Dataset Information

Patterns of instability of expanded CAG repeats at the ERDA1 locus in general populations.

ABSTRACT: A highly polymorphic CAG repeat locus, ERDA1, was recently described on human chromosome 17q21.3, with alleles as large as 50-90 repeats and without any disease association in the general population. We have studied allelic distribution at this locus in five human populations and have characterized the mutational patterns by direct observation of 731 meioses. The data show that large alleles (>/=40 CAG repeats) are generally most common in Asian populations, less common in populations of European ancestry, and least common among Africans. We have observed a high intergenerational instability (46. 3%+/-5.1%) of the large alleles. Although the mutation rate is not dependent on parental sex, paternal transmissions have predominantly resulted in contractions, whereas maternal transmissions have yielded expansions. Within this class of large alleles, the mutation rate increases concomitantly with increasing allele size, but the magnitude of repeat size change does not depend on the size of the progenitor allele. Sequencing of specific alleles reveals that the intermediate-sized alleles (30-40 repeats) have CAT/CAC interruptions within the CAG-repeat array. These results indicate that expansion and instability of trinucleotide repeats are not exclusively disease-associated phenomena. The implications of the existence of massively expanded alleles in the general populations are not yet understood.

SUBMITTER: Deka R

PROVIDER: S-EPMC1378090 | biostudies-other | 1999 Jul

REPOSITORIES: biostudies-other

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Patterns of instability of expanded CAG repeats at the ERDA1 locus in general populations.

Deka R R Guangyun S S Wiest J J Smelser D D Chunhua S S Zhong Y Y Chakraborty R R

American journal of human genetics 19990701 1

A highly polymorphic CAG repeat locus, ERDA1, was recently described on human chromosome 17q21.3, with alleles as large as 50-90 repeats and without any disease association in the general population. We have studied allelic distribution at this locus in five human populations and have characterized the mutational patterns by direct observation of 731 meioses. The data show that large alleles (>/=40 CAG repeats) are generally most common in Asian populations, less common in populations of Europea ...[more]

PMID: 10364532

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Project description:Huntingtons disease (HD) is a devastating neurodegenerative disease, with out effective treatment. Despite significant advances, our understanding of how an expanded CAG repeat in the amino terminus of the large ubiquitously expressed HD gene product remains incomplete. Augmented adult neurogenesis in response to acute and chronic injury, including Huntingtons disease, has been demonstrated, but its role development, disease, and recovery is largely unknown, as are the factors controlling it. The HD gene product, huntingtin (htt) is know to interact with a number of transcription factors which subsequently influence gene expression. Understanding the factors involved in controlling neurogenesis in response to disease would bridge a significant knowledge gap and have tremendous therapeutic potential. We propose to identify transcripts responsible for CAG repeat facilitated neurogenesis. Our hypothesis is that expanded CAG repeats in the Huntingtons disease gene facilitates neurogenesis by altering transcription of genes critical in neurogenesis. We have developed a model in which mouse embryonic stem cells (ESC) with expanded CAG repeats have facilitated neurogenesis. In this model more ESC with expanded CAG repeats transition to neuronal precursors and then develop into mature neurons more rapidly than control ESC. We propose to compare the gene expression profiles between ESC with expanded CAG repeats and control ESCs on days 4 and 6 of neuronal differentiation. Initial studies indicate that key transcriptional differences are occurring at these time points. Control ECS and a an ESC line with150 CAG repeats will be differentiated in triplicate, and RNA isolated form each replicate. It is anticipated that comparison of gene expression between the control and CAG repeat lines at each time point will identify transcripts involved in CAG repeat facilitated neurogenesis. Observed differences at day 4 may be more relevant to the transition from ESC to neuronal precursor whereas differences at day 6 may be more relevant to the neuronal precursor to neuron transition. Keywords: time-course

Project description:HuntingtonÂs disease (HD) is a devastating neurodegenerative disease, with out effective treatment. Despite significant advances, our understanding of how an expanded CAG repeat in the amino terminus of the large ubiquitously expressed HD gene product remains incomplete. Augmented adult neurogenesis in response to acute and chronic injury, including HuntingtonÂs disease, has been demonstrated, but its role development, disease, and recovery is largely unknown, as are the factors controlling it. The HD gene product, huntingtin (htt) is know to interact with a number of transcription factors which subsequently influence gene expression. Understanding the factors involved in controlling neurogenesis in response to disease would bridge a significant knowledge gap and have tremendous therapeutic potential. We propose to identify transcripts responsible for CAG repeat facilitated neurogenesis. Our hypothesis is that expanded CAG repeats in the HuntingtonÂs disease gene facilitates neurogenesis by altering transcription of genes critical in neurogenesis. We have developed a model in which mouse embryonic stem cells (ESC) with expanded CAG repeats have facilitated neurogenesis. In this model more ESC with expanded CAG repeats transition to neuronal precursors and then develop into mature neurons more rapidly than control ESC. We propose to compare the gene expression profiles between ESC with expanded CAG repeats and control ESCs on days 4 and 6 of neuronal differentiation. Initial studies indicate that key transcriptional differences are occurring at these time points. Control ECS and a an ESC line with150 CAG repeats will be differentiated in triplicate, and RNA isolated form each replicate. It is anticipated that comparison of gene expression between the control and CAG repeat lines at each time point will identify transcripts involved in CAG repeat facilitated neurogenesis. Observed differences at day 4 may be more relevant to the transition from ESC to neuronal precursor whereas differences at day 6 may be more relevant to the neuronal precursor to neuron transition.

Dataset Information

Patterns of instability of expanded CAG repeats at the ERDA1 locus in general populations.

Publications

Patterns of instability of expanded CAG repeats at the ERDA1 locus in general populations.

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