| Description |
Most genes in a diploid organism are thought to be expressed and regulated equally by the two parental alleles. However, a subset of genes referred to as monoallelically-expressed genes are expressed preferentially only on the maternal or paternal allele. Monoallelically-expressed genes include imprinted genes, which express either the maternal or paternal allele p referentially, as well as random monoallelic genes that choose to express one allele at random. Examples of in vivo random monoallelic genes include X-linked genes in females, immunoglobulins in B cells, clustered protocadherins, and olfactory receptors. However, these examples generally are thought to be rare in the mammalian genome and confined to a few genes that have a uniquely clustered organization in the genome. In this dissertation, new genome-wide analysis methods were developed to reveal the lands cape of epigenetic allelic effects in the mous e. Chapter 2 details the discovery of novel, noncanonical genomic imprinting effects that are enriched uniquely in the brain. Chapter 3 details the development of new genomics and statistical methods to identif y genes that express their alleles differentially in vivo through nongenetic mechanisms. This novel screening strategy was applied to reveal the landscape of epigenetic allelic effects in the mouse brain at different ages and to p rofile different tissue types. The dissertation describes the discovery of diverse forms of nongenetic differential allelic expression in mouse, macaque, and human brains, and demonstrates that these effects interact with heterozygous mutations and shape genetic architecture at the allelic and cellular level in vivo. The results challenge current thinking in the fields of genetics and epigenetic by revealing a new landscape of epigenetic allelic effects in vivo, and describe new mechanisms that may shape phenotypic variation and susceptibility to disease. Although the functions of these allelic effects are unknown, and the regulatory mechanisms involved have yet to be defined, the future of the field is discussed. |
