International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

A18. Epigenetic Properties of the Complex Imprinted Locus Gnas on Distal Chromosome 2

Coombes C.E.1, Williamson C.M.2, Skinner J.A.2, Peters J.2, Feil, R1. and Kelsey G.1
1 The Babraham Institute, Cambridge, UK
2 MRC Mammalian Genetics Unit, Harwell, UK.

The distal region of mouse chromosome (Chr) 2 is subject to genomic imprinting, as mice inheriting two maternal or two paternal copies of the region have ostensibly opposite anomalous phenotypes with behavioural, endocrine and viability components. To identify the genes responsible, we used methylation-sensitive representational difference analysis (Me-RDA) to clone HpaII fragments that are methylated differently on the maternal and paternal copies of distal Chr 2. From this screen, a complex imprinted locus at Gnas has emerged. Gnas, which is biallelically expressed in most tissues, encodes Gs-alpha, the predominant alpha-stimulatory G-protein subunit. In addition, the locus comprises two imprinted transcripts of distinct coding potential: Gnasxl has exclusively paternal expression and encodes an extra large Gs-alpha isoform; Nesp has maternal expression and encodes a secreted neuroendocrine protein. Remarkably, these genes form a single transcription unit, as they are alternatively spliced onto exon 2 of Gnas, with the gene order Nesp-Gnasxl-Gnas. We recently described that the locus also contains Nespas, a complex imprinted transcript with no apparent open reading frame antisense to Nesp. To identify elements that may control imprinting, we are examining the epigenetic properties of the region. Nesp and Gnasxl reside in unusually extensive CpG islands with, respectively, paternal-specific and maternal-specific methylation. DNaseI hypersensitive sites map at the CpG islands and in the region separating Nesp and Gnasxl. The ontogeny of parental-allele-specific epigenetic properties is being examined in androgenetic and parthenogenetic ES cells.

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