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Systemic injection of Mecp2Bnull/y mice with scAAV9/MeCP2 virus results in MeCP2 expression in different cell types in brain. Garg S K et al. J. Neurosci. 2013;33:13612-13620 ©2013 by Society for Neuroscience MeCP2 expressed from virus binds to DNA, restores normal neuronal somal size, and improves survival. Garg S K et al. J. Neurosci. 2013;33:13612-13620 ©2013 by Society for Neuroscience Inappropriate Silencing of Genes • Fragile-X Syndrome Fragile-X Syndrome Length Methylation Females Males Stable 6 to ~45 Unmethylated Not affected Not affected Gray zone ~45 to ~55 Unmethylated Not affected Not affected Premutation ~55 to ~200 Unmethylated Usually not affected Usually not affected Full mutation >200 Completely methylated ~50% affected All affected 11_05.jpg 11_05_2.jpg Skewed X-Chromosome inactivation in a family with Fragile X Southern Blot Analysis Blood sample Digest genomic DNA with EcoRI and EagI Electrophoresis and transfer to membrane Hybridize with FMR1 specific probe “A normal female will show an unmethylated 2.8-kb band and a 5.2-kb methylated band that correspond to the normal FMR1 gene present in the active and inactive X chromosome, respectively.” DNA Methylation • Beckwith-Wiedemann syndrome 12 DNA Methylation • Beckwith-Wiedemann syndrome – Above average birth weight – Increase growth after birth (>95% growth curve) – Enlarged organs – Hypoglycemic following birth – Increase risk of cancers • Imprinting defect located at 11p15.5 13 Beckwith-Wiedemann syndrome • Genetic causes of BWS: – Maternal DMR hypermethylation – UPD – Remainder unknown 14 15 The Journal of Pathology Volume 211, Issue 3, pages 261-268, 18 DEC 2006 DOI: 10.1002/path.2116 http://onlinelibrary.wiley.com/doi/10.1002/path.2116/full#fig1 The Journal of Pathology Volume 211, Issue 3, pages 261-268, 18 DEC 2006 DOI: 10.1002/path.2116 http://onlinelibrary.wiley.com/doi/10.1002/path.2116/full#fig3 Genes Dev. Vol. 11, No. 23, pp. 3128-3142, December 1, 1997 Mouse mutant embryos overexpressing IGF-II exhibit phenotypic features of the Beckwith-Wiedemann and Simpson-GolabiBehmel syndromes Jonathan Eggenschwiler,1 Thomas Ludwig,2 Peter Fisher,3 Philip A. Leighton,4,5 Shirley M. Tilghman,4 and Argiris Efstratiadis1,6 18 Figure 2 The epigenetic progenitor model of cancer. Feinberg AP et al. (2005) The epigenetic progenitor origin of human cancer Nat Rev gene. 7: 21–33 doi:10.1038/nri1748 Prader-Willi and Angelman Syndrome Prader-Willi Angelman Mild mental retardation endocrine abnormalities Severe impairment and loss of speech seizures and ataxia temper tantrums unprovoked laughter Obesity 1 in 15,000 hyperactivity 1 in 15,000 24 Prader-Willi and Angelman Syndrome • Angelman syndrome • Genes/proteins involved 15q11-13 • Prader-Willi syndrome • Genes/proteins involved 25 Prader-Willi and Angelman Syndrome • UBE3A is paternally silenced • This primarily occurs in brain, other tissues show biallelic expression 26 Prader-Willi and Angelman Syndrome • What happens in each pathologies? • If the maternal copy of chromosome 15 is missing, then genes normally expressed from this parental origin are not expressed • Consequences… 27 Prader-Willi and Angelman Syndrome • If paternal chromosome 15 is missing, then only the maternally expressed proteins are made • Consequence: UBE3A is ok, but other genes in the region are not expressed…Prader-Willi syndrome 28 Prader-Willi and Angelman Syndrome • Thus, two different diseases based on the cells “memory” of methylation – alter the memory, alter the phenotype 29 Prader-Willi and Angelman Syndrome • How do you “lose” chromosome 15? – Microdeletion of 15q11-13 on one chromsome – 70% – Single gene mutation – 15% of AS – Defect in imprinting centre (IC) – 5% – Uniparental Disomy – 30% of PWS, 5% AS 30 Prader-Willi and Angelman Syndrome 31 Uniparental Disomy • Receive two chromosomes from one parent • Eg. Paternal disomy – both of chromosome 15 are from father, thus both have silenced UBE3A 32 Uniparental Disomy • How does it happen? • Trisomic Rescue - majority • Monosomic Duplication 33 Meiosis I 34 Meiosis II 35 Meiosis I Non-disjunction 36 Meiosis I Non-disjunction Fertilization Trisomy Meiosis I non-disjunction always creates a problem 37 Meiosis II Non-disjunction Fertilization Fertilization Trisomy Normal 2/3 gametes following Meiosis II non-disjunction are normal 38 Trisomy • Trisomy for most autosomal chromosomes is lethal • BIG exception: Trisomy 21, smallest autosomal chromosome, fewest genes, not lethal • Under rare conditions, some autosomal trisomies can escape – Trisomic Rescue 39 Trisomic Rescue following Meiosis I Non-disjunction + Two copies of homologous, but not identical, chromosomes Maternal Anaphase lag Maternal Paternal M,M 1/3 M,P 1/3 M,P 1/3 40 Trisomic Rescue following Meiosis II Non-disjunction + Two copies of identical chromosomes Anaphase lag M,M 1/3 M,P 2/3 41 Uniparental Disomy • How does it happen? • Trisomic Rescue - majority • Monosomic Duplication 42 Monosomic Duplication + Two identical copies of paternal chromosome isodisomy P,P 43 Parental Origin Determines Phenotype 15 { Prader-Willi Syndrome M,M Prader-Willi Syndrome M,M Angelman Syndrome P,P 44 Prader-Willi and Angelman syndrome • Non-disjunction is more common in Meiosis I in females • In human females, Meiosis I starts before birth but is arrested at diplotene stage (late prophase I) • Oocytes sit like this for decades • Complete meiosis II once each month • While arrested at the diplotene stage, the tetrad chromosomes are held together by chiasmata (formed during recombination) • If a pair of chromosomes don’t undergo recombination, the lack of chiasmata can contribute to non-disjunction • Uniparental Disomy – 30% of PWS, 5% AS Maternal non-disjunction and trisomic rescue leading to the pair of maternal chromosomes 45 Uniparental Disomy and Human Disease Eric Engel. Some lessons from uniparental disomy (UPD) in the framework of contemporary cytogenetics and molecular biology. Atlas Genet Cytogenet Oncol Haematol. December 2003. 46 Trisomic rescue of Meiosis II nondisjunction can have other problems { Anaphase lag Pair of identical chromosomes (isochromosomes) 47 Uniparental disomy as a mechanism for human genetic disease. Spence JE, Perciaccante RG, Greig GM, Willard HF, Ledbetter DH, Hejtmancik JF, Pollack MS, O'Brien WE, Beaudet AL. Am J Hum Genet. 1988 Feb;42(2):217-26. CFTR-/+ CFTR-/- { CFTR+/+ Uniparental isodisomy and reduction to homozygosity Pair of identical Chromosome 7 Harboring CFTR mutation 48