Faculty Bibliography

Six restriction fragment length polymorphisms (RFLPs) detected in the human growth hormone-human chorionic somatomammotropin (hGH-hCS) gene cluster were studied in Mediterraneans, Northern Europeans, and American Blacks; the polymorphisms showed that, on the average, one of 500 bases in this cluster is variant. Haplotypes constructed for four of these RFLPs display strong nonrandom associations. However, the strongest associations were between RFLPs that are in homologous DNAs rather than between the physically closest RFLPs. From this and other evidence we argue that duplication of an ancestral hCS gene occurred at least twice, the second event being relatively recent. In other words, duplication of the hCS-L gene to produce the hCS-A gene occurred twice, so that hCS-A genes in humans may have independent origins. Our results imply that chromosomes with absent hCS genes (leading to hCS deficiency) may represent the nonduplicated ancestral unit rather than gene deletions.

Population genetic analysis of 15 restriction site polymorphisms demonstrates nonuniform recombination within the human beta-globin gene cluster. These DNA polymorphisms show two clusters of high nonrandom associations, one 5' and another 3' to the beta-globin structural gene, with no significant linkage disequilibrium between the two clusters. The 5'- and 3'-association clusters are 34.6 kilobases (kb) and 19.4 kb long, respectively, and are separated by 9.1 kb of DNA immediately 5' to the beta-globin gene. For each of these three DNA regions, we have observed a relationship between nonrandom associations and physical distance between the polymorphisms. However, this relationship differed for each of these regions. On the assumption that the effective population size (Ne) is 5,000-50,000, we estimate the total recombination rate to be 0.0017%-0.0002% in the 5' cluster, 0.0931%-0.0093% in the 3' cluster, and 0.2912%-0.0219% in the 9.1-kb region between them. The beta cluster thus shows nonuniformity in recombination. Moreover, the recombination rate in the 9.1-kb DNA segment is 3-30 times greater than expected and is thus a hot spot for meiotic recombination.

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.