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Single Amino-acid Substitutions as a Result of Unequal Crossing-over

Naturevolume 212pages545546 (1966) | Download Citation



SINCE Ingram demonstrated1 in 1957 the substitution of valine for glutamic acid in haemoglobin S (α2β26val), an increasing number of structural and enzyme proteins have been analysed for their normal amino-acid sequence and for mutational variations in this sequence. It is usually assumed that a substitution of a single amino-acid is the result of a point mutational change in the nucleotide code. The following model is offered as an alternative to such an assumption. It is an outgrowth and extension of the postulate by Ingram2 that the β and γ haemoglobin chains result from gene duplication and subsequent divergent evolution; the demonstration by Baglioni3 that haemoglobin Lepore most probably represents the product of a δ-β fusion gene arising from unequal crossing-over ; the discussions on the role of unequal crossing-over in the thalassaemias by Nance4 and in the haptoglobins and thalassaemias by Smithies5,6; and the application of possible unequal crossing-over in (δβ) thalassaemia by Comings and Motulsky7.

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  1. 1

    Ingram, V. M., Nature, 180, 326 (1957).

  2. 2

    Ingram, V. M., Nature, 189, 704 (1961).

  3. 3

    Baglioni, C., Proc. U.S. Nat. Acad. Sci., 48, 1880 (1962).

  4. 4

    Nance, W. E., Science, 141, 123 (1963).

  5. 5

    Smithies, O., Connell, G. E., and Dixon, G. H., Nature, 196, 232 (1962).

  6. 6

    Smithies, O., Cold Spr. Harb. Symp. Quant. Biol., 29, 309 (1964).

  7. 7

    Comings, D. E., and Motulsky, A. G., Blood, 28, 54 (1966).

  8. 8

    Bridges, C. B., Science, 83, 210 (1936).

  9. 9

    Sonneborn, T. M., in Evolving Genes and Proteins, edit. by Bryson, V., and Vogel, H. G., 377 (Academic Press, New York, 1965).

  10. 10

    Nirenberg, M., Leder, P., Bernfield, M., Brimacombe, R., Trupin, K., Rotman, F., and O'Neal, C., Proc. U.S. Nat. Acad. Sci., 53, 1161 (1965).

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    Present address: Department of Medical Genetics, City of Hope Medical Center, Duarte, California

  1. DAVID E. COMINGS: U.S. Public Health Service post-doctoral fellow.


  1. Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington



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