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

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).

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

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

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.

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