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Newcastle upon Tyne, United Kingdom

Azad J.,James Cook University | Brennan P.,Institute for Human Genetics | Carmichael A.J.,James Cook University
Clinical and Experimental Dermatology | Year: 2013

Background Erythropoietic protoporphyria (EPP; OMIM #177000) is a rare disease that usually presents in infancy or early childhood. The uncommon adult-onset EPP is often associated with acquired somatic mutations of the FECH gene, secondary to blood dyscracias. Methods We investigated two sisters with adult-onset EPP. Results We found a novel germline mutation in the FECH gene, in trans with the common hypomorphic IVS3-48C allele. Conclusions The adult presentation and identical genotypes of the two sisters suggests that the late development of the condition is to an extent a function of the mutation. The exact mechanism for this delayed penetrance is not clear, although these atypical cases raise the possibility of other genetic or nongenetic disease-modifying factors. © 2013 British Association of Dermatologists.

Li C.-Y.,University of California at San Francisco | Cha W.,University of California at San Francisco | Luder H.-U.,University of Zurich | Charles R.-P.,University of California at San Francisco | And 4 more authors.
Developmental Biology | Year: 2012

Stem cells are essential for the regeneration and homeostasis of many organs, such as tooth, hair, skin, and intestine. Although human tooth regeneration is limited, a number of animals have evolved continuously growing teeth that provide models of stem cell-based organ renewal. A well-studied model is the mouse incisor, which contains dental epithelial stem cells in structures known as cervical loops. These stem cells produce progeny that proliferate and migrate along the proximo-distal axis of the incisor and differentiate into enamel-forming ameloblasts. Here, we studied the role of E-cadherin in behavior of the stem cells and their progeny. Levels of E-cadherin are highly dynamic in the incisor, such that E-cadherin is expressed in the stem cells, downregulated in the transit-amplifying cells, re-expressed in the pre-ameloblasts and then downregulated again in the ameloblasts. Conditional inactivation of E-cadherin in the cervical loop led to decreased numbers of label-retaining stem cells, increased proliferation, and decreased cell migration in the mouse incisor. Using both genetic and pharmacological approaches, we showed that Fibroblast Growth Factors regulate E-cadherin expression, cell proliferation and migration in the incisor. Together, our data indicate that E-cadherin is an important regulator of stem cells and their progeny during growth of the mouse incisor. © 2012 Elsevier Inc.

Pellatt A.J.,University of Utah | Wolff R.K.,University of Utah | Torres-Mejia G.,National University of Costa Rica | John E.M.,Cancer Prevention Institute of California | And 9 more authors.
Genes Chromosomes and Cancer | Year: 2013

Telomeres are involved in maintaining genomic stability. Previous studies have linked both telomere length (TL) and telomere-related genes with cancer. We evaluated associations between telomere-related genes, TL, and breast cancer risk in an admixed population of US non-Hispanic white (1,481 cases, 1,586 controls) and U.S. Hispanic and Mexican women (2,111 cases, 2,597 controls) from the Breast Cancer Health Disparities Study. TL was assessed in 1,500 women based on their genetic ancestry. TL-related genes assessed were MEN1, MRE11A, RECQL5, TEP1, TERC, TERF2, TERT, TNKS, and TNKS2. Longer TL was associated with increased breast cancer risk [odds ratio (OR) 1.87, 95% confidence interval (CI) 1.38, 2.55], with the highest risk (OR 3.11, 95% CI 1.74, 5.67 p interaction 0.02) among women with high Indigenous American ancestry. Several TL-related single nucleotide polymorphisms had modest association with breast cancer risk overall, including TEP1 rs93886 (OR 0.82, 95% CI 0.70,0.95); TERF2 rs3785074 (OR 1.13, 95% CI 1.03,1.24); TERT rs4246742 (OR 0.85, 95% CI 0.77,0.93); TERT rs10069690 (OR 1.13, 95% CI 1.03,1.24); TERT rs2242652 (OR 1.51, 95% CI 1.11,2.04); and TNKS rs6990300 (OR 0.89, 95% CI 0.81,0.97). Several differences in association were detected by hormone receptor status of tumors. Most notable were associations with TERT rs2736118 (ORadj 6.18, 95% CI 2.90, 13.19) with estrogen receptor negative/progesterone receptor positive (ER-/PR+) tumors and TERT rs2735940 (ORadj 0.73, 95% CI 0.59, 0.91) with ER-/PR- tumors. These data provide support for an association between TL and TL-related genes and risk of breast cancer. The association may be modified by hormone receptor status and genetic ancestry. © 2013 Wiley Periodicals, Inc.

Zaitlen N.,Tel Aviv University | Pasaniuc B.,International Computer Science Institute | Gur T.,Tel Aviv University | Ziv E.,Institute for Human Genetics | And 2 more authors.
American Journal of Human Genetics | Year: 2010

Genome-wide association studies have been performed extensively in the last few years, resulting in many new discoveries of genomic regions that are associated with complex traits. It is often the case that a SNP found to be associated with the condition is not the causal SNP, but a proxy to it as a result of linkage disequilibrium. For the identification of the actual causal SNP, fine-mapping follow-up is performed, either with the use of dense genotyping or by sequencing of the region. In either case, if the causal SNP is in high linkage disequilibrium with other SNPs, the fine-mapping procedure will require a very large sample size for the identification of the causal SNP. Here, we show that by leveraging genetic variability across populations, we significantly increase the localization success rate (LSR) for a causal SNP in a follow-up study that involves multiple populations as compared to a study that involves only one population. Thus, the average power for detection of the causal variant will be higher in a joint analysis than that in studies in which only one population is analyzed at a time. On the basis of this observation, we developed a framework to efficiently search for a follow-up study design: our framework searches for the best combination of populations from a pool of available populations to maximize the LSR for detection of a causal variant. This framework and its accompanying software can be used to considerably enhance the power of fine-mapping studies. © 2010 The American Society of Human Genetics.

Stich B.,Max Planck Institute for Plant Breeding Research | Urbany C.,Max Planck Institute for Plant Breeding Research | Hoffmann P.,Institute for Human Genetics | Gebhardt C.,Max Planck Institute for Plant Breeding Research
Plant Breeding | Year: 2013

Genome-wide association (GWA) mapping in potato requires high-density genotyping. With the Illumina SolCAP potato single-nucleotide polymorphism (SNP) array, a first tool for GWA mapping in potato became available. Thirty-six tetraploid varieties and eight diploid breeding clones were genotyped for 8303 SNPs using this array. The objectives of our study were to examine in this set of germplasm: (i) the degree of polymorphism of the SolCAP SNPs in European germplasm, (ii) the population structure, (iii) temporal trends of genetic diversity and (iv) the genome-wide extent of linkage disequilibrium (LD). Three-quarters of the SNPs were polymorphic. In the principal coordinate analysis, a clear separation of tetraploid from diploid genotypes was observed, whereas no distinct subgroups among the tetraploid varieties were detected. The nonlinear trendline of the LD measure r2 vs. the physical map distance decayed within 275 bp to an r2 value of 0.10, indicating that theoretically, about 3 million equally distributed SNPs are required for GWA mapping in this diverse set of germplasm. As the LD decay changes with the population selected for GWA mapping, the number of required markers might be different in other germplasm. © 2013 The Authors. Plant Breeding published by Blackwell Verlag GmbH.

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