Genomic Imprinting

Mendelian genetics holds that everyone inherits two copies of their genes: one from their mother and one from their father. A gene is usually "active" on both copies, so no matter whether it is inherited from the mother or the father, an allele will have the same effect on the offspring's phenotype.

However, sometimes only one of these two copies is active (or functional), and the other is silenced. When this happens, we call it genomic imprinting!

Genomic imprinting definition

For starters, let's look at the definition of genomic imprinting. Genomic imprinting is a type of non-mendelian inheritance, as it does not follow Mendel's inheritance rules.

Genomic imprinting has been seen mostly in mammals such as humans and mice, and these imprinted genes tend to be found on autosomes (non-sex-linked genes). There are two types of imprinted genes:

• Maternally imprinted genes are genes that are silenced ("turned off") when inherited from the mother. So, only the allele from the father is expressed in the offspring.
• Paternally imprinted genes are genes that are silenced when inherited from the father. So, only the allele from the mother is expressed in the offspring.

Figure 1 shows a simple way of viewing maternal imprinting.

Figure 1. A simple vizualization of maternal Imprinting, StudySmarter Originals.

Figure 2 shows an example of maternal and paternal imprinting. Notice that the concept of dominance is meaningless for imprinted genes because imprinted loci are functionally hemizygous (they behave as if they only have one allele since the other one is inactive).

Genomic imprinting diagram

Genomic imprinting occurs in the ovum or sperm of the parents. Recall that normally, an oocyte (egg) containing the mother's component of the genome gets fertilized by a sperm containing the father's component of the genome. This creates a fertilized oocyte containing half of the mother's DNA and half of the father's DNA. But, if the phenomenon of genomic imprinting is present, then only one copy of the gene will be active (either the mother's or the father's copy) while the other copy will be silenced!

A common example of genomic imprinting is seen in a locus containing a pair of genes: igf2 and H19. Igf2 is a gene encoding for insulin-like growth factor 2, while H19 encodes for an untranslated mRNA of unknown function (Figure 3). Both the paternal and maternal chromosome contains these two genes, and they are separated by an insulator protein called CTCF. The enhancer region controls the expression of both genes by binding to an activator and recruiting transcription machinery to both genes.

In the maternal chromosome, notice that the Igf2 gene has been turned off. So, the insulator protects it from being transcribed. In this case, the activator will only activate the transcription of the H19 gene.

The opposite is true in the paternal chromosome. Here, notice that a segment of the chromosome where the insulator and the promoter of the H19 gene are found has been methylated (you will learn about DNA methylation in a bit!). This prevents the activator from activating the transcription of the H19 gene, so it will only activate igf2 transcription.

To keep things short, we can say that in the maternal chromosome, H19 is active, and igf2 is inactive (maternal imprinting). On the other hand, igf2 is active, and H19 is inactive on the paternal chromosome (paternal imprinting).

When researchers studied mice (Figure 4) to find out the outcomes of silencing the igf2 gene, they found that if the mutant igf2 allele was inherited from the mother, then the mice would have normal size as the mutant allele would be silenced and not expressed.

However, if the mutant igf2 allele was inherited from the father, then the mice would have a smaller size, as the mutant allele would be expressed, and the normal allele from the mother would be silenced. So, we can say that igf2 in mice is an example of maternal imprinting (i.e., the mother's allele is silenced) because the size trait (dwarf) is dependent on the expression of the paternal allele.

Process of genomic imprinting

The most common process that can lead to genomic imprinting is DNA methylation.

Let's explore the process of genomic imprinting by DNA methylation. Basically, a gene will turn off when a methyl group (-CH₃) gets attached to the DNA.

When the germline develops a gene that has evolved to be paternally imprinted, this gene will have a sequence tag that will let transcription factors know that that gene needs to be methylated ("turned off" by adding a methyl group to it) before gamete formation. Similarly, if a gene has evolved to be maternally imprinted, its sequence tag will be recognized by transcription factors, and it will become methylated (silenced) before making gametes.

Figure 5 shows a model for the inheritance of DNA methylation. In mammals, the methyl group gets added to the cytosine in a CG dinucleotide.

Genomic imprinting diseases

Normally, genetic imprinting is not harmful. However, sometimes disorders might arise if mutations or defects happen within the imprinting controlling regions of genes.

A common example of a genomic imprinting disease is Prader-Willi Syndrome (Figure 6). It can either be caused by the deletion of a certain region on chromosome 15 inherited from the father or by the inheritance of both copies of chromosome 15 from the mother that has been methylated (silenced). Some symptoms of Prader-Willi Syndrome include weak muscle tone, developmental delay, behavioral problems, and overeating (early childhood obesity).

Now, if the deletion of that same region on chromosome 15 is inherited by the mother, or both copies of the chromosome come from the father, then the offspring will develop Angelman Syndrome. As a result of this syndrome, individuals suffer from severe intellectual impairment, seizures, impaired speech, and inappropriate laughter.

Some cancers are also associated with errors/mutations in DNA methylation. For example, the silencing of tumor suppressor genes or the loss of imprinting (allowing the activation of genes that are normally suppressed) can lead to the development of cancer cells.

Genomic imprinting example

Lastly, let's take a look at an example involving genomic imprinting in plants. In mammals, imprinting can occur in embryos and in different adult tissues, while in plants, imprinting can only happen in the endosperm tissue.

While studying the Arabidopsis endosperm through classical experimental approaches, researchers found 11 imprinted genes: 8 maternally expressed and 3 paternally expressed. Then, using modern techniques such as RT-PCR, they were able to find another 112 maternally expressed genes and 9 paternally expressed genes.

These imprinted genes contained different functions in plants, such as involvement in regulating DNA methylation, hormone signaling components, and small RNA pathways!

Hopefully, you are now clear on what genomic imprinting is!