Mammalian Artificial Chromosomes (MACs)

Abstract

By analogy with yeast artificial chromosomes, a mammalian artificial chromosome (MAC) would be a molecule of defined structure comprising combinations of various cloned or synthesized chromosomal elements that had been individually manipulated, tested and optimized as part of a controlled construction process. De novo human chromosomes have been produced through cell‐mediated assembly processes and these, together with minichromosomes generated by manipulating existing chromosomes, are providing the basis for developing the first MAC‐based vectors for use in vertebrate cells.

Keywords: minichromosome; α‐satellite; epigenetics; telomere; origin

Figure 1.

Two main approaches used to generate mammalian chromosome‐based vector systems. In the bottom‐up approach, artificial human chromosomes have been formed de novo by introducing, into human HT1080 cells, cloned centromeric α‐satellite DNA. In the top‐down approach, defined minichromosomes have been generated in cultured cells by chromosome truncation mediated by integrating telomeric DNA into chromosome arms.

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References

Co DO, Borowski AH, Leung JD, et al. (2000) Generation of transgenic mice and germline transmission of a mammalian artificial chromosome introduced into embryos by pronuclear microinjection. Chromosome Research 8: 183–191.

Ebersole T, Ross A, Clark E, et al. (2000) Mammalian artificial chromosome formation from circular alphoid input DNA does not require telomere repeats. Human Molecular Genetics 9: 1623–1631.

Harrington JJ, Van Bokkelen G, Mays RW, Gustashaw K and Willard HF (1997) Formation of de novo centromeres and construction of first‐generation human artificial microchromosomes. Nature Genetics 15: 345–355.

Ikeno M, Grimes B, Okazaki T, et al. (1998) Construction of YAC‐based mammalian artificial chromosomes. Nature Biotechnology 16: 431–439.

Saffery R, Wong LH, Irvine DV, et al. (2001) Construction of neocentromere‐based human minichromosomes by telomere‐ associated chromosomal truncation. Proceedings of the National Academy of Sciences of the United States of America 98: 5705–5710.

Shen MH, Yang Y, Loupart M‐L, Smith A and Brown W (1997) Human mini‐chromosomes in mouse embryonal stem cells. Human Molecular Genetics 6: 1375–1382.

Shen M, Mee P, Nichols J, et al. (2000) A structurally defined mini‐chromosome vector for the mouse germ line. Current Biology 10: 31–34.

Shen M, Yang J, Pendon C and Brown W (2001) The accuracy of segregation of human mini‐chromosomes varies in different vertebrate cell lines, correlates with the extent of centromere formation and provides evidence for a trans‐acting centromere maintenance activity. Chromosoma 109: 524–535.

Spence JM, Critcher R, Ebersole TA, et al. (2002) Co‐localization of centromere activity, proteins and topoisomerase II within a subdomain of the major human X alpha‐satellite array. EMBO Journal 21: 5269–5280.

Yang J, Pendon C, Yang J, et al. (2000) Human mini‐chromosomes with minimal centromeres. Human Molecular Genetics 9: 1891–1902.

Further Reading

Auriche C, Carpani D, Conese M, et al. (2002) Functional human CFTR produced by a stable minichromosome. EMBO Journal of Reproductivity 3: 862–868.

Brown WRA, Mee PJ and Shen MH (2000) Artificial chromosomes: ideal vectors? Trends in Biotechnology 18: 218–223.

Grimes BR, Schindelhauer D, McGill NI, et al. (2001) Stable gene expression from a mammalian artificial chromosome. EMBO Journal of Reproductivity 2: 910–914.

Grimes BR, Rhoades AA and Willard HF (2002) Alpha‐satellite DNA and vector composition influence rates of human artificial chromosome formation. Molecular Therapy 5: 798–805.

Ikeno M, Inagaki H, Nagata K, et al. (2002) Generation of human artificial chromosomes expressing naturally controlled guanosine triphosphate cyclohydrolase 1 gene. Genes to Cells 7: 1021–1032.

Kereso J, Praznovszky T, Cserpan I, et al. (1996) De novo chromosome formation by large scale amplification of the centromeric region of mouse chromosomes. Chromosome Research 4: 226–239.

Kouprina, N, Ebersole, T, Koriabine et al. (2003) Cloning of human centromeres by transformation‐assciated recombination in yeast and generation of functional human artificial chromosomes. Nuclear Acids Research 31: 922–934.

Kuroiwa Y, Tomizuka K, Shinohara T, et al. (2000) Manipulation of human minichromosomes to carry greater than megabase‐sized chromosome inserts. Nature Biotechnology 18: 1086–1090.

Larin Z and Mejia JE (2002) Advances in human artificial chromosome technology. Trends Genetics 18: 313–9.

Mejia JE, Alazami A, Willmott A et al. (2002) Efficiency of de novo centromere formation in human artificial chromosomes. Genomics 79: 297–304.

Mejia JE, Willmott A, Levy E, Earnshaw WC and Larin Z (2001) Functional complementation of a genetic deficiency with human artificial chromosomes. American Journal of Human Genetics 69: 315–326.

Ohzeki J‐i, Nakano M, Okado T and Masumoto H (2002) CENP‐B box is required for de novo centromere chromatin assembly on human alphoid DNA. Journal of Cell Biology 159: 765–775.

Voet T, Vermeesch, J, Carens, A et al. (2001) Efficient male and female germline transmission of a human chromosomal vector in mice. Genome Research. 11: 124–136.

Warburton PE (1999) Making CENs of mammalian artificial chromosomes. Molecular Genetics and Metabolism 68: 152–160.

Willard HF (1998) Centromeres: the missing link in the development of human artificial chromosomes. Current Opinion in Genetics and Development 8: 219–225.

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How to Cite close
Farr, Christine J, and Spence, Jennifer M(Jan 2006) Mammalian Artificial Chromosomes (MACs). In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0005671]