Faculty Bibliography

We have constructed a genetic linkage map of 17 markers on the long arm of human chromosome 21, including six genes and two anonymous loci with a variable number of tandem repeats. The estimated length of the map is 103 cM in males and 140 cM in females, assuming Kosambi interference. Recombination in females was approximately twice that in males between proximal markers. However, over half of the recombination events in either sex occur distally, in 21q22.3, although this region accounts for only about 15% of the physical length of chromosome 21.

Using a family history questionnaire, we investigated the occurrence of dementia among relatives of patients with a clinical diagnosis of Alzheimer's disease (AD) and among the relatives of age-matched control subjects. Cumulative lifetime risk of developing AD-type dementia was greater among relatives of AD probands and was consistent with an autosomal dominant genetic mode of transmission. Although the lifetime risk of AD-type dementia was similar among relatives of early-onset and late-onset AD probands, relatives of early-onset probands tended to have an earlier onset of dementia than did relatives of late-onset AD probands. This result raises the possibility that age at onset of dementia in AD may be genetically determined.

The genes coding for apolipoproteins A1, C3, and A4 (APOA1, APOC3, APOA4) are closely linked and tandemly organized within a 15-kilobase (kb) DNA segment on the long arm of human chromosome 11. The nucleotide variability of a 61-kb DNA segment containing these genes and their flanking sequences was studied by restriction analysis of a sample of 18 unrelated Northern Europeans using seven different genomic DNA probes. Eleven restriction site polymorphisms located within this DNA segment were used for haplotype analysis of 129 Mediterranean and 67 American black chromosomes. Estimation of the extent of nonrandom association between these polymorphisms indicated considerable linkage disequilibrium within the APOA1-APOC3-APOA4 gene cluster. Several haplotypes arose by recombination, and the rate of recombination within this gene cluster was estimated to be at least 4 times greater than that expected based on uniform recombination. The polymorphism information content of each of these polymorphisms, taken individually, ranges between 0.053 and 0.375, while that of their haplotypes ranges between 0.858 and 0.862. Therefore, DNA polymorphism haplotypes in the APOA1-APOC3-APOA4 gene cluster constitute a highly informative genetic marker on the long arm of human chromosome 11.

New RFLPs are described for INP10 and interleukin 2. The 55 pairwise genetic linkage relationships for these two loci and nine additional loci on the long arm of chromosome 4 (4q) are reported. Fifteen new linkages are established, and new data are added to the four previously reported linkages on 4q. Tight linkage of interleukin 2 (T-cell growth factor), epidermal growth factor, and alcohol dehydrogenase is described. Significant differences were observed between male and female recombination rates. The female rate was estimated to be 1.27 times the male rate. On the basis of these pairwise results, the order for the 11 loci is D4S35-GC-(ALB/AFP)-MT2P1-D4S1-INP10-ADH3-( EGF/IL2)-(FBB/FBA/FBG)-MNS. This preliminary order can serve as a starting point for more detailed multipoint analysis.

The levels of gene diversity for 17 polymorphic loci in natural populations of wild rats were examined for three separate locations in North and South America. The level of gene diversity in the total sample for the RT1.A locus, the dominant class I histocompatibility locus in the major histocompatibility (RT1) complex of the rat, was 0.807. The degree of gene diversity for nonalloantigenic loci scattered throughout the rat genome was 0.215, a level comparable to, if not slightly higher than, that for other mammalian species. The large and consistent levels of diversity for individuals within each population suggest that significant deviations from random mating have occurred within each group. Conclusions from analyzing genetic distance and the index of genetic differentiation between the three populations are consistent with these populations' geographic isolation and small effective population size. Assuming that the separation of the North and South American groups has existed for approximately 300 years, the effective size of these populations is estimated to be approximately 1,500 individuals. Apparent differences in the distribution of the number and frequency of alleles in the major histocompatibility complexes of mice and rats and the level of genetic differentiation among separate rat populations may be due to the effects of genetic drift in small populations.

In the analysis of dominantly inherited diseases, the age-at-onset function is often estimated from the observed age-at-onset distribution of cases. This estimate is confounded with the age distribution of the population from which the cases were sampled and is accurate only if there are no competing causes of death. In this paper, we present a straightforward method for calculating a more accurate age-at-onset function under etiologic heterogeneity. We use the life-table approach and survival analysis methods. This method is illustrated using data on first-degree relatives of probands from two sets of families with high cancer incidence: one with breast/ovarian cancer and the other with colon cancer. A comparison of the estimated age-at-onset function obtained by the two methods is presented. In both cases, colon cancer as well as breast/ovarian cancer, the estimates of onset probabilities based on proportion of cases, are consistently higher than those obtained by the life-table method. For breast/ovarian cancer, this difference is not as striking as it is in the case of colon cancer; nevertheless, the method using proportion of cases tends to give a lower estimate of the age-at-onset function (higher probability of being affected at lower age) than the life-table approach.

There are two methods for calculating the posttests probability of paternity, viz., the nonexclusion probability method (E method) and the paternity index method (lambda method). This report reviews these two methods and explains the reasons behind them, in the hope that it might alleviate the current controversy between the advocates of these two methods. The emphasis throughout the paper is on exposition, using simple examples to illustrate certain principles or properties. A discussion follows the presentation of the two methods. The calculation of the paternity index is based on the genotype (or phenotype) of the accused man; and the value of the paternity index remains the same whether the accusation itself is true or false.