for 25 microsatellite markers surrounding the QTL on chromosome 9. We also analysed the correlated trait number of inseminations per service period in heifers. Both traits describe the heifer's ability to become pregnant after insemination. Linkage analysis, linkage disequilibrium and combined linkage and linkage disequilibrium analysis were used to analyse the data. Analysis of the families jointly by linkage analysis resulted in a significant but broad QTL peak for non-return rate. Results from the combined analysis gave a sharp QTL peak with a well-defined maximum in between markers BMS1724 and BM7209, at the same position as where the highest peak from the linkage disequilibrium analysis was found. One of the sire families segregated clearly at this position and the difference in effects between the two sire haplotypes was 2.9 percentage units in non-return rate. No significant results were found for the number of inseminations in the combined analysis. [source]

The genetics of inflammatory bowel disease

ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2001
T. Ahmad
Recent epidemiological, clinical and molecular studies have provided strong evidence that inherited predisposition is important in the pathogenesis of chronic inflammatory bowel diseases. The model most consistent with the epidemiological data suggests that Crohn's disease and ulcerative colitis are related polygenic diseases, sharing some but not all susceptibility genes. Investigators throughout the world have applied the complementary techniques of genome-wide scanning and candidate gene analysis. Four areas of linkage have been widely replicated on chromosomes 16 (IBD1), 12 (IBD2), 6 (IBD3,the HLA region), and most recently on chromosome 14. Fine mapping of these regions is underway. Of the ,positional' candidate genes, most attention has centred on the genes of the major histocompatibility complex. Genes within this region may determine disease susceptibility, behaviour, complications and response to therapy. Hope continues that studies of inflammatory bowel disease genetics will provide fresh insight into disease pathogenesis and soon deliver clinical applications. [source]

Genetics of human iris colour and patterns

PIGMENT CELL & MELANOMA RESEARCH, Issue 5 2009
Richard A. Sturm
Summary The presence of melanin pigment within the iris is responsible for the visual impression of human eye colouration with complex patterns also evident in this tissue, including Fuchs' crypts, nevi, Wolfflin nodules and contraction furrows. The genetic basis underlying the determination and inheritance of these traits has been the subject of debate and research from the very beginning of quantitative trait studies in humans. Although segregation of blue-brown eye colour has been described using a simple Mendelian dominant-recessive gene model this is too simplistic, and a new molecular genetic perspective is needed to fully understand the biological complexities of this process as a polygenic trait. Nevertheless, it has been estimated that 74% of the variance in human eye colour can be explained by one interval on chromosome 15 that contains the OCA2 gene. Fine mapping of this region has identified a single base change rs12913832 T/C within intron 86 of the upstream HERC2 locus that explains almost all of this association with blue-brown eye colour. A model is presented whereby this SNP, serving as a target site for the SWI/SNF family member HLTF, acts as part of a highly evolutionary conserved regulatory element required for OCA2 gene activation through chromatin remodelling. Major candidate genes possibly effecting iris patterns are also discussed, including MITF and PAX6. [source]

Fine mapping of the FecL locus influencing prolificacy in Lacaune sheep

ANIMAL GENETICS, Issue 6 2009
L. Drouilhet
Summary In the Lacaune sheep population, two major loci influencing ovulation rate are segregating: FecX and FecL. The FecXL mutation is a non-conservative substitution (p.Cys53Tyr) in BMP15 that prevents the processing of the protein. Using a statistical approach, FecL has been shown to be an autosomal major gene. A full genome scan localized the FecL locus on sheep chromosome 11. Fine mapping reduced the interval containing FecL to markers BM17132 and FAM117A, corresponding to a synteny block of 1.1 megabases on human chromosome 17, which encompasses 20 genes. The expression of 16 genes from this interval was observed in tissues of the reproductive axis, but expression was not affected in homozygous FecLL females. In this interval, a unique haplotype was associated with the FecLL mutation. This particular haplotype could be predicted by the DLX3:c.*803A>G SNP in the 3, UTR sequence of the DLX3 gene. This SNP provided accurate classification of animals (99.5%) as carriers or non-carriers of the mutation and therefore maybe useful in marker assisted selection. A synergistic action of FecLL and FecXL mutations on both ovulation rate and litter size was demonstrated. Until now, all the Fec genes identified in sheep belong to the bone morphogenetic protein (BMP) system. Based on the human orthologous region, none of the 20 genes in the FecL region corresponds to known molecules in the BMP system. The identification of the FecLL mutation could lead to the discovery of a new pathway involved in the regulation of ovulation rate. [source]

Fine mapping of the chicken salmonellosis resistance locus (SAL1)

ANIMAL GENETICS, Issue 6 2009
M. S. Fife
Summary Salmonella enterica serovar Typhimurium is a Gram-negative bacterium that has a significant impact on both human and animal health. It is one of the most common food-borne pathogens responsible for a self-limiting gastroenteritis in humans and a similar disease in pigs, cattle and chickens. In contrast, intravenous challenge with S. Typhimurium provides a valuable model for systemic infection, often causing a typhoid-like infection, with bacterial replication resulting in the destruction of the spleen and liver of infected animals. Resistance to systemic salmonellosis in chickens is partly genetically determined, with bacterial numbers at systemic sites in resistant lines being up to 1000-fold fewer than in susceptible lines. Identification of genes contributing to disease resistance will enable genetic selection of resistant lines that will reduce Salmonella levels in poultry flocks. We previously identified a novel resistance locus on Chromosome 5, designated SAL1. Through the availability of high-density SNP panels in the chicken, combined with advanced back-crossing of the resistant and susceptible lines, we sought to refine the SAL1 locus and identify potential positional candidate genes. Using a 6th generation backcross mapping population, we have confirmed and refined the SAL1 locus as lying between 54.0 and 54.8 Mb on the long arm of Chromosome 5 (F = 8.72, P = 0.00475). This region spans 14 genes, including two very striking functional candidates; CD27-binding protein (Siva) and the RAC -alpha serine/threonine protein kinase homolog, AKT1 (protein kinase B, PKB). [source]

Fine mapping of quantitative trait loci for mastitis resistance on bovine chromosome 11

ANIMAL GENETICS, Issue 4 2009
N. F. Schulman
Summary Quantitative trait loci (QTL) affecting clinical mastitis (CM) and somatic cell score (SCS) were mapped on bovine chromosome 11. The mapping population consisted of 14 grandsire families belonging to three Nordic red cattle breeds: Finnish Ayrshire (FA), Swedish Red and White (SRB) and Danish Red. The families had previously been shown to segregate for udder health QTL. A total of 524 progeny tested bulls were included in the analysis. A linkage map including 33 microsatellite and five SNP markers was constructed. We performed combined linkage disequilibrium and linkage analysis (LDLA) using the whole data set. Further analyses were performed for FA and SRB separately to study the origin of the identified QTL/haplotype and to examine if it was common in both populations. Finally, different two-trait models were fitted. These postulated either a pleiotropic QTL affecting both traits; two linked QTL, each affecting one trait; or one QTL affecting a single trait. A QTL affecting CM was fine-mapped. In FA, a haplotype having a strong association with a high negative effect on mastitis resistance was identified. The mapping precision of an earlier detected SCS-QTL was not improved by the LDLA analysis because of lack of linkage disequilibrium between the markers used and the QTL in the region. [source]

Characterization of the quantitative trait locus for haloperidol-induced catalepsy on distal mouse chromosome 1

GENES, BRAIN AND BEHAVIOR, Issue 2 2008
J. R. Hofstetter
We report here the confirmation of the quantitative trait locus for haloperidol-induced catalepsy on distal chromosome (Chr) 1. We determined that this quantitative trait locus was captured in the B6.D2- Mtv7a/Ty congenic mouse strain, whose introgressed genomic interval extends from approximately 169.1 to 191.3 Mb. We then constructed a group of overlapping interval-specific congenic strains to further break up the interval and remapped the locus between 177.5 and 183.4 Mb. We next queried single nucleotide polymorphism (SNP) data sets and identified three genes with nonsynonymous coding SNPs in the quantitative trait locus. We also queried two brain gene expression data sets and found five known genes in this 5.9-Mb interval that are differentially expressed in both whole brain and striatum. Three of the candidate quantitative trait genes were differentially expressed using quantitative real-time polymerase chain reaction analyses. Overall, the current study illustrates how multiple approaches, including congenic fine mapping, SNP analysis and microarray gene expression screens, can be integrated both to reduce the quantitative trait locus interval significantly and to detect promising candidate quantitative trait genes. [source]

Genome-wide association studies using haplotype clustering with a new haplotype similarity

GENETIC EPIDEMIOLOGY, Issue 6 2010
Lina Jin
Abstract Association analysis, with the aim of investigating genetic variations, is designed to detect genetic associations with observable traits, which has played an increasing part in understanding the genetic basis of diseases. Among these methods, haplotype-based association studies are believed to possess prominent advantages, especially for the rare diseases in case-control studies. However, when modeling these haplotypes, they are subjected to statistical problems caused by rare haplotypes. Fortunately, haplotype clustering offers an appealing solution. In this research, we have developed a new befitting haplotype similarity for "affinity propagation" clustering algorithm, which can account for the rare haplotypes primely, so as to control for the issue on degrees of freedom. The new similarity can incorporate haplotype structure information, which is believed to enhance the power and provide high resolution for identifying associations between genetic variants and disease. Our simulation studies show that the proposed approach offers merits in detecting disease-marker associations in comparison with the cladistic haplotype clustering method CLADHC. We also illustrate an application of our method to cystic fibrosis, which shows quite accurate estimates during fine mapping. Genet. Epidemiol. 34: 633,641, 2010. © 2010 Wiley-Liss, Inc. [source]

A two-step procedure for constructing confidence intervals of trait loci with application to a rheumatoid arthritis dataset

GENETIC EPIDEMIOLOGY, Issue 1 2006
Charalampos Papachristou
Abstract Preliminary genome screens are usually succeeded by fine mapping analyses focusing on the regions that signal linkage. It is advantageous to reduce the size of the regions where follow-up studies are performed, since this will help better tackle, among other things, the multiplicity adjustment issue associated with them. We describe a two-step approach that uses a confidence set inference procedure as a tool for intermediate mapping (between preliminary genome screening and fine mapping) to further localize disease loci. Apart from the usual Hardy-Weiberg and linkage equilibrium assumptions, the only other assumption of the proposed approach is that each region of interest houses at most one of the disease-contributing loci. Through a simulation study with several two-locus disease models, we demonstrate that our method can isolate the position of trait loci with high accuracy. Application of this two-step procedure to the data from the Arthritis Research Campaign National Repository also led to highly encouraging results. The method not only successfully localized a well-characterized trait contributing locus on chromosome 6, but also placed its position to narrower regions when compared to their LOD support interval counterparts based on the same data. Genet. Epidemiol. 30:18,29, 2006. © 2005 Wiley-Liss, Inc. [source]

Maximum-likelihood estimation of haplotype frequencies in nuclear families

GENETIC EPIDEMIOLOGY, Issue 1 2004
Tim Becker
Abstract The importance of haplotype analysis in the context of association fine mapping of disease genes has grown steadily over the last years. Since experimental methods to determine haplotypes on a large scale are not available, phase has to be inferred statistically. For individual genotype data, several reconstruction techniques and many implementations of the expectation-maximization (EM) algorithm for haplotype frequency estimation exist. Recent research work has shown that incorporating available genotype information of related individuals largely increases the precision of haplotype frequency estimates. We, therefore, implemented a highly flexible program written in C, called FAMHAP, which calculates maximum likelihood estimates (MLEs) of haplotype frequencies from general nuclear families with an arbitrary number of children via the EM-algorithm for up to 20 SNPs. For more loci, we have implemented a locus-iterative mode of the EM-algorithm, which gives reliable approximations of the MLEs for up to 63 SNP loci, or less when multi-allelic markers are incorporated into the analysis. Missing genotypes can be handled as well. The program is able to distinguish cases (haplotypes transmitted to the first affected child of a family) from pseudo-controls (non-transmitted haplotypes with respect to the child). We tested the performance of FAMHAP and the accuracy of the obtained haplotype frequencies on a variety of simulated data sets. The implementation proved to work well when many markers were considered and no significant differences between the estimates obtained with the usual EM-algorithm and those obtained in its locus-iterative mode were observed. We conclude from the simulations that the accuracy of haplotype frequency estimation and reconstruction in nuclear families is very reliable in general and robust against missing genotypes. © 2004 Wiley-Liss, Inc. [source]

Unified sampling approach for multipoint linkage disequilibrium mapping of qualitative and quantitative traits

GENETIC EPIDEMIOLOGY, Issue 4 2002
Fang-Chi Hsu
Abstract Rapid development in biotechnology has enhanced the opportunity to deal with multipoint gene mapping for complex diseases, and association studies using quantitative traits have recently generated much attention. Unlike the conventional hypothesis-testing approach for fine mapping, we propose a unified multipoint method to localize a gene controlling a quantitative trait. We first calculate the sample size needed to detect linkage and linkage disequilibrium (LD) for a quantitative trait, categorized by decile, under three different modes of inheritance. Our results show that sampling trios of offspring and their parents from either extremely low (EL) or extremely high (EH) probands provides greater statistical power than sampling in the intermediate range. We next propose a unified sampling approach for multipoint LD mapping, where the goal is to estimate the map position (,) of a trait locus and to calculate a confidence interval along with its sampling uncertainty. Our method builds upon a model for an expected preferential transmission statistic at an arbitrary locus conditional on the sampling scheme, such as sampling from EL and EH probands. This approach is valid regardless of the underlying genetic model. The one major assumption for this model is that no more than one quantitative trait locus (QTL) is linked to the region being mapped. Finally we illustrate the proposed method using family data on total serum IgE levels collected in multiplex asthmatic families from Barbados. An unobserved QTL appears to be located at ,, = 41.93 cM with 95% confidence interval of (40.84, 43.02) through the 20-cM region framed by markers D12S1052 and D12S1064 on chromosome 12. The test statistic shows strong evidence of linkage and LD (chi-square statistic = 18.39 with 2 df, P -value = 0.0001). Genet. Epidemiol. 22:298,312, 2002. © 2002 Wiley-Liss, Inc. [source]

Genetic analysis of collagen-induced arthritis in rats: a polygenic model for rheumatoid arthritis predicts a common framework of cross-species inflammatory/autoimmune disease loci

IMMUNOLOGICAL REVIEWS, Issue 1 2001
Marie M. Griffiths
Summary: Collagen-induced arthritis (CIA) is a useful model for dissecting the genetic patterns underlying susceptibility to rheumatoid arthritis (RA) and related chronic/inflammatory autoimmune diseases. CIA exhibits three phenotypes characteristic of autoimmune disease pathogenesis: abnormal levels of immune reactivity to self antigens; chronic inflammation of target organs expressing that specific autoantigen; activation and direct participation of invading mononuclear cells and resident tissue fibroblasts in organ damage. Over 25 different quantitative trait loci (QTL) regulating arthritis severity and autoantibody in rats with CIA are mapped. QTL-congenic strains show that certain CIA,QTLs can modulate arthritis independently. These monogenic models are proving to be highly informative for fine mapping and function studies, revealing gender effects and evidence of gene clusters. Recent genome scans of RA populations identified RA-susceptibility loci in chromosome regions homologous to rat chromosomal segments housing CIA,QTLs. Also, CIA,QTLs frequently co-localize with susceptibility QTLs mapped in other rat arthritis models induced with non-immunogenic adjuvant oils and/or in rat autoimmune models of multiple sclerosis and diabetes. Common autoimmunity genes and inflammation genes important to several human diseases are likely being detected in the various rat disease models. Continued dissection of the genetic underpinnings of rat arthritis models should provide candidate genes for investigation in human patients and lead to a clearer understanding of the complex genetics of RA. [source]

Identification of novel single nucleotide polymorphisms within the NOTCH4 gene and determination of association with MHC alleles

INTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 2 2003
R. Tazi-Ahnini
Summary Mapping of disease susceptibility loci within the MHC has been partly hampered by the high degree of polymorphism of the HLA genes and the high level of linkage disequilibrium (LD) between markers within the MHC region. It is therefore important to identify new markers and determine the level of LD between HLA alleles and non-HLA genes. The NOTCH4 gene lies at the centromeric end of the MHC class III region, approximately 335 kb telomeric of the DRB1 locus. The encoded protein is an oncogene that is important in regulating vascular development and remodelling. A recent report has linked polymorphisms within NOTCH4 with risk of developing schizophrenia. We have investigated if coding polymorphisms exist within this gene and have identified three single nucleotide polymorphisms; a synonomous T to C transition at +1297 (HGBASE accession number SNP000064386), a synonomous A to G transition at +3061 (SNP000064387) and an A to G transition at +3063 which results in a replacement of glycine with aspartic acid at amino acid 279 (SNP000064388). The allele frequencies of +1297T, +3061A and +3063G were 0.65, 0.66 and 0.66, respectively. Linkage disequilibrium was detected both between these markers and with MHC alleles. These findings can be used in the fine mapping of disease susceptibility alleles within the MHC. [source]

Genome-wide linkage and QTL mapping in porcine F2 families generated from Pietrain, Meishan and Wild Boar crosses

JOURNAL OF ANIMAL BREEDING AND GENETICS, Issue 6 2003
H. Geldermann
Summary Three informative pig F2 families based on European Wild Boar (W), Meishan (M) and Pietrain (P) crosses have been used for genome-wide linkage and quantitative trait loci (QTL) analysis. Altogether 129 microsatellites, 56 type I loci and 46 trait definitions (specific to growth, fattening, fat deposition, muscling, meat quality, stress resistance and body conformation) were included in the study. In the linkage maps of M × P, W × P and W × M families, average spacing of markers were 18.4, 19.7 and 18.8 cM, the numbers of informative meioses were 582, 534 and 625, and the total lengths of autosomes measured were 27.3, 26.0 and 26.2 Morgan units, respectively. Maternal maps were on average 1.3 times longer than paternal maps. QTLs contributing more than 3% of F2 phenotypic variance could be identified at p < 0.05 chromosome-wide level. Differences in the numbers and positions of QTLs were observed between families. Genome-wide significant QTL effects were mapped for growth and fattening traits on eight chromosomes (1, 2, 4, 13, 14, 17, 18 and X), for fat deposition traits on seven chromosomes (1, 2, 3, 4, 6, 7 and X), for muscling traits on 11 chromosomes (1, 2, 3, 4, 6, 7, 8, 12, 14, 15 and X), for meat quality and stress resistance traits on seven chromosomes (2, 3, 6, 13, 16, 18 and X), and QTLs for body-conformation traits were detected on 14 chromosomes. Closely correlated traits showed similar QTL profiles within families. Major QTL effects for meat quality and stress resistance traits were found on SSC6 in the interval RYR1-A1BG in the W × P and M × P families, and could be attributed to segregation of the RYR1 allele T derived from Pietrain, whereas no effect in the corresponding SSC6 interval was found in family W × M, where Wild Boar and Meishan both contributed the RYR1 allele C. QTL positions were mostly similar in two of the three families for body conformation traits and for growth, fattening, fat deposition and muscling traits, especially on SSC4 (interval SW1073-NGFB). QTLs with large effects were also mapped on SSC7 in the major histocompatibility complex (MHC) (interval CYP21A2-S0102) and affected body length, weight of head and many other traits. The identification of DNA variants in genes causative for the QTLs requires further fine mapping of QTL intervals and a positional cloning. However, for these subsequent steps, the genome-wide QTL mapping in F2 families represents an essential starting point and is therefore significant for animal breeding. Zusammenfassung Drei informative F2 -Familien, die aus Kreuzungen von Europäischem Wildschwein (W), Meishan (M) und Pietrain (P) erstellt worden waren, wurden für eine genomweite Kopplungs- und QTL-Analyse benutzt. Insgesamt wurden 129 Mikrosatellitenloci, 56 Type-I-Loci und 46 Merkmalsdefinitionen (für Wachstum, Mastleistung, Fettansatz, Bemuskelung, Fleischqualität, Stressresistenz und Körperform) in die Untersuchungen einbezogen. In den Kopplungskarten der Familien M × P, W × P und W × M wurden durchschnittliche Markerabstände von 18.4, 19.7 bzw. 18.8 cM erreicht und 582, 534 bzw. 625 informative Meiosen beobachtet. Für die Gesamtlängen der Autosomen wurden in den drei Familien 27.3, 26.0 bzw. 26.2 Morgan-Einheiten gemessen. Die maternalen Kopplungskarten waren durchschnittlich 1.3-fach länger als die paternalen. QTLs, die mehr als 3% der phänotypischen Varianz in der F2 -Generation erklärten, konnten mit p < 0.05 chromosomenweitem Signifikanzniveau nachgewiesen werden. Zwischen den Familien wurden Differenzen in den Anzahlen und Positionen der QTLs beobachtet. Genomweit signifikante QTL-Effekte wurden für Wachstum und Fettansatz auf acht Chromosomen (1, 2, 4, 13, 14, 17, 18 und X) kartiert, für Fettansatz auf sieben Chromosomen (1, 2, 3, 4, 6, 7 und X), für Bemuskelung auf elf Chromosomen (1, 2, 3, 4, 6, 7, 8, 12, 14, 15 und X), für Fleischqualität/Stressresistenz auf sieben Chromosomen (2, 3, 6, 13, 16, 18 und X), und QTLs für die Körperform wurden auf 14 Chromosomen kartiert. Eng korrelierte Merkmale zeigten ähnliche QTL-Profile innerhalb Familien. Die bedeutsamsten QTL-Effekte wurden für Fleischqualitäts- und Stressresistenzmerkmale auf Chromosom 6, Intervall RYR1-A1BG, in den Familien W × P und M × P gefunden, während in diesem Chromosomenintervall in der Familie W × M, in der der RYR1 -Locus keine segregierenden Exon-Allele aufwies, kein QTL zu erkennen war. Mehrere der QTL-Positionen waren für die Körperform wie auch für Wachstum, Mastleistung, Fettansatz und Bemuskelung in zwei von drei Familien ähnlich. Dies galt besonders für Chromosom 4 (Intervall SW1073-NGFB). QTLs mit großen Effekten wurden auf Chromosom 7 im MHC (Intervall CYP21A2-S0102) kartiert; sie beeinflussten Körperlänge, Kopfgewicht, aber auch viele weitere Merkmale. Zur Identifizierung der DNA-Varianten, die einem QTL zugrunde liegen, ist eine Feinkartierung von QTLs und positionale Klonierung erforderlich. Für diese nachfolgenden Untersuchungsmethoden ist jedoch die genomweite QTL-Kartierung in F2 -Familien ein entscheidender Ausgangspunkt; sie ist deshalb bedeutungsvoll für die Tierzüchtung. [source]

Congenic Strains of Mice for Verification and Genetic Decomposition of Quantitative Trait Loci for Femoral Bone Mineral Density,

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 2 2003
Kathryn L Shultz
Abstract Peak femoral volumetric bone mineral density (femoral bone mineral density) in C57BL/6J (B6) 4-month-old female mice is 50% lower than in C3H/HeJ (C3H) and 34% lower than in CAST/EiJ (CAST) females. Genome-wide analyses of (B6 × C3H)F2 and (B6 × CAST)F2 4-month-old female progeny demonstrated that peak femoral bone mineral density is a complex quantitative trait associated with genetic loci (QTL) on numerous chromosomes (Chrs) and with trait heritabilities of 83% (C3H) and 57% (CAST). To test the effect of each QTL on femoral bone mineral density, two sets of loci (six each from C3H and CAST) were selected to make congenic strains by repeated backcrossing of donor mice carrying a given QTL-containing chromosomal region to recipient mice of the B6 progenitor strain. At the N6F1 generation, each B6.C3H and B6.CAST congenic strain (statistically 98% B6-like in genomic composition) was intercrossed to obtain N6F2 progeny for testing the effect of each QTL on femoral bone mineral density. In addition, the femoral bone mineral density QTL region on Chr 1 of C3H was selected for congenic subline development to facilitate fine mapping of this strong femoral bone mineral density locus. In 11 of 12 congenic strains, 6 B6.C3H and 5 B6.CAST, femoral bone mineral density in mice carrying c3h or cast alleles in the QTL regions was significantly different from that of littermates carrying b6 alleles. Differences also were observed in body weight, femoral length, and mid-diaphyseal periosteal circumference among these 11 congenic strains when compared with control littermates; however, these latter three phenotypes were not consistently correlated with femoral bone mineral density. Analyses of eight sublines derived from the B6.C3H-1T congenic region revealed two QTLs: one located between 36.9 and 49.7 centiMorgans (cM) and the other located between 73.2 and 100.0 cM distal to the centromere. In conclusion, these congenic strains provide proof of principle that many QTLs identified in the F2 analyses for femoral bone mineral density exert independent effects when transferred and expressed in a common genetic background. Furthermore, significant differences in femoral bone mineral density among the congenic strains were not consistently accompanied by changes in body weight, femur length, or periosteal circumference. Finally, decomposition of QTL regions by congenic sublines can reveal additional loci for phenotypes assigned to a QTL region and can markedly refine genomic locations of quantitative trait loci, providing the opportunity for candidate gene testing. [source]

A new locus for hereditary hypotrichosis simplex maps to chromosome 13q12.12,12.3 in a Chinese family

JOURNAL OF CUTANEOUS PATHOLOGY, Issue 7 2010
Chao Xu
Background: Hereditary hypotrichosis simplex (MIM 146520, HHS) is a rare form of nonsyndromic alopecia. The locus for autosomal dominant HHS was mapped to 18p11.32-p11.23 and 6p21.3, respectively, suggestive of genetic heterogeneity. Aim: To identify the disease-causing gene for a four-generation Chinese family with dominant transmission of a form of HHS. The work was carried out at State Key Laboratory of Medical Genomics. Methods: Genome-wide screening was carried out in a Chinese family with HHS using microsatellite markers, and linkage analysis was performed using the MLINK program. Results: The highest two-point logarithm of the odds (LOD) score was obtained with the microsatellite marker D13S217 (LOD score of 4.041 at , = 0.00). After fine mapping and haplotype analysis, we defined a critical region of about 9.57 cM flanked by markers D13S1243 and D13S1299. The disease-causing gene was mapped to 13q12.12,12.3 in this family. Conclusions: A novel locus for HHS maps to chromosome 13q12.12,12.3 in a Chinese family. Xu C, Zhang L, Chen N, Su B, Pan C-M, Li J-Y, Zhang G-W, Liu Z, Sheng Y, Song H-D. A new locus for hereditary hypotrichosis simplex maps to chromosome 13q12.12,12.3 in a Chinese family. [source]

Genetic Analysis and Molecular Mapping of a Rolling Leaf Mutation Gene in Rice

JOURNAL OF INTEGRATIVE PLANT BIOLOGY, Issue 12 2007
Ji-Cai Yi
Abstract A rice mutant with rolling leaf, namely ,- rl, was obtained from M2 progenies of a native indica rice stable strain Qinghuazhan (QHZ) from mutagenesis of dry seeds by ,-rays. Genetic analysis using the F2 population from a cross between this mutant and QHZ indicated the mutation was controlled by a single recessive gene. In order to map the locus for this mutation, another F2 population with 601 rolling leaf plants was constructed from a cross between ,- rl and a japonica cultivar 02428. After primary mapping with SSR (simple sequence repeats) markers, the mutated locus was located at the short arm of chromosome 3, flanked by RM6829 and RM3126. A number of SSR, InDel (insertion/deletion) and SNP (single nucleotide polymorphism) markers within this region were further developed for fine mapping. Finally, two markers, SNP121679 and InDel422395, were identified to be flanked to this locus with genetic distances of 0.08 cM and 0.17 cM respectively, and two SNP markers, SNP75346 and SNP110263, were found to be co-segregated with this locus. These results suggested that this locus was distinguished from all loci for the rolling leaf mutation in rice reported so far, and thus renamed rl10(t). By searching the rice genome database with closely linked markers using BLAST programs, an e -physical map covering rl10(t) locus spanning about a 50 kb region was constructed. Expression analysis of the genes predicted in this region showed that a gene encoding putative flavin-containing monooxygenase (FMO) was silenced in ,- rl, thus this is the most likely candidate responsible for the rolling leaf mutation. [source]

Fine Mapping of Polymorphic Alcohol-Related Quantitative Trait Loci Candidate Genes Using Interval-Specific Congenic Recombinant Mice

Quantitative trait loci associated with soybean tolerance to low phosphorus stress based on flower and pod abscission

PLANT BREEDING, Issue 3 2010
D. Zhang
With 2 figures and 5 tables Abstract Low phosphorus (P) stress limits soybean production. A population of 152 recombinant inbred lines (RILs) derived from a cross between ,Bogao' (P sensitive variety) and ,Nannong 94-156' (P tolerant variety) and 248 markers were used to map quantitative trait loci (QTLs) for low-P tolerance. Two pot culture trials were conducted and low-P tolerance evaluated using flower and pod abscission rate under low P and normal P. Conditional QTLs and epistasis for tolerance to low P were also analysed. A conditional QTL (near Satt274) on linkage group D1b+W was identified which conferred low-P tolerance epistatic effects and coincided with previously discovered QTLs. An additive QTL, qFARLPG-07, for flower abscission rate under low P was detected with a LOD score of 7.79 and explained 32.3% of phenotypic variation. It was detected at the same interval of the corresponding QTL for other traits across years. This region coincided with two conditional QTLs (cqFARLPG-07 and cqPARLPG-07), from the P-tolerant parent ,Nannong 94-156' related to low-P tolerance. These results will provide a basis for further fine mapping and eventual cloning of the P-efficiency genes in soybean. [source]

Clustering of amplified fragment length polymorphism markers in a linkage map of rye

PLANT BREEDING, Issue 2 2002
B. Saal
Abstract Amplified fragment length polymorphisms (AFLPs) are now widely used in DNA fingerprinting and genetic diversity studies, the construction of dense genetic maps and in fine mapping of agronomically important traits. The AFLP markers have been chosen as a source to extend and saturate a linkage map of rye, which has previously been generated by means of restriction fragment length polymorphism, random amplified polymorphic DNA, simple sequence repeat and isozyme markers. Gaps between linkage groups, which were known to be part of chromosome 2R, have been closed, thus allowing the determination of their correct order. Eighteen EcoRI- MseI primer combinations were screened for polymorphism and yielded 148 polymorphic bands out of a total of 1180. The level of polymorphism among the different primer combinations varied from 5.7% to 33.3%. Eight primer combinations, which revealed most polymorphisms, were further analysed in all individuals of the F2 mapping population. Seventy-one out of 80 polymorphic loci could be integrated into the linkage map, thereby increasing the total number of markers to 182. However, 46% of the mapped AFLP markers constituted four major clusters located on chromosomes 2R, 5R and 7R, predominantly in proximity to the centromere. The integration of AFLP markers caused an increase of 215 cM, which resulted in a total map length of almost 1100 cM. [source]

Phosphoproteomics, oncogenic signaling and cancer research

PROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 21 2008
Poh-Kuan Chong
Abstract The past 5,years have seen an explosion of phosphoproteomics methods development. In this review, using epidermal growth-factor signaling as a model, we will discuss how phosphoproteomics, along with bioinformatics and computational modeling, have impacted key aspects of oncogenic signaling such as in the temporal fine mapping of phosphorylation events, and the identification of novel tyrosine kinase substrates and phosphorylation sites. We submit that the next decade will see considerable exploitation of phosphoproteomics in cancer research. Such a phenomenon is already happening as exemplified by its use in promoting the understanding of the molecular etiology of cancer and target-directed therapeutics. [source]

Inactivation of the UGPase1 gene causes genic male sterility and endosperm chalkiness in rice (Oryza sativa L.)

THE PLANT JOURNAL, Issue 2 2008
Mi-Ok Woo
Summary A rice genic male-sterility gene ms-h is recessive and has a pleiotropic effect on the chalky endosperm. After fine mapping, nucleotide sequencing analysis of the ms-h gene revealed a single nucleotide substitution at the 3,-splice junction of the 14th intron of the UDP-glucose pyrophosphorylase 1 (UGPase1; EC2.7.7.9) gene, which causes the expression of two mature transcripts with abnormal sizes caused by the aberrant splicing. An in vitro functional assay showed that both proteins encoded by the two abnormal transcripts have no UGPase activity. The suppression of UGPase by the introduction of a UGPase1-RNAi construct in wild-type plants nearly eliminated seed set because of the male defect, with developmental retardation similar to the ms-h mutant phenotype, whereas overexpression of UGPase1 in ms-h mutant plants restored male fertility and the transformants produced T1 seeds that segregated into normal and chalky endosperms. In addition, both phenotypes were co-segregated with the UGPase1 transgene in segregating T1 plants, which demonstrates that UGPase1 has functional roles in both male sterility and the development of a chalky endosperm. Our results suggest that UGPase1 plays a key role in pollen development as well as seed carbohydrate metabolism. [source]

A genome scan for quantitative trait loci affecting three ear traits in a White Duroc × Chinese Erhualian resource population

ANIMAL GENETICS, Issue 4 2009
J. Ma
Summary Chinese Erhualian pigs have larger and floppier ears compared with White Duroc pigs (small, half- or fully-pricked ears). To identify quantitative trait loci (QTL) for ear weight and area as well as erectness, a genome-wide scan with 194 microsatellites was performed in a White Duroc × Chinese Erhualian resource population (>1000 F2 animals). Twenty-three genome-wide significant QTL and 12 suggestive QTL were identified. All QTL for ear erectness and size detected in two previous studies, bar two on SSC6 and 9, were confirmed here. The 1% genome-wide significant QTL at 70 cM on SSC5 and at 58 cM on SSC7 have profound and pleiotropic effects on the three ear traits, with Erhualian alleles increasing weight and area but decreasing erectness. Notably, the 95% confidence interval of the QTL for weight and area on SSC7 spanned only 3 cM. New QTL reaching 1% genome-wide significance were found on SSC8 (at 37 cM) for all three ear traits, on SSC4 and 16 for weight and area, and on SSCX for area. Unexpectedly, Erhualian alleles at these loci were associated with lighter and smaller or erect ear. Some new suggestive QTL were also found on other chromosome regions. Almost all the QTL for weight and area had essentially additive effects, while the QTL for erectness on SSC2, 5 and 7 showed not only additive effects but also partial dominance effects of Erhualian alleles. The two most significant QTL on SSC7 and SSC5 could be promising targets for fine mapping and identification of the causative mutations. [source]

Genetical genomics in livestock: potentials and pitfalls

ANIMAL GENETICS, Issue 2006
C. Haley
Summary Genetical genomics combines gene mapping and gene expression approaches to identify loci controlling gene expression (eQTLs) that may underlie functional trait variation. The combination of genomic tools has great potential to facilitate dissection of complex traits, but studies need careful design and interpretation. Here we explore both the potential and the pitfalls of this approach with illustrations from actual studies. There are now an appreciable number of studies in model species and even humans demonstrating the feasibility of genetical genomics. However, most studies are too limited in size and design to unlock the full potential of the approach. Limited statistical power of studies exacerbates the problem of detection of false-positive eQTL and some reported results should be interpreted with caution. As one approach to more successful implementation of genetical genomics, we propose to combine expression studies with fine mapping of functional trait loci. This synergistic approach facilitates the implementation of genetical genomics for species without inbred resources but is equally applicable to model species. These properties make it particularly suitable for livestock populations where many QTL are already in the public domain and potentially very large pedigreed populations can be accessed. [source]

Linkage mapping of gene-associated SNPs to pig chromosome 11

ANIMAL GENETICS, Issue 3 2006
M. Sawera
Summary Single nucleotide polymorphisms (SNPs) were discovered in porcine expressed sequence tags (ESTs) orthologous to genes from human chromosome 13 (HSA13) and predicted to be located on pig chromosome 11 (SSC11). The SNPs were identified as sequence variants in clusters of EST sequences from pig cDNA libraries constructed in the Sino,Danish pig genome project. In total, 312 human gene sequences from HSA13 were used for similarity searches in our pig EST database. Pig ESTs showing significant similarity with HSA13 genes were clustered and candidate SNPs were identified. Allele frequencies for 26 SNPs were estimated in a group of 80 unrelated pigs from Danish commercial pig breeds: Duroc, Hampshire, Landrace and Large White. Eighteen of the 26 SNPs genotyped in the PiGMaP Reference Families were mapped by linkage analysis to SSC11. The EST-based SNPs published here are new genetic markers useful for linkage and association studies in commercial and experimental pig populations. This study represents the first gene-associated SNP linkage map of pig chromosome 11 and adds new comparative mapping information between SSC11 and HSA13. Furthermore, our data facilitate future studies aimed at the identification of interesting regions on pig chromosome 11, positional cloning and fine mapping of quantitative trait loci in pig. [source]