Genomic imprinting and parental allelic bias

Introduction

Genomic imprinting is a fascinating epigenetic phenomenon that results in the preferential expression of specific alleles depending on their parental origin. Unlike traditional Mendelian genetics, where both maternal and paternal alleles contribute equally to the phenotype of offspring, genomic imprinting leads to parental allelic bias, where genes inherited from one parent are preferentially expressed over those from the other parent. This unique mode of gene regulation has profound implications for development, physiology, and evolution, and its dysregulation is associated with a variety of human diseases. In this narrative, we explore the principles of genomic imprinting, its mechanisms, consequences, and significance in biology and medicine.

The concept of genomic imprinting was first proposed in the 1950’s based on observations of unusual inheritance patterns in certain genetic disorders, such as Prader-Willi syndrome and Angelman syndrome. These syndromes are caused by deletions or mutations in specific regions of chromosome 15, but the phenotypic manifestations depend on whether the affected chromosome is of maternal or paternal origin. This led to the hypothesis that certain genes are "imprinted" with epigenetic marks during gametogenesis, resulting in parent-specific silencing or activation of gene expression in offspring.

Description

Genomic imprinting is mediated by epigenetic modifications, such as DNA methylation and histone modifications, which regulate gene expression without altering the underlying DNA sequence. During gametogenesis, differential methylation patterns are established at imprinted loci, marking specific alleles as either methylated (silent) or unmethylated (active) depending on their parental origin. These epigenetic marks are maintained through mitotic divisions during embryonic development and are responsible for maintaining the parental-specific expression patterns of imprinted genes in somatic cells.

The mechanisms underlying genomic imprinting involve the interplay between imprinted genes and regulatory elements, such as Imprinting Control Regions (ICRs) and Differentially Methylated Regions (DMRs), which act as epigenetic switches that dictate the parent-of-origin-specific expression of nearby genes. ICRs typically contain binding sites for DNA-binding proteins, such as zinc finger proteins and insulator proteins, which recruit chromatin-modifying enzymes to establish and maintain allele-specific epigenetic marks. DMRs, on the other hand, are regions of differential DNA methylation that regulate the activity of nearby promoters or enhancers, thereby controlling the expression of imprinted genes.

The consequences of genomic imprinting are profound and multifaceted, affecting various aspects of development, physiology, and behavior. Imprinted genes play critical roles in embryonic growth and development, placental function, and postnatal growth regulation, as evidenced by the phenotypes of imprinted gene knockout mice, which exhibit growth defects, developmental abnormalities, and metabolic disturbances. Moreover, imprinted genes are involved in regulating key physiological processes such as nutrient transport, energy metabolism, and neurodevelopment, and their dysregulation is implicated in a variety of human diseases, including cancer, diabetes, and neurological disorders.

In cancer, aberrant imprinting of tumor suppressor genes and oncogenes can contribute to tumorigenesis and tumor progression by disrupting normal growth control mechanisms and promoting cell proliferation, survival, and metastasis. For example, Loss of Imprinting (LOI) at the Insulin-Like Growth Factor 2 (IGF2) locus, resulting in biallelic expression of IGF2, is associated with increased risk of various cancers, including colorectal cancer, hepatocellular carcinoma, and Wilms tumor. Similarly, aberrant imprinting of the H19 and IGF2 genes, located in the imprinted gene cluster on chromosome 11p15.5, is implicated in the pathogenesis of Beckwith-Wiedemann Syndrome (BWS), a congenital overgrowth disorder associated with increased risk of embryonal tumors such as Wilms tumor and hepatoblastoma.

In addition to their roles in development and disease, imprinted genes are also involved in regulating social and behavioral traits, such as maternal nurturing behavior, social bonding, and aggression, through their effects on brain development and function. For example, the imprinted gene UBE3A, which is maternally expressed in neurons, plays a critical role in synaptic plasticity and learning and memory, and its dysregulation is implicated in Angelman syndrome, a neurodevelopmental disorder characterized by intellectual disability and behavioral abnormalities. Similarly, the imprinted gene OXTR, which encodes the oxytocin receptor, is involved in social bonding and maternal behavior, and its dysregulation is associated with Autism Spectrum Disorders (ASD) and schizophrenia.

Conclusion

Genomic imprinting is a fascinating epigenetic phenomenon that results in parental allelic bias and plays critical roles in development, physiology, and behavior. Imprinted genes are regulated by epigenetic mechanisms, such as DNA methylation and histone modifications, which establish and maintain parent-of-origin-specific expression patterns in offspring. Dysregulation of genomic imprinting is associated with a variety of human diseases, including cancer, diabetes, and neurodevelopmental disorders, highlighting the importance of understanding the mechanisms and consequences of imprinting for biology and medicine. As our knowledge of genomic imprinting continues to expand, so too will our understanding of its role in health and disease, paving the way for novel diagnostic and therapeutic strategies to treat imprinted gene-associated disorders.