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Human Imprintome Genomic Map

19 July 2022: Genomic imprinting is a unique epigenetic form of gene regulation that evolved in marsupials and placental mammals about 150 million years ago (Imprinting Evolution in Mammals). It results in only one copy of a gene being expressed in a parent-of-origin dependent manner. Thus, imprinted genes are disease susceptibility loci since a single genetic or epigenetic event can alter their function.

Imprinted genes are heavily involved in metabolism and growth regulation. An epigenetic tug-of-war between the mother's and father's imprinted genes during development has been postulated to explain the evolution of imprinting (Moore and Haig, 1991), and variations in the fetal origins of metabolic disorders such as obesity and type 2 diabetes, as well as cancer, and a spectrum of mental disorders ranging from autism to schizophrenia (Badcock and Crespi, 2008).

Using whole genome bisulfite sequencing, our investigation identified 1,488 hemimethylated DNA candidate imprint control regions (ICRs) in the human genome that potentially regulate parental-specific expression of imprinted genes, The Human Imprintome (Jima et al., 2022). Furthermore, gamete methylation approached 0% or 100% in 332 ICRs (178 paternally and 154 maternally methylated), supporting parent-of-origin-specific methylation (Imprintome Website).

Many of the novel ICRs identified are in regions previously implicated in the pathogenesis of human diseases. For example, candidate differentially methylated ICRs are located within the Down syndrome (DS) critical region at chromosome 21q22, and within the DiGeorge syndrome critical region at chromosome location 22q11.2. A total of 98 candidate ICRs are also identified on the human X-chromosome. DHRSX resides in pseudoautosomal region 1, but interestingly, most ICRs on the X chromosome are not in pseudoautosomal regions.

The imprintome consists of the hemimethylated genomic regions that control monoallelic expression of imprinted genes; it is NOT the repertoire of these genes. A novel tool for scientists, the human imprintome, will help elucidate the role of imprinted genes in the development of diseases and disorders and in the evolution of mammals. Furthermore, since ICRs are established before tissue differentiation, cell samples used in environmental epigenomic studies can be those readily available to epidemiologists (e.g., white blood cells and buccal epithelial cells).