Key Points
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In a small fraction of mammalian genes, one of the two alleles is partially or completely switched off. The decision as to which one is silenced depends on which allele was inherited from the mother and which from the father.
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Imprinted genes have a key role in growth regulation, and maternally and paternally expressed genes have antagonistic actions in this process. This has led to the view that imprinted genes might arise from differing interests of the male and female genomes in the physiology and behaviour of offspring, resulting in a form of intragenomic conflict.
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Early work with mouse chimaeras indicated that imprinted genes have important effects on brain size and development, and raised the possibility that maternal and paternal genomes could have dissociable effects on the organization of functionally distinct brain systems.
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Recent evidence suggests that brain-expressed imprinted gene products interact with molecular signalling pathways that coordinate the patterning, pruning and differentiation of brain cells.
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The actions of imprinted genes in the brain have functional consequences, for example, for behaviours that mediate mother–infant interactions.
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The persistent expression of imprinted genes in the brain has enduring effects that last into adulthood.
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Some imprinted genes might be associated with a risk of neuropsychiatric disorders, notably autism spectrum disorders and the phenotypically overlapping conditions Angelman syndrome and Rett syndrome.
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Many issues remain controversial, including the extent to which genomic-imprinting effects on the brain and on behaviour can be accommodated within existing evolutionary theories.
Abstract
In a small fraction of mammalian genes — at present estimated at less than 1% of the total — one of the two alleles that is inherited by the offspring is partially or completely switched off. The decision as to which one is silenced depends on which allele was inherited from the mother and which from the father. These idiosyncratic loci are known as imprinted genes, and their existence is an evolutionary enigma, as they effectively nullify the advantages of diploidy. Although they are small in number, these genes have important effects on physiology and behaviour, and many are expressed in the brain. There is increasing evidence that imprinted genes influence brain function and behaviour by affecting neurodevelopmental processes.
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Acknowledgements
Our work is funded by a Cardiff University link chair, the Biotechnology and Biological Sciences Research Council UK, the Medical Research Council (MRC) UK, GlaxoSmithKline plc, Lilly UK (L.S.W.), the Beebe Trust and Health Foundation UK (A.I.) and Research Councils United Kingdom (W.D.). We would like to thank our collaborator P. Burgoyne and colleagues G. Kelsey, W. Reik, and A. Holland. L.S.W. is a member of the MRC Co-operative on Imprinting in Health and Disease.
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DATABASES
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FURTHER INFORMATION
Glossary
- Parthenogenetic embryos
-
Embryos that develop in the absence of fertilization by a male. Parthenogenetic cells contain two copies of the maternal genome, but have no paternal contribution.
- Androgenetic embryos
-
Embryos that develop in the absence of a contribution from a female. Androgenetic cells contain two copies of the paternal genome.
- Yeast two-hybrid screen
-
A molecular method for determining whether proteins interact. The binding and activation domains of the transcription factor GAL4 are split and fused to the proteins in the assay. If the two proteins interact, the reconstituted GAL4 initiates the transcription of a reporter gene.
- BAX
-
A well characterized regulator of apoptosis that exerts its effects through heterodimerization with BCL2.
- Angelman syndrome
-
A neurodevelopmental disorder that is characterized by mental retardation, ataxia and a 'happy' disposition. It results from a lack of maternally expressed genes on chromosome 15, at positions q11–q13.
- Wnt1 promoter
-
Wnt1 encodes a secreted signalling protein that is involved in developmental processes, including the induction of the mesencephalon and the cerebellum.
- Prader–Willi syndrome
-
A neurodevelopmental disorder that is characterized by early hypotonia, followed by compulsive eating, mild mental retardation, several behavioural abnormalities and hypogonadism. It results from a lack of paternally expressed genes on chromosome 15, at positions q11–q13.
- SH2-containing adaptor protein
-
A protein that is an accessory to the main proteins in a signal transduction pathway and that contains an SH-2 domain (which binds phosphorylated tyrosine residues).
- Epidermal growth factor-like homeotic family
-
A group of proteins that are involved in cell signalling and subsequent neurodevelopment or neural patterning and which have homology with epidermal growth factor.
- Disomies
-
The presence of two sets of chromosomes—the normal situation in diploid organisms such as humans and mice. In uniparental disomies, both sets of chromosomes originate from one parent.
- Linkage
-
A technique for identifying candidate chromosomal regions that underlie a particular trait, based on the extent to which that trait is co-inherited with certain genetic markers.
- Autism spectrum disorders
-
(ASD). A number of phenotypically overlapping neurodevelopmental conditions, including autism, Asperger's disorder, childhood disintegrative disorder and pervasive developmental disorder—not otherwise specified.
- Linkage peaks
-
Chromosomal regions, identified by linkage analysis, that contain closely linked markers that are often co-inherited in probands.
- Epigenetic hotspot
-
A region of the genome that is especially sensitive to perturbation of gene expression through effects on DNA methylation and/or histone modification.
- Rett syndrome
-
A neurodevelopmental disorder that occurs mainly in females and is characterized by cognitive impairments and autism-like behaviours. In most cases, the disorder is caused by a mutation in the X-linked methyl CpG binding protein 2 gene. In males, this mutation is nearly always lethal.
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Wilkinson, L., Davies, W. & Isles, A. Genomic imprinting effects on brain development and function. Nat Rev Neurosci 8, 832–843 (2007). https://doi.org/10.1038/nrn2235
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DOI: https://doi.org/10.1038/nrn2235
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The contribution of imprinted genes to neurodevelopmental and neuropsychiatric disorders
Translational Psychiatry (2022)
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Astroblastomas exhibit radial glia stem cell lineages and differential expression of imprinted and X-inactivation escape genes
Nature Communications (2022)
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Imprinting methylation predicts hippocampal volumes and hyperintensities and the change with age in later life
Scientific Reports (2021)