Faculty Bibliography

A method is proposed to calculate the maximum likelihood estimate of gene frequency and linkage disequilibrium from disease-codominant marker conditional data. The method is illustrated using data on sickle-cell anemia and Duchenne muscular dystrophy and linked polymorphic restriction endonuclease cleavage sites.

Although only a small proportion of common cancers show familial aggregation, studying such families can elucidate the roles of shared environment and genes in the development of neoplasia. We report an analysis of nine colon cancer pedigrees using new nonparametric objective methods to measure familial aggregation as a means of determining the existence of heterogeneity in the data. Each family was selected through a proband with nonpolyposis colon cancer who had a first-degree relative with documented colon cancer. To assess the aggregation of different cancers in these families we employ a method which evaluates both excess number of cases as well as distribution by risk in family members. We find that eight of the nine families exhibit significant aggregation of colon cancer: endometrial cancer aggregates in three families, breast in none, kidney in one, and all sites in eight. In this way, we show that two families fit the criteria for Cancer Family Syndrome, and that one is not a high-risk cancer family.

Within a family, associations between a disease and a marker locus are often inferred when affected offspring share marker alleles more often than is expected by chance. Generally, this is due to nonrandom parental transmission of marker alleles and specifically could be due to linkage, epistatic gene action, or segregation distortion at the marker locus. In this paper, we discuss the statistical properties of a general test of nonrandom segregation of a marker gene. The exact probability distribution of the test under the null hypothesis of random segregation is derived, as is the distribution under the alternative hypothesis of genetic linkage. We compute the mean and variance of these distributions as a means of judging the adequacy of random segregation to explain disease-marker data but also provide a method for computing the exact significance value under the null hypothesis. These methods have been utilized for studying HLA segregation in families with tuberculoid leprosy. On the assumption that this type of leprosy is autosomal recessive, we find evidence that a gene controlling susceptibility to infection by Mycobacterium leprae resides on human chromosome 6, approximately 13 map units away from the HLA locus in males.

Deletion of a chromosome region containing a polymorphic marker may result in apparent parental exclusion at that locus. We present a general method for calculating the probability that deletion at a specific locus would have such an effect. For many autosomal loci this probability is substantial, justifying attempts at deletion mapping in most cases. This method may be especially valuable in assigning DNA restriction fragment polymorphisms to chromosome regions.