Genomic imprinting#Regulation

In diploid organisms (like humans), the somatic cells possess two copies of the genome, one inherited from the male and one from the female. Each autosomal gene is therefore represented by two copies, or alleles, with one copy inherited from each parent at fertilization. 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 male. Although imprinting accounts for a small proportion of mammalian genes, they play an important role in embryogenesis particularly in the formation of visceral structures and the nervous system.{{cite journal | vauthors = Butler MG | title = Genomic imprinting disorders in humans: a mini-review | journal = Journal of Assisted Reproduction and Genetics | volume = 26 | issue = 9–10 | pages = 477–486 | date = October 2009 | pmid = 19844787 | pmc = 2788689 | doi = 10.1007/s10815-009-9353-3 }}

The term "imprinting" was first used to describe events in the insect Pseudococcus nipae.{{Cite journal |vauthors=Schrader F |year=1921 |title=The chromosomes in Pseudococcus nipæ |url=http://www.biolbull.org/cgi/content/abstract/40/5/259 |journal=Biological Bulletin |volume=40 |issue=5 |pages=259–270 |doi=10.2307/1536736 |jstor=1536736 |access-date=2008-07-01}} 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.{{cite journal | vauthors = Brown SW, Nur U | title = Heterochromatic Chromosomes in the Coccids | journal = Science | volume = 145 | issue = 3628 | pages = 130–136 | date = July 1964 | pmid = 14171547 | doi = 10.1126/science.145.3628.130 | bibcode = 1964Sci...145..130B }}{{Cite book |title=Cytology of Coccids (Coccoïdea-Homoptera) |vauthors=Hughes-Schrader S |year=1948 |isbn=9780120176021 |series=Advances in Genetics |volume=35 |pages=127–203 |doi=10.1016/S0065-2660(08)60468-X |pmid=18103373 |issue=2}}{{cite journal | vauthors = Nur U | title = Heterochromatization and euchromatization of whole genomes in scale insects (Coccoidea: Homoptera) | journal = Development | volume = 108 | pages = 29–34 | year = 1990 | pmid = 2090427 | doi = 10.1242/dev.108.Supplement.29 }}

That imprinting might be a feature of mammalian development was suggested in breeding experiments in mice carrying reciprocal chromosomal translocations.{{cite journal | vauthors = Lyon MF, Glenister PH | title = Factors affecting the observed number of young resulting from adjacent-2 disjunction in mice carrying a translocation | journal = Genetical Research | volume = 29 | issue = 1 | pages = 83–92 | date = February 1977 | pmid = 559611 | doi = 10.1017/S0016672300017134 | doi-access = free }} 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 embryos derived from parthenogenesis (called parthenogenones, with two maternal or egg genomes) and androgenesis (called 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 (in a 1984 paper).{{cite journal | vauthors = Barton SC, Surani MA, Norris ML | title = Role of paternal and maternal genomes in mouse development | journal = Nature | volume = 311 | issue = 5984 | pages = 374–376 | year = 1984 | pmid = 6482961 | doi = 10.1038/311374a0 | bibcode = 1984Natur.311..374B | author-link2 = Azim Surani | s2cid = 4321070 }} {{closed access}}{{cite journal | vauthors = Mann JR, Lovell-Badge RH | title = Inviability of parthenogenones is determined by pronuclei, not egg cytoplasm | journal = Nature | volume = 310 | issue = 5972 | pages = 66–67 | year = 1984 | pmid = 6738704 | doi = 10.1038/310066a0 | bibcode = 1984Natur.310...66M | s2cid = 4336389 }}{{cite journal | vauthors = McGrath J, Solter D | title = Completion of mouse embryogenesis requires both the maternal and paternal genomes | journal = Cell | volume = 37 | issue = 1 | pages = 179–183 | date = May 1984 | pmid = 6722870 | doi = 10.1016/0092-8674(84)90313-1 | doi-access = free }} Nevertheless, in 2018 genome editing allowed for bipaternal and viable bimaternal{{cite journal | vauthors = Sagi I, Bar S, Benvenisty N | title = Mice from Same-Sex Parents: CRISPRing Out the Barriers for Unisexual Reproduction | language = English | journal = Cell Stem Cell | volume = 23 | issue = 5 | pages = 625–627 | date = November 2018 | pmid = 30388415 | doi = 10.1016/j.stem.2018.10.012 | s2cid = 53252140 | doi-access = free }}{{cite journal | vauthors = Li ZK, Wang LY, Wang LB, Feng GH, Yuan XW, Liu C, Xu K, Li YH, Wan HF, Zhang Y, Li YF, Li X, Li W, Zhou Q, Hu BY | display-authors = 6 | title = Generation of Bimaternal and Bipaternal Mice from Hypomethylated Haploid ESCs with Imprinting Region Deletions | language = English | journal = Cell Stem Cell | volume = 23 | issue = 5 | pages = 665–676.e4 | date = November 2018 | pmid = 30318303 | doi = 10.1016/j.stem.2018.09.004 | s2cid = 205251810 | doi-access = free }} mouse and even (in 2022) parthenogenesis, still this is far from full reimprinting.{{cite journal | vauthors = Wei Y, Yang CR, Zhao ZA | title = Viable offspring derived from single unfertilized mammalian oocytes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 119 | issue = 12 | pages = e2115248119 | date = March 2022 | pmid = 35254875 | pmc = 8944925 | doi = 10.1073/pnas.2115248119 | doi-access = free | bibcode = 2022PNAS..11915248W }} Finally in March 2023 viable bipaternal embryos were created.{{Cite journal |last1=Ledford |first1=Heidi |last2=Kozlov |first2=Max |date=2023-03-09 |title=The mice with two dads: scientists create eggs from male cells |url=https://www.nature.com/articles/d41586-023-00717-7 |journal=Nature |volume=615 |issue=7952 |pages=379–380 |language=en |doi=10.1038/d41586-023-00717-7|pmid=36894725 |bibcode=2023Natur.615..379L |s2cid=257428648 |url-access=subscription }}

No naturally occurring cases of parthenogenesis exist in mammals because of imprinted genes. However, in 2004, experimental manipulation by Japanese researchers of a paternal methylation imprint controlling the Igf2 gene led to the birth of a mouse (named Kaguya) with two maternal sets of chromosomes, though it is not a true parthenogenone since cells from two different female mice were used. The researchers were able to succeed by using one egg from an immature parent, thus reducing maternal imprinting, and modifying it to express the gene Igf2, which is normally only expressed by the paternal copy of the gene.

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.{{cite journal | vauthors = Wood AJ, Oakey RJ | title = Genomic imprinting in mammals: emerging themes and established theories | journal = PLOS Genetics | volume = 2 | issue = 11 | pages = e147 | date = November 2006 | pmid = 17121465 | pmc = 1657038 | doi = 10.1371/journal.pgen.0020147 | doi-access = free }}{{cite journal | vauthors = Isles AR, Holland AJ | title = Imprinted genes and mother-offspring interactions | journal = Early Human Development | volume = 81 | issue = 1 | pages = 73–77 | date = January 2005 | pmid = 15707717 | doi = 10.1016/j.earlhumdev.2004.10.006 }}{{cite journal | vauthors = Morison IM, Ramsay JP, Spencer HG | title = A census of mammalian imprinting | journal = Trends in Genetics | volume = 21 | issue = 8 | pages = 457–465 | date = August 2005 | pmid = 15990197 | doi = 10.1016/j.tig.2005.06.008 }}{{cite journal | author1 = Reik W |author-link1 =Wolf Reik| author2 = Lewis A | title = Co-evolution of X-chromosome inactivation and imprinting in mammals | journal = Nature Reviews. Genetics | volume = 6 | issue = 5 | pages = 403–410 | date = May 2005 | pmid = 15818385 | doi = 10.1038/nrg1602 | s2cid = 21091004 }} Hybrid offspring of two species may exhibit unusual growth due to the novel combination of imprinted genes.{{Cite news |date=2000-04-30 |title=Gene Tug-of-War Leads to Distinct Species |publisher=Howard Hughes Medical Institute |url=http://www.hhmi.org/news/tilghman.html |access-date=2008-07-02 |archive-date=2013-03-28 |archive-url=https://web.archive.org/web/20130328144948/http://www.hhmi.org/news/tilghman.html |url-status=dead }}

Various methods have been used to identify imprinted genes. In swine, Bischoff et al. compared transcriptional profiles using DNA microarrays to survey differentially expressed genes between parthenotes (2 maternal genomes) and control fetuses (1 maternal, 1 paternal genome).{{cite journal | vauthors = Bischoff SR, Tsai S, Hardison N, Motsinger-Reif AA, Freking BA, Nonneman D, Rohrer G, Piedrahita JA | display-authors = 6 | title = Characterization of conserved and nonconserved imprinted genes in swine | journal = Biology of Reproduction | volume = 81 | issue = 5 | pages = 906–920 | date = November 2009 | pmid = 19571260 | pmc = 2770020 | doi = 10.1095/biolreprod.109.078139 }} An intriguing study surveying the transcriptome of murine brain tissues revealed over 1300 imprinted gene loci (approximately 10-fold more than previously reported) by RNA-sequencing from F1 hybrids resulting from reciprocal crosses.{{cite journal | vauthors = Gregg C, Zhang J, Weissbourd B, Luo S, Schroth GP, Haig D, Dulac C | title = High-resolution analysis of parent-of-origin allelic expression in the mouse brain | journal = Science | volume = 329 | issue = 5992 | pages = 643–648 | date = August 2010 | pmid = 20616232 | pmc = 3005244 | doi = 10.1126/science.1190830 | bibcode = 2010Sci...329..643G }} 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.{{cite journal | vauthors = Hayden EC | title = RNA studies under fire | journal = Nature | volume = 484 | issue = 7395 | pages = 428 | date = April 2012 | pmid = 22538578 | doi = 10.1038/484428a | bibcode = 2012Natur.484..428C | doi-access = free }}{{cite journal | vauthors = DeVeale B, van der Kooy D, Babak T | title = Critical evaluation of imprinted gene expression by RNA-Seq: a new perspective | journal = PLOS Genetics | volume = 8 | issue = 3 | pages = e1002600 | year = 2012 | pmid = 22479196 | pmc = 3315459 | doi = 10.1371/journal.pgen.1002600 | doi-access = free }}

In domesticated livestock, single-nucleotide polymorphisms in imprinted genes influencing foetal growth and development have been shown to be associated with economically important production traits in cattle, sheep and pigs.{{cite journal | vauthors = Magee DA, Spillane C, Berkowicz EW, Sikora KM, MacHugh DE | title = Imprinted loci in domestic livestock species as epigenomic targets for artificial selection of complex traits | journal = Animal Genetics | volume = 45 | issue = Suppl 1 | pages = 25–39 | date = August 2014 | pmid = 24990393 | doi = 10.1111/age.12168 }}{{cite journal | vauthors = Magee DA, Sikora KM, Berkowicz EW, Berry DP, Howard DJ, Mullen MP, Evans RD, Spillane C, MacHugh DE | display-authors = 6 | title = DNA sequence polymorphisms in a panel of eight candidate bovine imprinted genes and their association with performance traits in Irish Holstein-Friesian cattle | journal = BMC Genetics | volume = 11 | pages = 93 | date = October 2010 | pmid = 20942903 | pmc = 2965127 | doi = 10.1186/1471-2156-11-93 | doi-access = free }}

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.{{cite journal | vauthors = Cattanach BM, Kirk M | title = Differential activity of maternally and paternally derived chromosome regions in mice | journal = Nature | volume = 315 | issue = 6019 | pages = 496–498 | year = 1985 | pmid = 4000278 | doi = 10.1038/315496a0 | bibcode = 1985Natur.315..496C | s2cid = 4337753 }}{{cite journal | vauthors = McLaughlin KJ, Szabó P, Haegel H, Mann JR | title = Mouse embryos with paternal duplication of an imprinted chromosome 7 region die at midgestation and lack placental spongiotrophoblast | journal = Development | volume = 122 | issue = 1 | pages = 265–270 | date = January 1996 | pmid = 8565838 | doi = 10.1242/dev.122.1.265 }} The generation of a series of such uniparental disomies, which together span the entire genome, allowed the creation of an imprinting map.{{Cite web |year=2008 |title=Mouse Imprinting Data and References |url=http://www.har.mrc.ac.uk/research/genomic_imprinting/ |url-status=dead |archive-url=https://web.archive.org/web/20120703103129/http://har.mrc.ac.uk/research/genomic_imprinting/ |archive-date=2012-07-03 |access-date=2008-07-02 |publisher=MRC Harwell |vauthors=Beechey C, Cattanach BM, Lake A, Peters J}} 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.{{cite journal | vauthors = Bartolomei MS, Tilghman SM | title = Genomic imprinting in mammals | journal = Annual Review of Genetics | volume = 31 | pages = 493–525 | year = 1997 | pmid = 9442905 | pmc = 3941233 | doi = 10.1146/annurev.genet.31.1.493 }} Around 80% of imprinted genes are found in clusters such as these, called imprinted domains, suggesting a level of co-ordinated control.{{cite journal | author1 = Reik W |author-link1 =Wolf Reik | author2=Walter J | title = Genomic imprinting: parental influence on the genome | journal = Nature Reviews. Genetics | volume = 2 | issue = 1 | pages = 21–32 | date = January 2001 | pmid = 11253064 | doi = 10.1038/35047554 | s2cid = 12050251 }} 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 gene expression profiling microarrays,{{cite journal | vauthors = Kobayashi H, Yamada K, Morita S, Hiura H, Fukuda A, Kagami M, Ogata T, Hata K, Sotomaru Y, Kono T | display-authors = 6 | title = Identification of the mouse paternally expressed imprinted gene Zdbf2 on chromosome 1 and its imprinted human homolog ZDBF2 on chromosome 2 | journal = Genomics | volume = 93 | issue = 5 | pages = 461–472 | date = May 2009 | pmid = 19200453 | doi = 10.1016/j.ygeno.2008.12.012 | doi-access = free }} allele-specific gene expression using SNP genotyping microarrays,{{cite journal | vauthors = Bjornsson HT, Albert TJ, Ladd-Acosta CM, Green RD, Rongione MA, Middle CM, Irizarry RA, Broman KW, Feinberg AP | display-authors = 6 | title = SNP-specific array-based allele-specific expression analysis | journal = Genome Research | volume = 18 | issue = 5 | pages = 771–779 | date = May 2008 | pmid = 18369178 | pmc = 2336807 | doi = 10.1101/gr.073254.107 }} transcriptome sequencing,{{cite journal | vauthors = Babak T, Deveale B, Armour C, Raymond C, Cleary MA, van der Kooy D, Johnson JM, Lim LP | display-authors = 6 | title = Global survey of genomic imprinting by transcriptome sequencing | journal = Current Biology | volume = 18 | issue = 22 | pages = 1735–1741 | date = November 2008 | pmid = 19026546 | doi = 10.1016/j.cub.2008.09.044 | s2cid = 10143690 | doi-access = free | bibcode = 2008CBio...18.1735B }} and in silico prediction pipelines.{{cite journal | vauthors = Luedi PP, Dietrich FS, Weidman JR, Bosko JM, Jirtle RL, Hartemink AJ | title = Computational and experimental identification of novel human imprinted genes | journal = Genome Research | volume = 17 | issue = 12 | pages = 1723–1730 | date = December 2007 | pmid = 18055845 | pmc = 2099581 | doi = 10.1101/gr.6584707 }}

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{{cite journal |author1 = Reik W |author-link1 =Wolf Reik |author2 = Dean W|author3 = Walter J | title = Epigenetic reprogramming in mammalian development | journal = Science | volume = 293 | issue = 5532 | pages = 1089–1093 | date = August 2001 | pmid = 11498579 | doi = 10.1126/science.1063443 | s2cid = 17089710 }} 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.

Recently, a new study{{cite journal | vauthors = Court F, Tayama C, Romanelli V, Martin-Trujillo A, Iglesias-Platas I, Okamura K, Sugahara N, Simón C, Moore H, Harness JV, Keirstead H, Sanchez-Mut JV, Kaneki E, Lapunzina P, Soejima H, Wake N, Esteller M, Ogata T, Hata K, Nakabayashi K, Monk D | display-authors = 6 | title = Genome-wide parent-of-origin DNA methylation analysis reveals the intricacies of human imprinting and suggests a germline methylation-independent mechanism of establishment | journal = Genome Research | volume = 24 | issue = 4 | pages = 554–569 | date = April 2014 | pmid = 24402520 | pmc = 3975056 | doi = 10.1101/gr.164913.113 }} has suggested a novel inheritable imprinting mechanism in humans that would be specific of placental tissue and that is independent of DNA methylation (the main and classical mechanism for genomic imprinting). This was observed in humans, but not in mice, suggesting development after the evolutionary divergence of humans and mice, ~80 Mya. Among the hypothetical explanations for this novel phenomenon, two possible mechanisms have been proposed: either a histone modification that confers imprinting at novel placental-specific imprinted loci or, alternatively, a recruitment of DNMTs to these loci by a specific and unknown transcription factor that would be expressed during early trophoblast differentiation.

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 antisense Igf2r RNA (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.{{cite journal | vauthors = Mancini-Dinardo D, Steele SJ, Levorse JM, Ingram RS, Tilghman SM | title = Elongation of the Kcnq1ot1 transcript is required for genomic imprinting of neighboring genes | journal = Genes & Development | volume = 20 | issue = 10 | pages = 1268–1282 | date = May 2006 | pmid = 16702402 | pmc = 1472902 | doi = 10.1101/gad.1416906 }}

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.{{cite journal | vauthors = Jin B, Li Y, Robertson KD | title = DNA methylation: superior or subordinate in the epigenetic hierarchy? | journal = Genes & Cancer | volume = 2 | issue = 6 | pages = 607–617 | date = June 2011 | pmid = 21941617 | pmc = 3174260 | doi = 10.1177/1947601910393957 }}

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) and a fungus gnat (Sciara).{{Cite journal |vauthors=Metz CW |year=1938 |title=Chromosome behavior, inheritance and sex determination in Sciara |journal=American Naturalist |volume=72 |issue=743 |pages=485–520 |doi=10.1086/280803 |jstor=2457532 |s2cid=83550755}} 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.{{cite journal | vauthors = Alleman M, Doctor J | title = Genomic imprinting in plants: observations and evolutionary implications | journal = Plant Molecular Biology | volume = 43 | issue = 2–3 | pages = 147–161 | date = June 2000 | pmid = 10999401 | doi = 10.1023/A:1006419025155 | s2cid = 9499846 }}

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.{{cite journal | vauthors = Tycko B, Morison IM | title = Physiological functions of imprinted genes | journal = Journal of Cellular Physiology | volume = 192 | issue = 3 | pages = 245–258 | date = September 2002 | pmid = 12124770 | doi = 10.1002/jcp.10129 | s2cid = 42971427 | doi-access = free }} Other imprinted genes are involved in post-natal development, with roles affecting suckling and metabolism.{{cite journal | author1 =Constância M| author2 = Pickard B| author3 = Kelsey G | author4 = Reik W |author-link4 =Wolf Reik | title = Imprinting mechanisms | journal = Genome Research | volume = 8 | issue = 9 | pages = 881–900 | date = September 1998 | pmid = 9750189 | doi = 10.1101/gr.8.9.881 | doi-access = free }}

A widely accepted hypothesis for the evolution of genomic imprinting is the "parental conflict hypothesis".{{cite journal | vauthors = Moore T, Haig D | title = Genomic imprinting in mammalian development: a parental tug-of-war | journal = Trends in Genetics | volume = 7 | issue = 2 | pages = 45–49 | date = February 1991 | pmid = 2035190 | doi = 10.1016/0168-9525(91)90230-N }} 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.{{cite journal | vauthors = Haig D | title = Parental antagonism, relatedness asymmetries, and genomic imprinting | journal = Proceedings. Biological Sciences | volume = 264 | issue = 1388 | pages = 1657–1662 | date = November 1997 | pmid = 9404029 | pmc = 1688715 | doi = 10.1098/rspb.1997.0230 | bibcode = 1997RSPSB.264.1657H | author-link = David Haig (biologist) }}{{Cite journal |vauthors=Haig D |year=2000 |title=The kinship theory of genomic imprinting |journal=Annual Review of Ecology and Systematics |volume=31 |issue=1 |pages=9–32 |doi=10.1146/annurev.ecolsys.31.1.9|bibcode=2000AnRES..31....9H }} 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. 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{{cite journal | vauthors = McElroy JP, Kim JJ, Harry DE, Brown SR, Dekkers JC, Lamont SJ | title = Identification of trait loci affecting white meat percentage and other growth and carcass traits in commercial broiler chickens | journal = Poultry Science | volume = 85 | issue = 4 | pages = 593–605 | date = April 2006 | pmid = 16615342 | doi = 10.1093/ps/85.4.593 | doi-access = free }}{{cite journal | vauthors = Tuiskula-Haavisto M, Vilkki J | title = Parent-of-origin specific QTL--a possibility towards understanding reciprocal effects in chicken and the origin of imprinting | journal = Cytogenetic and Genome Research | volume = 117 | issue = 1–4 | pages = 305–312 | year = 2007 | pmid = 17675872 | doi = 10.1159/000103192 | s2cid = 27834663 }} where there is relatively little post-fertilisation resource transfer and therefore less parental conflict. A small number of imprinted genes are fast evolving under positive Darwinian selection possibly due to antagonistic co-evolution.{{cite journal | vauthors = O'Connell MJ, Loughran NB, Walsh TA, Donoghue MT, Schmid KJ, Spillane C | title = A phylogenetic approach to test for evidence of parental conflict or gene duplications associated with protein-encoding imprinted orthologous genes in placental mammals | journal = Mammalian Genome | volume = 21 | issue = 9–10 | pages = 486–498 | date = October 2010 | pmid = 20931201 | doi = 10.1007/s00335-010-9283-5 | s2cid = 6883377 }} The majority of imprinted genes display high levels of micro-synteny conservation and have undergone very few duplications in placental mammalian lineages.

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.{{cite journal | vauthors = Keverne EB, Curley JP | title = Epigenetics, brain evolution and behaviour | journal = Frontiers in Neuroendocrinology | volume = 29 | issue = 3 | pages = 398–412 | date = June 2008 | pmid = 18439660 | doi = 10.1016/j.yfrne.2008.03.001 | url = http://champagnelab.psych.columbia.edu/docs/frontiers.pdf | url-status = dead | access-date = 2011-01-06 | s2cid = 10697086 | archive-url = https://web.archive.org/web/20100622154417/http://champagnelab.psych.columbia.edu/docs/frontiers.pdf | archive-date = 2010-06-22 }}

Another hypothesis proposed is that some imprinted genes act coadaptively to improve both fetal development and maternal provisioning for nutrition and care.{{cite journal | vauthors = Wolf JB | title = Cytonuclear interactions can favor the evolution of genomic imprinting | journal = Evolution; International Journal of Organic Evolution | volume = 63 | issue = 5 | pages = 1364–1371 | date = May 2009 | pmid = 19425202 | doi = 10.1111/j.1558-5646.2009.00632.x | s2cid = 29251471 }} In it, a subset of paternally expressed genes are co-expressed in both the placenta and the mother's hypothalamus. This would come about through selective pressure from parent-infant coadaptation to improve infant survival. Paternally expressed 3 (PEG3) is a gene for which this hypothesis may apply.

Others have approached their study of the origins of genomic imprinting from a different side, arguing that natural selection is operating on the role of epigenetic marks as machinery for homologous chromosome recognition during meiosis, rather than on their role in differential expression.{{cite journal | vauthors = Pardo-Manuel de Villena F, de la Casa-Esperón E, Sapienza C | title = Natural selection and the function of genome imprinting: beyond the silenced minority | journal = Trends in Genetics | volume = 16 | issue = 12 | pages = 573–579 | date = December 2000 | pmid = 11102708 | doi = 10.1016/S0168-9525(00)02134-X }} This argument centers on the existence of epigenetic effects on chromosomes that do not directly affect gene expression, but do depend on which parent the chromosome originated from.{{cite journal | vauthors = de la Casa-Esperón E, Sapienza C | title = Natural selection and the evolution of genome imprinting | journal = Annual Review of Genetics | volume = 37 | pages = 349–370 | year = 2003 | pmid = 14616065 | doi = 10.1146/annurev.genet.37.110801.143741 }} This group of epigenetic changes that depend on the chromosome's parent of origin (including both those that affect gene expression and those that do not) are called parental origin effects, and include phenomena such as paternal X inactivation in the marsupials, nonrandom parental chromatid distribution in the ferns, and even mating type switching in yeast. This diversity in organisms that show parental origin effects has prompted theorists to place the evolutionary origin of genomic imprinting before the last common ancestor of plants and animals, over a billion years ago.

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.{{cite journal | vauthors = Barlow DP | title = Methylation and imprinting: from host defense to gene regulation? | journal = Science | volume = 260 | issue = 5106 | pages = 309–310 | date = April 1993 | pmid = 8469984 | doi = 10.1126/science.8469984 | bibcode = 1993Sci...260..309B | s2cid = 6925971 }} 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.{{cite journal | vauthors = Chai JH, Locke DP, Ohta T, Greally JM, Nicholls RD | title = Retrotransposed genes such as Frat3 in the mouse Chromosome 7C Prader-Willi syndrome region acquire the imprinted status of their insertion site | journal = Mammalian Genome | volume = 12 | issue = 11 | pages = 813–821 | date = November 2001 | pmid = 11845283 | doi = 10.1007/s00335-001-2083-1 | s2cid = 13419814 }}

Unfortunately, the relationship between the phenotype and genotype of imprinted genes is solely conceptual. The idea is frameworked using two alleles on a single locus and hosts three different possible classes of genotypes.{{cite journal | vauthors = Lawson HA, Cheverud JM, Wolf JB | title = Genomic imprinting and parent-of-origin effects on complex traits | journal = Nature Reviews. Genetics | volume = 14 | issue = 9 | pages = 609–617 | date = September 2013 | pmid = 23917626 | pmc = 3926806 | doi = 10.1038/nrg3543 }} The reciprocal heterozygotes genotype class contributes to understanding how imprinting will impact genotype to phenotype relationship. Reciprocal heterozygotes have a genetically equivalent, but they are phenotypically nonequivalent.{{cite journal | vauthors = de Koning DJ, Rattink AP, Harlizius B, van Arendonk JA, Brascamp EW, Groenen MA | title = Genome-wide scan for body composition in pigs reveals important role of imprinting | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 14 | pages = 7947–7950 | date = July 2000 | pmid = 10859367 | pmc = 16650 | doi = 10.1073/pnas.140216397 | bibcode = 2000PNAS...97.7947D | doi-access = free }} Their phenotype may not be dependent on the equivalence of the genotype. This can ultimately increase diversity in genetic classes, expanding flexibility of imprinted genes.{{Cite book |title=Handbook of Statistical Genetics |vauthors=Hoeschele I |date=2004-07-15 |publisher=John Wiley & Sons, Ltd |isbn=0-470-02262-0 |chapter=Mapping Quantitative Trait Loci in Outbred Pedigrees |doi=10.1002/0470022620.bbc17}} This increase will also force a higher degree in testing capabilities and assortment of tests to determine the presences of imprinting.

When a locus is identified as imprinted, two different classes express different alleles. Inherited imprinted genes of offspring are believed to be monoallelic expressions. A single locus will entirely produce one's phenotype although two alleles are inherited. This genotype class is called parental imprinting, as well as dominant imprinting.{{cite journal | vauthors = Wolf JB, Cheverud JM, Roseman C, Hager R | title = Genome-wide analysis reveals a complex pattern of genomic imprinting in mice | journal = PLOS Genetics | volume = 4 | issue = 6 | pages = e1000091 | date = June 2008 | pmid = 18535661 | pmc = 2390766 | doi = 10.1371/journal.pgen.1000091 | doi-access = free }} Phenotypic patterns are variant to possible expressions from paternal and maternal genotypes. Different alleles inherited from different parents will host different phenotypic qualities. One allele will have a larger phenotypic value and the other allele will be silenced. Underdominance of the locus is another possibility of phenotypic expression. Both maternal and paternal phenotypes will have a small value rather than one hosting a large value and silencing the other.

Statistical frameworks and mapping models are used to identify imprinting effects on genes and complex traits. Allelic parent-of-origin influences the vary in phenotype that derive from the imprinting of genotype classes. These models of mapping and identifying imprinting effects include using unordered genotypes to build mapping models. These models will show classic quantitative genetics and the effects of dominance of the imprinted genes.

{{Anchor|disorders}}Imprinting may cause problems in cloning, with clones having DNA that is not methylated in the correct positions. 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.{{cn|date=July 2019}}

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).{{cite journal | vauthors = Lazaraviciute G, Kauser M, Bhattacharya S, Haggarty P, Bhattacharya S | title = A systematic review and meta-analysis of DNA methylation levels and imprinting disorders in children conceived by IVF/ICSI compared with children conceived spontaneously | journal = Human Reproduction Update | volume = 20 | issue = 6 | pages = 840–852 | year = 2014 | pmid = 24961233 | doi = 10.1093/humupd/dmu033 | doi-access = free }}

Epigenetic deregulations at H19 imprinted gene in sperm have been observed associated with male infertility.{{cite journal | vauthors = Rotondo JC, Selvatici R, Di Domenico M, Marci R, Vesce F, Tognon M, Martini F | title = Methylation loss at H19 imprinted gene correlates with methylenetetrahydrofolate reductase gene promoter hypermethylation in semen samples from infertile males | journal = Epigenetics | volume = 8 | issue = 9 | pages = 990–997 | date = September 2013 | pmid = 23975186 | pmc = 3883776 | doi = 10.4161/epi.25798 }} Indeed, methylation loss at H19 imprinted gene has been observed associated with MTHFR gene promoter hypermethylation in semen samples from infertile males.

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.

• Paternal inheritance of a deletion of this region is associated with Prader-Willi syndrome (characterised by hypotonia, obesity, and hypogonadism).
• Maternal inheritance of the same deletion is associated with Angelman syndrome (characterised by epilepsy, tremors, and a perpetually smiling facial expression).

{{Excerpt|Imprinted brain hypothesis}}

DIRAS3 is a paternally expressed and maternally imprinted gene located on chromosome 1 in humans. Reduced DIRAS3 expression is linked to an increased risk of ovarian and breast cancers; in 41% of breast and ovarian cancers the protein encoded by DIRAS3 is not expressed, suggesting that it functions as a tumor suppressor gene.{{cite journal | vauthors = Yu Y, Xu F, Peng H, Fang X, Zhao S, Li Y, Cuevas B, Kuo WL, Gray JW, Siciliano M, Mills GB, Bast RC | display-authors = 6 | title = NOEY2 (ARHI), an imprinted putative tumor suppressor gene in ovarian and breast carcinomas | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 1 | pages = 214–219 | date = January 1999 | pmid = 9874798 | pmc = 15119 | doi = 10.1073/pnas.96.1.214 | bibcode = 1999PNAS...96..214Y | doi-access = free }} 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.{{Cite book |url=https://books.google.com/books?id=_aqrvxbSiTcC&pg=PA440 |title=Epigenetics |vauthors=Allis CD, Jenuwein T, Reinberg D |publisher=CSHL Press |year=2007 |isbn=978-0-87969-724-2 |pages=440 |access-date=10 November 2010}}

Transient neonatal diabetes mellitus can also involve imprinting.{{Cite book |url=https://books.google.com/books?id=AzvFFxY-3CMC&pg=PA113 |title=Development of the Pancreas and Neonatal Diabetes |vauthors=Scharfmann R |publisher=Karger Publishers |year=2007 |isbn=978-3-8055-8385-5 |pages=113– |access-date=10 November 2010}}

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

In insects, imprinting affects entire chromosomes. In some insects the entire paternal genome is silenced in male offspring, and thus is involved in sex determination. The imprinting produces effects similar to the mechanisms in other insects that eliminate paternally inherited chromosomes in male offspring, including arrhenotoky.{{Cite book |title=Genomic Imprinting |vauthors=Herrick G, Seger J |publisher=Springer Berlin Heidelberg |year=1999 |isbn=978-3-662-21956-0 |veditors=Ohlsson R |series=Results and Problems in Cell Differentiation |volume=25 |pages=41–71 |chapter=Imprinting and Paternal Genome Elimination in Insects |doi=10.1007/978-3-540-69111-2_3 |pmid=10339741}}

In social honey bees, the parent of origin and allele-specific genes has been studied from reciprocal crosses to explore the epigenetic mechanisms underlying aggressive behavior. Bresnahan et al., "Examining parent-of-origin effects on transcription and RNA methylation in mediating aggressive behavior in honey bees (Apis mellifera)", BMC Genomics 24: 315 (2023), https://bmcgenomics.biomedcentral.com/articles/10.1186/s12864-023-09411-4

In placental species, parent-offspring conflict can result in the evolution of strategies, such as genomic imprinting, for embryos to subvert maternal nutrient provisioning. Despite several attempts to find it, genomic imprinting has not been found in the platypus, reptiles, birds, or fish. The absence of genomic imprinting in a placental reptile, the Pseudemoia entrecasteauxii, is interesting as genomic imprinting was thought to be associated with the evolution of viviparity and placental nutrient transport.{{cite journal | vauthors = Griffith OW, Brandley MC, Belov K, Thompson MB | title = Allelic expression of mammalian imprinted genes in a matrotrophic lizard, Pseudemoia entrecasteauxii | journal = Development Genes and Evolution | volume = 226 | issue = 2 | pages = 79–85 | date = March 2016 | pmid = 26943808 | doi = 10.1007/s00427-016-0531-x | s2cid = 14643386 }}

Studies in domestic livestock, such as dairy and beef cattle, have implicated imprinted genes (e.g. IGF2) in a range of economic traits,{{cite journal | vauthors = Magee DA, Berry DP, Berkowicz EW, Sikora KM, Howard DJ, Mullen MP, Evans RD, Spillane C, MacHugh DE | display-authors = 6 | title = Single nucleotide polymorphisms within the bovine DLK1-DIO3 imprinted domain are associated with economically important production traits in cattle | journal = The Journal of Heredity | volume = 102 | issue = 1 | pages = 94–101 | date = January 2011 | pmid = 20817761 | doi = 10.1093/jhered/esq097 | doi-access = free }}{{cite journal | vauthors = Sikora KM, Magee DA, Berkowicz EW, Berry DP, Howard DJ, Mullen MP, Evans RD, Machugh DE, Spillane C | display-authors = 6 | title = DNA sequence polymorphisms within the bovine guanine nucleotide-binding protein Gs subunit alpha (Gsα)-encoding (GNAS) genomic imprinting domain are associated with performance traits | journal = BMC Genetics | volume = 12 | pages = 4 | date = January 2011 | pmid = 21214909 | pmc = 3025900 | doi = 10.1186/1471-2156-12-4 | doi-access = free }} including dairy performance in Holstein-Friesian cattle.{{cite journal | vauthors = Berkowicz EW, Magee DA, Sikora KM, Berry DP, Howard DJ, Mullen MP, Evans RD, Spillane C, MacHugh DE | display-authors = 6 | title = Single nucleotide polymorphisms at the imprinted bovine insulin-like growth factor 2 (IGF2) locus are associated with dairy performance in Irish Holstein-Friesian cattle | journal = The Journal of Dairy Research | volume = 78 | issue = 1 | pages = 1–8 | date = February 2011 | pmid = 20822563 | doi = 10.1017/S0022029910000567 | hdl-access = free | hdl = 11019/377 }}

In sheep, the CLPG gene ("callipyge" from Greek, meaning "beautiful buttocks") produces a 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.{{Cite news |date=2001-05-07 |title=The Legacy of Solid Gold |url=http://www.genomenewsnetwork.org/articles/05_01/Callipyge_sheep_imprinting.shtml |publisher=Genome News Network |vauthors=Winstead ER}} The CLPG locus is encompassed by Dlk1-Gtl2, an imprinted region of the mammalian genome, and the atypical presentation of this gene is a result of this imprinting.{{Cite journal |last=Lewis |first=Annabelle |last2=Redrup |first2=Lisa |date=26 April 2005 |title=Genetic Imprinting: Conflict at the Callipyge Locus |url=https://www.sciencedirect.com/science/article/pii/S096098220500374X |journal=Current Biology |volume=15 |issue=8 |doi=10.1016/j.cub.2005.04.003 |via=Science Direct}}

Foraging behavior in mice studied is influenced by a sexually dimorphic allele expression implicating a cross-gender imprinting influence that varies throughout the body and may dominate expression and shape a behavior.{{cite journal | vauthors = Bonthuis PJ, Steinwand S, Stacher Hörndli CN, Emery J, Huang WC, Kravitz S, Ferris E, Gregg C | display-authors = 6 | title = Noncanonical genomic imprinting in the monoamine system determines naturalistic foraging and brain-adrenal axis functions | journal = Cell Reports | volume = 38 | issue = 10 | pages = 110500 | date = March 2022 | pmid = 35263575 | pmc = 9128000 | doi = 10.1016/j.celrep.2022.110500 }}{{cite web | vauthors = Robitzski D | title = Mouse Foraging Behavior Shaped by Opposite-Sex Parent's Genes | work = The Scientist | date = 12 April 2022 | url = https://www.the-scientist.com/news-opinion/genomic-imprinting-from-opposite-sex-parent-shapes-mouse-foraging-69900?_hsmi=216252693 }}

A similar imprinting phenomenon has also been described in flowering plants (angiosperms).{{cite journal | vauthors = Garnier O, Laoueillé-Duprat S, Spillane C | title = Genomic imprinting in plants | journal = Epigenetics | volume = 3 | issue = 1 | pages = 14–20 | year = 2008 | pmid = 18259119 | doi = 10.4161/epi.3.1.5554 | doi-access = free }} During fertilization 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 2:1 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.{{cite journal | vauthors = Nowack MK, Shirzadi R, Dissmeyer N, Dolf A, Endl E, Grini PE, Schnittger A | title = Bypassing genomic imprinting allows seed development | journal = Nature | volume = 447 | issue = 7142 | pages = 312–315 | date = May 2007 | pmid = 17468744 | doi = 10.1038/nature05770 | bibcode = 2007Natur.447..312N | hdl-access = free | s2cid = 4396777 | hdl = 11858/00-001M-0000-0012-3877-6 }} 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.{{cite journal | vauthors = Köhler C, Mittelsten Scheid O, Erilova A | title = The impact of the triploid block on the origin and evolution of polyploid plants | journal = Trends in Genetics | volume = 26 | issue = 3 | pages = 142–148 | date = March 2010 | pmid = 20089326 | doi = 10.1016/j.tig.2009.12.006 }} Several computational methods to detect imprinting genes in plants from reciprocal crosses have been proposed. {{Cite book |title=Plant Epigenetics and Epigenomics |vauthors=Picard CL, Gehring M |date=2020 |publisher=Springer US |isbn=978-1-0716-0178-5 |veditors=Spillane C, McKeown P |series=Methods in Molecular Biology |volume=2093 |location=New York, NY |pages=173–201 |chapter=Identification and Comparison of Imprinted Genes Across Plant Species |doi=10.1007/978-1-0716-0179-2_13 |pmid=32088897 |s2cid=211261218}}{{cite journal | vauthors = Wyder S, Raissig MT, Grossniklaus U | title = Consistent Reanalysis of Genome-wide Imprinting Studies in Plants Using Generalized Linear Models Increases Concordance across Datasets | journal = Scientific Reports | volume = 9 | issue = 1 | pages = 1320 | date = February 2019 | pmid = 30718537 | pmc = 6362150 | doi = 10.1038/s41598-018-36768-4 | bibcode = 2019NatSR...9.1320W }}{{cite journal | vauthors = Anderson SN, Zhou P, Higgins K, Brandvain Y, Springer NM | title = Widespread imprinting of transposable elements and variable genes in the maize endosperm | journal = PLOS Genetics | volume = 17 | issue = 4 | pages = e1009491 | date = April 2021 | pmid = 33830994 | pmc = 8057601 | doi = 10.1371/journal.pgen.1009491 | doi-access = free }}

• Bookmarking
• Female sperm
• Male egg
• Metabolic imprinting
• Original antigenic sin, immunological imprinting

{{Reflist|32em}}

• [http://geneimprint.com/ geneimprint.com]
• [http://igc.otago.ac.nz/ Imprinted Gene and Parent-of-origin Effect Database]
• [https://web.archive.org/web/20120627084815/http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Imprinting.html J. Kimball's Imprinted Genes Site]
• {{MeshName|Genomic+imprinting}}
• [https://web.archive.org/web/20120703103129/http://har.mrc.ac.uk/research/genomic_imprinting/ Harwell Mouse Imprinting Map]
• [https://plantimprinting.wi.mit.edu/ Gehring Lab (MIT) Imprinting Database]

{{Gene expression}}

{{Genomic imprinting}}

{{DEFAULTSORT:Genomic Imprinting}}

Category:Epigenetics

Category:Gene expression

Category:Molecular genetics