Person:

Gimelbrant, Alexander

Background: Random monoallelic expression defines an unusual class of genes displaying random choice for expression between the maternal and paternal alleles. Once established, the allele-specific expression pattern is stably maintained and mitotically inherited. Examples of random monoallelic genes include those found on the X-chromosome and a subset of autosomal genes, which have been most extensively studied in humans. Here, we report a genome-wide analysis of random monoallelic expression in the mouse. We used high density mouse genome polymorphism mapping arrays to assess allele-specific expression in clonal cell lines derived from heterozygous mouse strains. Results: Over 1,300 autosomal genes were assessed for allele-specific expression, and greater than 10% of them showed random monoallelic expression. When comparing mouse and human, the number of autosomal orthologs demonstrating random monoallelic expression in both organisms was greater than would be expected by chance. Random monoallelic expression on the mouse autosomes is broadly similar to that in human cells: it is widespread throughout the genome, lacks chromosome-wide coordination, and varies between cell types. However, for some mouse genes, there appears to be skewing, in some ways resembling skewed X-inactivation, wherein one allele is more frequently active. Conclusions: These data suggest that autosomal random monoallelic expression was present at least as far back as the last common ancestor of rodents and primates. Random monoallelic expression can lead to phenotypic variation beyond the phenotypic variation dictated by genotypic variation. Thus, it is important to take into account random monoallelic expression when examining genotype-phenotype correlation.

We hypothesize that the phenomenon of allele-specific methylation (ASM) may underlie the phenotypic effects of multiple variants identified by Genome-Wide Association studies (GWAS). We evaluate ASM in a human population and document its genome-wide patterns in an initial screen at up to 380,678 sites within the genome, or up to 5% of the total genomic CpGs. We show that while substantial inter-individual variation exists, 5% of assessed sites show evidence of ASM in at least six samples; the majority of these events (81%) are under genetic influence. Many of these cis-regulated ASM variants are also eQTLs in peripheral blood mononuclear cells and monocytes and/or in high linkage-disequilibrium with variants linked to complex disease. Finally, focusing on autoimmune phenotypes, we extend this initial screen to confirm the association of cis-regulated ASM with multiple complex disease-associated variants in an independent population using next-generation bisulfite sequencing. These four variants are implicated in complex phenotypes such as ulcerative colitis and AIDS progression disease (rs10491434), Celiac disease (rs2762051), Crohn's disease, IgA nephropathy and early-onset inflammatory bowel disease (rs713875) and height (rs6569648). Our results suggest cis-regulated ASM may provide a mechanistic link between the non-coding genetic changes and phenotypic variation observed in these diseases and further suggests a route to integrating DNA methylation status with GWAS results.