Genomic imprinting as a cause of disease

Genomic imprinting, defined as gene expression dependent on the parent of origin,¹ has been increasingly recognised over the past decade as a mechanism contributing to human disease. The topic now features as a core part of any genetics curriculum, appears in postgraduate medical examinations, and is a term familiar to many clinicians. Recently abnormalities of genomic imprinting have been discussed in the context of assisted reproductive technologies. So what exactly is genomic imprinting, and how does it occur?

For many years a gene was assumed to have the same function, whether it was inherited from the mother or the father. We now know this is not the case, as the DNA of some genes is modified during gametogenesis and as a result may have altered expression, becoming either inactivated or activated. Genes that are susceptible to parent specific modification in this way (termed epigenetic, because the modification does not entail mutation of the DNA code) are referred to as imprinted genes.² The mechanism of imprinting is still not entirely clear but in most cases entails the process of methylation, with imprinted genes showing differences in methylation between the maternal and paternal alleles. Methylation alters chromatin structure, rendering it less open and thereby preventing transcription of genes in that region. Imprinted genes tend to occur in clusters, often in association with imprinting control elements, DNA sequences that regulate imprinting throughout the whole region. The parental imprint is erased and reset between each generation during gametogenesis.

Some genes show tissue specific imprinting, being expressed from both parental genomes in some tissues and exclusively from one parent in others. Choosing the correct tissues for study is therefore of paramount importance. Disorders of imprinting may come about because of deletions or point mutations in imprinted genes themselves, if an individual inherits two copies of one gene from one parent and none from the other (uniparental disomy), if the imprinting centre is not functioning normally, or if a chance (stochastic) error prevents normal setting of the imprint. Some imprinted disorders may be familial, and genetic counselling for these conditions is not for the faint hearted.³

Which disorders are due to altered imprinting? Perhaps the best known examples are the two conditions which arise due to abnormalities of the chromosome 15q11-13 region. Altered paternal expression of genes within this region gives rise to Prader-Willi syndrome, a condition causing neonatal hypotonia with subsequent hyperphagia and obesity. Altered maternal expression of the UBE3A (ubiquitin protein ligase E3A) gene, which lies in the same region, causes Angelman's syndrome, a neurodevelopmental disorder associated with characteristic movements and a sociable disposition. Every school for children with learning difficulties is likely to have a pupil with one or other of these conditions, showing that imprinted disorders are not always very rare. Other imprinted disorders include Beckwith-Wiedemann syndrome, an overgrowth syndrome caused by altered expression of genes within the 11p15 region⁴ and transient neonatal diabetes mellitus.⁵ Strategies that have been devised to screen the genome for imprinted genes have enabled the identification of over 60 genes so far, and the Harwell imprinting website provides up to date statistics (www.mgu.har.mrc.ac.uk/imprinting/imprinting.html).

Assisted reproductive technologies

Evidence from human embryo studies shows that reprogramming of the parental imprint occurs during early embryonic development. Reports of an increased incidence of imprinted disorders, most notably Beckwith-Wiedemann syndrome and Angelman's syndrome, among children conceived by in vitro fertilisation or intracytoplasmic sperm injection, have caused concern about both assisted reproductive technologies and cloning.⁶,⁷ The observation of an increased number of children with Beckwith-Wiedemann syndrome after assisted reproductive technologies is particularly notable because it was already established that sheep and cattle embryos exposed in vitro to various environmental changes soon after fertilisation may develop “large offspring syndrome,”⁸ a phenotype that mimics Beckwith-Wiedemann syndrome. The question therefore arises whether specific elements of assisted reproductive technologies—such as the stimulation protocol, culture media, and timing of embryo transfer—are critical in determining whether genes will be imprinted normally. Wider concerns have been raised about environmental effects on genomic imprinting with a growing interest, for example, in the role of genomic imprinting and tumour development. In Wilms' tumour there is loss of imprinting of the insulin-like growth factor 2 gene, a growth enhancer, and the same observation has been made in lung cancer and colorectal cancer.⁹ The implication is that in some tumours environmental factors may cause epigenetic modification of DNA and alter imprinted gene expression, potentially leading to cancer.

Why does imprinting occur? The ability to imprint genes has been conserved through evolution and must therefore serve an important purpose. One argument is that if a female conceives offspring by more than one male then it is in the father's interest to inactivate genes that normally slow down embryonic growth. His offspring will then grow at a greater rate and are better able to compete with offspring of other males. The mother is compromised by the excessive fetal growth and evolves a mechanism of silencing growth promoting genes.¹⁰ Although not proved, this argument would explain the phenomenon generally observed, whereby genes enhancing growth are usually paternally expressed and maternally inactivated and vice versa.

Wilkins and Haig, in a review on this subject, also propose that imprinting exists because it enhances the ability of an organism to evolve and enables adaptation in a changing environment.¹¹ It is fair to say, however, that no truly satisfactory explanation for genomic imprinting has been elucidated. There is a great deal more to learn about this subject, and the implications of imprinting are likely to be relevant to an increasing number of clinicians. Perhaps more importantly, the fact that imprinting occurs because of an epigenetic modification of DNA raises the possibility of treatments or effective preventive measures for some imprinted disorders.