Genomic Imprinting

Written 2005-03 J Keith Killian
National Institutes of Health, National Cancer Institute, Laboratory of Pathology, Bldg. 10 Room 2N212, Bethesda, MD 20892, USA
Genomic imprinting: a mark about parental origin
Genomic imprinting is the biological process whereby a gene or genomic domain is biochemically marked with information about its parental origin. Genomic imprints may be covalent (DNA methylation) or non-covalent (DNA-protein and DNA-RNA interactions, genomic localization in nuclear space), and the process of imprinting encompasses the specialized nuclear enzymatic machinery which maintains parental epigenetic markings throughout the cell cycle.

When are parental imprints established?
Parental imprints are established during gametogenesis as homologous DNA passes uniquely through sperm or egg; subsequently during embryogenesis and into adulthood, alleles of imprinted genes are maintained in two "conformational"/epigenetic states: paternal or maternal.
Thus, genomic imprints template their own replication, are heritable, can be identified by molecular analysis, and serve as markers of the parental origin of genomic regions.

Functional consequence: unbalanced gene expression
Beyond merely labeling homologous genetic alleles as descendent from father or mother, genomic imprints have the significant functional consequence of stifling gene expression from one of the parental alleles, resulting in unbalanced gene expression between homologous alleles.
As a result of imprinting, there is biased allelic expression that favors expression from one parental locus over the other. Imprinting is oftentimes equated with parent-of-origin òmonoallelic expression, yet parental allelic exclusion is seldom 100% efficient; one usually finds various degrees of òleaky expression from the silenced allele.

Pathologic phenotype in heterozygous knockout animals
Nevertheless, the relative diminished expression from one parental locus is sufficient to create a pathologic phenotype in heterozygous knockout animals in which the imprint gene null allele is inherited through the dominant/expressing parent. Similarly, in human uniparental disomies that encompass imprinted loci, diminished expression from imprinted loci is often syndromic. In fact, one strategy for identifying imprinted genes is based upon UPD genotype-phenotype correlations.
Thus, the diminished gene expression from the stifled parental allele may be considered biologically insufficient to support a healthy phenotype, and imprinted gene mutations are usually dominant when they affect the expressed allele. Feedback regulation of transcription at imprinted loci does not allow sufficient upregulation of transcription from the silenced allele, and organisms do not have recourse to the silenced otherwise wild-type allele in the event that the expressed allele is null.

Imprinted genes are functionally haploid, erasing benefits of diploidy at these loci.
It is estimated that approximately 1-2% of human genes are subject to parental imprinting, but currently fewer than 100 distinct named genes have been demonstrated to be parentally imprinted.

Clinical diseases
Clinical human diseases and syndromes stemming from the unique vulnerabilities of imprinted loci include: gestational trophoblastic disease, teratomas, Beckwith-Wiedemann syndrome, Prader-Willi syndrome, Angelman syndrome, Silver-Russell syndrome, transient neonatal diabetes, /and social-cognitive defects in Turner syndrome, and multiple neoplasias associated with loss of imprinting at oncogene loci. OMIM (On-line Mendelian (!) Inheritance in Man) database of the NCBI (United States National Center for Biotechnology Information) contains detailed entries on many imprinted genes and syndromes.

Imprinted genes code for what?
Although a majority of the known imprinted genes code for proteins, others code for untranslated RNA transcripts.
Another category of parental genomic imprint, to be contrasted with well characterized examples of monoallelically expressed genes, are those methylation parental imprints scattered throughout the genome which are not demonstrated to be functional or associated with specific genes.

Maybe a more pervasive process
Keeping this final category in mind underscores the idea that ògenomic imprinting may be a more pervasive process than simply a mechanism to monoallelically silence a handful of genes, as in the broad sense parental genomic imprints are not required to be associated with transcriptionally active chromatin.
Moreover, beyond the estimated 500 genes thought to be imprinted, it is unknown how many parental imprints may be stamped throughout the genome, or what their pattern and periodicity may be; perhaps foretelling are imprint gene discovery experiments based on whole genome scanning, which uncover mostly domains not known to be associated with transcriptional units.

Mules, hinnies, and Plato
Elucidating the phenomenon of imprinting has provided much insight into molecular developmental and cancer biology, but also helps explain centuries-old biological observations. Mule breeders 3 millenia ago observed that a mare crossed with a donkey yields a mule, whereas a stallion crossed with a donkey produces a hinny, which has shorter ears, a thicker mane and tail, and stronger legs than the mule; thus indicating parental sex-dependent influence on phenotype. Although ancestral donkey crossers would likely have no problem with the concept and reality of parental genomic imprinting, imprinting more recently carries an iconoclastic aura, evidence of the powerful influence Gregor Mendelès writings have exerted;indeed, the phenomenon of imprinting has been classified within the realm of non-Mendelian genetics, as if Mendels laws represent the Platonic ideal of genetic behavior.Modern evolutionary biologists welcome the finding of parental influence on the genome, for it spawns debate over the hypothetical selective pressures which could be driving and maintaining such a deleterious process.


Killian JK

Atlas of Genetics and Cytogenetics in Oncology and Haematology 2005-03-01

Genomic Imprinting

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