TY - JOUR
T1 - Ionizing radiation and genetic risks VII. The concept of mutation component and its use in risk estimation for Mendelian diseases
AU - Chakraborty, R.
AU - Yasuda, N.
AU - Denniston, C.
AU - Sankaranarayanan, K.
N1 - Funding Information:
This work was carried out within the framework of a Task Group of the International Commission on Radiological Protection (ICRP) and we are grateful to ICRP for the encouragement received. Partly, this work was supported by the Atomic Energy Control Board of Canada (AECB Project number 7.219.1 to R.C.) and by the European Union (Contract numbers FI3P-CT-92-0005 and FI4P-CT-96-0041 to K.S.). We thank Dr. W.J. Schull and Dr. J.F. Crow for their valuable comments and Dr. Y. Zhong for his help in preparing the figures.
PY - 1998/5/25
Y1 - 1998/5/25
N2 - The responsiveness of Mendelian diseases to an increase in the mutation rate is studied by using the concept of the mutation component (MC) of genetic diseases. Algebraic expressions to evaluate MC at any specific generation following either a one-time or a permanent increase in mutation rate are derived and are illustrated with numerical examples. For a one-time increase in mutation rate, the analysis shows that the first generation MC for autosomal dominant diseases is equal to the selection coefficient; this is also true for X-linked diseases (adjusted for the proportion of X- chromosomes in males). For autosomal recessive diseases the first generation MC is substantially smaller than that for autosomal dominants. In subsequent generations MC gradually decays to zero. Under conditions of a permanent increase in the mutation rate, the MC for autosomal dominant, X-linked and completely recessive autosomal disorders progressively increases to reach a value of one at the new equilibrium. For incompletely recessive autosomal disorders, however, the MC at equilibrium can be larger than one. The rates of approach to the new equilibrium are different for the different classes of diseases, dictated by selection and time (in generations) following radiation exposure. The effects of increases in mutation rate on MC are more pronounced for autosomal dominants, followed by X-linked and are far less for autosomal recessives. Even for autosomal dominants, the early generation effects of radiation exposures would not be appreciable unless the heterozygotes have a severely reduced fitness.
AB - The responsiveness of Mendelian diseases to an increase in the mutation rate is studied by using the concept of the mutation component (MC) of genetic diseases. Algebraic expressions to evaluate MC at any specific generation following either a one-time or a permanent increase in mutation rate are derived and are illustrated with numerical examples. For a one-time increase in mutation rate, the analysis shows that the first generation MC for autosomal dominant diseases is equal to the selection coefficient; this is also true for X-linked diseases (adjusted for the proportion of X- chromosomes in males). For autosomal recessive diseases the first generation MC is substantially smaller than that for autosomal dominants. In subsequent generations MC gradually decays to zero. Under conditions of a permanent increase in the mutation rate, the MC for autosomal dominant, X-linked and completely recessive autosomal disorders progressively increases to reach a value of one at the new equilibrium. For incompletely recessive autosomal disorders, however, the MC at equilibrium can be larger than one. The rates of approach to the new equilibrium are different for the different classes of diseases, dictated by selection and time (in generations) following radiation exposure. The effects of increases in mutation rate on MC are more pronounced for autosomal dominants, followed by X-linked and are far less for autosomal recessives. Even for autosomal dominants, the early generation effects of radiation exposures would not be appreciable unless the heterozygotes have a severely reduced fitness.
KW - Genetic risk
KW - Ionizing radiation
KW - Mendelian disease
KW - Mutation component
UR - http://www.scopus.com/inward/record.url?scp=0032565513&partnerID=8YFLogxK
U2 - 10.1016/S0027-5107(98)00020-7
DO - 10.1016/S0027-5107(98)00020-7
M3 - Article
C2 - 9685709
AN - SCOPUS:0032565513
SN - 0027-5107
VL - 400
SP - 541
EP - 552
JO - Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
JF - Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
IS - 1-2
ER -