Summary
Cases of unstable hemoglobin and hemoglobin M disease that have appeared as de novo mutants over a span of approximately 50 years were used in derivingminimal, direct estimates of mutation rates per nucleotide per generation in man. The estimates are based upon analysis of data related to 40 cases of unstable Hbs and 15 of Hbs M that arose in 13 countries. The estimated rate calculated using all de novo β-gene mutants is 7.4×10-9 per nucleotide per generation; that derived using de novo α-gene mutants is 10.0×10-9. Subsequent calculations of mutation rates per α- and β-chain gene and extrapolation of these rates to a hypothetical gene of 1000 nucleotides yield an estimated mutation rate of 8.6×10-6 per 1000 nucleotides per generation. Even though some instances of false paternity may have biased these estimates in an upward direction, underreporting of Hb M cases, and particularly of unstable hemoglobins, makes it likely that the cited values are minimal estimates of mutation rates at the molecular level.
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Bradley TB, Wohl RC, Murphy SB, Oski FA, Bunn HF (1972) Properties of hemoglobin Bryn Mawr, Evidence for a gonadspecific receptor for H-Y antigen: Binding of exogenous H-Y antigen to gonadal cells is independent ofβ 85 Phe→Ser, a new spontaneous mutation producing an unstable hemoglobin with high oxygen affinity. Blood 40:947
Bunn HF, Bradley TB, Davis WE, Drysdale JW, Burke JF, Beck WS, Laver MB (1972) Structural and functional studies on hemoglobin Bethesda (α 2 β 2 145His), a variant associated with compensatory erythrocytosis. J Clin Invest 51:2299–2309
Forget BG (1977) Nucleotide sequence of human β globin messenger RNA. Hemoglobin 1:879–881
Forget BG, Wilson JT, Wilson LB, Cavallesco C, Reddy VB, deRiel JK, Biro AP, Ghosh PK, Weissman SM (1979) Globin mRNA structure: general features and sequence homology. In: Stamatoyannopoulos G, Nienhuis AW (eds) Cellular and molecular regulation of hemoglobin switching. Grune and Stratton, New York, pp 569–591
Farmer MB, Lehmann H, Raine DN (1964) Two unrelated patients with congenital cyanosis due to haemoglobinopathy M. Lancet II: 786–789
Ingram VM (1963) Hemoglobins in genetics and evolution. Columbia Univ Press, New York
International Hemoglobin Information Center (1979a) List of variants. Hemoglobin 3:104–115
International Hemoglobin Information Center (1979b) Variants of the alpha chain. Hemoglobin 3:376–395
International Hemoglobin Information Center (1979c) Variants of the beta chain. Hemoglobin 3:482–513
Josephson AM, Weinstein MS, Yakulis VJ, Singer L, Heller P (1962) A new variant of hemoglobin M disease: Hemoglobin MChicago. J Lab Clin Med 59:918–925
Kimura M, Ohta T (1973) Mutation and evolution at the molecular level. Genetics 73 (Suppl): 19–35
Lehmann H, Carrell RW (1969) Variations in the structure of human haemoglobin with particular reference to the unstable haemoglobins. Br Med Bull 25:14–23
Motulsky AG (1968) Some evolutionary implications of biochemical variants in man. Proc. VIII Int. Congr. Anthropol. Ethnol. Sci. 1:364–365
Neel JV, Rothman ED (1978) Indirect estimates of mutation rates in tribal Amerindians. Proc Natl Acad Sci USA 75:5585–5588
Neel JV, Satoh C, Hamilton HB, Otake M, Goriki K, Kageoka T, Fujita M, Neriishi S, Asakawa S (1980) Search for mutations affecting protein structure in children of atomic bomb survivors: preliminary report. Proc Natl Acad Sci USA 77:4221–4225
Outeirino J, Casey R, White JM, Lehmann H (1974) Haemoglobin Madrid β115 (G17) alanine → proline: an unstable variant associated with haemolytic anaemia. Acta Haematol 52:53–60
Sahawi E, Hunger H, Betke K (1962) Sporadisches Auftreten von Hb M (Boston-typ?) in einer mitteldeutschen Familie. Schweiz Med Wochenschr 92:1090–1094
Stamatoyannopoulos G, Nute PE, Miller M (1981) De novo mutations producing unstable Hbs of Hbs M. I. Establishment of a depository and use of data to test for an association of de novo mutation with advanced parental age. Hum Genet 58:396–404
Vogel F, Rathenberg R (1975) Spontaneous mutations in man. Adv Hum Genet 5:223–318
Wajcman H, Pagnier J, Labie D, Boivin P (1971) Hémoglobine Köln; physiopathologie d'une hémoglobine perdant spontanément son hème. Nouv Rev Fr Hematol 11:317–330
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Stamatoyannopoulos, G., Nute, P.E. De novo mutations producing unstable Hbs or Hbs M.. Hum Genet 60, 181–188 (1982). https://doi.org/10.1007/BF00569709
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DOI: https://doi.org/10.1007/BF00569709