vidual autosomal dominant diseases published by Childs (1981) and Vogel and Motulsky (1997) were used, irrespective of whether these diseases have high or low prevalence or high or low mutation rates. However, the analysis took into account the numbers of genes thus far known or estimated to underlie each of these disease phenotypes (Vogel and Motulsky 1997; Sankaranarayanan 1998; McKusick 2000). This represents an important departure from earlier estimates based on disease phenotypes alone, which generally assumed a one-to-one relationship between mutation and disease. Details of these diseases, estimates of mutation rates, and selection coefficients are given in Table 4-2. The (unweighted) average mutation rate derived from these data (for some 26 autosomal dominant phenotypes with an esti

TABLE 4-2 Database for Estimating Average Spontaneous Mutation Rate of Human Autosomal Genes Associated with Autosomal Dominant Diseases and Their Selection Coefficients(s)

Disease Phenotype

Estimated

No. of Loci

Mutation Rate (× 106)a

Selection Coefficient(s)b

Achondroplasia

1

11.0

0.8

Amelogenesis imperfecta

1

1.0

0

Aniridia

2

3.8

0.1

Apert’s syndrome

1

3.5

0

Blindness

9

10.0

0.7

Cataracts (early onset)

30

6.0

0.3

Cleft lip

1

1.0

0.2

Deaf mutism

15

24.0

0.7

Dentinogenesis imperfecta

2

1.0

0

Huntington disease

1

5.0

0.2

Hypercholesterolemia

1

20.0

0

Marfan syndrome

1

5.0

0.3

Multiple exotoses

3

7.7

0.3

Myotonic dystrophy

1

18.0

0.3

Neurofibromatosis

2

70.0

0.5

Osteogenesis imperfecta

2

10.0

0.4

Osteopetrosis

1

1.0

0.2

Otosclerosis

1

20.0

0

Polyposis of intestine

1

10.0

0.2

Polycystic kidney disease

2

87.5

0.2

Porphyria

2

1.0

0.05

Primary basilar impression

1

10.0

0.2

Rare diseases (early onset)

50

30.0

0.5

Retinoblastoma

1

8.7

0.5

Spherocytosis

1

22.0

0.2

Tuberous sclerosis

2

8.0

0.8

Total

135

 

Average

 

( 2.95 ± 0.64)

0.294

aFor some entries, mutation rate estimates are uncertain (see Childs 1981 for details).

bEstimated from reproductive fitness.

SOURCE: Childs (1981); Vogel and Motulsky (1997).

mated 135 loci) is (2.95 ± 0.64) × 10−6 per locus per generation. This figure is within the range of 0.5 × 10−5 to 0.5 × 10−6 per locus used in the 1972 BEIR I report (NRC 1972).

The list of autosomal dominant diseases used to provide the basis for the prevalence estimate (P in Equation (4-3)) encompasses many more than the 26 diseases used in the above calculations (Sankaranarayanan 1998); these other diseases could not be included in the present analysis because of lack of information on mutation rates. Further, the mutation rate estimates for X-linked phenotypes have not been included in these calculations; instead, it has been assumed that the average spontaneous mutation rate for autosomal dominant genes calculated above can also be used for X-linked genes. The justification for this assumption rests on the following lines of reasoning: (1) among Mendelian diseases, autosomal dominants constitute the most important group from the standpoint of genetic risks, and (2) although X-linked recessive diseases are also expected to respond directly to an increase in mutation rate, since their prevalence is an order of magnitude lower than that of autosomal dominants (i.e., 0.15% versus 1.5%) the assumption of similar spontaneous rates of mutations for autosomal dominants and X-linked recessives is unlikely to result in any significant underestimation of the total risk. In fact, for this reason, these two classes of diseases are considered together in risk estimation.

The Average Rate of Induced Mutations in Mice

To calculate the average rate of induced mutations in mice, the committee used all available data on rates of induced mutations in defined genes in mice; these relate to recessive specific locus mutations at 12 loci, biochemical mutations (null enzyme mutations, also recessive at a large number of loci), and autosomal dominant mutations at 4 loci incidentally detected in the course of the specific locus experiments. The data on these autosomal dominant mutations are all from studies carried out in Harwell; comparable data from Oak Ridge studies were unavailable. Inclusion of the data on dominant mutations in mutation rate calculations was dictated by the consideration that although the underlying genes were not well defined at the time these experiments were performed (but mutations were “frequently” observed and recorded, indicating that they were among the more radiation-mutable loci), we now know not only their identity (and the molecular nature of the mutations) but also their human counterparts (the mouse Sl, W, Sp, and T correspond to, respectively, the MGF, KIT, PAX3, and T genes in humans; see McKusick 2000). All of the data considered here come from experiments involving stem cell spermatogonia.

The data from female mice have not been used because there is uncertainty about whether mouse immature oocytes are a good model for assessing the mutational radiosensitivity of human immature oocytes (UNSCEAR 1988). The arguments rest on (1) the strikingly higher sensitivity of mouse



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