Wong J.T.-F.,Applied Genomics
Frontiers in Bioscience - Landmark | Year: 2014
This study tracks the rise, evolution and postevolution of the genetic information system through emergence of life. The major stages traversed include prebiotic synthesis, functional RNA selection by metabolite, RNA World, peptidated RNA world, co-evolution of genetic code and amino acid biosynthesis, last universal common ancestor, Darwinian evolution and synthetic life.
Diskin S.J.,Applied Genomics
Journal of the National Cancer Institute | Year: 2014
TP53 is the most frequently mutated gene in human malignancies; however, de novo somatic mutations in childhood embryonal cancers such as neuroblastoma are rare. We report on the analysis of three independent case-control cohorts comprising 10290 individuals and demonstrate that rs78378222 and rs35850753, rare germline variants in linkage disequilibrium that map to the 3' untranslated region (UTR) of TP53 and 5' UTR of the Δ133 isoform of TP53, respectively, are robustly associated with neuroblastoma (rs35850753: odds ratio [OR] = 2.7, 95% confidence interval [CI] = 2.0 to 3.6, P combined = 3.43×10(-12); rs78378222: OR = 2.3, 95% CI = 1.8 to 2.9, P combined = 2.03×10(-11)). All statistical tests were two-sided. These findings add neuroblastoma to the complex repertoire of human cancers influenced by the rs78378222 hypomorphic allele, which impairs proper termination and polyadenylation of TP53 transcripts. Future studies using whole-genome sequencing data are likely to reveal additional rare variants with large effect sizes contributing to neuroblastoma tumorigenesis.
Carter M.T.,Hospital for Sick Children |
Scherer S.W,Applied Genomics |
Scherer S.W,University of Toronto
Clinical Genetics | Year: 2013
Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders affecting social communication, language and behavior. The underlying cause(s) in a given individual is often elusive, with the exception of clinically recognizable genetic syndromes with readily available molecular diagnosis, such as fragile X syndrome. Clinical geneticists approach patients with ASDs by ruling out known genetic and genomic syndromes, leaving more than 80% of families without a definitive diagnosis and an uncertain risk of recurrence. Advances in microarray technology and next-generation sequencing are revealing rare variants in genes with important roles in synapse formation, function and maintenance. This review will focus on the clinical approach to ASDs, given the current state of knowledge about their complex genetic architecture. © 2013 John Wiley & Sons A/S.
Prasad A.,Applied Genomics
G3 (Bethesda, Md.) | Year: 2012
The identification of rare inherited and de novo copy number variations (CNVs) in human subjects has proven a productive approach to highlight risk genes for autism spectrum disorder (ASD). A variety of microarrays are available to detect CNVs, including single-nucleotide polymorphism (SNP) arrays and comparative genomic hybridization (CGH) arrays. Here, we examine a cohort of 696 unrelated ASD cases using a high-resolution one-million feature CGH microarray, the majority of which were previously genotyped with SNP arrays. Our objective was to discover new CNVs in ASD cases that were not detected by SNP microarray analysis and to delineate novel ASD risk loci via combined analysis of CGH and SNP array data sets on the ASD cohort and CGH data on an additional 1000 control samples. Of the 615 ASD cases analyzed on both SNP and CGH arrays, we found that 13,572 of 21,346 (64%) of the CNVs were exclusively detected by the CGH array. Several of the CGH-specific CNVs are rare in population frequency and impact previously reported ASD genes (e.g., NRXN1, GRM8, DPYD), as well as novel ASD candidate genes (e.g., CIB2, DAPP1, SAE1), and all were inherited except for a de novo CNV in the GPHN gene. A functional enrichment test of gene-sets in ASD cases over controls revealed nucleotide metabolism as a potential novel pathway involved in ASD, which includes several candidate genes for follow-up (e.g., DPYD, UPB1, UPP1, TYMP). Finally, this extensively phenotyped and genotyped ASD clinical cohort serves as an invaluable resource for the next step of genome sequencing for complete genetic variation detection.
Mengel M.,Applied Genomics
Current Opinion in Nephrology and Hypertension | Year: 2010
PURPOSE OF REVIEW: In renal transplantation, significant improvements in short-term allograft survival have been accomplished, but do not translate into comparable extension of long-term function. Thus, late allograft failure is the challenge while the underlying disease processes are mostly elusive. The purpose of this review is to summarize new diagnostic insights into the identification of specific causes of late allograft failure. RECENT FINDINGS: In 2005, the Banff working group for allograft pathology eliminated the term 'chronic allograft nephropathy'. This became necessary due to the fact that this generic term, summarizing all disease processes causing chronic allograft damage, mutated in the literature into an entity explaining most kidney allograft failures. Since 2005, pathologists have been urged to assign a specific diagnosis instead of using the nonspecific term chronic allograft nephropathy. Simultaneously, considerable research efforts (i.e. the Genome Canada Project and Deterioration of Kidney Allograft Function study) were implemented to identify specific causes of renal allograft failure. In 2009, results from these initiatives were presented indicating that antibody-mediated rejection and recurrent/de-novo glomerulonephritis are the major causes of late renal allograft failure. SUMMARY: With new diagnostic tools available, a disease-specific approach in renal allograft damage becomes feasible. This will allow for designing entity-specific trials and establishment of specific treatments, eventually improving long-term allograft function. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.