Genetics of Childhood Disorders: XII. Genomic Imprinting: Breaking the Rules

Abstract

Genomic imprinting refersto a process that distinguishes paternally derived chromosomes from maternally derived chromosomes. Imprinting plays a critical role in gene expression, mammalian development, and human disease. However, the biological requirement for imprinting remains a mystery. In the first 2 columns on the topic, we will reviewhow imprinting was initially identified, present some hypotheses about the mechanisms of imprinting, and speculate on the evolutionary forces maintaining this phenomenon. The subsequent 2 columns will discuss the molecular basesfor 2 disorders in which imprinting is involved, namely, Prader-Willi and Angelman syndromes. Genomic imprinting might be considered the exception that proves the rule. Until the late 1980s, Gregor Mendel's laws of inheritance were thought to be inviolate. All autosomal genes were believedto be expressedequally, regardless of whether they were inherited from the mother or the father. For most genes, this is true. However, it is now recognized that a small subset of genesareviolators of Mendel's lawsand are expresseddifferently depending on the parent from whom they are inherited. Genomic imprinting refers to the normal process whereby specificgenes or DNA segments are reversiblymodified during gametogenesis in a parent-specific fashion. Although research on exactlyhow this occurs is not yet understood, one modification that is believed to playa role is the reversible addition of methyl groups to specific cytosine residues within the DNA sequence, a process that occurs differently in generation of the egg and the sperm. Genomic imprinting is called an epigenetic phenomenon, since the gene structure-the actual sequence of nucleotides-is not affected as occurs during the mutations that were discussed in previous columns. Rather, the imprint is erased during gametogenesis and must be reapplied in a gender-specific manner. For example, in the normal situation, a methylated gene inherited by a male from his mother will be unmethylated during spermatogenesis, and this unmethylated gene, when passed on to his daughter, must be remethylated during oogenesis. As a result of this differential methylation, the maternally inherited copy of an imprinted DNA segment differs from the paternally inherited copy. What has recently been discovered is that these differences may also be reflected in differences in gene expression, even though the nucleotide sequences of the 2 segments are identical. The imprinting process leads to an inactivation of either the paternally or maternally inherited