Imprinting allows for transient changes in expression of a gene without mutation in the gene, affects many genes that can have significant impact on development, behavior, and cancer susceptibility
Genomic imprinting is one of the most intriguing subtleties of modern genetics. The term “imprinting” refers to parent-of-origin-dependent gene expression. The presence of imprinted genes can cause cells with a full parental complement of functional autosomal genes to specifically express one allele but not the other, resulting in monoallelic expression of the imprinted loci. Genomic imprinting plays a critical role in fetal growth and behavioral development, and it is regulated by DNA methylation and chromatin structure. This paper summarizes the Genomic Imprinting and Environmental Disease Susceptibility Conference held 8-10 October 1998 at Duke University, Durham, North Carolina. The conference focused on the importance of genomic imprinting in determining susceptibility to environmentally induced diseases. Conference topics included rationales for imprinting: parental antagonism and speciation; methods for imprinted gene identification: allelic message display and monochromosomal mouse/human hybrids; properties of the imprinted gene cluster human 11p15.5 and mouse distal 7; the epigenetics of X-chromosome inactivation; variability in imprinting: imprint erasure, non-Mendelian inheritance ratios, and polymorphic imprinting; imprinting and behavior: genetics of bipolar disorder, imprinting in Turner syndrome, and imprinting in brain development and social behavior; and aberrant methylation: methylation and chromatin structure, methylation and estrogen exposure, methylation of tumor-suppressor genes, and cancer susceptibility. Environmental factors are capable of causing epigenetic changes in DNA that can potentially alter imprint gene expression and that can result in genetic diseases including cancer and behavioral disorders. Understanding the contribution of imprinting to the regulation of gene expression will be an important step in evaluating environmental influences on human health and disease.
Genomic Imprinting and Behavioral Development
Genetic studies of bipolar disorder: is there a parent-of-origin effect?
Recent work has suggested that one or more regions of human chromosome 18 are involved in bipolar disorder and related depressive conditions (1J). Patients with these syndromes have an episodic disorder characterized by manic and depressive episodes in addition to intervals without these episodes. Depressed or manic patients have symptoms that primarily affect their mood, vitality, and self-attitude. The severe form of the disease, bipolar I, occurs in approximately 1% of the population in the United States. A milder form of the illness, bipolar II, with less intense, briefer manic periods has recently been discovered. Its prevalence in the population is unknown but it was diagnosed more frequently than other phenotypes (bipolar I or recurrent major depression) in the families ascertained at Johns Hopkins University (Baltimore, MD) for one of the two large genome-wide studies. These genome scans of 70 and 96 families, respectively, have not established robust linkage to any loci, suggesting that the strong familial clustering of the illness relies in large part on multigenic mechanisms.
Recent clinical and linkage studies conducted independently in a National Institute of Mental Health (Bethesda, MD) collaboration and at Johns Hopkins focused on chromosome 18. Both studies suggest a parent-of-origin effect in multiplex bipolar families (with excess maternal transmission). In addition, linkage to chromosome 18 is also indicated in a subset of the families with paternal transmission of the phenotype. Several other multiplex samples show the same excess of maternal transmission. However, at least one consecutive series sample suggests that excess maternal transmission is seen in the multiplex families. It is not apparent in families studied without regard to the number of affected individuals in the family. Similarly, other studies demonstrate mixed results concerning linkage to chromosome 18 and whether it occurs primarily in families with paternal transmission. Further studies are needed to resolve the genetics of bipolar disorder and the possibility of a parent-of-origin effect.
Imprinting; the X chromosome, and the male brain
Turner syndrome is a rare disorder of females that causes social adjustment problems and short stature but normal intelligence in most individuals. X chromosome deletion or loss is frequent in Turner syndrome females. Thus, haploinsufficiency of genes that are not subject to X inactivation is thought to be one possible mechanism to account for many features of the Turner phenotype. Some findings suggest that imprinted loci may exist on both the paternal and maternal X chromosomes, and that these loci serve different functions in brain development.
Turner syndrome was studied in a group of monosomic females, approximately twothirds of which carried the maternal X (45,Xm) and one-third of which carried the paternal X (45,XP). All of these females showed slightly reduced nonverbal intelligence skills and normal verbal skills. Comparison of social adjustment skills indicated that the 45,Xm females showed twice as great an impairment. Specific neuropsychologic tests were conducted with samples of 46,XY males; 46,XX females; 45,Xm females; and 45,XP females. Normal females performed better than normal males on a test of the ability to recall certain sorts of verbal material from memory, but 45,Xm females were significantly impaired relative to 45,XP females. This observation is consistent with the hypothesis that the disorder is associated with an imprinted locus on the X chromosome at which the paternal allele is expressed and the maternal allele is silenced. Sex differences between normal males and females may reflect the fact that in normal 46,XX females the imprinted locus on the paternal X chromosome would be expressed. In 46,XY males, whose single X is always maternal in origin, the locus would be silenced. On measures of social adjustment in which 45,Xm females perform less well than 45,XP females, males performed less well than normal females, suggesting that the putative imprinted locus may predispose to sexual dimorphism in certain behavioral traits. The neuropsychologic correlates of these traits are currently under investigation. It is possible that sexual dimorphism in social communication abilities could be associated with greater male vulnerability to developmental disorders of language and social cognition such as autism, which is considerably more common among males than females.
Evidence also suggests that recall of a complex pattern was performed considerably better by 45,Xm females than by 45,XP females. This visuospatial memory task was performed equally well by normal males and females. This suggests the possibility of an imprinted gene expressed only from the maternal X chromosome that is shared by normal males and females, and which corresponds to some aspect of visuospatial or motor memory. Both the verbal and the visuospatial memory functions mapped to two distinct areas of the brain in which structural deficits could be detected that may correspond to the functional deficiencies observed.in the 45,Xm and the 45,XP patients respectively. Turner syndrome patients show alterations in cognition behavior that have a genetic parent-of-origin-dependent component. The altered behavior patterns in these patients may also relate to behavior differences that exist between normal females and males.
Methylation, Epigenetics, and the Environment
CpG demethyiation ofthe uterine lactoferrin gene in adult mice treated neonatally with diethylstilbestrol
Studies of the estrogen-regulated lactoferrin gene in the mouse uterus provide another example of an environmental influence on DNA methylation. Prenatal or neonatal exposure to the synthetic estrogen, diethylstilbestrol, can alter lactoferrin expression and lead to uterine tumors. This effect is mediated by diethylstilbestrol-induced changes in the methylation state of a lactoferrin promoter CpG site. However, it also requires that estrogen be present, because it does not occur in ovariectomized animals. Diethylstilbestrol exposure may have additional affects on CpG methylation in the mouse genome.
Liver microsomal cytochrome P450 genes may also affect the physiologic and pathologic responses to xenochemical exposure. Cytochrome P450 genes play a major role in metabolic detoxification/activation of xenochemicals and exhibit sexually dimorphic expression due to developmentally regulated promoter methylation.
- Read and download the full study (free access) Genomic imprinting and environmental disease susceptibility, on the NCBI, PubMed, PMC1637980, 2000 Mar.
- Image credit Jude Buffum, via harvardmagazine.