HEREDITARY EFFECTS OF RADIATION United Nations Scientific Committee on the Effects of Atomic Radiation UNSCEAR 2001 Report to the General Assembly, with Scientific Annex UNITED NATIONS New York, 2001 NOTE The report of the Committee without its scientific annex appears as Official Records of the General Assembly. Fifty-sixth Session, Supplement No. 46 (N56146). The designation employed and the presentation of material in this publication do not imply the expression of any opinion whatsoever on the pad of the Secretariat of the United Nationsconcerning the legal status of any country, temtory, city orarea, or of its authorities, or concerning the delimitation of its frontiers or boundaries. The country names used in this document are, In most cases, those that were in use at the time the data were collected or the text prepared. In othercases, however, the names have been updated, where this was posslble and appropriate, to reflect political changes. UNITED NATIONS PUBLICATION Sales No. E.O1 .IX.2 ISBN 92-1-1 42244-2 ANNEX Hereditary effects of radiation CONTENTS Page INTRODUCTION ....................................................... 8 I. THE HUMAN GENOME.............................................9 A. GENE NUMBER AND SIZE .......................................9 B. GENE ORGANIZATION AND FUNCTION ..........................9 II. MENDELIAN DISEASES ...........................................10 A. MOLECULAR NATURE OF MUTATIONS .........................10 B. MUTATIONAL SPECIFICITIES ..................................10 C. GENOTYPE-PHENOTYPE RELATIONSHIPS.......................11 1. Mutations in the same gene causing different clinical phenotypes.......11 2. Mutations in different genes causing similar phenotypes..............12 3. Identical mutations with different phenotypes ......................13 4. Mutations in the same genes inherited as both dominant and recessive . 13 5. Mosaicism, genomic imprinting, and uniparental disomy..............14 6. Allelic expansion (dynamic mutations)............................15 7. Summary...................................................16 D. BASELINE FREQUENCIES OF MENDELIAN DISEASES.............17 1. Autosomal dominant diseases...................................17 2. Autosomal recessive diseases ...................................17 3. X-linked diseases.............................................17 4. Revision of the total birth frequency estimates......................18 5. Population/ethnic differences ...................................18 6. Summary...................................................19 E. SPONTANEOUS MUTATION RATES .............................19 1. The concept of equilibrium between mutation and selection ...........19 2. Spontaneous mutation rates for autosomal dominant and X-linked diseases .........................................19 3. Sex differences in mutation rates and paternal age effects.............20 4. Relevance of sex differences in spontaneous mutation rates and paternal age effects in humans ...............................21 5. Summary...................................................22 III. MULTIFACTORIAL DISEASES ......................................22 A. CONGENITAL ABNORMALITIES ................................22 1. Overall prevalences...........................................23 2. Aetiological heterogeneity......................................23 3. Isolated congenital abnormalities ................................23 4. Summary...................................................24 6 UNSCEAR 2001 REPORT Page B. MODELS OF INHERITANCE ....................................24 1. The multifactorial threshold model ...............................24 2. Other models and concepts.....................................26 3. Summary...................................................26 C. COMMON MULTIFACTORIAL DISEASES ........................27 1. General concepts.............................................27 2. Overall prevalences and epidemiological features ...................28 3. Diabetes mellitus .............................................28 4. Essential hypertension.........................................31 5. Coronary heart disease.........................................33 D. MECHANISMS OF MAINTENANCE OF MULTIFACTORIAL TRAITS IN THE POPULATION..................................37 IV. THE MUTATION COMPONENT FOR GENETIC DISEASES..............38 A. BACKGROUND ...............................................38 B. DEFINITION OF MUTATION COMPONENT.......................39 C. MUTATION COMPONENT FOR AUTOSOMAL DOMINANT DISEASES ............................39 1. Mutation component in the absence of sporadics ....................39 2. Mutation component in the presence of sporadics ...................41 D. MUTATION COMPONENT FOR X-LINKED AND AUTOSOMAL RECESSIVE DISEASES .......................41 E. MUTATION COMPONENT FOR MULTIFACTORIAL DISEASES......41 1. Rationale for the development of a finite-locus threshold model........41 2. The model and its predictions...................................42 F. SUMMARY ...................................................45 V. CANCER PREDISPOSITION, RADIOSENSITIVITY, AND THE RISK OF RADIATION-INDUCED CANCERS .................45 A. FAMILIAL CANCER GENES ....................................46 1. The RB1 gene and retinoblastoma ................................47 2. The p53 gene and Li-Fraumeni syndrome..........................47 3. BRCA1 and BRCA2 genes and breast and ovarian cancers.............47 4. Hereditary colorectal cancers ...................................48 5. Ataxia-telangiectasia..........................................49 6. Functions of familial cancer genes and mechanisms of cancer predisposition ..........................50 7. Summary...................................................51 B. RADIATION SENSITIVITY OF CANCER-PREDISPOSED INDIVIDUALS ..........................52 1. Human epidemiological and molecular studies......................52 2. Mouse models...............................................53 3. The rat model for the human tuberous sclerosis-2....................54 4. Summary...................................................54 C. COMPUTATIONAL MODELLING TO ESTIMATE RADIATION RISK IN A HETEROGENEOUS POPULATION ...........................54 1. Numerical illustration for an irradiated population ...................54 2. Results of computational modelling ..............................55 3. Summary...................................................56 VI. OTHER RELEVANT STUDIES .......................................57 A. HUMAN STUDIES .............................................57 1. Genetic disease in offspring of long-term survivors of childhood and adolescent cancer ...............................57 2. Reproductive outcome in women irradiated during infancy for skin haemangiomas ........................................57 3. Possible genetic effects of radiation exposures resulting from the Chernobyl accident or from living in the vicinity of a nuclear power plant .........57 4. Summary...................................................59 ANNEX: HEREDITARY EFFECTS OF RADIATION 7 Page B. ANIMAL STUDIES.............................................60 1. Radiation-induced minisatellite mutations in mouse germ cells .........60 2. Genetic effects in mice exposed in the Chernobyl accident ............60 3. Cytogenetic nature of radiation-induced germ-line mutations in the mouse 61 4. Summary...................................................62 C. MOSAIC MUTATIONS AND MUTATION CLUSTERS ...............62 1. General comments............................................62 2. Mosaic mutations in humans....................................63 3. Mosaic mutations and clusters in mice and their relevance for risk estimation ............................................63 4. Summary...................................................64 VII. CONCEPTS, DATA AND ANALYSES USED FOR THE ESTIMATION OF GENETIC RISKS ..............................65 A. FREQUENCIES OF GENETIC DISEASES IN HUMANS ..............65 B. THE DOUBLING DOSE .........................................65 1. The average rate of spontaneous mutations in humans ................66 2. The average rate of induced mutations in mice......................67 3. The doubling-dose estimate .....................................67 4. Summary...................................................68 C. MUTATION COMPONENT......................................68 D. THE CONCEPT OF POTENTIAL RECOVERABILITY CORRECTION FACTOR ........................................69 1. Background .................................................69 2. Differences between spontaneous and radiation-induced mutations ......69 3. Radiation-induced mutations and their recoverability in radiation mutagenesis studies .................................70 4. Criteria for recoverability and the potential recoverability correction factor (PRCF) concept ........................................71 5. Potential recoverability correction factor for autosomal dominant and X-linked diseases .........................................72 6. Potential recoverability correction factor for autosomal recessive diseases 73 7. Potential recoverability correction factor for multifactorial diseases .....73 8. Summary...................................................74 E. MULTISYSTEM DEVELOPMENTAL ABNORMALITIES AS MANIFESTATIONS OF RADIATION-INDUCED GENETIC DAMAGE IN HUMANS................................74 1. Background .................................................74 2. Insights from studies of human microdeletion