Mechanisms of change in gene copy number

Nature Reviews Genetics

Volumn 10, Issue 8, 2009, Pages 551-564

  Hastings, P J ^a   Lupski, James R ^a,b,c   Rosenberg, Susan M ^a,b   Ira, Grzegorz ^a  

^a Department of Molecular and Human Genetics ^*  (United States)

^b BAYLOR COLLEGE OF MEDICINE   (United States)

^c TEXAS CHILDREN S HOSPITAL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CHROMOSOME DELETION; CHROMOSOME DUPLICATION; COPY NUMBER VARIATION; DNA REPAIR; DNA REPLICATION; DOUBLE STRANDED DNA BREAK; EVOLUTIONARY ADAPTATION; HOMOLOGOUS RECOMBINATION; HUMAN; NON HOMOLOGOUS END JOINING; NONHUMAN; PRIORITY JOURNAL; REVIEW; STRUCTURAL CHROMOSOME ABERRATION;

GENE DOSAGE; GENOME-WIDE ASSOCIATION STUDY; HUMANS; MODELS, GENETIC; RECOMBINATION, GENETIC;

EID: 67651098662     PISSN: 14710056     EISSN: 14710064     Source Type: Journal    
DOI: 10.1038/nrg2593     Document Type: Review

References (157)

1. Iafrate, A. J. et al. Detection of large-scale variation in the human genome. Nature Genet. 36, 949-951 (2004).
2. Kidd, J. M. et al. Mapping and sequencing of structural variation from eight human genomes. Nature 453, 56-64 (2008).
3. Korbel, J. O. et al. Paired-end mapping reveals extensive structural variation in the human genome. Science 318, 420-426 (2007).
4. Redon, R. et al. Global variation in copy number in the human genome. Nature 444, 444-454 (2006). A survey of 270 individuals from the human HapMap samples using SNP arrays and comparative genomic hybridization.
5. Sebat, J. et al. Large-scale copy number polymorphism in the human genome. Science 305, 525-528 (2004).
6. Wong, K. K. et al. A comprehensive analysis of common copy-number variations in the human genome. Am. J. Hum. Genet. 80, 91-104 (2007).
7. Bruder, C. E. G. et al. Phenotypically concordant and discordant monozygotic twins display different DNA copy-number-variation profiles. Am. J. Hum. Genet. 82, 1-9 (2008).
8. Piotrowski, A. et al. Somatic mosaicism for copy number variation in differentiated human tissues. Hum. Mutat. 29, 1118-1124 (2008).
9. Beckmann, J. S., Estivill, X. & Antonarakis, S. E. Copy number variants and genetic traits: closer to the resolution of phenotypic to genotypic variability. Nature Rev. Genet. 8, 639-646 (2007).
10. Dumas, L. et al. Gene copy number variation spanning 60 million years of human and primate evolution. Genome Res. 17, 1266-1277 (2007). This paper traces the history of copy number variation through the evolution of the primate lineage.
11. Nahon, J. L. Birth of 'human-specific' genes during primate evolution. Genetica 118, 193-208 (2003).
12. Bailey, J. A. & Eichler, E. E. Primate segmental duplications: crucibles of evolution, diversity and disease. Nature Rev. Genet. 7, 552-564 (2006).
13. Stankiewicz, P., Shaw, C. J., Withers, M., Inoue, K. & Lupski, J. R. Serial segmental duplications during primate evolution result in complex human genome architecture. Genome Res. 14, 2209-2220 (2004).
14. Marques-Bonet, T. et al. A burst of segmental duplications in the genome of the African great ape ancestor. Nature 457, 877-881 (2009).
15. Inoue, K. & Lupski, J. R. Molecular mechanisms for genomic disorders. Annu. Rev. Genomics Hum. Genet. 3, 199-242 (2002).
16. Ohno, S. Evolution by Gene Duplication (Springer, Berlin, New York, 1970).
17. Rotger, M. et al. Partial deletion of CYP2B6 owing to unequal crossover with CYP2B7. Pharmacogenet. Genomics 17, 885-890 (2007).
18. Zhang, F. et al. The DNA replication FoSTeS/MMBIR mechanism can generate human genomic, genic, and exon shuffling rearrangements. Nature Genet. 41, 849-853 (2009). Studies of disease associated rearrangements in proximal chromosome 17p reveal complex rearrangements of varying size and occurrence during mitosis with potential implications for genetic counselling regarding recurrence risk.
19. Volik, S. et al. Decoding the fine-scale structure of a breast cancer genome and transcriptome. Genome Res. 16, 394-404 (2006).
20. Brodeur, G. M. & Hogarty, M. D. in The Genetic Basis of Human Cancer (eds. Vogelstein, B. & Kinzler, K. W.) 161-172 (McGraw-Hill, New York, 1998).
21. Frank, B. et al. Copy number variant in the candidate tumor suppressor gene MTUS1 and familial breast cancer risk. Carcinogenesis 28, 1442-1445 (2007).
22. Lupski, J. R. Genomic disorders: structural features of the genome can lead to DNA rearrangement and human disease traits. Trends Genet. 14, 417-422 (1998).
23. Stranger, B. E. et al. Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science 315, 848-853 (2007).
24. Hastings, P. J., Ira, G. & Lupski, J. R. A microhomology-mediated break-induced replication model for the origin of human copy number variation. PLoS Genet. 5, e1000327 (2009). This review presents the MMBIR model for chromosomal rearrangement with detail of the evidence on which it is based.
25. Friedberg, E. C. et al. DNA Repair and Mutagenesis (ASM, Washington DC, 2005).
26. Lee, J. A., Carvalho, C. M. & Lupski, J. R. A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 131, 1235-1247 (2007). Description of the complex structure and microhomology of non-recurrent duplications seen in patients with a genomic disorder.
27. Nobile, C. et al. Analysis of 22 deletion breakpoints in dystrophin intron 49. Hum. Genet. 110, 418-421 (2002).
28. Carvalho, C. M. et al. Complex rearrangements in patients with duplications of MECP2 can occur by Fork Stalling and Template Switching. Hum. Mol. Genet. 18, 2188-2203 (2009).
29. Chen, J. M., Chuzhanova, N., Stenson, P. D., Férec, C. & Cooper, D. N. Intrachromosomal serial replication slippage in trans gives rise to diverse genomic rearrangements involving inversions. Hum. Mutat. 26, 362-373 (2005).
30. Gajecka, M. et al. Unexpected complexity at breakpoint junctions in phenotypically normal individuals and mechanisms involved in generating balanced translocations t(1;22)(p36;q13). Genome Res. 18, 1733-1742 (2008).
31. Sheen, C. R. et al. Double complex mutations involving F8 and FUNDC2 caused by distinct break-induced replication. Hum. Mutat. 28, 1198-2006 (2007).
32. Vissers, L. E. et al. Complex chromosome 17p rearrangements associated with low-copy repeats in two patients with congenital anomalies. Hum. Genet. 121, 697-709 (2007).
33. Stankiewicz, P. et al. Genome architecture catalyzes nonrecurrent chromosomal rearrangements. Am. J. Hum. Genet. 72, 1101-1116 (2003).
34. Lee, J. A. et al. Role of genomic architecture in PLP1 duplication causing Pelizaeus-Merzbacher disease. Hum. Mol. Genet. 15, 2250-2265 (2006).
35. Lee, J. A. et al. Spastic paraplegia type 2 associated with axonal neuropathy and apparent PLP1 position effect. Ann. Neurol. 59, 398-403 (2006).
36. Lovett, S. T., Hurley, R. L., Sutera, V. A. Jr, Aubuchon, R. H. & Lebedeva, M. A. Crossing over between regions of limited homology in Escherichia coli. RecA-dependent and RecA-independent pathways. Genetics 160, 851-859 (2002).
37. Liskay, R. M., Letsou, A. & Stachelek, J. L. Homology requirement for efficient gene conversion between duplicated chromosomal sequences in mammalian cells. Genetics 115, 161-167 (1987).
38. Reiter, L. T. et al. Human meiotic recombination products revealed by sequencing a hotspot for homologous strand exchange in multiple HNPP deletion patients. Am. J. Hum. Genet. 62, 1023-1033 (1998).
39. Stankiewicz, P. & Lupski, J. R. Genome architecture, rearrangements and genomic disorders. Trends Genet. 18, 74-82 (2002).
40. Krogh, B. O. & Symington, L. S. Recombination proteins in yeast. Annu. Rev. Genet. 38, 233-271 (2004).
41. Pâques, F. & Haber, J. E. Multiple pathways of recombination induced by double-strand breaks in Saccharomyces cerevisiae. Microbiol. Mol. Biol. Rev. 63, 349-404 (1999).
42. Esposito, M. S. Evidence that spontaneous mitotic recombination occurs at the two-strand stage. Proc. Natl Acad. Sci. USA 75, 4436-4440 (1978).
43. Stark, J. M. & Jasin, M. Extensive loss of heterozygosity is suppressed during homologous repair of chromosomal breaks. Mol. Cell. Biol. 23, 733-743 (2003).
44. Dupaigne, P. et al. The Srs2 helicase activity is stimulated by Rad51 filaments on dsDNA: implications for crossover incidence during mitotic recombination. Mol. Cell. 29, 243-254 (2008).
45. Sun, W. et al. The FANCM ortholog Fml1 promotes recombination at stalled replication forks and limits crossing over during DNA double-strand break repair. Mol. Cell 32, 118-128 (2008).
46. Ira, G., Malkova, A., Liberi, G., Foiani, M. & Haber, J. E. Srs2 and Sgs1-Top3 suppress crossovers during double-strand break repair in yeast. Cell 115, 401-411 (2003).
47. Prakash, R. et al. Yeast Mph1 helicase dissociates Rad51-made D-loops: implications for crossover control in mitotic recombination. Genes Dev. 23, 67-79 (2009).
48. Wu, L. & Hickson, I. D. The Bloom's syndrome helicase suppresses crossing over during homologous recombination. Nature 426, 870-874 (2003).
49. Prado, F. & Aguilera, A. Control of cross-over by single-strand DNA resection. Trends. Genet. 19, 428-431 (2003).
50. Smith, C. E., Llorente, B. & Symington, L. S. Template switching during break-induced replication. Nature 447, 102-105 (2007). This paper shows experimental evidence from yeast on the nature of BIR. Specifically, template switching between homologous chromosomes (or sometimes non-homologous chromosomes, which causes translocation). It showed replication out to the telomere after switching.
51. Bauters, M. et al. Nonrecurrent MECP2 duplications mediated by genomic architecture-driven DNA breaks and break-induced replication repair. Genome Res. 18, 847-858 (2008).
52. Deem, A. et al. Defective break-induced replication leads to half-crossovers in Saccharomyces cerevisiae. Genetics 179, 1845-1860 (2008).
53. Narayanan, V. & Lobachev, K. S. Intrachromosomal gene amplification triggered by hairpin-capped breaks requires homologous recombination and is independent of nonhomologous end-joining. Cell Cycle 6, 1814-1818 (2007).
54. Payen, C., Koszul, R., Dujon, B. & Fischer, G. Segmental duplications arise from Pol32-dependent repair of broken forks through two alternative replication-based mechanisms. PLoS Genet. 4, e1000175 (2008). Evidence from yeast that LCRs arise by a replicative mechanism, specifically one involving BIR.
55. Schmidt, K. H., Wu, J. & Kolodner, R. D. Control of translocations between highly diverged genes by Sgs1, the Saccharomyces cerevisiae homolog of the Bloom's syndrome protein. Mol. Cell. Biol. 26, 5406-5420 (2006).
56. Lin, F. L., Sperle, K. & Sternberg, N. Model for homologous recombination during transfer of DNA into mouse L cells: role for DNA ends in the recombination process. Mol. Cell. Biol. 4, 1020-1034 (1984).
57. Sweigert, S. E. & Carroll, D. Repair and recombination of X-irradiated plasmids in Xenopus laevis oocytes. Mol. Cell. Biol. 10, 5849-5856 (1990).
58. Haber, J. E. Exploring the pathways of homologous recombination. Curr. Opin. Cell Biol. 4, 401-412 (1992).
59. Elliott, B., Richardson, C. & Jasin, M. Chromosomal translocation mechanisms at intronic Alu elements in mammalian cells. Mol. Cell 17, 885-894 (2005).
60. Rayssiguier, C., Thaler, D. S. & Radman, M. The barrier to recombination between Escherichia coli and Salmonella typhimurium is disrupted in mismatch repair mutants. Nature 342, 396-401 (1989).
61. Unal, E. et al. DNA damage response pathway uses histone modification to assemble a double-strand break-specific cohesin domain. Mol. Cell 16, 991-1002 (2004).
62. Strom, L., Lindroos, H. B., Shirahige, K. & Sjogren, C. Postreplicative recruitment of cohesin to doublestrand breaks is required for DNA repair. Mol. Cell 16, 1003-1015 (2004).
63. Kim, J. S., Krasieva, T. B., LaMorte, V., Taylor, A. M. & Yokomori, K. Specific recruitment of human cohesin to laser-induced DNA damage. J. Biol. Chem. 277, 45149-45153 (2002).
64. Sjogren, C. & Nasmyth, K. Sister chromatid cohesion is required for postreplicative double-strand break repair in Saccharomyces cerevisiae. Curr. Biol. 11, 991-995 (2001).
65. Kobayashi, T., Horiuchi, T., Tongaonkar, P., Vu, L. & Nomura, M. SIR2 regulates recombination between different rDNA repeats, but not recombination within individual rRNA genes in yeast. Cell 117, 441-453 (2004).
66. Kobayashi, T. & Ganley, A. R. Recombination regulation by transcription-induced cohesin dissociation in rDNA repeats. Science 309, 1581-1584 (2005).
67. Kaye, J. A. et al. DNA breaks promote genomic instability by impeding proper chromosome segregation. Curr. Biol. 14, 2096-2106 (2004).
68. Soutoglou, E. et al. Positional stability of single double-strand breaks in mammalian cells. Nature Cell Biol. 9, 675-682 (2007).
69. Oh, S. D. et al. BLM ortholog, Sgs1, prevents aberrant crossing-over by suppressing formation of multichromatid joint molecules. Cell 130, 259-272 (2007).
70. Jain, S. et al. A recombination execution checkpoint regulates the choice of homologous recombination pathway during DNA double-strand break repair. Genes Dev. 23, 291-303 (2009).
71. McVey, M. & Lee, S. E. MMEJ repair of doublestrand breaks (director's cut): deleted sequences and alternative endings. Trends Genet. 24, 529-538 (2008).
72. Lieber, M. R. The mechanism of human nonhomologous DNA end joining. J. Biol. Chem. 283, 1-5 (2008).
73. Daley, J. M., Palmbos, P. L., Wu, D. & Wilson, T. E. Nonhomologous end joining in yeast. Annu. Rev. Genet. 39, 431-451 (2005).
74. Haviv-Chesner, A., Kobayashi, Y., Gabriel, A. & Kupiec, M. Capture of linear fragments at a double-strand break in yeast. Nucleic Acids Res. 35, 5192-5202 (2007).
75. Yu, X. & Gabriel, A. Ku-dependent and Ku-independent end-joining pathways lead to chromosomal rearrangements during double-strand break repair in Saccharomyces cerevisiae. Genetics 163, 843-856 (2003).
76. Nickoloff, J. A., De Haro, L. P., Wray, J. & Hromas, R. Mechanisms of leukemia translocations. Curr. Opin. Hematol. 15, 338-345 (2008).
77. McClintock, B. Chromosome organization and genic expression. Cold Spring Harb. Symp. Quant. Biol. 16, 13-47 (1951).
78. Tanaka, H. & Yao, M. C. Palindromic gene amplification - an evolutionarily conserved role for DNA inverted repeats in the genome. Nature Rev. Cancer 9, 216-224 (2009).
79. Tanaka, H., Bergstrom, D. A., Yao, M. C. & Tapscott, S. J. Large DNA palindromes as a common form of structural chromosome aberrations in human cancers. Hum. Cell 19, 17-23 (2006).
80. Coquelle, A., Pipiras, E., Toledo, F., Buttin, G. & Debatisse, M. Expression of fragile sites triggers intrachromosomal mammalian gene amplification and sets boundaries to early amplicons. Cell 89, 215-225 (1997).
81. Shaw, C. J. & Lupski, J. R. Non-recurrent 17p11.2 deletions are generated by homologous and non-homologous mechanisms. Hum. Genet. 116, 1-7 (2005).
82. Arlt, M. F. et al. Replication stress induces genomewide copy number changes in human cells that resemble polymorphic and pathogenic variants. Am. J. Hum. Genet. 84, 339-350 (2009).
83. Durkin, S. G. et al. Replication stress induces tumor-like microdeletions in FHIT/FRA3B. Proc. Natl Acad. Sci. USA 105, 246-251 (2008).
84. Kuo, M. T., Vyas, R. C., Jiang, L. X. & Hittelman, W. N. Chromosome breakage at a major fragile site associated with P-glycoprotein gene amplification in multidrug-resistant CHO cells. Mol. Cell Biol. 14, 5202-5211 (1994).
85. Coquelle, A., Rozier, L., Dutrillaux, B. & Debatisse, M. Induction of multiple double-strand breaks within an hsr by meganucleaseI-SceI expression or fragile site activation leads to formation of double minutes and other chromosomal rearrangements. Oncogene 21, 7671-7679 (2002).
86. Michel, B., Ehrlich, S. D. & Uzest, M. DNA doublestrand breaks caused by replication arrest. EMBO J. 16, 430-438 (1997).
87. Albertini, A. M., Hofer, M., Calos, M. P. & Miller, J. H. On the formation of spontaneous deletions: the importance of short sequence homologies in the generation of large deletions. Cell 29, 319-328 (1982).
88. Farabaugh, P. J., Schmeissner, U., Hofer, M. & Miller, J. H. Genetic studies of the lac repressor. VII. On the molecular nature of spontaneous hotspots in the lacI gene of Escherichia coli. J. Mol. Biol. 126, 847-857 (1978).
89. Ikeda, H., Shimizu, H., Ukita, T. & Kumagai, M. A novel assay for illegitimate recombination in Escherichia coli: stimulation of lambda bio transducing phage formation by ultra-violet light and its independence from RecA function. Adv. Biophys. 31, 197-208 (1995).
90. Shimizu, H. et al. Short-homology-independent illegitimate recombination in Escherichia coli: distinct mechanism from short-homology-dependent illegitimate recombination. J. Mol. Biol. 266, 297-305 (1997).
91. Bi, X. & Liu, L. F. recA-independent and recA dependent intramolecular plasmid recombination: differential homology and requirement and distance effect. J. Mol. Biol. 235, 414-423 (1994).
92. Mazin, A. V., Kuzminov, A. V., Dianov, G. L. & Salganik, R. I. Mechanisms of deletion formation in Escherichia coli plasmids. II. Deletions mediated by short direct repeats. Mol. Gen. Genet. 228, 209-214 (1991).
93. Chedin, F., Dervyn, E., Dervyn, R., Ehrlich, S. D. & Noirot, P. Frequency of deletion formation decreases exponentially with distance between short direct repeats. Mol. Microbiol. 12, 561-569 (1994).
94. Lovett, S. T., Gluckman, T. J., Simon, P. J., Sutera Jr, V. A. & Drapkin, P. T. Recombination between repeats in Escherichia coli by a recA- independent, proximity-sensitive mechanism. Mol. Gen. Genet. 254, 294-300 (1994).
95. Bierne, H., Vilette, D., Ehrlich, S. D. & Michel, B. Isolation of a dnaE mutation which enhances RecAindependent homologous recombination in the Escherichia coli chromosome. Mol. Microbiol. 24, 1225-1234 (1997).
96. Saveson, C. J. & Lovett, S. T. Enhanced deletion formation by aberrant DNA replication in Escherichia coli. Genetics 146, 457-470 (1997).
97. Bzymek, M. & Lovett, S. T. Instability of repetitive DNA sequences: the role of replication in multiple mechanisms. Proc. Natl Acad. Sci. USA 98, 8319-8325 (2001).
98. Lovett, S. T. & Feshenko, V. V. Stabilization of diverged tandem repeats by mismatch repair: evidence for deletion formation via a misaligned replication intermediate. Proc. Natl Acad. Sci. USA 93, 7120-7124 (1996).
99. Cairns, J. & Foster, P. L. Adaptive reversion of a frameshift mutation in Escherichia coli. Genetics 128, 695-701 (1991).
100. Slack, A., Thornton, P. C., Magner, D. B., Rosenberg, S. M. & Hastings, P. J. On the mechanism of gene amplification induced under stress in Escherichia coli. PLoS Genet. 2, e48 (2006). Experimental evidence from E. coli suggesting that chromosomal structural change occurs by a replicative mechanism, and also revealing that the characteristics of amplification in E. coli are similar to those of non-recurrent changes seen in human genomic disorders. Proposes CNV formation by template switching between forks.
101. Kugelberg, E., Kofoid, E., Reams AB, Andersson, D. I. & Roth, J. R. Multiple pathways of selected gene amplification during adaptive mutation. Proc. Natl Acad. Sci. USA 103, 17319-17324 (2006).
102. Allgood, N. D. & Silhavy, T. J. Escherichia coli xonA(sbcB) mutants enhance illegitimate recombination. Genetics 127, 671-680 (1991).
103. Bzymek, M., Saveson, C. J., Feschenko, V. V. & Lovett, S. T. Slipped misalignment mechanisms of deletion formation: in vivo susceptibility to nucleases. J. Bacteriol. 181, 477-482 (1999).
104. Lydeard, J. R., Jain, S., Yamaguchi, M. & Haber, J. E. Break-induced replication and telomeraseindependent telomere maintenance require Pol32. Nature 448, 820-823 (2007).
105. VanHulle, K. et al. Inverted DNA repeats channel repair of distant double-strand breaks into chromatid fusions and chromosomal rearrangements. Mol. Cell. Biol. 27, 2601-2614 (2007).
106. Davis, A. P. & Symington, L. S. RAD51-dependent break-induced replication in yeast. Mol. Cell. Biol. 24, 2344-2351 (2004).
107. McVey, M., Adams, M., Staeva-Vieira, E. & Sekelsky, J. J. Evidence for multiple cycles of strand invasion during repair of double-strand gaps in Drosophila. Genetics 167, 699-705 (2004).
108. Bindra, R. S., Crosby, M. E. & Glazer, P. M. Regulation of DNA repair in hypoxic cancer cells. Cancer Metastasis Rev. 26, 249-260 (2007).
109. Huang, L. E., Bindra, R. S., Glazer, P. M. & Harris, A. L. Hypoxia-induced genetic instability - a calculated mechanism underlying tumor progression. J. Mol. Med. 85, 139-148 (2007).
110. Bindra, R. S. & Glazer, P. M. Repression of RAD51 gene expression by E2F4/p130 complexes in hypoxia. Oncogene. 26, 2048-2057 (2007).
111. Coquelle, A., Toledo, F., Stern, S., Bieth, A. & Debatisse, M. A new role for hypoxia in tumor progression: induction of fragile site triggering genomic rearrangements and formation of complex DMs and HSRs. Mol. Cell 2, 259-265 (1998).
112. Hastings, P. J., Bull, H. J., Klump, J. R. & Rosenberg, S. M. Adaptive amplification: an inducible chromosomal instability mechanism. Cell 103, 723-731 (2000).
113. Lombardo, M.-J., Aponyi, I. & Rosenberg, S. M. General stress response regulator RpoS in adaptive mutation and amplification in Escherichia coli. Genetics 166, 669-680 (2004).
114. Ponder, R. G., Fonville, N. C. & Rosenberg, S. M. A switch from high-fidelity to error-prone DNA doublestrand break repair underlies stress-induced mutation. Mol. Cell 19, 791-804 (2005).
115. Mullighan, C. G. et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 446, 758-764 (2007).
116. Shao, L. et al. Identification of chromosome abnormalities in subtelomeric regions by microarray analysis: a study of 5,380 cases. Am. J. Med. Genet. A 146A, 2242-2251 (2008).
117. Yatsenko, S. A. et al. Molecular mechanisms for subtelomeric rearrangements associated with the 9q34.3 microdeletion syndrome. Hum. Mol. Genet. 18, 1924-1936 (2009).
118. Zhang, L., Lu, H. H., Chung, W. Y., Yang, J. & Li, W. H. Patterns of segmental duplication in the human genome. Mol. Biol. Evol. 22, 135-141 (2005).
119. She, X. et al. The structure and evolution of centromeric transition regions within the human genome. Nature 430, 857-864 (2004).
120. Nguyen, D. Q., Webber, C. & Ponting, C. P. Bias of selection on human copy-number variants. PLoS Genet. 2, e20 (2006).
121. Visser, R. et al. Identification of a 3.0-kb major recombination hotspot in patients with Sotos syndrome who carry a common 1.9-Mb microdeletion. Am. J. Hum. Genet. 76, 52-67 (2005).
122. de Smith, A. J. et al. Small deletion variants have stable breakpoints commonly associated with Alu elements. PLoS ONE 3, e3104 (2008).
123. Bacolla, A. et al. Breakpoints of gross deletions coincide with non-B DNA conformations. Proc. Natl Acad. Sci. USA 101, 14162-14167 (2004).
124. Bacolla, A., Wojciechowska, M., Kosmider, B., Larson, J. E. & Wells, R. D. The involvement of non-B DNA structures in gross chromosomal rearrangements. DNA Repair (Amst.) 5, 1161-1170 (2006).
125. Inagaki, H. et al. Chromosomal instability mediated by non-B DNA: cruciform conformation and not DNA sequence is responsible for recurrent translocation in humans. Genome Res. 19, 191-198 (2009).
126. Myers, S., Freeman, C., Auton, A., Donnelly, P. & McVean, G. A common sequence motif associated with recombination hot spots and genome instability in humans. Nature Genet. 40, 1124-1129 (2008).
127. Shaw, C. J. & Lupski, J. R. Implications of human genome architecture for rearrangement-based disorders: the genomic basis of disease. Hum. Mol. Genet. 13, R57-R64 (2004).
128. Bi, W. et al. Increased LIS1 expression affects human and mouse brain development. Nature Genet. 41, 168-177 (2009).
129. Galhardo, R. S., Hastings, P. J. & Rosenberg, S. M. Mutation as a stress response and the regulation of evolvability. Crit. Rev. Biochem. Mol. Biol. 42, 399-435 (2007). A broad review of stress-induced mutation and its meaning for evolution.
130. Rosenberg, S. M. Evolving responsively: adaptive mutation. Nature Rev. Genet. 2, 504-515 (2001).
131. Cirz, R. T. et al. Inhibition of mutation and combating the evolution of antibiotic resistance. PLoS Biol. 3, e176 (2005).
132. Riesenfeld, C., Everett, M., Piddock, L. J. & Hall, B. G. Adaptive mutations produce resistance to ciprofloxacin. Antimicrob. Agents Chemother. 41, 2059-2060 (1997).
133. Bindra, R. S. S. et al. Down-regulation of Rad51 and decreased homologous recombination in hypoxic cancer cells. Mol. Cell. Biol. 24, 8504-8518 (2004). This paper shows that HR enzymes are downregulated by stress in human cells, and that this is accompanied by reduction in HR.
134. Mihaylova, V. T. et al. Decreased expression of the DNA mismatch repair gene Mlh1 under hypoxic stress in mammalian cells. Mol. Cell. Biol. 23, 3265-3273 (2003).
135. Kolodner, R. D. et al. Germ-line msh6 mutations in colorectal cancer families. Cancer Res. 59, 5068-5074 (1999).
136. Loeb, L. A. Mutator phenotype may be required for multistage carcinogenesis. Cancer Res. 51, 3075-3079 (1991).
137. Modrich, P. Mismatch repair, genetic stability and tumour avoidance. Phil. Trans. R. Soc. Lond. B 347, 89-95 (1995).
138. Nguyen, D. Q. et al. Reduced purifying selection prevails over positive selection in human copy number variant evolution. Genome Res. 18, 1711-1723 (2008).
139. Perry, G. H. et al. Diet and the evolution of human amylase gene copy number variation. Nature Genet. 39, 1256-1260 (2007).
140. Gonzalez, E. et al. The influence of CCL3L1 genecontaining segmental duplications on HIV-1/AIDS susceptibility. Science 307, 1434-1440 (2005).
141. Higgs, D. R. et al. A review of the molecular genetics of the human alpha-globin gene cluster. Blood 73, 1081-1104 (1989).
142. Nozawa, M., Kawahara, Y. & Nei, M. Genomic drift and copy number variation of sensory receptor genes in humans. Proc. Natl Acad. Sci. USA 104, 20421-20426 (2007).
143. Jakobsson, M. et al. Genotype, haplotype and copynumber variation in worldwide human populations. Nature 451, 998-1003 (2008).
144. Locke, D. P. et al. Linkage disequilibrium and heritability of copy-number polymorphisms within duplicated regions of the human genome. Am. J. Hum. Genet. 79, 275-290 (2006).
145. Sharp, A. J. et al. Segmental duplications and copynumber variation in the human genome. Am. J. Hum. Genet. 77, 78-88 (2005).
146. Fortna, A. et al. Lineage-specific gene duplication and loss in human and great ape evolution. PLoS Biol. 2, E207 (2004).
147. McCarroll, S. A. et al. Integrated detection and population-genetic analysis of SNPs and copy number variation. Nature Genet. 40, 1166-1174 (2008).
148. Turner, D. J. et al. Germline rates of de novo meiotic deletions and duplications causing several genomic disorders. Nature Genet. 40, 90-95 (2008).
149. Lam, K. W. & Jeffreys, A. J. Processes of copy-number change in human DNA: the dynamics of α-globin gene deletion. Proc. Natl Acad. Sci. USA 103, 8921-8927 (2006).
150. Lam, K. W. & Jeffreys, A. J. Processes of de novo duplication of human α-globin genes. Proc. Natl Acad. Sci. USA 104, 10950-10955 (2007).
151. Flores, M. et al. Recurrent DNA inversion rearrangements in the human genome. Proc. Natl Acad. Sci. USA 104, 6099-6106 (2007).
152. Liang, Q., Conte, N., Skarnes, W. C. & Bradley, A. Extensive genomic copy number variation in embryonic stem cells. Proc. Natl Acad. Sci. USA 105, 17453-17456 (2008).
153. Lupski, J. R. Genomic rearrangements and sporadic disease. Nature Genet. 39, S43-47 (2007).
154. van Ommen G. J. Frequency of new copy number variation in humans. Nature Genet. 37, 333-334 (2005).
155. Tuzun, E., Bailey, J. A. & Eichler, E. E. Recent segmental duplications in the working draft assembly of the brown Norway rat. Genome Res. 14, 493-506 (2004).
156. Graubert, T. A. et al. A high-resolution map of segmental DNA copy number variation in the mouse genome. PLoS Genet. 3, e3 (2007).
157. Lovett, S. T. Encoded errors: mutations and rearrangements mediated by misalignment at repetitive DNA sequences. Mol. Microbiol. 52, 1243-1253 (2004).