Genomic imprinting

Genomic imprinting is a genetic phenomenon by which certain genes are expressed in a parent-of-origin-specific manner. Imprinted genes are either expressed only from the allele inherited from the mother (eg. CDKN1C), or in other instances from the allele inherited from the father (eg. IGF2). Forms of genomic imprinting have been demonstrated in insects, mammals and flowering plants.

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Overview

In diploid organisms somatic cells possess two copies of the genome. Each autosomal gene is therefore represented by two copies, or alleles, with one copy inherited from each parent at fertilisation. For the vast majority of autosomal genes, expression occurs from both alleles simultaneously. In mammals however, a small proportion (<1%) of genes are imprinted, meaning that gene expression occurs from only one allele. The expressed allele is dependent upon its parental origin. For example, the gene encoding Insulin-like growth factor 2 (IGF2/Igf2) is only expressed from the allele inherited from the father (DeChiara et al., 1991).

Discovery of imprinting

The phrase "imprinting" was first used to described events in the insect Pseudococcus nipae (Schrader 1921). In Pseudococcids or mealybugs (Homoptera, Coccoidea) both the male and female develop from a fertilised egg. In females, all chromosomes remain euchromatic and functional. In embryos destined to become males, one haploid set of chromosomes becomes heterochromatinised after the sixth cleavage division and remains so in most tissues; males are thus functionally haploid (Brown and Nur 1964; Hughes-Schrader 1948; Nur 1990). In insects, imprinting describes the silencing of the paternal genome in males, and thus is involved in sex determination. In mammals, genomic imprinting describes the processes involved in introducing functional inequality between two parental alleles of a gene (Feil and Berger, 2007).

Imprinted genes in mammals

Experimental manipulation of mouse embryos in the early 1980s showed that normal development requires the contribution of both the maternal and paternal genomes. Gynogenetic embryos (containing two female genomes) show relatively normal embryonic development, but poor placental development. In contrast, androgenetic embryos (containing two male genomes) show very poor embryonic development but normal placental development. Further investigation identified that these phenotypes were the result of unbalanced imprinted gene expression (Barton et al., 1984; McGrath and Solter, 1984).

The gynogenetic embryos have twice the normal level of maternally expressed genes, and completely lack expression of paternally expressed genes, whereas the reverse is true for androgenetic embryos. It is now known that there are approximately 80 imprinted genes in humans and mice, many of which are involved in embryonic and placental growth and development (Isles and Holland, 2005; Morison et al., 2005; Reik and Lewis, 2005; Wood and Oakey, 2006).

No naturally occurring cases of parthenogenesis exist in mammals because of imprinted genes. Experimental manipulation of a paternal methylation imprint controlling the Igf2 gene has, however, recently allowed the creation of rare individual mice with two maternal sets of chromosomes - but this is not a true parthenogenote. Hybrid offspring of two species may exhibit unusual growth due to the novel combination of imprinted genes.^[1]

Genetic mapping of imprinted genes

At the same time as the generation of the gynogenetic and androgenetic embryos discussed above, mouse embryos were also being generated that contained only small regions that were derived from either a paternal or maternal source (Cattanach and Kirk, 1985; McLaughlin et al., 1996). The generation of a series of such uniparental disomies, which together span the entire genome, allowed the creation of an imprinting map.^[2] Those regions which when inherited from a single parent result in a discernable phenotype contain imprinted gene(s). Further research showed that within these regions there were often numerous imprinted genes (Bartolomei and Tilghman 1997. Around 80% of imprinted genes are found in clusters such as these, called imprinted domains, suggesting a level of co-ordinated control (Reik and Walter 2001).

Imprinting mechanisms

Imprinting is a dynamic process. It must be possible to erase and re-establish the imprint through each generation. The nature of the imprint must therefore be epigenetic (modifications to the structure of the DNA rather than the sequence). In germline cells the imprint is erased, and then re-established according to the sex of the individual; i.e. in the developing sperm, a paternal imprint is established, whereas in developing oocytes, a maternal imprint is established. This process of erasure and reprogramming is necessary such that the current imprinting status is relevant to the sex of the individual. In both plants and mammals there are two major mechanisms that are involved in establishing the imprint; these are DNA methylation and histone modifications.

Regulation

The grouping of imprinted genes within clusters allows them to share common regulatory elements, such as non-coding RNAs and differentially methylated regions (DMRs). When these regulatory elements control the imprinting of several genes in a given region, they are known as imprinting control regions (ICR). The expression of non-coding RNAs, such as Air on mouse chromosome 17 and KCNQ1OT1 on human chromosome 11p15.5, have been shown to be essential for the imprinting of genes in their corresponding regions.

Differentially methylated regions are generally segments of DNA rich in cytosine and guanine nucleotides, with the cytosine nucleotides methylated on one copy but not on the other. Contrary to expectation, methylation does not necessarily mean silencing; instead, the effect of methylation depends upon the default state of the region.

Functions of imprinted genes

The control of expression of specific genes by genomic imprinting is unique to placental mammals (eutherians and marsupials) and flowering plants. Imprinting of whole chromosomes has been reported in mealybugs (Brown and Nur. 1964; Hughes-Schrader. 1948; Schrader 1921; Nur. 1990) and the fungus gnat (Sciara) (Metz. 1938). It has also been established that X-chromosome inactivation occurs in an imprinted manner in the extra-embryonic tissues of mice, where it is always the paternal X-chromosome which is silenced (Alleman and Doctor, 2000; Reik and Walter, 2001).

The majority of imprinted genes in mammals have been found to have roles in the control of embryonic growth and development, including development of the placenta (Isles and Holland 2005; Tycko and Morison 2002). Other imprinted genes are involved in post-natal development, with roles affecting suckling and metabolism (Constancia et al., 2004; Tycko and Morison, 2002).

Theories on the origins of imprinting

Imprinting appears to be able to increase the evolutionary fitness of genes in two ways, so either or both could be responsible for its origins.

Perhaps the most widely accepted explanation for the occurrence of genomic imprinting is the "parental conflict hypothesis" (Moore and Haig 1991). This hypothesis states that the inequality between parental genomes due to imprinting is a result of the differing interests of each parent in terms of the evolutionary fitness of their genes. The father is more interested in the growth of his offspring, at the expense of the mother. The mother's interest is to conserve resources for her own survival while providing sufficient nourishment to current and subsequent litters. Accordingly, paternally expressed genes tend to be growth promoting whereas maternally expressed genes tend to be growth limiting (Moore and Haig 1991).

Another hypothesis behind the origins of genomic imprinting is that this phenomenon evolved to silence foreign DNA elements, such as genes of viral origin. There appears to be an over-representation of retrotransposed genes, that is to say genes that are inserted into the genome by viruses, among imprinted genes. It has also been postulated that if the retrotransposed gene is inserted close to another imprinted gene, it may just acquire this imprint (Chai et. al 2001).

Problems associated with imprinting

Imprinting may cause problems in cloning, with clones having DNA that is not methylated in the correct position. It is possible that this is due to a lack of time for reprogramming to be completely achieved. When a nucleus is added to an egg during somatic cell nuclear transfer, the egg starts dividing in minutes, as compared to the days or months it takes for reprogramming during embryonic development. If time is the responsible factor, it may be possible to delay cell division in clones, giving time for proper reprogramming to occur.

An allele of the "callipyge" (from the Greek for "beautiful buttocks"), or CLPG, gene in sheep produces large buttocks consisting of muscle with very little fat. The large-buttocked phenotype only occurs when the allele is present on the copy of chromosome 18 inherited from a sheep's father and is not on the copy of chromosome 18 inherited from that sheep's mother.^[3]

Examples

Prader-Willi and Angelman Syndrome

Several genetic diseases that map to 15q11 (band 11 of the long arm of chromosome 15) in humans are due to abnormal imprinting. This region is differently imprinted in maternal and paternal chromosomes, and both imprintings are needed for normal development. It is possible for an individual to fail to inherit a properly imprinted 15q11 from one parent, as a result either of deletion of the 15q11 region from that parent's chromosome 15 or, less frequently, of uniparental disomy (in which both copies have been taken from the other parent's genes).

• If neither copy of 15q11 has paternal imprinting, the result is Prader-Willi syndrome (characterised by hypotonia, obesity, and hypogonadism).
• If neither copy has maternal imprinting, the result is Angelman syndrome (characterised by epilepsy, tremors, and a perpetually smiling facial expression).

NOEY2

NOEY2 is a maternally expressed imprinted gene located on chromosome 1 in humans. Loss of NOEY2 expression is linked to an increased risk of ovarian and breast cancers; in 41% of breast and ovarian cancers the protein transcribed by NOEY2 is not expressed, suggesting that it functions as a tumour suppressor^[4] Therefore, if a person inherits both chromosomes from the mother, the gene will not be expressed and the individual is put at a greater risk for breast and ovarian cancer.

Imprinted genes in plants

Decades after imprinting was demonstrated in the mouse, a similar phenomena was observed in flowering plants (angiosperms). During fertilisation of the embryo in flowers, a second separate fertilisation event gives rise to the endosperm, an extraembryonic structure that nourishes the seed similar to the mammalian placenta. Unlike the embryo, the endosperm often contains two copies of the maternal genome and fusion with a male gamete results in a triploid genome. This uneven ratio of maternal to paternal genomes appears to be critical for seed development. Some genes are found to be expressed from both maternal genomes while others are expressed exclusively from the lone paternal copy (Nowack et al., 2007).

See also

• Metabolic imprinting
• Bookmarking
• Epigenetics

Notes

1. ^ http://www.hhmi.org/news/tilghman.html
2. ^ http://www.mgu.har.mrc.ac.uk/research/imprinting/largemap.html
3. ^ "The Legacy of Solid Gold", Genome News Network, May 7, 2001. 
4. ^ "NOEY2 (ARHI), an imprinted putative tumor suppressor gene in ovarian and breast carcinomas", The National Academy of Sciences, January 5, 1999. 

References

Scientific journals

• Bartolomei, M. S. and Tilghman, S. M. (1997). "Genomic imprinting in mammals" (subscription required). Annu Rev Genet 31: 493-525. doi:10.1146/annurev.genet.31.1.493.
• Barton, S. C.; et al (1984). "Role of paternal and maternal genomes in mouse development". Nature 311 (5984): 374-376. doi:10.1038/311374a0. PMID 6482961.
• Brown S.W. and Nur U. (1964). "Heterochromatic chromosomes in the coccids". Science 145: 130-136. doi:10.1126/science.145.3628.130. PMID 14171547.
• Cattanach, B. M. and Kirk, M. 1985. Differential activity of maternally and paternally derived chromosome regions in mice. Nature 315(6019), pp. 496-498
• Chai, J.H. et al. 2001. Retrotransposed genes such as Frat3 in the mouse Chromosome 7C Prader-Willi syndrome region acquire the imprinted status of their insertion site. Mamm. Genome 12, 813–821
• Constancia, M. et al. 2004. Resourceful imprinting. Nature 432(7013), pp. 53-57
• DeChiara, T. M. et al. 1991. Parental imprinting of the mouse insulin-like growth factor II gene. Cell 64(4), pp. 849-859
• Feil, R and Berger, F 2007. Convergent evolution of genomic imprinting in plants and mammals. Trends in Genetics 23(4) pp. 192-199
• Hughes-Schrader, S. 1948. Cytology of Coccids (Coccoidea-Homoptera). Adv. Genet. 2, pp127-203.
• Isles, A. R. and Holland, A. J. 2005. Imprinted genes and mother-offspring interactions. Early Hum Dev 81(1), pp. 73-77.
• McGrath, J. and Solter, D. 1984. Completion of mouse embryogenesis requires both the maternal and paternal genomes. Cell 37(1), pp. 179-183.
• McLaughlin, K. J. et al. 1996. Mouse embryos with paternal duplication of an imprinted chromosome 7 region die at midgestation and lack placental spongiotrophoblast. Development 122(1), pp. 265-270.
• Metz, C.W. 1938. Chromosome behavior, inheritance and sex determination in Sciara. Am. Nat. 72, pp. 485-520.
• Moore, T. and Haig, D. 1991. Genomic imprinting in mammalian development: a parental tug-of-war. Trends Genet 7(2), pp. 45-49
• Morison, I. M. et al. 2005. A census of mammalian imprinting. Trends Genet 21(8), pp. 457-465.
• Nowack et al. 2007. Bypassing genomic imprinting allows seed development. Nature 447, pp. 312-316.
• Nur, U. (1990). Heterochromatization and euchromatization of whole genome in scale insects (Coccoidea:Homoptera). Development Suppl. 29-34.
• Reik, W. and Lewis, A. 2005. Co-evolution of X-chromosome inactivation and imprinting in mammals. Nat Rev Genet 6(5), pp. 403-410.
• Reik, W. and Walter, J. 2001. Genomic imprinting: parental influence on the genome. Nat Rev Genet 2(1), pp. 21-32.
• Schrader, F. 1921. The chromosomes of Pseudococcus nipae. Biol Bull. 40, pp 259-270.
• Tycko, B. and Morison, I. M. 2002. Physiological functions of imprinted genes. J Cell Physiol 192(3), pp. 245-258
• Wood, A.J. and Oakey, R.J. 2006. Genomic Imprinting in Mammals: Emerging Themes and Established Theories. PLoS Genetics 2(11), e147.