PERSPECTIVES Evidence of genomic imprinting TIMELINE Early observations, particularly in insects and plants, indicated that the appearance of Genomic imprinting: the emergence a particular visible trait in offspring could differ depending on whether it was transmit- of an epigenetic paradigm ted from the mother or the father. In some of the early studies, imprinting effects were observed cytogenetically and, as such, were Anne C. Ferguson-Smith seen to affect whole chromosomes. However, Abstract | The emerging awareness of the contribution of epigenetic processes to genetic experiments suggested that parental- origin effects could also act at the level of genome function in health and disease is underpinned by decades of research in the gene. model systems. In particular, many principles of the epigenetic control of genome function have been uncovered by studies of genomic imprinting. The phenomenon Whole chromosome effects. Historically, of genomic imprinting, which results in some genes being expressed in a parental- there have been several examples of -origin-specific manner, is essential for normal mammalian growth and parental-origin-specific ‘marking’ of whole chromosomes documented in the litera- development and exemplifies the regulatory influences of DNA methylation, ture. Indeed, the term ‘imprinting’ was first chromatin structure and non-coding RNA. Setting seminal discoveries in this field coined by the cytogeneticist Helen Crouse1 alongside recent progress and remaining questions shows how the study of in 1960 to describe the programmed imprinting continues to enhance our understanding of the epigenetic control elimination of one or two paternally derived of genome function in other contexts. X chromosomes in sciarid flies. Sciarid zygotes inherit two paternally derived and one maternally derived X chromosome. In Genomic imprinting is a remarkable epige- well-established roles in many other contexts, female embryos, a single paternally inherited netically regulated process that causes genes such as in stem cell programming, cancer epi- X chromosome is eliminated, but in males to be expressed in a parental-origin-specific genetics and cis-acting mechanisms of gene both paternally inherited X chromosomes manner rather than from both chromosome regulation. As such, genomic imprinting was are selectively lost from somatic nuclei. homologues. Thus some imprinted genes one of the first, and remains one of the most Crouse recognized that the imprint iden- are expressed from the paternally inherited informative, paradigms for understanding tifying the X chromosome as maternal or allele, and other genes are expressed from the the consequences of interactions between the paternal in origin was determined by the maternally inherited allele. Parental-origin genome and the epigenome. sex of the germ line through which it was effects in plants, insects and mammals were A historical perspective of some of these inherited1. Parental-origin effects were also noted around 40 years ago. However, it was discoveries is presented here (with key described in the sex determination mecha- the subsequent elegant embryological and events shown in the TIMELINE), illustrating nism of coccid insects2. These insects lack sex genetic manipulations in the mouse that how embryological studies, combined with chromosomes and in males the paternally placed imprinting on the map and led to its classical and molecular genetic studies, have derived chromosome set becomes hetero- recognition as an important paradigm of provided a framework for the more sophis- chromatic, inactive and is not transmitted to epigenetic inheritance. This, coupled with ticated epigenetic and genomic approaches offspring. Epigenetic differences between the detailed genome mapping studies on human that are applied today. This Timeline article maternally and paternally inherited coccid patients with disorders exhibiting parental- includes consideration of the wider implica- chromosome sets have been described but origin effects in their patterns of inheritance, tions of the chromosomal secrets revealed the underlying processes that establish the provided the molecular basis for the iden- through imprinting research and their parent-specific imprint are not understood. tification of the first endogenous imprinted impact on our understanding of epigenetic Sex chromosome dosage compensation genes and the genomic features and epi- inheritance. The extent and functional is a well-established whole chromosome genetic mechanisms responsible for their implications of genomic imprinting are con- model in which parental-origin effects are mono-allelic expression. These early studies sidered, its regulatory mechanisms reviewed studied. In mammals, females with two X of genomic imprinting established essential and its contribution to health and disease chromosomes achieve parity with males in roles for differential DNA methylation, allele- discussed. Finally, some of the unresolved their X-linked gene dosage through epige- specific histone modifications, large non-coding issues and wider questions that are emerging netic inactivation of one X chromosome. RNAs and dynamic developmental changes are suggested, thus providing a glimpse of In marsupials, X-chromosome inactivation in the epigenetic programme. These factors the challenges and exciting prospects facing is imprinted, with the paternally inherited that influence imprinted domains now have the future of this field. X chromosome being inactive in somatic NATURE REVIEWS | GENETICS VOLUME 12 | AUGUST 2011 | 565 © 2011 Macmillan Publishers Limited. All rights reserved PERSPECTIVES Timeline | Key events in imprinting research Pronuclear transfer experiments Johnson6 describes a Preferential paternal prove the functional Identification21,23,24,26 of the The term ‘imprinting’ mouse mutant with X-chromosome inactivation non-equivalence of parental PWS identified as an imprinted first imprinted genes in is coined1 parental-origin effects is described in mammals4 genomes in the mouse13,14 disorder in humans40 mammals: Igf2r, Igf2 and H19 1960 1970 1974 1975 1980 1984 1985 1989 1990 1991 An imprinted gene is first Lubinksy et al.111 identify Recognition of uniparental Specific genomic regions are Publication of the first recognized in plants5 parental-origin effects in BWS disomy in humans38 discovered that function differently imprinting map in the mouse112 depending on their parental origin9 BWS, Beckwith–Wiedemann syndrome; CTCF, CCCTC-binding factor; ICR, imprinting control region; Igf2, insulin-like growth factor 2; Igf2r, IGF2 receptor; piRNA, PIWI-interacting RNA; PWS, Prader–Willi syndrome; RNA-seq, high-throughput RNA sequencing. cells3. Interestingly, in mice, X-chromosome Genetic studies in the mouse also con- abnormalities in their behaviour, growth inactivation is similarly imprinted, but ducted in the 1970s suggested evidence and/or viability. Although the effects of egg specifically during pre-implantation stages for imprinting on autosomes. In 1974, cytoplasm or the uterine environment were and in extra-embryonic lineages including Johnson6 described a deletion at the Tme not excluded8, these results suggested dif- the placenta4. In mice, random inactiva- locus that showed in utero lethality when ferential expression from the two parental tion initiates in all embryonic components maternally inherited but not when transmit- chromosome homologues. Over subsequent around the time of implantation. The ted through the male germ line. Mapping years, Cattanach and colleagues9,10 used this molecular mechanism that distinguishes the of the phenotype for this and other Tme approach to screen the whole mouse genome paternal from the maternal X chromosome deletions indicated that the parental-origin for defective outcomes that were caused and establishes imprinted X-chromosome effect localized to a 0.8–1.1 Mb region of by altering the dosage of parental chromo- inactivation is currently unknown. In par- chromosome 17. This provided the basis for somes. Those studies identified around 13 ticular, it will be interesting to learn the the identification of the first endogenous subchromosomal regions for which there extent to which the underlying epigenetic imprinted gene (see below). is a requirement for both a maternally and features conferring parental-origin-specific Around the same time, Cattanach, paternally inherited chromosome region identity in phenomena involving whole Beechey and Searle were working with mice for normal development (see also the chromosomes overlap with those regulating harbouring either Robertsonian translocations MouseBook imprinting catalogue). Most the imprinted expression and repression of or reciprocal translocations, and they were able murine imprinted genes identified to date individual genes. to manipulate the parental origin of par- map to these regions. Uniparental disomy ticular chromosome regions. Their research conceptuses and their wild-type littermates Early evidence that specific genes are extended the earlier work of Snell7, who continue to be used to understand imprint- imprinted. In 1970, one of the first convinc- had first observed a genetic outcome now ing phenotypes and for molecular analyses in ing pieces of experimental evidence for the coined ‘non-complementation lethality’ in which expression and epigenetic features on imprinting of specific genes was described translocation intercross mice. Translocation the maternally versus the paternally inher- in plants. Through rigorous experiments