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Genomic Imprinting and Penetrance – Explanation, Types

Aug 24, 2022
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Genomic Imprinting and Penetrance 

Genomic Imprinting and Penetrance key concepts

introductionIntroduction

In our discussions on Mendelian genetics and the chromosomal basis of heredity, we have assumed that a given allele has the same effect, whether it is inherited from the mother or the father. 

Most of the time, this is generally a safe assumption. Consider an example, when Mendel crossed purple-flowered pea plants with white-flowered pea plants, he found the same results irrespective of whether the purple-flowered parent produced the eggs or the sperm. 

In recent years, geneticists have discovered several features in mammals that are dependent on which parent handed the alleles for those traits down to the offspring. 

Such variation in the phenotype relying on whether an allele is inherited from the male, or the female parent is called genomic imprinting. Unlike sex-linked genes, most imprinted genes are on autosomes. 

About 100 imprinted genes in humans and 125 in mice have been discovered using newer DNA sequence-based approaches. 

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Explanation: 

Genomic imprinting: 

Genomic imprinting takes place during gamete production and leads to the silencing of a particular allele of certain genes.  

Since these genes are imprinted differently in sperm and eggs, the offspring only expresses one allele of an imprinted gene, the one inherited from one of the parents—either the female or male parent, depending on the gene. The imprints are then transmitted to all body cells during development. 

In gamete-producing cells, old imprints are “erased” with each generation, and the chromosomes of developing gametes are imprinted with new imprints based on the sex of the individual making the gametes. The imprinted genes in a given species are always imprinted in the same way. For example, a gene imprinted for maternal allele expression is every time imprinted this way, from generation after generation. 

Fig. 1. Genomic imprinting takes place during gamete production 

Consider the insulin-like growth factor 2 (Igf2) gene in mice, which was one of the first imprinted genes discovered. Although this growth factor is essential for normal prenatal growth, only the paternal allele is expressed.  

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Crosses between normal-sized (wild-type) mice and dwarf (mutant) mice homozygous for a recessive mutation in the Igf2 gene provided the first evidence that the Igf2 gene is imprinted. The phenotypes of heterozygous offspring (those with one normal and one mutant allele) varied based on whether the mutant allele came from the mother or the father. 

(a) Homozygote: a mouse homozygous for the wild-type Igf2 allele is normal-sized. Only the paternal allele for this gene is expressed. 

(b) Heterozygotes: Heterozygotes have different phenotypes based on which allele is contributed by each parent. Crosses between a wild-type mice and those homozygous for the recessive mutant Igf2 allele produce heterozygous offspring. Since the maternal Igf2 is not expressed, the dwarf phenotype is seen only when the father contributes the mutant allele. 

Methylation in genomic imprinting: 

What exactly is a genomic imprint? It turns out that imprinting can include either silencing or activating an allele in one type of gamete (egg or sperm). 

In many cases, the imprint appears to be made up of methyl (—CH3) groups added to one of the alleles’ cytosine nucleotides. The allele may be silenced due to the methylation, which is consistent with evidence that extensively methylated genes are usually inactive. 

However, methylation has been found to activate allele expression in a few genes. The Igf2 genes are an example of this: Methylation of specific cytosines on the paternal chromosome leads to the expression of the paternal Igf2 allele via an indirect mechanism involving chromatin structure and protein-DNA interactions. 

Methylation 

Genomic imprinting may affect only a tiny percentage of the genes in mammalian genomes, but the majority of the known imprinted genes are vital for embryonic development.  

In experiments that involved mice, embryos engineered to inherit both copies of specific chromosomes from the same parent, whether male or female, usually die before birth. 

However, A few years ago, scientists in Japan created a zygote by combining the genetic material from two eggs while allowing expression of the Igf2 gene, along with numerous other imprinted genes, from only one of the egg nuclei. The zygote apparently developed into a healthy mouse.  

Normal development tends to require that the embryonic cells must have precisely one active copy—not zero, not two—of specific genes. Improper imprinting and its association with abnormal development and certain cancers have encouraged ongoing studies of how different genes are imprinted. 

Penetrance: 

Phenotypic ratios can be influenced by dominant relationships between alleles for a specific trait, but interactions between genes can also have an impact on phenotype. 

Such traits that arise from the interactions between multiple genes and their environment are called complex traits. 

So, given a specific trait, how can we recognize whether it is complex? 

Inconsistent inheritance patterns in subsequent generations are one technique to identify a complex characteristic. 

For example, a dominant trait might skip an entire generation and still be expressed in the next generation. How is this possible? 

The answer to this question lies in the concepts of penetrance and expressivity. 

While studying the relationships between genotypes and phenotypes, it is very important to study the statistical appearance of phenotypes in a group of known genotypes. For example, given a group of known genotypes for one trait, how many similar genotypes show the related phenotype? 

However, A surprising fact is that the phenotype does not occur as often as the genotype for some traits. 

To explain, let us consider that everyone in a given population carries the same W allele combinations for a specific trait, yet it occurs that only 85% of the population actually expresses the phenotype. The proportion of genotypes that actually shows the phenotypes is called penetrance. 

Thus, we can say that in the above example, the penetrance is 85%. This value is calculated by analyzing a population whose genotypes are known to us. 

Complete penetrance: 

Complete penetrance occurs when all individuals in a group who carry a certain genotype exhibit the same phenotype. But some of the genes do not show complete penetrance.  

For precise measurements of penetrance, it is essential to record genotypes and phenotypes in a large population. It is vital to remember that penetrance simply describes whether or not individuals express a trait or not. 

It is not used for describing individual variations in the degree of expression of a specific gene, which is known as expressivity. 

Incomplete penetrance: 

Incomplete penetrance occurs when less than 100% of people with a given genotype express the corresponding phenotype. 

Polydactyly (extra fingers and/or toes) in humans is an example of incomplete penetrance. Polydactyly is produced by a dominant allele in humans, though not all people with the trait have the extra digits. 

The penetrance of expression in different age groups of a population might also vary. Reduced penetrance is most likely caused by a combination of genetic, environmental, and lifestyle variables, many of which are unknown. 

Fig 5. Complete and Incomplete penetrance 

Fig 5. Complete and Incomplete penetrance 

Significance: Penetrance can make it difficult for geneticists to understand a person’s medical history and anticipate the risk of passing a genetic disorder to future generations. 

Summary

  • Genomic imprinting takes place during gamete production and leads to the silencing of a particular allele of certain genes.
  • Since these genes are imprinted differently in sperm and eggs, the offspring only expresses one allele of an imprinted gene, the one inherited from one of the parentseither the female or male parent, depending on the gene.
  • In gamete-producing cells, old imprints are “erased” with each generation, and the chromosomes of developing gametes are imprinted with new imprints based on the sex of the individual making the gametes.
  • In many cases, the imprint appears to be made up of methyl groups added to one of the alleles’ cytosine nucleotides. The allele may be silenced due to the methylation, which is consistent with evidence that extensively methylated genes are usually inactive.
  • However, methylation has been found to activate allele expression in a few genes.
  • Genomic imprinting may affect only a tiny percentage (less than 1% of the genes in mammalian genomes, but the majority of the known imprinted genes are vital for embryonic development.
  • Penetrance refers to the percentage of people in a population who have a particular gene and express the associated trait.
  • Complete penetrance occurs when all individuals in a group who carry a certain genotypeexhibit the same phenotype. However, some genes do not show complete penetrance.
  • Incomplete penetrance occurs when less than 100% of people with a given genotype express the corresponding phenotype.

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