Genomic imprinting and its relevance to genetic diseases

Summary Genomic imprinting is a biological phenomenon determined by an evolutionally acquired, underlying system that may control harmonious development and growth in mammals. It is also relevant to some genetic disorders in man. In this article, lines of biological evidence of imprinting, characteristics of the mouse and human imprinted genes, and findings and mechanisms on the occurrence of several human imprinting disorders are reviewed.     

Sources of behavioral deviation modeled by early color preferences in quail. III. Developmental stability and normative canalization

Successful artificial selection of quail (C. coturnix japonica) for divergent early approach preferences for, and imprintabilities to, the wavelength characteristics of otherwise identical visual stimuli decreased the trait's developmental stability. The developmental error that resulted from selecting for extreme initial preferences was associated with enhanced imprintabilities. Conversely, the developmental error that resulted from selecting for extreme imprintabilities was associated with enhanced expression of directional gene effects in extreme initial preferences. The data are attributed to selectively relaxed normative canalization of trait development, and to related enhanced expression of genetic, environmental, and stochastic influences in trait deviations.     

Differentiating molecular etiologies of Angelman syndrome through facial phenotyping using deep learning

Angelman syndrome (AS) is caused by several genetic mechanisms that impair the expression of maternally‐inherited UBE3A through deletions, paternal uniparental disomy (UPD), UBE3A pathogenic variants, or imprinting defects. Current methods of differentiating the etiology require molecular testing, which is sometimes difficult to obtain. Recently, computer‐based facial analysis systems have been used to assist in identifying genetic conditions based on facial phenotypes. We sought to understand if the facial‐recognition system DeepGestalt could find differences in phenotype between molecular subtypes of AS. Images and molecular data on 261 individuals with AS ranging from 10 months through 32 years were analyzed by DeepGestalt in a cross‐validation model with receiver operating characteristic (ROC) curves generated. The area under the curve (AUC) of the ROC for each molecular subtype was compared and ranked from least to greatest differentiable phenotype. We determined that DeepGestalt demonstrated a high degree of discrimination between the deletion subtype and UPD or imprinting defects, and a lower degree of discrimination with the UBE3A pathogenic variants subtype. Our findings suggest that DeepGestalt can recognize subclinical differences in phenotype based on etiology and may provide decision support for testing.     

Parental origin of de novo chromosome 9 deletions in del(9p) syndrome

Parental origin of de novo deletions in the short arm of chromosome 9 in patients with a clinical diagnosis of del(9p) syndrome was assessed in 13 patients using polymerase chain reaction (PCR) analysis of highly polymorphic dinucleotide repeat micro-satellite markers located in the putative deleted region. The deletion was found to be of paternal origin in 9 cases and of maternal origin in the remaining 4 cases, suggesting that the molecular event resulting in the deletion occurs in both male and female gametogenesis and that genomic imprinting does not appear to play a role in the patho-genesis of del(9p) syndrome. © 1995 Wiley-Liss, Inc.     

Selective recognition of malaria antigens by human serum antibodies is not genetically determined but demonstrates some features of clonal imprinting

Malaria infection induces the production of serum antibodiesto a variety of malaria antigens but the prevalence of antibodiesto any particular antigen ins typically mucb less than 100%.It has been assumed that non-responsiveness to defined antigensin malaria immune subjects is due to HLA mediated restricutionof the Immune response. In this study we have investigated therole of HLA and non-HLA genes in the antibody response to twomerozoite surface antigens (MSP1 and MSP2) and a sexual stageantigen (Pfs260/230) opf P{lasmodium falcpartum, and concludethat host genotype is not a major determinant of responsiveness.Although antibody levels vary in accordance with seasonal variationsin malaria transmission in semi-immune children, antibiody levelsremain stable in clncall immine adults.     

Reproductive epigenetics

Epigenetics refers to covalent modifications of DNA and core histones that regulate gene activity without altering DNA sequence. To date, the best-characterized DNA modification associated with the modulation of gene activity is methylation of cytosine residues within CpG dinucleotides. Human disorders associated with epigenetic abnormalities include rare imprinting diseases, molar pregnancies, and childhood cancers. Germ cell development and early embryo development are critical times when epigenetic patterns are initiated or maintained. This review focuses on the epigenetic modification DNA methylation and discusses recent progress that has been made in understanding when and how epigenetic patterns are differentially established in the male and female germlines, the mouse, and human disorders associated with abnormalities in epigenetic programming in germ cells and early embryos, as well as genetic and other modulators (e.g. nutrition and drugs) of reproductive epigenetic events.     

No evidence of PEG1/MEST gene mutations in Silver‐Russell syndrome patients

Silver‐Russell syndrome (SRS) is characterized by prenatal and postnatal growth retardation with morphologic anomalies. Maternal uniparental disomy 7 has been reported in some SRS patients. PEG1/MEST is an imprinted gene on chromosome 7q32 that is expressed only from the paternal allele and is a candidate gene for SRS. To clarify its biological function and role in SRS, we screened PEG1/MEST abnormalities in 15 SRS patients from various standpoints. In the lymphocytes of SRS patients, no aberrant expression patterns of two splice variants (α and β) of PEG1/MEST were detected when they were compared with normal samples. Direct sequence analysis failed to detect any mutations in the PEG1/MEST α coding region, and there were no significant mutations in the 5′‐flanking upstream region containing the predicted promoter and the highly conserved human/mouse genomic region. Differential methylation patterns of the CpG island for PEG1/MEST α were normally maintained and resulted in the same pattern as in the normal control, suggesting that there was no loss of imprinting. These findings suggest that PEG1/MEST can be excluded as a major determinant of SRS. © 2001 Wiley‐Liss, Inc.     

Comparative analysis of isodisomic and heterodisomic segments in cases with maternal uniparental disomy 14 suggests more than one imprinted region

The results of molecular investigations of 21 cases with complete or segmental maternal uniparental disomy (UPD) 14 published in the literature were compared with respect to isodisomic and heterodisomic segments. The aim of the study was to find hints toward imprinted regions other than the recently defined imprinted segment 14q32. Three regions with no isodisomic molecular marker were found. The most distal of these regions located on 14q32.12 and 14q32.13 supports the hypothesis of genomic imprinting as the cause of the maternal UPD 14 phenotype by synteny to the maternally imprinted region on mouse distal chromosome 12 and correlation with the recently defined imprinting cluster on human chromosome 14q32. The other two heterodisomic areas located on 14q11.2-->14q12 and 14q21.1-->14q31.2 are hints toward one or more additional regions of genomic imprinting on human chromosome 14.     

Intrauterine growth restriction—genetic causes and consequences

Intrauterine growth restriction is known to be associated with many medical problems for the baby, both before and after delivery. The mechanisms involved in fetal growth are not well understood, with an increasing range of metabolic diseases being implicated. Several key genes involved in normal embryonic and fetal growth and development are now known to be imprinted. Disruption of this parent-specific mono-allelic expression causes phenotypic changes, many of which are important for growth and development. Two growth disorders, Beckwith–Wiedemann syndrome and Silver–Russell syndrome, are discussed in detail as they represent well-characterized phenotypes that arise as a consequence of disrupted imprinting. These human models will allow us to elucidate key genes and mechanisms important in normal fetal growth.