A Microhomology-Mediated Break-Induced Replication Model for the Origin of Human Copy Number Variation 英文参考文献.docVIP

Review AMicrohomology-MediatedBreak-InducedReplication ModelfortheOriginofHumanCopyNumberVariation P.J.Hastings1*,GrzegorzIra1,JamesR.Lupski1,2,3 1Department ofMolecularandHumanGenetics,BaylorCollegeofMedicine,Houston,Texas,UnitedStates ofAmerica, 2DepartmentofPediatrics,BaylorCollegeof Medicine,Houston,Texas,UnitedStatesofAmerica,3TexasChildren’sHospital,Houston,Texas,UnitedStatesofAmerica recombination between segments that already occur as two or more copies. When this happens, sequences that lie between the Abstract: Chromosome structural changes with nonre- current endpoints associated with genomic disorders offer windows into the mechanism of origin of copy number variation (CNV). A recent report of nonrecurrent repeats that recombine will be either duplicated or deleted, thus changingthecopynumber.Thisprocessisreferredtoasnonallelic homologous recombination, or NAHR [18]. The repeated duplications associated with Pelizaeus-Merzbacher dis- sequencesthatrecombinemightoccasionallybehighlyrepetitive ease identified three distinctive characteristics. First, the sequences that occur widely in the human genome [19] but are majority of events can be seen to be complex, showing usually sequences that occur only twice or a few times (i.e., low- discontinuousduplicationsmixedwithdeletions,inverted duplications, and triplications. Second, junctions at end- pointsshowmicrohomologyof2–5basepairs(bp).Third, copyrepeats, LCRs,or segmental duplications,SDs).TheLCRs tendtooccurinclustersinhighlycomplexregionsofthegenome. endpoints occur near pre-existing low copy repeats (LCRs). Using these observations and evidence from DNA repair in other organisms, we derive a model of microhomology-mediated break-induced replication (MMBIR) for the origin of CNV and, ultimately, of LCRs. Weproposethatbreakageofreplicationforksinstressed cells that are deficient in homologous recombination inducesanaberrantrepairprocesswithfeaturesofbreak- induced replication (BIR). Under the