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FRCPath Part 1 Self Help Session. Patterns of Inheritance Helene Schlecht.

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FRCPath Part 1 Self Help Session


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    1. FRCPath Part 1 Self Help Session Patterns of Inheritance Helene Schlecht

    2. What is a pseudogene and how do pseudogenes originate? Illustrate your answer with examples from the human genome, indicating how pseudogenes can be involved in human disease and outlining current hypotheses on the associated mechanisms (2010 paper)

    3. Keywords • Non-processed pseudogenes • Processed pseudogenes/ retropseudogenes • Gene duplication : NAHR; NHEJ; FoSTeS/MMBIR • Gene conversion: DSBR; SDSA; Double HJ dissolution

    4. What is a pseudogene • A defective copy of a functional gene to which they show significant sequence homology.

    5. What is a pseudogene • Approx. 10% of 21000 human protein –coding genes have at least one pseudogene. • Thought to be evolutionarily advantages. • A significant number are transcribed and could regulate parent gene. • Directly implicated in production of endogenous siRNAs.

    6. What is a pseudogene • Nonprocessed pseudogenes – gDNA. • Processed/ retrotransposed pseudogenes – cDNA. • RNA pseudogenes. • Mitochondrial pseudogenes.

    7. Non-processed pseudogenes How do they originate? • Gene duplication • Accumulation of mutations via gene conversion mechanisms (genetic drift). • Inactivating mutations results in Pseudogenes.

    8. Gene Duplication • Non-allelic homologous recombination (NAHR) • Non-homologous end-joining (NHEJ) • Fork Stalling and Template Switching (FoSTeS/MMBIR)

    9. Gene Duplication- NAHR • Low-copy repeats (LCRs). • Misalignment during meiosis or mitosis. • LCRs on same chromosome and in direct orientation – duplication.

    10. Gene Duplication- NAHR Gu et al. 2008 PathoGenetics 1:4

    11. Gene Duplication- NHEJ • Major mechanism in repair of DSBs • With DSB homologous repair can result in duplications.

    12. Gene Duplication- NHEJ Lee et al. 2006 Human Molecular Genetics 15:2250

    13. Gene Duplication- FoSTeS Gu et al. 2008 PathoGenetics 1:4

    14. Pseudogenes in human disease • Gene conversion between pseudogene and parent gene can introduce mutations.

    15. Gene Conversion a Non-allelic (or interlocus) gene conversion in trans - sister chromatids or homologous chromosomes b Non-allelic gene-conversion events in cis c Interallelic gene-conversion between alleles on homologous chromosomes. Chen et al. 2007 Nature 8: 762

    16. Gene conversion Chen et al. 2007 Nature 8: 762

    17. Gene conversion - DSBR Chen et al. 2007 Nature 8: 762

    18. Gene conversion - SDSA Chen et al. 2007 Nature 8: 762

    19. Gene conversion – double HJ dissolution Chen et al. 2007 Nature 8: 762

    20. Gene conversion Chen et al. 2007 Nature 8: 762

    21. Pseudogenes in human disease Interlocus gene-conversion • Congenital Adrenal Hyperplasia CYP21A2 and CYP21A1P • Gaucher disease GBA and GBAP • Schwachman-Bodiam-Diamond Syndrome SBDS and SBDSP

    22. Pseudogenes in human disease • Generally >95% homologous • Donor in gene conversion is always the pseudogene. • Usually non-functional. • Usually on same chromosome.

    23. Pseudogenes in human disease Examples • Spinal Muscular Atrophy SMN1 and SMN2 • Von Willebrand atrophy VWF and VWFP

    24. Pseudogenes in human disease • Usually non-functional – except: SMN1 and SMN2 have about 99% similarity. SMN2 expression is impaired by a translationally silent SNP, which causes skipping of exon 7 in most transcripts.

    25. Pseudogenes in human disease • Usually on same chromosome – except: von Willebrand. VWF and VWFP are chromosomes 12 and 22. 97% homology Unexpected high freq gene conversion, due to position of VWF near end of chromosome 12 – known hot spots.

    26. References • Gene duplication: Gu et al. 2008 PathoGenetics 1:4 (genomic rearrangements) Hastings 2009 PLoS Genetics 5(1) (MMBIR) Lee et al. 2006 Hum Mol Genet 15:2250 (FoSTeS) Zhang et al. 2009 Nature Genetics 41:849 (FoSTeS/MMBIR) • Gene conversion: Chen et al. 2007 Nature 8: 762 • Retropseudogenes Ding et al. 2006 IUBMB Life 58:677