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Abstract
The inheritance pattern of a number of major genetic disorders suggests the possible involvement of genes that are expressed from one allele and silent on the other, but such genes are difficult to detect. Since DNA methylation in regulatory regions is often a mark of gene silencing, we modified existing microarray-based assays to detect both methylated and unmethylated DNA sequences in the same sample, a variation we term the MAUD assay. We probed a 65 Mb region of mouse Chr 7 for gene-associated sequences that show two distinct DNA methylation patterns in the mouse CNS. Selected genes were then tested for allele-specific expression in clonal neural stem cell lines derived from reciprocal F1 (C57BL/6×JF1) hybrid mice. In addition, using a separate approach, we directly analyzed allele-specific expression of a group of genes interspersed within clusters of OlfR genes, since the latter are subject to allelic exclusion. Altogether, of the 500 known genes in the chromosomal region surveyed, five show monoallelic expression, four identified by the MAUD assay (Agc1, p (pink-eyed dilution), P4ha3 and Thrsp), and one by its proximity to OlfR genes (Trim12). Thrsp (thyroid hormone responsive SPOT14 homolog) is expressed in hippocampus, but the human protein homolog, S14, has also been implicated in aggressive breast cancer. Monoallelic expression of the five genes is not coordinated at a chromosome-wide level, but rather regulated at individual loci. Taken together, our results suggest that at least 1% of previously untested genes are subject to allelic exclusion, and demonstrate a dual approach to expedite their identification.
Highlights
A number of genetic disorders are characterized by a,50% discordance rate between identical twins [1]
The results shown for p might suggest the possibility of imprinting, since the maternal allele is expressed in each of the 5 clonal lines assayed; the biallelic pattern seen in F1 (B66JF1) brain RNA for both reciprocal crosses (Figure S3) suggests that this is not the case for most CNS cells
We have detected five genes that are monoallelically expressed in the CNS by analysis of DNA methylation patterns or proximity to OlfR genes, followed by the direct assay of F1 hybrid clonal cell lines
Summary
A number of genetic disorders are characterized by a ,50% discordance rate between identical twins [1]. These include schizophrenia, multiple sclerosis, bipolar disorder and type 1 diabetes. Multiple genes have been implicated in the etiology of these diseases, allelic exclusion (i.e., random monoallelic expression) of any one of the genes could account for the observed pattern of inheritance in each case. An increasing number of genes undergoing allelic exclusion are known. A few allelically excluded genes with other functions have been reported as well [11,12,13]. Epigenetic factors contributing to monoallelic expression include DNA methylation differences at regulatory regions as well as DNA replication asynchrony; these epigenetic changes may occur early in development, providing markers for subsequent allele-specific expression (reviewed in [14] and [15])
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