This is an RSS newsfeed from BioMed Central It is intended to be used with an RSS reader. For more information about RSS newsfeeds from BioMed Central, visit http://www.biomedcentral.com/info/about/rss/ http://www.biomedcentral.com/bmcgenet/ The latest articles from BMC Genetics (ISSN 1471-2156) published by BioMed Central Background: We introduce a QTL-mapping algorithm based on Statistical Machine Learning (SML) that is conceptually quite different to existing methods as there is a strong focus on generalisation ability. Our approach combines ridge regression, recursive feature elimination, and estimation of generalisation performance and marker effects using bootstrap resampling. Model performance and marker effects are determined using independent testing samples (individuals), thus providing better estimates. We compare the performance of SML against Composite Interval Mapping (CIM), Bayesian Interval Mapping (BIM) and single Marker Regression (MR) on synthetic datasets and a multi-trait and multi-environment dataset of the progeny for a cross between two barley cultivars. Results: In an analysis of the synthetic datasets, SML accurately predicted the number of QTL underlying a trait while BIM tended to underestimate the number of QTL. The QTL identified by SML for the barley dataset broadly coincided with known QTL locations. SML reported approximately half of the QTL reported by either CIM or MR, not unexpected given that neither CIM nor MR incorporates independent testing. The latter makes these two methods susceptible to producing overly optimistic estimates of QTL effects, as we demonstrate for MR. The QTL resolution (peak definition) afforded by SML was consistently superior to MR, CIM and BIM, with QTL detection power similar to BIM. The precision of SML was underscored by repeatedly identifying, at around 1-cM precision, three QTL for four partially related traits (heading date, plant height, lodging and yield). The set of QTL obtained using a arawa and a acurateda version of the same genotypic dataset were more similar to each other for SML than for CIM or MR. Conclusions: The SML algorithm produces better estimates of QTL effects because it eliminates the optimistic bias in the predictive performance of other QTL methods. It produces narrower peaks than other methods (except BIM) and hence identifies QTL with greater precision. It is more robust to genotyping and linkage mapping errors, and identifies markers linked to QTL in the absence of a genetic map. http://www.biomedcentral.com/1471-2156/9/35 Justin Bedo, Peter Wenzl, Adam Kowalczyk and Andrzej Kilian BMC Genetics 2008, 9:35 2008-05-02 doi:10.1186/1471-2156-9-35 BMC Genetics 1471-2156 9 35 2008-05-02 Background: The identification of novel genes is critical to understanding the molecular basis of body weight. Towards this goal, we have identified secretogranin V (Scg5; also referred to as Sgne1), as a candidate gene for growth traits. Results: Through a combination of DNA microarray analysis and quantitative PCR we identified a strong expression quantitative trait locus (eQTL) regulating Scg5 expression in two mouse chromosome 2 congenic strains and three additional F2 intercrosses. More importantly, the eQTL was coincident with a body weight QTL in congenic mice and Scg5 expression was negatively correlated with body weight in two of the F2 intercrosses. Analysis of haplotype blocks and genomic sequencing of Scg5 in high (C3H/HeJ, DBA/2J, BALB/cByJ, CAST/EiJ) and low (C57BL/6J) expressing strains revealed mutations unique to C57BL/6J and possibly responsible for the difference in mRNA abundance. To evaluate the functional consequence of Scg5 overexpression we measured the pituitary levels of 7B2 protein and PCSK2 activity and found both to be increased. In spite of this increase, the level of pituitary alpha-MSH, a PCSK2 processing product, was unaltered. Conclusions: Together, these data support a role for Scg5 in the modulation of body weight. http://www.biomedcentral.com/1471-2156/9/34 Charles R. Farber, James Chitwood, Sang-Nam Lee, Ricardo A Verdugo, Alma Islas-Trejo, Gonzalo Rincon, Iris Lindberg and Juan F Medrano BMC Genetics 2008, 9:34 2008-04-25 doi:10.1186/1471-2156-9-34 BMC Genetics 1471-2156 9 34 2008-04-25 Background: Marbling score (MS) is the major quantitative trait that affects carcass quality in beef cattle. In this study, we examined the association between genetic polymorphisms of the micromolar calcium-activated neutral protease gene (micro-calpain, CAPN1) and carcass traits in Korean cattle (also known as Hanwoo). Results: By direct DNA sequencing in 24 unrelated Korean cattle, we identified 39 sequence variants within exons and their flanking regions in CAPN1. Among them, 12 common polymorphic sites were selected for genotyping in the beef cattle (n=421). Statistical analysis revealed that a polymorphism in the 3'UTR (c.2151*479C>T) showed significant association with MS (Pcor.=0.02). Conclusions: Our findings suggest that polymorphisms in CAPN1 might be one of the important genetic factors involved in carcass quality in beef cattle, although it could be false positive association. http://www.biomedcentral.com/1471-2156/9/33 Hyun Sub Cheong, Du-Hak Yoon, Byung Lae Park, Lyoung Hyo Kim, Joon Seol Bae, Sohg Namgoong, Hae Won Lee, Chang Soo Han, Ji On Kim, Il-Cheong Cheong and Hyoung Doo Shin BMC Genetics 2008, 9:33 2008-04-19 doi:10.1186/1471-2156-9-33 BMC Genetics 1471-2156 9 33 2008-04-19 Background: The Y chromosome of Drosophila melanogaster harbors several genes required for male fertility. The genes for these fertility factors are very large in size and contain conspicuous amounts of repetitive DNA and transposons. Three of these loci (ks-1, kl-3 and kl-5) have the ability to develop giant lampbrush-like loops in primary spermatocytes, a cytological manifestation of their active state in these cells. Y-loops bind a number of non-Y encoded proteins, but the mechanisms regulating their development and their specific functions are still to be elucidated. Results: Here we report the results of a screen of 726 male sterile lines to identify novel autosomal genes controlling Y-loop function. We analyzed mutant testis preparations both in vivo and by immunofluorescence using antibodies directed against Y-loop-associated proteins. This screen enabled us to isolate 17 mutations at 15 loci whose wild-type function is required for proper Y-loop morphogenesis. Six of these loci are likely to specifically control loop development, while the others display pleiotropic effects on both loops and meiotic processes such as spermiogenesis, sperm development and maturation. We also determined the map position of the mutations affecting exclusively Y-loop morphology. Conclusions: Our cytological screening permitted us to identify novel genetic functions required for male spermatogenesis, some of which show pleiotropic effects. Analysis of these mutations also shows that loop development can be uncoupled from meiosis progression. These data represent a useful framework for the characterization of Y-loop development at a molecular level and for the study of the genetic control of heterochromatin. http://www.biomedcentral.com/1471-2156/9/32 Francesca Ceprani, Grazia D Raffa, Romano Petrucci and Roberto Piergentili BMC Genetics 2008, 9:32 2008-04-11 doi:10.1186/1471-2156-9-32 BMC Genetics 1471-2156 9 32 2008-04-11 Background: The melanocortin 1 receptor gene (MC1R) is responsible for normal pigment variation in humans and is highly polymorphic with numerous population-specific alleles. Some MC1R variants have been associated with skin cancer risk. Results: Allele frequency data were compiled on 55 single nucleotide polymorphisms from seven geographically distinct human populations (n = 2306 individuals). MC1R nucleotide diversity, π, was much higher (10.1 × 10-4) than in other genes for all subjects. A large degree of population differentiation, determined by FST, was also present, particularly between Asia and all other populations, due to the p.R163Q (c.488 G>A) polymorphism. The least amount of differentiation was between the United States, Northern Europe, and Southern Europe. Tajima's D statistic suggested the presence of positive selection in individuals from Europe. Conclusion: This study further quantifies the degree of population-specific genetic variation and suggests that positive selection may be present in European populations in MC1R. http://www.biomedcentral.com/1471-2156/9/31 Sharon A Savage, Meg R Gerstenblith, Alisa M Goldstein, Lisa Mirabello, Maria Concetta Fargnoli, Ketty Peris and Maria Teresa Landi BMC Genetics 2008, 9:31 2008-04-10 doi:10.1186/1471-2156-9-31 BMC Genetics 1471-2156 9 31 2008-04-10 Background: The Gpnmb gene encodes a transmembrane protein whose function(s) remain largely unknown. Here, we assess if a mutant allele of Gpnmb confers susceptibility to glaucoma by altering immune functions. DBA/2J mice have a mutant Gpnmb gene and they develop a form of glaucoma preceded by a pigment dispersing iris disease and abnormalities of the immunosuppressive ocular microenvironment. Results: We find that the Gpnmb genotype of bone-marrow derived cell lineages significantly influences the iris disease and the elevation of intraocular pressure. GPNMB localizes to multiple cell types, including pigment producing cells, bone marrow derived F4/80 positive antigen-presenting cells (APCs) of the iris and dendritic cells. We show that APCs of DBA/2J mice fail to induce antigen induced immune deviation (a form of tolerance) when treated with TGFβ2. This demonstrates that some of the immune abnormalities previously identified in DBA/2J mice result from intrinsic defects in APCs. However, the tested APC defects are not dependent on a mutant Gpnmb gene. Finally, we show that the Gpnmb mediated iris disease does not require elevated IL18 or mature B or T lymphocytes. Conclusion: These results establish a role for Gpnmb in bone marrow derived lineages. They suggest that affects of Gpnmb on innate immunity influence susceptibility to glaucoma in DBA/2J mice. http://www.biomedcentral.com/1471-2156/9/30 Michael G Anderson, K Saidas Nair, Leslie A Amonoo, Adrienne Mehalow, Colleen M Trantow, Sharmila Masli and Simon WM John BMC Genetics 2008, 9:30 2008-04-10 doi:10.1186/1471-2156-9-30 BMC Genetics 1471-2156 9 30 2008-04-10 Background: Glutathione S-transferases (GSTs) is a genetic factor for many diseases and exhibits great diversities among various populations. We assessed association of the genotypes of Glutathione S-transferases Omega-1 (GSTO1) A140D with ethnicity in China. Results: Peripheral blood samples were obtained from 1314 individuals from 14 ethnic groups. Polymorphisms of GSTO1 A140D were measured using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Logistic regression was employed to adjustment for regional factor. The frequency of GSTO1 140A allele was 15.49% in the total 14 ethnic populations. Compared to Han ethnic group, two ethnic populations were more likely to have AA or CA genotype [odds ratio (OR): 1.77, 95% confidence interval (95% CI): 1.05–2.98 for Uygur and OR: 1.78, 95% CI: 1.18–2.69 for Hui]. However, there were no statistically significant differences across 14 ethnic groups when region factor was adjusted. In Han ethnicity, region was significantly associated with AA or CA genotype. Han individuals who resided in North-west of China were more likely to have these genotypes than those in South of China (OR: 1.63, 95% CI: 1.21–2.20). Conclusion: The prevalence of the GSTO1 140A varied significantly among different regional populations in China, which showed that geography played a more important role in the population differentiation for this allele than the ethnicity/race. http://www.biomedcentral.com/1471-2156/9/29 Songbo Fu, Jie Wu, Feng Chen, Dianjun Sun and Songbin Fu BMC Genetics 2008, 9:29 2008-04-10 doi:10.1186/1471-2156-9-29 BMC Genetics 1471-2156 9 29 2008-04-10 Background: A major boost to cystic fibrosis disease research was given by the generation of various mouse models using gene targeting in embryonal stem cells. Moreover, the introduction of the same mutation on different inbred strains generating congenic strains facilitated the search for modifier genes. From the original CftrTgH(neoim)Hgu mouse model with a divergent genetic background (129/Sv, C57BL/6, HsdOla:MF1) two inbred mutant mouse strains CF/1-CftrTgH(neoim)Hgu and CF/3-CftrTgH(neoim)Hgu had been generated using strict brother × sister mating. CF/1-CftrTgH(neoim)Hgu and CF/3-CftrTgH(neoim)Hgu mice were fertile and showed normal growth and lifespan. In this work the CftrTgH(neoim)Hgu insertional mutation was backcrossed from CF/3-CftrTgH(neoim)Hgu onto the inbred backgrounds C57BL/6J and DBA/2J generating congenic animals in order to clarify the differential impact of the Cftr mutation and the genetic background on the disease phenotype of the cystic fibrosis mutant mice. Clinical and electrophysiological features of the two congenic strains were compared with those of CF/1-CftrTgH(neoim)Hgu and CF/3-CftrTgH(neoim)Hgu and wild type controls. Results: Under the standardized housing conditions of the animal facility, the four mouse strains CF/1-CftrTgH(neoim)Hgu, CF/3-CftrTgH(neoim)Hgu, D2.129P2(CF/3)-CftrTgH(neoim)Hgu and B6.129P2(CF/3)-CftrTgH(neoim)Hgu exhibited normal life expectancy. Growth of congenic cystic fibrosis mice was comparable with that of wild type controls. All mice but D2.129P2(CF/3)-CftrTgH(neoim)Hgu females were fertile. Short circuit current measurements revealed characteristic response profiles of the HsdOla:MF1, DBA/2J and C57BL/6J backgrounds in nose, ileum and colon. All cystic fibrosis mouse lines showed the disease-typical hyperresponsiveness to amiloride in the respiratory epithelium. The mean chloride secretory responses to carbachol or forskolin were 15–100% of those of the cognate wild type control animals. Conclusion: The amelioration of the clinical features and of the basic defect that had emerged during the generation of CF/3-CftrTgH(neoim)Hgu mice was retained in the congenic mice indicating that the Cftr linkage group or other loci shared between the inbred strains contain(s) the major modifier(s) of attenuation of cystic fibrosis symptoms. http://www.biomedcentral.com/1471-2156/9/28 Balázs Tóth, Martina Wilke, Frauke Stanke, Martina Dorsch, Silke Jansen, Dirk Wedekind, Nikoletta Charizopoulou, Alice Bot, Marion Burmester, Sabine Leonhard-Marek, Hugo R de Jonge, Hans-Jürgen Hedrich, Gerhard Breves and Burkhard Tümmler BMC Genetics 2008, 9:28 2008-04-09 doi:10.1186/1471-2156-9-28 BMC Genetics 1471-2156 9 28 2008-04-09 Background: DNA sequence diversity within the human genome may be more greatly affected by copy number variations (CNVs) than single nucleotide polymorphisms (SNPs). Although the importance of CNVs in genome wide association studies (GWAS) is becoming widely accepted, the optimal methods for identifying these variants are still under evaluation. We have previously reported a comprehensive view of CNVs in the HapMap DNA collection using high density 500 K EA (Early Access) SNP genotyping arrays which revealed greater than 1,000 CNVs ranging in size from 1 kb to over 3 Mb. Although the arrays used most commonly for GWAS predominantly interrogate SNPs, CNV identification and detection does not necessarily require the use of DNA probes centered on polymorphic nucleotides and may even be hindered by the dependence on a successful SNP genotyping assay. Results: In this study, we have designed and evaluated a high density array predicated on the use of non-polymorphic oligonucleotide probes for CNV detection. This approach effectively uncouples copy number detection from SNP genotyping and thus has the potential to significantly improve probe coverage for genome-wide CNV identification. This array, in conjunction with PCR-based, complexity-reduced DNA target, queries over 1.3 M independent NspI restriction enzyme fragments in the 200 bp to 1100 bp size range, which is a several fold increase in marker density as compared to the 500 K EA array. In addition, a novel algorithm was developed and validated to extract CNV regions and boundaries. Conclusion: Using a well-characterized pair of DNA samples, close to 200 CNVs were identified, of which nearly 50% appear novel yet were independently validated using quantitative PCR. The results indicate that non-polymorphic probes provide a robust approach for CNV identification, and the increasing precision of CNV boundary delineation should allow a more complete analysis of their genomic organization. http://www.biomedcentral.com/1471-2156/9/27 Fan Shen, Jing Huang, Karen R Fitch, Vivi B Truong, Andrew Kirby, Wenwei Chen, Jane Zhang, Guoying Liu, Steven A McCarroll, Keith W Jones and Michael H Shapero BMC Genetics 2008, 9:27 2008-03-28 doi:10.1186/1471-2156-9-27 BMC Genetics 1471-2156 9 27 2008-03-28 Background: Genetic markers conferring susceptibility to diabetes specific renal disease remains to be identified for early prediction and development of effective drugs and therapies. Inconsistent results obtained from analysis of genes from classical pathways generate need for examination of unconventional genetic markers having role in regulation of renal function. Experimental and clinical evidences suggest that dopamine is an important natriuretic hormone. Therefore, various genes involved in regulation of dopamine bioavailability could play a role in diabetic chronic renal insufficiency (CRI). We investigated the contribution of 12 polymorphisms from five Dopaminergic pathway genes to CRI among type-2 diabetic Asian Indian subjects. Methods: Genetic association of 12 polymorphisms (SNPs) from five genes namely-dopamine receptor-1 (DRD1), DRD2, DRD3, DRD4, andcatechol-O-methyltransferase (COMT) with diabetic CRI was investigated using a case-control approach. Logistic regression analysis was carried out to correlate various clinical parameters with genotypes, and to study pair wise interactions between SNPs of different genes. Results: SNPs -141 ins/del C and G>A (1 kb upstream from exon 2) in DRD2 gene showed significant allelic and genotypic association. Allele -141 insC and genotype -141 insC/insC of -141 ins/del C polymorphism, and allele A of G>A SNP were found to be predisposing to CRI. Our result of allelic and genotypic association of -141 insC/delC SNP was also reflected in the haplotypic association. Heterozygous genotype of polymorphism 900 ins/del C in COMT gene was predisposing towards CRI. Conclusion: Some polymorphisms in DRD2 and COMT genes are significantly associated with susceptibility to CRI in the Asian Indian population which, if confirmed would be consistent with a suggested role of dopamine metabolism in disease occurrence. http://www.biomedcentral.com/1471-2156/9/26 Pushplata Prasad, KM Prasanna Kumar, AC Ammini, Arvind Gupta, Rajeev Gupta and BK Thelma BMC Genetics 2008, 9:26 2008-03-22 doi:10.1186/1471-2156-9-26 BMC Genetics 1471-2156 9 26 2008-03-22