Diseases associated with genomic imprinting

Abstract

Genomic imprinting is the phenomenon where the expression of a locus differs between the maternally and paternally inherited alleles. Typically, this manifests as transcriptional silencing of one of the alleles, although many genes are imprinted in a tissue- or isoform-specific manner. Diseases associated with imprinted genes include various cancers, disorders of growth and metabolism, and disorders in neurodevelopment, cognition, and behavior, including certain major psychiatric disorders. In many cases, the disease phenotypes associated with dysfunction at particular imprinted loci can be understood in terms of the evolutionary processes responsible for the origin of imprinting. Imprinted gene expression represents the outcome of an intragenomic evolutionary conflict, where natural selection favors different expression strategies for maternally and paternally inherited alleles. This conflict is reasonably well understood in the context of the early growth effects of imprinted genes, where paternally inherited alleles are selected to place a greater demand on maternal resources than are maternally inherited alleles. Less well understood are the origins of imprinted gene expression in the brain, and their effects on cognition and behavior. This chapter reviews the genetic diseases that are associated with imprinted genes, framed in terms of the evolutionary pressures acting on gene expression at those loci. We begin by reviewing the phenomenon and evolutionary origins of genomic imprinting. We then discuss diseases that are associated with genetic or epigenetic defects at particular imprinted loci, many of which are associated with abnormalities in growth and/or feeding behaviors that can be understood in terms of the asymmetric pressures of natural selection on maternally and paternally inherited alleles. We next described the evidence for imprinted gene effects on adult cognition and behavior, and the possible role of imprinted genes in the etiology of certain major psychiatric disorders. Finally, we conclude with a discussion of how imprinting, and the evolutionary-genetic conflicts that underlie it, may enhance both the frequency and morbidity of certain types of diseases.