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/duplicationGene Dossage ChangeDecease.• NAHR explains recurrent rearrangements, non- recurrent

ones still have breakpoints within repeats! They may be explain by the NHEJ repair mechanism