Academic literature on the topic 'Forensic genetics Genomic imprinting. Gene mapping'

Genomic imprinting in mammals results in the expression of genes from only one parental allele. Imprinting occurs as a consequence of epigenetic marks set down either in the father's or the mother's germ line and affects a very specific category of mammalian gene. A greater understanding of this distinctive phenomenon can be gained from studies using large genomic clones, called bacterial artificial chromosomes (BACs). Here, we review the important applications of BACs to imprinting research, covering physical mapping studies and the use of BACs as transgenes in mice to study gene expression patterns, to identify imprinting centres, and to isolate the consequences of altered gene dosage. We also highlight the significant and unique advantages that rapid BAC engineering brings to genomic imprinting research.

Abstract P transposon induced modifier mutations of position-effect variegation (PEV) were isolated with the help of hybrid dysgenic crosses (pi 2 strain) and after transposition of the mutator elements pUChsneory+ and P[lArB]. Enhancer mutations were found with a ten times higher frequency than suppressors. The 19 pUChsneory(+)- and 15 P[lArB]-induced enhancer mutations can be used for cloning of genomic sequences at the insertion sites of the mutator elements via plasmid rescue. Together with a large sample of X-ray-induced (48) and spontaneous (93) enhancer mutations a basic genetic analysis of this group of modifier genes was performed. On the basis of complementation and mapping data we estimate the number of enhancer genes at about 30 in the third chromosome and between 50 and 60 for the whole autosome complement. Therefore, enhancer of PEV loci are found in the Drosophila genome as frequently as suppressor genes. Many of the enhancer mutations display paternal effects consistent with the hypothesis that some of these mutations can induce genomic imprinting. First studies on the developmentally regulated gene expression of PEV enhancer genes were performed by beta-galactosidase staining in P[lArB] induced mutations.

WBS is an overgrowth malformation syndrome characterized by highly variable expressivity, associated with predisposition to different types of pediatric tumors including Wilms' tumor (WT), adrenocortical carcinoma (ADCC), rhabdomyosarcoma (RMS) and hepatoblastoma (HEP). Most cases are sporadic, however 15% of the cases are familial. Cytogenetic, genetic and molecular analysis of the different forms of this syndrome and associated tumors have provided increasing evidence that the gene (or genes) map to 11p15.5 and that genomic imprinting can account for the strange genetics of this syndrome/tumors [1]. Two candidate genes, H19 and Igf2, which are both imprinted, but in opposite direction, map close to but not within one of the two smallest region(s) defined both by constitutional and tumoral rearrangements. These two genes, H19 and Igf2, and their specific parental imprint, may thus account for the pattern of inheritance observed, the variable expressivity, the specific loss of alleles and the loss of imprint. However, that these genes map 400 kb away from one cluster of breakpoints observed in the cytogenetic cases of WBS suggests that other genes could be involved. Indeed, although mapping to a different subregion, a sequence wit the properties of a tumor Suppressor (rhabdomyosarcoma cell line) has recently been isolated [2].Furthermore, neither reduplication of the active Igf2 paternal allele nor relaxation of Igf2 imprinting is sufficient for tumorigenesis, thus indicating that other mutation(s) must occur. The phenotypic consequences of these aberrant expressions will be better understood when the tissues, the stage of development or the state of differentiation are precisely identified [3-5].

Abstract Background Angelman syndrome (AS) is a neurodevelopmental disorder that is caused by maternal genetic deficiency of a gene that encodes E6-AP ubiquitin-protein ligase (gene symbol UBE3A) mapping to chromosome 15q11-q13. AS leads to stiff and jerky gait, excess laughter, seizures, and severe intellectual disability. In some parts of the brain, the paternally inherited UBE3A gene is subject to genomic imprinting by the action of the UBE3A-antisense transcript (UBE3A-ATS) on the paternally inherited allele. Consequently, only the maternally inherited UBE3A gene is expressed in mature neurons. AS occurs due to deletions of the maternal 15q11 − 13 region, paternal uniparental disomy (UPD), imprinting center defects, mutations in the maternal UBE3A gene, or other unknown genetic malfunctions that result in a silenced maternal UBE3A gene in the specific imprinted regions of the brain. Results A potential treatment strategy for AS is to increase methylation of UBE3A-ATS to promote expression of the paternal UBE3A gene and thus ameliorate the clinical phenotypes of AS. We treated two sets of male identical twins with class I deletions with a 1 year treatment trial of either betaine and folic acid versus placebo. We found no statistically significant changes in the clinical parameters tested at the end of the 1 year trial, nor did we find any significant adverse events. Conclusions This study tested the hypothesis that by increasing the methylation of the UBE3A-antisense transcript in Angelman syndrome to promote expression of the silenced paternal UBE3A gene we may ameliorate the clinical phenotypes of AS. We treated two sets of identical twins with placebo versus betaine and folic acid. Although this study represented a novel approach to treating Angelman syndrome, the differences in the developmental testing results was not significant. This paper also discusses the value of monozygotic twin studies in minimizing confounding variables and its utility in conducting small treatment studies. Trial registration NCT00348933. Registered 6 July 2006.