Down syndrome is the most frequently identified cause of major mental retardation in the United States. The general nature of the chromosomal abnormality responsible for Down syndrome has been clear for some time. Virtually nothing is known, however, regarding the biochemical basis of the syndrome. Understanding of the basic genetic and biochemical processes associated with Down syndrome is essential so that rational methods of prevention or amelioration of symptoms can be devised. Certainly, a valid approach to the problem is to attempt to understand what genes are located on or controlled by human chromosome 21 and to learn something about the structure of these genes and about regulation of their expression. In this way, it might be possible to make some rational, testable hypotheses regarding which of these genes are involved in the pathology associated with Down syndrome. Available evidence strongly suggests that only the genes on a small portion of chromosome 21 need be trisomic in order for an individual to develop the pathology of Down syndrome. Thus, we propose in this program project application to utilize the logic and methods of somatic cell genetics, especially the study of particularly informative human/hamster hybrids, to learn as much as possible regarding the number and identity of the genes on the relevant segment of chromosome 21, to begin to understand the mechanisms by which these genes are regulated, and to understand how these genes affect the regulation of genes on other chromosomes. Studies are proposed to isolate relevant genes and DNA sequences, to study the structure and location of these genes in order to gain information regarding their regulation, to examine the effects these genes might have on cellular metabolism and on cell surface structure, to examine which genes on chromosome 21 control expression of specific proteins, and to study mechanisms of nondisjunction which may lead to Down syndrome. It is our belief that a multifaceted approach such as the one described here which involves a combination of sophisticated biochemical, molecular, genetic and immunological procedures offers the best opportunity to obtain information relevant to Down syndrome.