An extra copy of chromosome 21(HSA21, trisomy 21) occurs frequently in man (in 1/700-1/1000 births) and results in Down syndrome (DS); one of the most common know causes of metal retardation. The DS phenotype has a wide array of major and minor abnormalities but all individuals do not display all the of the array. DS is characterized by specific features, which, like the phenotypic consequences of other trisomies, make it distinct, suggesting that there is a direct relationship between specific genes that are at dosage imbalance and the resultant phenotype. For example, DS is characterized by dysmorphia features of the face and head, congenital anomalies of the heart, immunodeficiency, mental retardation, and dermatoglyphic changes. Current research on DS focuses on the identification and molecular analysis of genes on HSA 21, the characterization of the minimum region of HSA 21 that is responsible for a subset of the major phenotypic features of the syndrome, the molecular basis of chromosomal nondisjunction, and the use of mouse models (either those that are trisomic or partially trisomic for conserved regions of HSA21 on mouse chromosomes (MMU) 16, 17, or 10, or mice produced through transgenic technologies) to help elucidate the mechanisms by which extra copies of chromosomal segments or genes exert their effects on phenotype. Over the past five years, we have made significant research progress towards a better understanding of DS biology through the use of recombinant DNA technology in the analysis of HSA 21 and MMU16, the development of reagents for the analysis of large, cloned DNA segments as yeast artificial chromosomes (YACs), and the transfer of YACs into the mouse germ line, generating mouse models for study. In this competitive renewal application, we propose experiments: 1) that will lead to a better understanding of which genes, when present in triplicate, lead to the DS phenotype, particularly with respect to the neurobiologic consequences, through the use of segmental aneuploidy in the mouse and transgenic ice carrying large segments of HSA21 cloned in YACs; 2) that will improve methodologies for YAC cloning, manipulation, and transfer, and 3) that will gain insights into the determinants important for meiosis I chromosome disjunction.