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Genomic imprinting

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Title: Genomic imprinting  
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Subject: Prader–Willi syndrome, Epigenetics, Angelman syndrome, Randy Jirtle, Post-transcriptional regulation
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Genomic imprinting

Genomic imprinting is the phenomenon by which certain genes are expressed in a parent-of-origin-specific manner. It is an inheritance process independent of the classical Mendelian inheritance. If the allele inherited from the father is imprinted and thereby silenced, then only (or primarily) the allele from the mother is expressed (e.g. in the case of the genes H19 or CDKN1C). If the allele from the mother is imprinted, then only the allele from the father is expressed (e.g. in the case of the gene IGF-2). Forms of genomic imprinting have been demonstrated in fungi, plants and animals.[1] Genomic imprinting is a fairly rare phenomenon in mammals; most genes are not imprinted.

Genomic imprinting is an epigenetic process that involves DNA methylation and histone methylation in order to achieve the expression of only one allele without altering the genetic sequence. These epigenetic marks are established ("imprinted") in the germline (sperm or egg cells) of the parents and are maintained through mitotic cell divisions in the somatic cells of an organism.

Appropriate expression of imprinted genes is important for normal development. Diseases involving genomic imprinting include Angelman syndrome and Prader–Willi syndrome.


In somatic cells possess two copies of the genome, one inherited from the father and one from the mother. 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.[2] 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; this is called paternal imprinting.[3]

The term "imprinting" was first used to describe events in the insect Pseudococcus nipae.[4] In Pseudococcids (mealybugs) (Hemiptera, 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.[5][6][7] 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.[8]

Genetic imprinting may also ensure that transposable elements remain epigenetically silenced throughout gametogenic reprogramming to maintain genome integrity.[9]

Imprinted genes in mammals

That imprinting might be a feature of mammalian development was suggested in breeding experiments in mice carrying reciprocal translocations.[10] Nucleus transplantation experiments in mouse zygotes in the early 1980s confirmed that normal development requires the contribution of both the maternal and paternal genomes. The vast majority of mouse parthenogenones/gynogenones (with two maternal or egg genomes) and androgenones (with two paternal or sperm genomes) die at, or before, the blastocyst/implantation stage. In the rare instances that they develop to postimplantation stages, gynogenetic embryos show better embryonic development relative to placental development, while for androgenones, the reverse is true. Nevertheless, for the latter, only a few have been described.[11][12][13]

Parthenogenetic/gynogenetic embryos have twice the normal expression level of maternally derived genes, and lack expression of paternally expressed genes, while the reverse is true for androgenetic embryos. It is now known that there are at least 80 imprinted genes in humans and mice, many of which are involved in embryonic and placental growth and development.[14][15][16][17] Various methods have been used to identify imprinted genes. In swine, Bischoff et al. 2009 compared transcriptional profiles using short-oligonucleotide microarrays (Affymetrix Porcine GeneChip) to survey differentially expressed genes between parthenotes (2 maternal genomes) and control fetuses (1 maternal, 1 paternal genome)[18] An intriguing study surveying the transcriptome of murine brain tissues revealed over 1300 imprinted gene loci (approximately 10-fold more than previously reported) by Illumina RNA-sequencing (RNA-Seq) technology from F1 hybrids resulting from reciprocal crosses.[19] The result however has been challenged by others who claimed that this is an overestimation by an order of magnitude due to flawed statistical analysis.[20][21]

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 parthenogenone. Hybrid offspring of two species may exhibit unusual growth due to the novel combination of imprinted genes.[22]

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.[23][24] The generation of a series of such uniparental disomies, which together span the entire genome, allowed the creation of an imprinting map.[25] Those regions which when inherited from a single parent result in a discernible phenotype contain imprinted gene(s). Further research showed that within these regions there were often numerous imprinted genes.[26] Around 80% of imprinted genes are found in clusters such as these, called imprinted domains, suggesting a level of co-ordinated control.[27] More recently, genome-wide screens to identify imprinted genes have used differential expression of mRNAs from control fetuses and parthenogenetic or androgenetic fetuses hybridized to expression arrays,[28] allele-specific gene expression using SNP genotyping arrays,[29] transcriptome sequencing,[30] and in silico prediction pipelines.[31]

Imprinting mechanisms

Imprinting is a dynamic process. It must be possible to erase and re-establish imprints through each generation so that genes that are imprinted in an adult may still be expressed in that adult's offspring. (For example the maternal genes that control insulin production will be imprinted in a male but will be expressed in any of the male's offspring that inherit these genes.) The nature of imprinting must therefore be epigenetic rather than DNA sequence dependent. In germline cells the imprint is erased and then re-established according to the sex of the individual, i.e. in the developing sperm (during spermatogenesis), a paternal imprint is established, whereas in developing oocytes (oogenesis), a maternal imprint is established. This process of erasure and reprogramming[32] is necessary such that the germ cell 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.


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 one or more genes, 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.[33]

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 therian mammals (placental mammals and marsupials) and flowering plants. Imprinting of whole chromosomes has been reported in mealybugs (Genus: Pseudococcus).[4][5][6][7] and a fungus gnat (Sciara).[34] It has also been established that X-chromosome inactivation occurs in an imprinted manner in the extra-embryonic tissues of mice and all tissues in marsupials, where it is always the paternal X-chromosome which is silenced.[27][35]

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.[14][36] Other imprinted genes are involved in post-natal development, with roles affecting suckling and metabolism.[36][37]

Theories on the origins of imprinting

A widely accepted hypothesis for the evolution of genomic imprinting is the "parental conflict hypothesis."[38] Also known as the kinship theory of genomic imprinting, 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.[39][40] The father's genes that encode for imprinting gain greater fitness through the success of the offspring, at the expense of the mother. The mother's evolutionary imperative is often 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.[38] In support of this hypothesis, genomic imprinting has been found in all placental mammals, where post-fertilisation offspring resource consumption at the expense of the mother is high; although it has also been found in oviparous birds[41][42] where there is relatively little post-fertilisation resource transfer and therefore less parental conflict.

However, our understanding of the molecular mechanisms behind genomic imprinting show that it is the maternal genome that controls much of the imprinting of both its own and the paternally-derived genes in the zygote, making it difficult to explain why the maternal genes would willingly relinquish their dominance to that of the paternally-derived genes in light of the conflict hypothesis.[43] Several other hypotheses that propose a coadaptive reason for the evolution of genomic imprinting have been proposed.[43][44]

Others have approached their study of the origins of genomic imprinting from a different side, arguing that [45]

Natural selection for genomic imprinting requires genetic variation in a population. A hypothesis for the origin of this genetic variation states that the host-defense system responsible for silencing foreign DNA elements, such as genes of viral origin, mistakenly silenced genes whose silencing turned out to be beneficial for the organism.[47] 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.[48]

Disorders 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.[49]

In vitro fertilisation, including ICSI, is associated with an increased risk of imprinting disorders, with an odds ratio of 3.7 (95% confidence interval 1.4 to 9.7).[50]


The first imprinted genetic disorders to be described in humans were the reciprocally inherited Prader-Willi syndrome and Angelman syndrome. Both syndromes are associated with loss of the chromosomal region 15q11-13 (band 11 of the long arm of chromosome 15). This region contains the paternally expressed genes SNRPN and NDN and the maternally expressed gene UBE3A.


NOEY2 is a paternally 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 encoded by NOEY2 is not expressed, suggesting that it functions as a tumor suppressor gene[51] Therefore, if uniparental disomy occurs and 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.


Other conditions involving imprinting include Beckwith-Wiedemann syndrome, Silver-Russell syndrome, and pseudohypoparathyroidism.[52]

Transient neonatal diabetes mellitus can also involve imprinting.[53]

The "imprinted brain theory" argues that unbalanced imprinting may be a cause of autism and psychosis.

Imprinted genes in plants

A similar imprinting phenomenon has also been described in flowering plants (angiosperms). During fertilisation of the egg cell, a second, separate fertilization event gives rise to the endosperm, an extraembryonic structure that nourishes the embryo in a manner analogous to the mammalian placenta. Unlike the embryo, the endosperm is often formed from the fusion of two maternal cells with a male gamete. This results in a triploid genome. The 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.[54] It has been suggested that these imprinted genes are responsible for the triploid block effect in flowering plants that prevents hybridization between diploids and autotetraploids.[55]

See also


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