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Plan

Plan. Understand Meiotic recombination Understand NAHR: Duplication amplification/deletion NAHR mediated inversion 8p23: NAHR mediated Polymorphism + NAHR mediated the rearrangements. NAHR and genomic disorders NAHR(?) and cancer: i(17q) example. Meiosis.

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Plan

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  1. Plan • Understand Meiotic recombination • Understand NAHR: • Duplication amplification/deletion • NAHR mediated inversion • 8p23: NAHR mediated Polymorphism + NAHR mediated the rearrangements. • NAHR and genomic disorders • NAHR(?) and cancer: i(17q) example

  2. Meiosis Whitby, M.C. Making crossovers during meiosis, Biochem. Soc. Trans. (2005) 33

  3. Basic NAHR mediated rearrangements. • Genomic Disorders can be classified by their molecular characteristics in: those with RB and those with NON RB • Duplications/Deletion of LCRs • Inversions • Interchromatid rearrangement • 8p rearrangements: • Polymorphic inversion. • Deletion of inverted region in heterozygous. • NAHR is a model that explains the observed rearrangements and whose predictions have been confirmed: DiGeorge (HSA22, CMTA1).

  4. Cancer & Repeats/NAHR • i(17q) is mediated by highly identical repeats within the SMS reagion • T(9;22) translocation (need to confirm breakpoints)

  5. i(17q) Barbouti A., Stankiewicz P , Nusbaum C, et. Al; Am J Hum Genet Mar 2004

  6. NAHR what is known • NAHR detected are those that result in progeny that survives but is easy to pick out (They are sick!). 8p, 17 (SMS/CMT), 15 (PW/AS), 22 (DiGeorge) provides evidence of its strength to increase variability and decease. • Somatic Recombination is a plausible explanation for cancer rearrangements.

  7. Interesting facts • NAHR may be mediated most often in LCR that are in recombination cold spots. CMT1A are shows reduced recombination rates. • NAHR also occurs in hotspots (breakpoints can be mapped to a few hundred of bases). • NAHR mediated rearrangements and decease: Deletion/duplicationGene Dossage ChangeDecease. • NAHR explains recurrent rearrangements, non- recurrent ones still have breakpoints within repeats! They may be explain by the NHEJ repair mechanism

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