IONIZING-RADIATION AND GENETIC RISKS - 9 - ESTIMATES OF THE FREQUENCIES OF MENDELIAN-DISEASES AND SPONTANEOUS MUTATION-RATES IN HUMAN-POPULATIONS - A 1998 PERSPECTIVE

Citation
K. Sankaranarayanan, IONIZING-RADIATION AND GENETIC RISKS - 9 - ESTIMATES OF THE FREQUENCIES OF MENDELIAN-DISEASES AND SPONTANEOUS MUTATION-RATES IN HUMAN-POPULATIONS - A 1998 PERSPECTIVE, Mutation research. Reviews in mutation research, 411(2), 1998, pp. 129-178
Citations number
276
Language
INGLESE
art.tipo
Review
Categorie Soggetti
Genetics & Heredity",Toxicology,"Biothechnology & Applied Migrobiology
ISSN journal
1383-5742
Volume
411
Issue
2
Year of publication
1998
Pages
129 - 178
Database
ISI
SICI code
1383-5742(1998)411:2<129:IAGR-9>2.0.ZU;2-D
Abstract
This paper is focused on baseline frequencies of mendelian diseases an d the conceptual basis for calculating doubling doses both of which ar e relevant for the doubling dose method of estimating genetic risks of exposure of human populations to ionizing radiation. With this method , the risk per unit dose is obtained as a product of three quantities, namely, the baseline frequency of the disease class under considerati on, the relative mutation risk (which is the reciprocal of the doublin g dose, which in turn, is calculated as a ratio of spontaneous and ind uction rates of mutations) and mutation component, i.e., the responsiv eness of the disease class to an increase in mutation rate. The estima tes of baseline frequencies of mendelian diseases that are currently u sed in risk estimation date back to the late 1970s. Advances in human genetics during the past two decades now permit an upward revision of these estimates. The revised estimates are 150 per 10(4) live births f or autosomal dominants (from the earlier estimate of 95 per 10(4)), 75 per 10(4) live births for autosomal recessives (from 25 per 10(4)) an d to 15 per 10(4) livebirths for X-linked diseases (from 5 per 10(4)). The revised total frequency of mendelian diseases is thus 240 per 10( 4) live births and is about twice the earlier figure of 125 per 10(4) live births. All these estimates, however, pertain primarily to Wester n European and Western European-derived populations. The fact that in several population isolates or ethnic groups, some of these diseases ( especially the autosomal recessives) are more common as a result of fo under effects and/or genetic drift is well known and many more recent examples have come to light. These data are reviewed and illustrated w ith data from studies of the Ashkenazi Jewish, Finnish, French Canadia n, Afrikaner and some other populations to highlight the need for caut ion in extrapolating radiation risks between populations. The doubling dose of 1 Gy that has been used for the past 20 years for risk estima tion is based on mouse data for both spontaneous and induction rates o f mutations. In extrapolating the mouse-data-based doubling dose to hu mans, it is assumed that the spontaneous rates in mice and humans are similar. This assumption is incorrect because of the fact that in huma ns, for several well-studied mendelian diseases, the mutation rate dif fers between the two sexes and it increases with paternal age. In esti mates of spontaneous mutation rates in humans (which represent average s over both sexes), however, paternal age effects are automatically in corporated. In the mouse, these effects an expected to be much less (i f they exist at all), but the problem has not been specifically addres sed. The complexities and uncertainties associated with assessing the potential impact of spontaneous mutations which arise as germinal mosa ics (and which can result in clusters of mutations in the following ge neration) on mutation rate estimates (in the mouse) and on mutation ra te estimates and disease frequencies (in humans) are discussed. In vie w of (i) the lack of comparability of spontaneous mutation rates in mi ce and humans and (ii) the fact that these estimates for human genes a lready include both paternal age effects and correction for clusters ( if they had occurred), it is suggested that a prudent procedure now is to base doubling dose calculations on spontaneous mutation rates of h uman genes (and induction rates of mouse genes, in the absence of a be tter alternative). This concept, however, is not new and was used by t he US National Academy's Committee on the Biological Effects of Ionizi ng Radiation in its 1972 report. (C) 1998 Elsevier Science B.V. All ri ghts reserved.