Genomic Imprinting
Genomic imprinting is an epigenetic chromosomal modification that describes the preferential expression of a specific parental allele. Genomic imprinting is a complex genetic phenomenon, that is difficult to define, and as of June, 2001, no adequate explanation has been found for why genomic imprinting exists.
Genomic imprinting is normal genetic process where only one allele of a gene is expressed while the other allele remains genetically silent. Which allele is expressed and which remains silent depends on from which parent the genes are inherited.
Genomic imprinting would appear to contradict Mendel's observation that both parents make an equal genetic contribution to the offspring. While this is true for the inheritance of most genes, there exists a small subset of approximately 50 genes, where only one parent contributes a functioning gene to the offspring.
Following fertilization of a mammalian embryo most of the genes contributed by each parent begin to function equally. When a gene is expressed, the copy inherited from the mother (maternal allele), and the copy inherited from the father (paternal allele), are transcribed equally (bialleleic expression) and the RNA is translated into the protein product.
However, imprinted genes are an exception. For some unknown reason these genes are marked so only one allele is transcribed while the other is silent (i.e., imprinted). For example, in humans the insulin-like growth factor 2 gene (IGF2, chromosome 11p15.5), which is an important fetal growth factor, is only expressed from the paternally inherited allele while the maternal allele is imprinted and never normally expressed. Similarly, the H19 gene, which is located adjacent to IGF2 at 11p15.5, is normally only expressed from the maternally inherited allele, while the paternal allele is silent.
The genetic mechanism of genomic remains uncertain but it is clear that some form of reversible genetic modification (epigenetic modification) such as DNA methylation is involved. The gonads of each sex are able to mark or erase the genomic imprint of specific imprinted genes, which were inherited from their own parents, by either adding or removing DNA methylation from the imprinted gene. For example, in a normal and female there are two H19 gene alleles, one inherited from the father, and one inherited from the mother. The paternal H19 allele is methylated and cannot be expressed but the maternal allele is not methylated and is active. When the male forms gametes in his testes the unmethylated, maternally inherited allele is methylated, so all H19 alleles produced in the male gametes are methylated and genetically silent. When the female forms gametes in the ovary, the paternal methylation mark is erased, so in all her gametes the H19 genes are unmethylated. At fertilisation in the zygote the parental methylation marks are retained so in the developing embryo only the maternally inherited allele is active.
Genomic imprinting is a normal process and has no affect on the normal individual. However, imprinted genes are important in the development of some genetic disorders and in cancer.
The Prader-Willi syndrome is a sporadic genetic disorder associated with either small deletions of chromosome 15 at 15q11-13 or uniparental disomy of 15q12-13. These children are born with hypotonia (floppy muscles) and have poor feeding. They later have developmental delay, short stature, obesity, or other eating disorders. Genetic analysis of the chromosome deletions show they always involve the paternal chromosome, while uniparental disomy always involves the maternally inherited chromosome. The chromosome 15q11-13 region is an imprinted domain containing several imprinted genes. One of these imprinted genes, SNRPN, is only expressed from the paternally inherited chromosome. Since the maternal SNRPN allele has been silenced by imprinting, deletion of the paternal allele leads to complete loss of SNRPN expression. Maternal uniparental disomy of 15q11-13 also causes Prader-Willi syndrome because affected individual have two maternally imprinted alleles and no paternal gene expression.
Imprinted genes are also involved in the development of some cancers. The imprinted fetal growth factor gene, IGF2, is commonly expressed in cancers such as Wilms tumor of the kidney, and cancers of the breast, lung, liver, and colon. In these cancers the maternal IGF2 imprint has been lost and both gene alleles are expressed (biallelic expression), this is termed "relaxation of imprinting".
There are many theories for why genomic imprinting exists. One of the most favored (in accord with the most current data), proposed David Haig, (the Haig Hypothesis) suggests that imprinting is a form of genetic reproductive conflict between the sexes each vying for a different reproductive outcome. Males desire large offspring males so over express growth factors such as the paternally expressed fetal growth factor IGF2. However, females needing to limit fetal growth to ensure their successful birth have repressed growth factor expression by imprinting the gene.
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