MMB (MGPG) Non traditional Inheritance Epigenetics. A.Turco

Transcription

1 MMB (MGPG) 2017 Non traditional Inheritance Epigenetics A.Turco

2 NON TRADITIONAL INHERITANCE EXCEPTIONS TO MENDELISM - Genetic linkage (2 loci close to each other) - Complex or Multifactorial Disease (MFD) - Variable expression (same mutation, different severity) - Codominace (AB0 blood group) - Genomic Imprinting (see Epigenetics) - Uniparental Disomy - Mitochondrial inheritance (maternal) - Dynamic mutations (triplet repeat expansions) - others.. (Pritchard, Korf, 2013)

3 .changes in gene expression (active versus inactive genes) that does not involve changes of the DNA sequence - a change in phenotype without a change in genotype. Epigenetic change is a regular and natural occurrence but can also be influenced by several factors including age, the environment/lifestyle, and disease state. Epigenetic modifications occur in cell differentiation processes. Or, epigenetic change can have more damaging effects that can result in diseases like cancer. At least three systems including DNA methylation, histone modification and non-coding RNA (ncrna)-associated gene silencing are currently considered to initiate and sustain epigenetic change. ncrna Histone modifications GENE SILENCING DNA methylation

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6 Methyl groups (CH3) in red, «turn off» gene activity

7 Histone Acetylation/Deacetylation

8 Chromatin Conformation: DNA methylation and the histone code

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10 Genome Res 2009

11 Surprise..!

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15 DNA: the hidden bases How many DNA bases are there?...4? Not really. Maybe SEVEN! 1. Adenine 2. Guanine 3. Thymine 4. Cytosine 5. Methylcytosine (5-mC) C 5-mC 6. Hydroxymethylcytosine (5-hmC) 7. 5-Formylcytosine (5-fC) 5-hmC

16 GENOME REGULATION

17 Genomic Medicine Past and Future

18 The classic Mendel «rule» The Maternal (A) and the Paternal (a) alleles are functionally equivalent That s not always the case!

19 Non correspondence between the M and the P genomes Il genoma paterno e materno anche se geneticamente quasi identici, si comportano in modo diverso. Solo gli oociti in cui vengono combinati un genoma paterno e un genoma materno danno origine a un embrione normale

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26 PWS and AS gene products (NOT proteins)

27 NON TRADITIONAL INHERITANCE EXCEPTIONS TO MENDELISM - Genetic linkage (2 loci close to each other) - Complex or Multifactorial Disease (MFD) - Variable expression (same mutation, different severity) - Codominace (AB0 blood group) - Genomic Imprinting (see Epigenetics) - Uniparental Disomy - Mitochondrial inheritance (maternal) - Dynamic mutations (triplet repeat expansions) - others.. (Pritchard, Korf, 2013)

28 Types of Mutations Single base pair substitutions missense, nonsense, splice site Deletions Duplications Inversions Insertions Repeat Expansions

29 Trinucleotide repeat: a type of short tandem repeat CAG 7 repeats 8 repeats The size of repeat region varies between individuals and is polymorphic in normal individuals For some trinucleotide repeats, when the number of repeats exceeds a certain threshold, a neurological disease results

30 NON CODING EXPANSIONS

31 Syndromic XLID X-Linked Intellectual Disability

32 FMR1 in FRAXA Mental Retardation 17 exon FMR1 gene cloned in 1991 Highest FMR1 expression in neurons and spermatogonia FMR1P associates with translating ribososmes and is involved in nucleocytoplasmic shuttling Approximate repeat ranges: 6-45 CGGs (0-3 AGGs) Unmethylated, Stable, Normal CGGs (0-2 AGGs) Unmethylated, +/- Instability, Normal CGGs Unmethylated, Premutation - Unstable, Normal > 200 CGGs - Methylated, no FMR1, Unstable, Affected

33 Characteristics Mild to Moderate Mental Retardation Long, narrow face Large, protuberant ears Macroorchidism (enlarged testicles)

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37 Pfxa2 sequence

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42 Verona

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44 Chromatin conformation and Histone modifications

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46 Chromosome 11p15.5 imprinted regions Mat Pat Mat. = Maternal allele. Pat = Paternal allele Red box = Unmethylated (expressed) gene. Blue box = Methylated (inactive) gene