LD Mapping Research Articles

Improved Current and MTPA Control Characteristics Using FEM-Based Inductance Maps for Vector-Controlled IPM Motor

Some major problems in the motor drive are the overshoot or undershoot of transient response characteristics and a parameter mismatch due to magnetic saturation. This study proposed a 3D inductance map combined with a maximum-torque-per-ampere (MTPA) map based on a finite-element (FE) motor model considering a cross-coupling magnetic saturation impact to overcome this problem. The proposed FE motor model has a high accuracy of no-load back electromotive force (e.m.f.) around 98.3% compared to the measurement results. Then, nine scenarios of vector control combinations of inductance maps and current supply variations of β 0°, 45°, and MTPA were investigated. As a result, the transient response improvement for β 0°, 45°, and MTPA without the map and with Ld and Lq maps is 63%, 10%, and 15%, respectively. Moreover, for the steady-state response, the average torque improvement between MTPA and Idref 0 A control is 9.21%, 8.97%, and 8.98% for the no-map, ave-map, and 3D-inductance-map conditions, respectively. The MTPA trajectory characteristic was also updated to illustrate the actual MTPA condition compared to the conventional MTPA control. In detail, the proposed method has reduced the parameter mismatch for the current control loop in the transient state and improved the MTPA control trajectory for the steady-state response. Finally, the improvement of vector control characteristics of the proposed method was verified by an FE simulation and experimental measurement results.

Genome-wide SNP discovery and genetic linkage map construction in sunflower (Helianthus annuus L.) using a genotyping by sequencing (GBS) approach

Recently developed plant genomics approaches (LD mapping and genome-wide selection) require many molecular markers distributed throughout the plant genome. As a result, the availability of an increasing number of markers is essential for maintaining highly efficient and accurate plant breeding programs. In this study, we identified SNP loci in sunflower using a genotyping by sequencing (GBS) approach in an intraspecific F2 mapping population. A total of 271,445,770 reads were generated by the Genome Analyzer II next-generation sequencing platform and 29.2 % of the reads were aligned to unique locations in the genome. A total of 46,278 SNP loci were identified and 7646 SNP loci were validated in an F2 population. In addition, a SNP-based linkage map was constructed. This is the first report of SNP discovery in sunflower by GBS. The SNP markers and SNP-based linkage map will be valuable molecular genetics tools for sunflower breeding.

Pencarian Alel untuk Identifikasi Gen Ketahanan Penyakit Hawar Daun Bakteri, Xa7 pada Plasma Nutfah Padi Lokal Indonesia

<p>Allele Mining of Bacterial Blight Resistance Gene, Xa7 on<br />Indonesian Local Rice Germplasm. Dwinita W. Utami,<br />Endang M. Septiningsih, Trini S. Kadir, Fatimah, and Siti<br />Yuriyah. The abundance of novel genetic variation existing<br />in germplasm collections is the foundation for variety<br />improvement in plant breeding program. Nevertheless,<br />studies on Indonesian genetic diversity rice germplasm<br />using molecular markers are still poorly. Recent advances in<br />utilizing of simple sequence repeat (SSR) in QTL mapping<br />and whole rice genome sequences were positive support on<br />genetic diversity of rice germplasm research. Based on these<br />advance technology, we developed the research to discover<br />new alleles at important gene loci that can be used for rice<br />improvement. This approach is recognized as allele mining<br />technology. On this study the target genes for allele mining<br />research is the resistance gene for bacterial leaf blight<br />pathogen, Xa7. This point was introduced by identify the<br />genetic diversity of 96 accessions Indonesian local rice<br />germplasm. The Xa7 allele mining was done by SNP (single<br />nucleotide polymorphism) designing primers based on DNA<br />sequence around the gene target. The significant LD map<br />was detected by association mapping between phenotype<br />and SNP genotyping data of the selected germplasm which<br />having superior performance on BLB resistance and<br />representing on genetic diversity clustering. The results<br />shown that Xa7 allele variation were found in Parekaligolara<br />(Indica, 15141), and Gajah Mada (Indica, 5856), which<br />resistant to BLB races IV and VIII on generative stage and<br />field condition. The significant Xa7-SNP8 and Xa7-SNP11<br />markers were associating with the LD map position of Xa7<br />gene on 28, 05-28,1Mb of chromosome 6 in rice genome.</p>

A Genome-wide Combinatorial Strategy Dissects Complex Genetic Architecture of Seed Coat Color in Chickpea.

The study identified 9045 high-quality SNPs employing both genome-wide GBS- and candidate gene-based SNP genotyping assays in 172, including 93 cultivated (desi and kabuli) and 79 wild chickpea accessions. The GWAS in a structured population of 93 sequenced accessions detected 15 major genomic loci exhibiting significant association with seed coat color. Five seed color-associated major genomic loci underlying robust QTLs mapped on a high-density intra-specific genetic linkage map were validated by QTL mapping. The integration of association and QTL mapping with gene haplotype-specific LD mapping and transcript profiling identified novel allelic variants (non-synonymous SNPs) and haplotypes in a MATE secondary transporter gene regulating light/yellow brown and beige seed coat color differentiation in chickpea. The down-regulation and decreased transcript expression of beige seed coat color-associated MATE gene haplotype was correlated with reduced proanthocyanidins accumulation in the mature seed coats of beige than light/yellow brown seed colored desi and kabuli accessions for their coloration/pigmentation. This seed color-regulating MATE gene revealed strong purifying selection pressure primarily in LB/YB seed colored desi and wild Cicer reticulatum accessions compared with the BE seed colored kabuli accessions. The functionally relevant molecular tags identified have potential to decipher the complex transcriptional regulatory gene function of seed coat coloration and for understanding the selective sweep-based seed color trait evolutionary pattern in cultivated and wild accessions during chickpea domestication. The genome-wide integrated approach employed will expedite marker-assisted genetic enhancement for developing cultivars with desirable seed coat color types in chickpea.

A genome-scale integrated approach aids in genetic dissection of complex flowering time trait in chickpea.

A combinatorial approach of candidate gene-based association analysis and genome-wide association study (GWAS) integrated with QTL mapping, differential gene expression profiling and molecular haplotyping was deployed in the present study for quantitative dissection of complex flowering time trait in chickpea. Candidate gene-based association mapping in a flowering time association panel (92 diverse desi and kabuli accessions) was performed by employing the genotyping information of 5724 SNPs discovered from 82 known flowering chickpea gene orthologs of Arabidopsis and legumes as well as 832 gene-encoding transcripts that are differentially expressed during flower development in chickpea. GWAS using both genome-wide GBS- and candidate gene-based genotyping data of 30,129 SNPs in a structured population of 92 sequenced accessions (with 200-250 kb LD decay) detected eight maximum effect genomic SNP loci (genes) associated (34% combined PVE) with flowering time. Six flowering time-associated major genomic loci harbouring five robust QTLs mapped on a high-resolution intra-specific genetic linkage map were validated (11.6-27.3% PVE at 5.4-11.7 LOD) further by traditional QTL mapping. The flower-specific expression, including differential up- and down-regulation (>three folds) of eight flowering time-associated genes (including six genes validated by QTL mapping) especially in early flowering than late flowering contrasting chickpea accessions/mapping individuals during flower development was evident. The gene haplotype-based LD mapping discovered diverse novel natural allelic variants and haplotypes in eight genes with high trait association potential (41% combined PVE) for flowering time differentiation in cultivated and wild chickpea. Taken together, eight potential known/candidate flowering time-regulating genes [efl1 (early flowering 1), FLD (Flowering locus D), GI (GIGANTEA), Myb (Myeloblastosis), SFH3 (SEC14-like 3), bZIP (basic-leucine zipper), bHLH (basic helix-loop-helix) and SBP (SQUAMOSA promoter binding protein)], including novel markers, QTLs, alleles and haplotypes delineated by aforesaid genome-wide integrated approach have potential for marker-assisted genetic improvement and unravelling the domestication pattern of flowering time in chickpea.

Inferring the evolutionary history of outcrossing populations through computing a multiallelic linkage–linkage disequilibrium map

Summary Linkage disequilibrium (LD), the non‐random association of alleles at different loci, has been used as an important parameter to study the genetic diversity and evolutionary history of natural populations. A joint analysis of LD with the linkage of the same marker pair has proven to gain more insight into the genetic signature of population diversification than LD analysis alone. We develop a unifying framework for simultaneously estimating the linkage and LD across pairs of multiallelic markers. The framework has particular power to construct the LD map from any markers with an arbitrary number of alleles per locus. We provide an efficient strategy to manipulate disequilibrium parameters whose number increases exponentially with the number of alleles. The model was tested through extensive simulation studies and validated by analysing a real marker data set from a population genetic research project of euphrates poplar, a desert tree, distributed in the north‐western China. For widespread undomesticated natural populations, compared with biallelic markers, multiallelic markers with a high level of polymorphism are more powerful to study their genetic structure and organization of an outcrossing population. The model developed will potentially have an immediate implication for population and evolutionary genetic studies.

A genome-wide SNP scan accelerates trait-regulatory genomic loci identification in chickpea.

We identified 44844 high-quality SNPs by sequencing 92 diverse chickpea accessions belonging to a seed and pod trait-specific association panel using reference genome- and de novo-based GBS (genotyping-by-sequencing) assays. A GWAS (genome-wide association study) in an association panel of 211, including the 92 sequenced accessions, identified 22 major genomic loci showing significant association (explaining 23–47% phenotypic variation) with pod and seed number/plant and 100-seed weight. Eighteen trait-regulatory major genomic loci underlying 13 robust QTLs were validated and mapped on an intra-specific genetic linkage map by QTL mapping. A combinatorial approach of GWAS, QTL mapping and gene haplotype-specific LD mapping and transcript profiling uncovered one superior haplotype and favourable natural allelic variants in the upstream regulatory region of a CesA-type cellulose synthase (Ca_Kabuli_CesA3) gene regulating high pod and seed number/plant (explaining 47% phenotypic variation) in chickpea. The up-regulation of this superior gene haplotype correlated with increased transcript expression of Ca_Kabuli_CesA3 gene in the pollen and pod of high pod/seed number accession, resulting in higher cellulose accumulation for normal pollen and pollen tube growth. A rapid combinatorial genome-wide SNP genotyping-based approach has potential to dissect complex quantitative agronomic traits and delineate trait-regulatory genomic loci (candidate genes) for genetic enhancement in crop plants, including chickpea.

Association mapping of brassinosteroid candidate genes and plant architecture in a diverse panel of Sorghum bicolor.

This first association analysis between plant architecture and BR candidate genes in sorghum suggests that natural allelic variation has significant and pleiotropic effects on plant architecture phenotypes. Sorghum bicolor (L) Moench is a self-pollinated species traditionally used as a staple crop for human consumption and as a forage crop for livestock feed. Recently, sorghum has received attention as a bioenergy crop due to its water use efficiency and biomass yield potential. Breeding for superior bioenergy-type lines requires knowledge of the genetic mechanisms controlling plant architecture. Brassinosteroids (BRs) are a group of hormones that determine plant growth, development, and architecture. Biochemical and genetic information on BRs are available from model species but the application of that knowledge to crop species has been very limited. A candidate gene association mapping approach and a diverse sorghum collection of 315 accessions were used to assess marker-trait associations between BR biosynthesis and signaling genes and six plant architecture traits. A total of 263 single nucleotide polymorphisms (SNPs) from 26 BR genes were tested, 73 SNPs were significantly associated with the phenotypes of interest and 18 of those were associated with more than one trait. An analysis of the phenotypic variation explained by each BR pathway revealed that the signaling pathway had a larger effect for most phenotypes (R (2)=0.05-0.23). This study constitutes the first association analysis between plant architecture and BR genes in sorghum and the first LD mapping for leaf angle, stem circumference, panicle exsertion and panicle length. Markers on or close to BKI1 associated with all phenotypes and thus, they are the most important outcomes of this study and will be further validated for their future application in breeding programs.

Large-scale East-Asian eQTL mapping reveals novel candidate genes for LD mapping and the genomic landscape of transcriptional effects of sequence variants.

Profiles of sequence variants that influence gene transcription are very important for understanding mechanisms that affect phenotypic variation and disease susceptibility. Using genotypes at 1.4 million SNPs and a comprehensive transcriptional profile of 15,454 coding genes and 6,113 lincRNA genes obtained from peripheral blood cells of 298 Japanese individuals, we mapped expression quantitative trait loci (eQTLs). We identified 3,804 cis-eQTLs (within 500 kb from target genes) and 165 trans-eQTLs (>500 kb away or on different chromosomes). Cis-eQTLs were often located in transcribed or adjacent regions of genes; among these regions, 5′ untranslated regions and 5′ flanking regions had the largest effects. Epigenetic evidence for regulatory potential accumulated in public databases explained the magnitude of the effects of our eQTLs. Cis-eQTLs were often located near the respective target genes, if not within genes. Large effect sizes were observed with eQTLs near target genes, and effect sizes were obviously attenuated as the eQTL distance from the gene increased. Using a very stringent significance threshold, we identified 165 large-effect trans-eQTLs. We used our eQTL map to assess 8,069 disease-associated SNPs identified in 1,436 genome-wide association studies (GWAS). We identified genes that might be truly causative, but GWAS might have failed to identify for 148 out of the GWAS-identified SNPs; for example, TUFM (P = 3.3E-48) was identified for inflammatory bowel disease (early onset); ZFP90 (P = 4.4E-34) for ulcerative colitis; and IDUA (P = 2.2E-11) for Parkinson's disease. We identified four genes (P<2.0E-14) that might be related to three diseases and two hematological traits; each expression is regulated by trans-eQTLs on a different chromosome than the gene.

Genome-wide Two-marker linkage disequilibrium mapping of quantitative trait loci

BackgroundIn a natural population, the alleles of multiple tightly linked loci on the same chromosome co-segregate and are passed non-randomly from generation to generation. Capitalizing on this phenomenon, a group of mapping methods, commonly referred to as the linkage disequilibrium-based mapping (LD mapping), have been developed recently for detecting genetic associations. However, most current LD mapping methods mainly employed single-marker analysis, overlooking the rich information contained within adjacent linked loci.ResultsWe extend the single-marker LD mapping to include two linked loci and explicitly incorporate their LD information into genetic mapping models (tmLD). We establish the theoretical foundations for the tmLD mapping method and also provide a thorough examination of its statistical properties. Our simulation studies demonstrate that the tmLD mapping method significantly improves the detection power of association compared to the single-marker based and also haplotype based mapping methods. The practical usage and properties of the tmLD mapping method were further elucidated through the analysis of a large-scale dental caries GWAS data set. It shows that the tmLD mapping method can identify significant SNPs that are missed by the traditional single-marker association analysis and haplotype based mapping method. An R package for our proposed method has been developed and is freely available.ConclusionsThe proposed tmLD mapping method is more powerful than single marker mapping generally used in GWAS data analysis. We recommend the usage of this improved method over the traditional single marker association analysis.

Family and/or Friends? Gene Mapping at Crossroads

Mapping gene(s) underlying a specific trait offers an opportunity to plant breeders to apply marker assisted selection. All gene mapping approaches except LD mapping use family based segregation populations developed by crossing two or more parents. These family based gene mapping approaches include simple interval mapping, composite interval mapping, multiple interval mapping and Bayesian mapping etc. Each approach has its own advantages and disadvantages based on type of population and underlying statistical model. Unlike family based approaches, LD mapping uses population of unrelated individuals which are like friends belonging to different family backgrounds. Relative pros and cons of family and friends based approaches make them complementary to each other. Family based approaches identify wide chromosomal region underlying the trait of interest with relatively lower markers density, and therefore, have low mapping resolution. Conversely, friends based LD mapping identifies chromosomal region of interest with higher resolution using higher marker density. The integration of family and friends based approaches addresses their respective pros and cons successfully to enhance mapping resolution for more valid application of marker assisted selection.

Hypospadias and Genes Related to Genital Tubercle and Early Urethral Development

We determined whether variants in genes associated with genital tubercle (the anlage for the penis) and early urethral development were associated with hypospadias in humans. We examined 293 relatively common tag single nucleotide polymorphisms in BMP4, BMP7, FGF8, FGF10, FGFR2, HOXA13, HOXD13, HOXA4, HOXB6, SRY, WT1, WTAP, SHH, GLI1, GLI2 and GLI3. The analysis included 624 cases (81 mild, 319 moderate, 209 severe, 15 undetermined severity) and 844 population based nonmalformed male controls born in California from 1990 to 2003. There were 28 single nucleotide polymorphisms for which any of the comparisons (ie overall or for a specific severity) had a p value of less than 0.01. The homozygous variant genotypes for 4 single nucleotide polymorphisms in BMP7 were associated with at least a twofold increased risk of hypospadias regardless of severity. Five single nucleotide polymorphisms for FGF10 were associated with threefold to fourfold increased risks, regardless of severity. For 4 of them the results were restricted to whites. For GLI1, GLI2 and GLI3 there were 12 associated single nucleotide polymorphisms but results were inconsistent by severity and race/ethnicity. For SHH 1 single nucleotide polymorphism was associated with a 2.4-fold increased risk of moderate hypospadias. For WT1 6 single nucleotide polymorphisms were associated with approximately a twofold increased risk, primarily for severe hypospadias. This study provides evidence that single nucleotide polymorphisms in several genes that contribute to genital tubercle and early urethral development are associated with hypospadias risk.

A 2-Stage Genome-Wide Association Study to Identify Single Nucleotide Polymorphisms Associated with Development of Urinary Symptoms After Radiotherapy for Prostate Cancer

We identified single nucleotide polymorphisms associated with change in the AUA Symptom Score after radiotherapy for prostate cancer. A total of 723 patients treated with brachytherapy with or without external beam radiation therapy were assessed at baseline and annually after radiotherapy using the AUA Symptom Score. A 2-stage genome-wide association study was performed with the primary end point of change in AUA Symptom Score from baseline at each of 4 followup periods. Single nucleotide polymorphism associations were assessed using multivariable linear regression adjusting for pre-radiotherapy AUA Symptom Score severity category and clinical variables. Fisher's trend method was used to calculate combined p values from the discovery and replication cohorts. A region on chromosome 9p21.2 containing 8 single nucleotide polymorphisms showed the strongest association with change in AUA Symptom Score (combined p values 8.8×10(-6) to 6.5×10(-7) at 2 to 3 years after radiotherapy). These single nucleotide polymorphisms form a haplotype block that encompasses the inflammation signaling gene IFNK. These single nucleotide polymorphisms were independently associated with change in AUA Symptom Score after adjusting for clinical predictors including smoking history, hypertension, α-blocker use and pre-radiotherapy AUA Symptom Score. An additional 24 single nucleotide polymorphisms showed moderate significance for association with change in AUA Symptom Score. Several of these single nucleotide polymorphisms were more strongly associated with change in specific AUA Symptom Score items, including rs13035033 in the MYO3B gene, which was associated with straining (beta coefficient 0.9, 95% CI 0.6-1.2, p = 5.0×10(-9)). If validated, these single nucleotide polymorphisms could provide insight into the biology underlying urinary symptoms following radiotherapy and could lead to development of an assay to identify patients at risk for experiencing these effects.

A large scale genome simulation model incorporating patterns of linkage disequilibrium

Evaluation of multiple hypotheses is a common problem, especially in genome wide association studies. False Discovery Rate control is often used to correct for multiple comparisons. However, this approach is influenced by linkage disequilibrium and needs to be evaluated. For such evaluation, first a model needs to be developed with a simulated linkage disequilibrium pattern that matches as closely as possible the observed linkage disequilibrium structure. This paper outlines the steps involved in the development of such a model, using mouse genome data as an example. References http://gscan.well.ox.ac.uk/ K. G. Ardlie, L. Kruglyak, and M. Seielstad. Patterns of linkage disequilibrium in the human genome. Nature Reviews Genetics, 3(4):299--309, 2002. doi:10.1038/nrg777 J. C. Barrett, B. Fry, J. Maller, and M. J. Daly. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics, 21(2):263, 2005. doi:10.1093/bioinformatics/bth457 Y. Benjamini and Y. Hochberg. Controlling the false discovery rate: a practical and powerful approach to multiple testing. Journal of the Royal Statistical Society. Series B (Methodological), 57(1):289--300, 1995. http://www.jstor.org/pss/2346101 M. S. Khatkar, F. W. Nicholas, A. R. Collins, K. R. Zenger, J. A. L. Cavanagh, W. Barris, R. D. Schnabel, J. F. Taylor, and H. W. Raadsma. Extent of genome-wide linkage disequilibrium in Australian Holstein--Friesian cattle based on a high-density SNP panel. BMC genomics, 9(1):187, 2008. doi:10.1186/1471-2164-9-187 L. Kruglyak. Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nature genetics, 22:139--144, 1999. doi:10.1038/9642 C. C. Laurie, D. A. Nickerson, A. D. Anderson, B. S. Weir, R. J. Livingston, M. D. Dean, K. L. Smith, E. E. Schadt, and M. W. Nachman. Linkage disequilibrium in wild mice. PLoS Genetics, 3(8):e144, 2007. doi:10.1371/journal.pgen.0030144 W. Valdar, L. C. Solberg, D. Gauguier, S. Burnett, P. Klenerman, W. O. Cookson, M. S. Taylor, J. N. P. Rawlins, R. Mott, and J. Flint. Genome-wide genetic association of complex traits in heterogeneous stock mice. Nature genetics, 38(8):879--887, 2006. doi:10.1038/ng1840

Allelic Variation in Cell Wall Candidate Genes Affecting Solid Wood Properties in Natural Populations and Land Races of Pinus radiata

Forest trees are ideally suited to association mapping due to their high levels of diversity and low genomic linkage disequilibrium. Using an association mapping approach, single-nucleotide polymorphism (SNP) markers influencing quantitative variation in wood quality were identified in a natural population of Pinus radiata. Of 149 sites examined, 10 demonstrated significant associations (P < 0.05, q < 0.1) with one or more traits after accounting for population structure and experimentwise error. Without accounting for marker interactions, phenotypic variation attributed to individual SNPs ranged from 2 to 6.5%. Undesirable negative correlations between wood quality and growth were not observed, indicating potential to break negative correlations by selecting for individual SNPs in breeding programs. Markers that yielded significant associations were reexamined in an Australian land race. SNPs from three genes (PAL1, PCBER, and SUSY) yielded significant associations. Importantly, associations with two of these genes validated associations with density previously observed in the discovery population. In both cases, decreased wood density was associated with the minor allele, suggesting that these SNPs may be under weak negative purifying selection for density in the natural populations. These results demonstrate the utility of LD mapping to detect associations, even when the power to detect SNPs with small effect is anticipated to be low.

Fine mapping quantitative trait loci affecting milk production traits on bovine chromosome 6 in a Chinese Holstein population

To fine map the previously detected quantitative trait loci (QTLs) affecting milk production traits on bovine chromosome 6 (BTA6), 15 microsatellite markers situated within an interval of 14.3 cM spanning from BMS690 to BM4528 were selected and 918 daughters of 8 sires were genotyped. Two mapping approaches, haplotype sharing based LD mapping and single marker regression mapping, were used to analyze the data. Both approaches revealed a quantitative trait locus (QTL) with significant effects on milk yield, fat yield and protein yield located in the segment flanked by markers BMS483 and MNB209, which spans a genetic distance of 0.6 cM and a physical distance of 1.5 Mb. In addition, the single marker regression mapping also revealed a QTL affecting fat percentage and protein percentage at marker DIK2291. Our fine mapping work will facilitate the cloning of candidate genes underlying the QTLs for milk production traits.

High Differentiation among Eight Villages in a Secluded Area of Sardinia Revealed by Genome-Wide High Density SNPs Analysis

To better design association studies for complex traits in isolated populations it's important to understand how history and isolation moulded the genetic features of different communities. Population isolates should not “a priori” be considered homogeneous, even if the communities are not distant and part of a small region. We studied a particular area of Sardinia called Ogliastra, characterized by the presence of several distinct villages that display different history, immigration events and population size. Cultural and geographic isolation characterized the history of these communities. We determined LD parameters in 8 villages and defined population structure through high density SNPs (about 360 K) on 360 unrelated people (45 selected samples from each village). These isolates showed differences in LD values and LD map length. Five of these villages show high LD values probably due to their reduced population size and extreme isolation. High genetic differentiation among villages was detected. Moreover population structure analysis revealed a high correlation between genetic and geographic distances. Our study indicates that history, geography and biodemography have influenced the genetic features of Ogliastra communities producing differences in LD and population structure. All these data demonstrate that we can consider each village an isolate with specific characteristics. We suggest that, in order to optimize the study design of complex traits, a thorough characterization of genetic features is useful to identify the presence of sub-populations and stratification within genetic isolates.

Canine RD3 mutation establishes rod-cone dysplasia type 2 (rcd2) as ortholog of human and murine rd3.

Rod-cone dysplasia type 2 (rcd2) is an autosomal recessive disorder that segregates in collie dogs. Linkage disequilibrium and meiotic linkage mapping were combined to take advantage of population structure within this breed and to fine map rcd2 to a 230-kb candidate region that included the gene C1orf36 responsible for human and murine rd3, and within which all affected dogs were homozygous for one haplotype. In one of three identified canine retinal RD3 splice variants, an insertion was found that cosegregates with rcd2 and is predicted to alter the last 61 codons of the normal open reading frame and further extend the open reading frame. Thus, combined meiotic linkage and LD mapping within a single canine breed can yield critical reduction of the disease interval when appropriate advantage is taken of within-breed population structure. This should permit a similar approach to tackle other hereditary traits that segregate in single closed populations.

Refinement of the basis and impact of common 11q23.1 variation to the risk of developing colorectal cancer

The common single-nucleotide polymorphism (SNP) rs3802842 at 11q23.1 has recently been reported to be associated with risk of colorectal cancer (CRC). To examine this association in detail we genotyped rs3802842 in eight independent case-control series comprising a total of 10 638 cases and 10 457 healthy individuals. A significant association between the C allele of rs3802842 and CRC risk was found (per allele OR = 1.17; 95% confidence interval [CI]: 1.12-1.22; P = 1.08 x 10(-12)) with the risk allele more frequent in rectal than colonic disease (P = 0.02). In combination with 8q21, 8q24, 10p14, 11q, 15q13.3 and 18q21 variants, the risk of CRC increases with an increasing numbers of variant alleles for the six loci (OR(per allele) = 1.19; 95% CI: 1.15-1.23; P(trend) = 7.4 x 10(-24)). Using the data from our genome-wide association study of CRC, LD mapping and imputation, we were able to refine the location of the causal locus to a 60 kb region and screened for coding changes. The absence of exonic mutations in any of the transcripts (FLJ45803, LOC120376, C11orf53 and POU2AF1) mapping to this region makes the association likely to be a consequence of non-coding effects on gene expression.

Bayesian survival analysis in genetic association studies

Motivation: Large-scale genetic association studies are carried out with the hope of discovering single nucleotide polymorphisms involved in the etiology of complex diseases. There are several existing methods in the literature for performing this kind of analysis for case-control studies, but less work has been done for prospective cohort studies. We present a Bayesian method for linking markers to censored survival outcome by clustering haplotypes using gene trees. Coalescent-based approaches are promising for LD mapping, as the coalescent offers a good approximation to the evolutionary history of mutations.Results: We compare the performance of the proposed method in simulation studies to the univariate Cox regression and to dimension reduction methods, and we observe that it performs similarly in localizing the causal site, while offering a clear advantage in terms of false positive associations. Moreover, it offers computational advantages. Applying our method to a real prospective study, we observe potential association between candidate ABC transporter genes and epilepsy treatment outcomes.Availability: R codes are available upon request.Contact: ioanna.tachmazidou@imperial.ac.ukSupplementary information: Supplementary data are available at Bioinformatics online.