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Szatmari P.,McMaster University | Liu X.-Q.,University of Manitoba | Goldberg J.,McMaster University | Zwaigenbaum L.,University of Alberta | And 6 more authors.
American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics

The implications of the well known sex differences in the prevalence of autism spectrum disorder (ASD) are not well understood. The aim of this paper was to investigate whether these differences might be associated with differences in genetic liability. Individuals with ASD (970 families, 2,028 individuals) were recruited as part of the Autism Genome Project (AGP). The families were differentiated into families containing a female (either female-female or male-female) and those with only males. If the sex with the lower prevalence is associated with a greater genetic liability necessary to cross sex-specific thresholds, the males from female containing families should be more severely affected than males from male only families. Affected subjects from the different types of families with ASD were sampled and compared on the social reciprocity and repetitive behavior scores from the Autism Diagnostic Interview-Revised (ADI-R). In general, females had lower repetitive behavior scores than males. More importantly, males from female containing families had higher repetitive behavior scores than males from male-male families. No such differences were apparent on the social reciprocity scores. These results support the hypothesis of a multiple threshold model of genetic liability of ASD with females having a higher liability for affectation status, at least on the repetitive behavior dimension of the disorder. These data also support the dissociation of the different phenotypic dimensions of ASD in terms of its genetic architecture. The implications of these results for linkage and association studies are discussed. © 2011 Wiley Periodicals, Inc. Source

Goula A.-V.,French Institute of Health and Medical Research | Pearson C.E.,Genetics and Genome Biology | Pearson C.E.,University of Toronto | Della Maria J.,University of Maryland Baltimore County | And 4 more authors.

Expansion of CAG/CTG repeats is the underlying cause of >14 genetic disorders, including Huntington's disease (HD) and myotonic dystrophy. The mutational process is ongoing, with increases in repeat size enhancing the toxicity of the expansion in specific tissues. In many repeat diseases, the repeats exhibit high instability in the striatum, whereas instability is minimal in the cerebellum. We provide molecular insights into how base excision repair (BER) protein stoichiometry may contribute to the tissue-selective instability of CAG/CTG repeats by using specific repair assays. Oligonucleotide substrates with an abasic site were mixed with either reconstituted BER protein stoichiometries mimicking the levels present in HD mouse striatum or cerebellum, or with protein extracts prepared from HD mouse striatum or cerebellum. In both cases, the repair efficiency at CAG/CTG repeats and at control DNA sequences was markedly reduced under the striatal conditions, likely because of the lower level of APE1, FEN1, and LIG1. Damage located toward the 5′ end of the repeat tract was poorly repaired, with the accumulation of incompletely processed intermediates as compared to an AP lesion in the center or at the 3′ end of the repeats or within control sequences. Moreover, repair of lesions at the 5′ end of CAG or CTG repeats involved multinucleotide synthesis, particularly at the cerebellar stoichiometry, suggesting that long-patch BER processes lesions at sequences susceptible to hairpin formation. Our results show that the BER stoichiometry, nucleotide sequence, and DNA damage position modulate repair outcome and suggest that a suboptimal long-patch BER activity promotes CAG/CTG repeat instability. © 2012 American Chemical Society. Source

Lopez Castel A.,Genetics and Genome Biology
Epigenetics : official journal of the DNA Methylation Society

Most epigenetic studies assess methylation of 5'-CpG-3' sites but recent evidence indicates that non-CpG cytosine methylation occurs at high levels in humans and other species. This is most prevalent at 5'-CHG-3', where H = A, C or T, and it preferentially occurs at 5'-CpA-3' and 5'-CpT-3' sites. With the goal of facilitating the detection of non-CpG methylation, the restriction endonucleases ApeKI, BbvI, EcoP15I, Fnu 4HI, MwoI and TseI were assessed for their sensitivity to 5-methylcytosine at GpCpA, GpCpT, GpCpC or GpCpG sites, where methylation is catalyzed by the DNA 5-cytosine 5'-GpC-3' methyltransferase M.CviPI. We tested a variety of sequences including various plasmid-based sites, a cloned disease-associated (CAG)83•(CTG)83 repeat and in vitro synthesized tracts of only (CAG)500•(CTG)500 or (CAG)800•(CTG)800. The repeat tracts are enriched for the preferred CpA and CpT motifs. We found that none of the tested enzymes can cleave their recognition sequences when they are 5'-GpC-3' methylated. A genomic site known to convert its non-CpG methylation levels upon C2C12 differentiation was confirmed through the use of these enzymes. These enzymes can be useful in rapidly and easily determining the most common non-CpG methylation status in various sequence contexts, as well as at expansions of (CAG)n•(CTG)n repeat tracts associated with diseases like myotonic dystrophy and Huntington disease. Source

Nakamori M.,University of Rochester | Pearson C.E.,Genetics and Genome Biology | Pearson C.E.,University of Toronto | Thornton C.A.,University of Rochester
Human Molecular Genetics

More than 12 neurogenetic disorders are caused by unstable expansions of (CTG)•(CAG) repeats. The expanded repeats are unstable in germline and somatic cells, with potential consequences for disease severity. Previous studies have shown that contractions of (CAG)95 are more frequent when the repeat tract is transcribed. Here we determined whether transcription can promote repeat expansion, using (CTG)•(CAG) repeat tracts in the size range that is typical for myotonic dystrophy type 1. We derived normal human fibroblasts having single-copy genomic integrations of 800 CTG repeats. The repeat tract showed modest instability when it was not transcribed, yielding an estimated mutation rate of 0.28% per generation. Instability was enhanced several-fold by transcription in the forward or reverse transcription, and 30-fold by bidirectional transcription, yielding many expansions and contractions of more than 200 repeats. These results suggest that convergent bidirectional transcription, which has been reported at several disease loci, could contribute to somatic instability of highly expanded (CTG)•(CAG) repeats. © The Author 2010. Published by Oxford University Press. All rights reserved. Source

News Article
Site: http://phys.org/biology-news/

At 10 times the size of the human genome, the sugar pine genome is the largest ever sequenced for any organism. It is expected to provide valuable information that may help preserve the iconic but imperiled tree. "Having the genome sequence allows us to discover the underlying genetic determinants of disease resistance, which will greatly facilitate reforestation efforts," said professor and principal investigator David Neale, a UC Davis forest tree geneticist. "We can now give forest managers modern, rapid genetic tools to identify resistant trees." Neale collaborated on the Pine Reference Sequences project with geneticist Charles Langley and bioinformatics researcher Kristian Stevens, both of UC Davis, as well as researchers from other universities and the U.S. Forest Service. The genome for the sugar pine has been publicly released and is available through open access at the Pine Reference Sequences website. The sugar pine (Pinus lambertiana) is one of the tallest tree species in the world. It is endemic primarily to California, stretching south into parts of Baja Mexico and north into Oregon. The stately tree's pinecones, averaging 10 to 20 inches in length, are among the longest of any conifer species. "The sugar pine has important environmental value as a key component of California forests, ecological and recreational value throughout the Sierra Nevada, and economic value as a source of timber," Neale said. Around 1930, white pine blister rust was introduced into California. The fungal pathogen is a significant threat to sugar pines and other species of "white pines." In fact, of the commercially important white pines in North America, sugar pine is most susceptible to white pine blister rust. In addition, sugar pine survival is threatened by damage from bark beetles, and the ongoing drought and lack of snowpack in the Sierra. Pine trees and other ancient conifers are dominant species in forests found in temperate regions of the world. The genus Pinus includes over 100 species of pine trees, which fall into two major subgroups—the yellow pines and the white pines. The loblolly pine, a member of the yellow pine subgroup, was sequenced by Neale, Langley and colleagues last year. The newly sequenced sugar pine has a genome 1.5 times larger than the loblolly pine, which itself was considered large when it was sequenced. These two new reference sequences serve as foundations for future studies and applications in pine trees. "The sequencing and assembly of these two pine genomes reaches the present-day limits of genomic technologies and methods," said Professor Langley. "Like the human genome reference sequence, they are not yet complete, but they do provide an almost complete 'parts list' and a draft of the 'instructions.'" Bohun Kinloch, an emeritus research geneticist with the U.S. Forest Service, used traditional breeding methods and progeny testing over many years, before sequencing existed, to detect a rare blister rust resistance gene in sugar pine "parent trees" in 1970. "The U.S. Forest Service plants seedlings from resistant parent trees into forests, so the new diagnostic tools derived from the reference sequences will speed the finding of disease-resistant parent trees directly, bypassing costly progeny testing. Seeds planted from these parents will help protect new generations of sugar pine trees from the devastating blister rust pathogen," Kinloch said. This information is of great interest to environmental agencies such as the U.S. Forest Service and timber companies such as Sierra Pacific Industries that manage the natural range of sugar pine. The sugar pine genomic information has been made freely available by the U.S. Department of Agriculture's National Institute of Food and Agriculture, which funded the project; UC Davis; and the other research partners. A report of the sequencing and analyses of the sugar pine genome is pending publication in a scientific journal. The scientific reports of the loblolly genome sequencing appeared last year in the journals Genetics and Genome Biology.

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