Project description:Structural genetic variants like copy number variants (CNVs) comprise a large part of human genetic variation and may be inherited as well as somatically acquired. Recent studies have reported the presence of somatically acquired structural variants in the human genome and it has been suggested that they may accumulate in elderly individuals. To further explore the presence and the age-related acquisition of somatic structural variants in the human genome, we investigated CNVs acquired over a period of 10 years in 86 elderly Danish twins as well as CNV discordances between co-twins of 18 monozygotic twin pairs. Furthermore, the presence of mosaic structural variants was explored.
Project description:Climate change is impacting human health through a historic rise in wildfire smoke across the United States and the world. Whereas the deleterious effects of wildfire smoke and associated air pollution on asthma outcomes are well-established epidemiologically, genetic risks and molecular mechanisms of how wildfire smoke affects asthma are unknown. This knowledge gap hinders the identification of high-risk individuals and the creation of targeted therapies or recommendations to protect these individuals. Here, we employ a genetic approach to identify common variant (minor allele frequency > 0.05) exposure-conditional genetic risk variants that localize with genomic responses to wood smoke particles (WSP), a model of wildfire smoke exposure, and associate with asthma in the Genetic Epidemiology Research on Aging (GERA) cohort. Our novel approach used nascent transcriptional signatures derived from WSP-exposed Beas-2B airway epithelial cells to reduce the genome sequence for discovery and allow a permutation-based statistical approach to identify 52 candidate SNPs. We applied biologic and bioinformatic filters to prioritize variants for direct testing of allele-dependent transcriptional regulatory function in plasmid reporters. The rs3861144 variant identified by this approach controls WSP responses of airway epithelial cells to SPRY2, which we showed is involved in mechanical injury repair in cell culture. Our results demonstrate that wildfire particulates contribute to asthma risk at the molecular level, and we have identified mechanistic targets and genetic variant candidates to apply for clinical risk prediction and development of targeted therapies for high-risk individuals.
Project description:Forensic association of hair shaft evidence with individuals is currently assessed by comparing mitochondrial DNA haplotypes of reference and casework samples, primarily for exclusionary purposes. Present work tests and validates more recent proteomic approaches to extract quantitative transcriptional and genetic information from hair samples of monozygotic twin pairs, which would be predicted to partition away from unrelated individuals if the datasets contain identifying information. Protein expression profiles and polymorphic, genetically variant hair peptides were generated from 10 pairs of monozygotic twins. Profiling using the protein tryptic digests revealed that samples from identical twins were considerably more alike in profile than unrelated individuals among the twins. The data did not indicate that the degree of difference within twin pairs increased with age. In parallel, data from the digests were used to detect genetically variant peptides that result from common non-synonymous single nucleotide polymorphisms in genes expressed in the hair follicle. Compilation of the variants permitted sorting of the samples by hierarchical clustering, permitting accurate matching of twin pairs. The results demonstrate that genetic differences are detectable by proteomic methods and provide a framework for developing quantitative statistical estimates of personal identification that increase the value of hair shaft evidence.
Project description:GenomEUtwin is EU FP6 funded study aiming to capitalize special advantages of Europe in population genetics by efficient collaboration of twin researchers, genetic epidemiologists, molecular geneticists and mathematicians. Our goal is to identify critical genetic and life-style risk factors for common diseases using European strengths in genetics, epidemiology and biocomputing.
Project description:RATIONALE: The Genetic Epidemiology and Risk Assessment program may be more effective than usual care in increasing the number of healthy participants who regularly receive screening for colorectal cancer.
PURPOSE: This randomized clinical trial is studying the Genetic Epidemiology and Risk Assessment program to see how well it works compared with usual care to increase colorectal cancer screening in healthy participants.
Project description:This project contains genome-wide DNA methylation data generated using the HumanMethylation450 BeadChip (Illumina), for 79 rheumatoid arthritis (RA) discordant monozygotic twin pairs. By investigating disease discordant monozygotic twins, DNA methylation can be assessed without the confounding influence of genetic heterogeneity which often affects case-control epigenome-wide association studies of common diseases. Twins were recruited from two cohorts; Arthritis Research UK in Manchester and TwinsUK in London.