MECHANISMS OF HUMAN CHROMOSOME ABNORMALITIES

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Abnormalities of chromosome structure or number are the most common identified class of genetic defect leading to mental retardation and/or other developmental anomalies. Chromosome defects are present in about 1 in 160 livebirths, most with significant physical or intellectual abnormalities. The longterm goal of this Program is to understand the molecular basis for chromosome abnormalities in humans, to relate the causes and specific nature of such abnormalities to phenotype, and to elucidate general features of chromosome structure and function that are relevant to the etiology of genetic disease. While extensive population cytogenetic studies have determined the incidence of various classes of chromosome abnormality, relatively little is known about the causes of either numerical or structural chromosome defects. In this revised application, we propose to use a combination of molecular and cytogenetic approaches to study the most common and clinically significant of these disorders. In studies of trisomy 21, we will utilize our well-established registry of over 1000 Down syndrome individuals to investigate the genesis of non-disfunction of chromosome 21, and we will use a novel gene mapping approach to identify genes involved in specific phenotype components of the syndrome. In studies of paternally- derived aneuploidy, we will use fluorescence in situ hybridization and single sperm PCR to analyze directly the male gametes, to study the incidence and etiology of paternal non-disfunction in trisomy 21 and in Klinefelter syndrome. In studies of Robertsonian translocations, the most common structural chromosome abnormality in humans, we will combine molecular and cytogenetic techniques to study the formation and meiotic behavior of these rearrangements. Finally, in studies of X chromosome abnormalities, we will determine the molecular nature of abnormal chromosomes detected in Turner syndrome and in variants of Turner syndrome with mental retardation and severe developmental effects, analyze the effect of different pericentromeric structures on mitotic chromosome segregation, and test a novel mechanism potentially important in the severe phenotypes seen associated with a subset of such chromosomes.