Imprinting

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Imprinting Summary

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Imprinting

Imprinting refers to the chemical modification of the DNA in some genes that affects how or whether those genes are expressed. One particular kind of DNA imprinting found in mammals is known as parental genomic imprinting, in which the sex of the parent from whom a gene is inherited determines how the gene is modified. While imprinting has been found in only about fifty human genes to date, some estimates suggest it may occur in several hundred more, in perhaps up to 1 percent of all genes. Imprinting defects are responsible for several human diseases, including some forms of cancer. Imprinting also occurs in other organisms, from yeast to plants to fruit flies.

Gene Expression in Imprinted and Nonimprinted Genes

Chromosomes, and the genes they contain, are inherited in pairs, with one copy of each supplied from each parent. For most genes, both members of the pair, called the maternal and paternal alleles, are used equally. Both are expressed (read by the transcription machinery to make protein) in roughly equal amounts.

In contrast, for most imprinted genes, only one allele is expressed, while the other copy is silenced by imprinting. For some genes it is the maternal copy, for others it is the paternal copy. This is an exception to the Mendelian assumption that the two parents contribute equally to the phenotype controlled by autosomal genes. For some genes, both alleles are expressed, but one copy is expressed much more than the other. For some genes, the silencing occurs in some tissues but not others.

Imprinted genes should not be confused with sex-linked genes, which are carried on the X or Y chromosome. Most imprinted alleles are located on autosomes, but are "stamped" with the sex of the parent that contributed them.

Imprinting should also not be confused with dominant and recessive alleles, in which one allele always controls the phenotype at the expense ofthe other, because of differences in the alleles themselves. The "dominance" seen in imprinting is determined by the sex of the parent contributing the allele, not any property of the allele itself. Thus, a particular allele will appear to be recessive when inherited from one parent, but dominant when inherited from the other. Such an effect, in which the expression difference is not due to the alleles but to forces acting on them from outside, is termed an "epigenetic effect."

Imprinting silences a gene based on the sex of the parent it came from. The imprint is reset in each new generation.

Imprinting is thought to be responsible for many cases of incomplete penetrance, an inheritance pattern in which a dominant gene (as for a genetic disease) is not expressed in some individuals despite being present. Imprinting offers a mechanism by which a particular allele can be turned on or turned off as it is passed down through successive generations.

Timing and Mechanism of Imprinting

Although the details of imprinting are still unknown, it is clear that imprinting must occur either during the formation of the gametes or immediately after fertilization, while the two chromosome sets are still distinct. The imprint must be reliably passed on to each new daughter chromosome during DNA replication.

The exact molecular mechanism of imprinting is also unknown, but it is thought to involve the modification of a gene's promoter. The promoter is the upstream region to which RNA polymerase binds to begin transcription. Imprinting prevents or restricts binding of RNA polymerase, thus preventing gene transcription.

One method by which a gene becomes imprinted is believed to be by the addition of methyl groups (-CH₃) to cytosine nucleotides in the promoter region. The evidence for methylation is strong. Methylation is a common mechanism for gene silencing, because these bulky side groups interfere with the efficient binding of the various transcription factors required to attract the polymerase enzyme. Methylation patterns are known to be altered during gamete formation, and are reliably passed on during replication. Further evidence comes from the observation that altered methylation patterns in some imprinted genes are associated with the aberrant expression of the normally silent allele.

Methylation of the promoter region is believed to be an important silencing region.

Example of Imprinting: the Igf2 Gene

One of the best-studied imprinted genes is the one that encodes an insulin-like growth factor called growth factor 2 (IGF2). In this gene, the paternal copy is active, whereas the maternal copy is inactive. Imagine that two parents have produced a female child. During egg formation in the mother (or shortly after fertilization), the mother's copy of the IGF2 gene is methylated, rendering it transcriptionally silent. The child uses only the paternal allele to make the growth factor. However, when this child makes her own eggs, neither copy of the gene will remain active, because the alleles will have been "restamped" as coming from a female. The active allele she used throughout life is passed on in an inactive form to her children.

The protein encoded by the IGF2 gene is a growth factor, which stimulates the growth of target cells. Failure to properly imprint the maternal allele, or inheritance of two copies of the male allele, can have important consequences. For example, the expression of two copies of the IGF2 gene is associated with Beckwith-Wiedemann syndrome, a growth disorder, accompanied by an increase in a type of cancer called Wilms tumor. Other human cancers are also associated with improper imprinting (of other genes), causing either too much or too little gene expression.

Uniparental Disomy and Human Disease

Inheritance of two copies of one parent's chromosome (or part of it) is called uniparental disomy, a type of chromosome aberration. Detection of uni-parental disomy in individuals with genetic disorders was one of the first clues that imprinting had important developmental and medical consequences.

Prader-Willi syndrome and Angelman syndrome can both be caused by uniparental disomy of chromosome 15, which carries a maternally expressed, paternally imprinted gene. Two maternal copies of the gene causes Prader-Willi syndrome, which is marked by mild mental retardation, decreased growth of the gonads, and obesity. Two paternal copies of this same gene causes Angelman syndrome, marked by severe mental retardation, small head size, seizures, inappropriate laughter, and distinctive facial features. (The gene itself codes for a protein involved in degrading other proteins.) Imprinting defects can also cause these syndromes in the absence of uniparental disomy, since the result is the same: either zero or two copies of the gene are expressed.

Why Imprint?

The evolutionary reason for imprinting is not yet clear, although some scientists propose that, at least in mammals, it arose from an evolutionary tugof war between males and females. In this scheme, fathers (who contribute only sperm) benefit when the embryo grows as fast as possible. Thus, silencing genes that slow down embryonic growth is in their interest, even if it depletes resources from the mother. Mothers, on the other hand, need to conserve their resources. Silencing genes that promote rapid growth is therefore in their interest. Supporting this hypothesis is the fact that many of the known imprinted genes regulate growth. Paternally expressed (maternally imprinted) genes such as IGF2 tend to promote growth, whereas maternally expressed (paternally imprinted) genes tend to inhibit it.