ETIOLOGY OF NONDISJUNCTION IN HUMANS

Aneuploidy is the most common class of chromosome abnormality in human s, occurring in at least 0.3% of newborns and approximately 50% of spo ntaneous abortions. Considered os a class, it is the most common known cause of mental retardation and the leading cause of pregnancy loss. Despite the high frequency of aneuploidy, its obvious clinical importa nce, its severe impact on human reproduction, and the 35 years of rese arch since the first human chromosome abnormality was described, we st ill know very little about its causes, let alone the contribution of e nvironmental exposures. Recently, however, with the advent of molecula r and molecular cytogenetic techniques and advances in reproductive bi ology, a body of evidence has been generated that is beginning to shed light on the incidence, origin, and etiology of human aneuploid condi tions. The bulk of this evidence comes from two sources. 1) studies of the incidence of aneuploidy in the cells of origin, namely oocytes an d sperm; and 2) examinations of meiotic stage, parent of origin, and m eiotic recombination in trisomic conceptuses, both liveborn and abortu ses. Using a multicolor fluorescence in situ hybridization (FISH) appr oach, it is now possible to screen an extremely large number of human sperm to determine chromosome-specific rates of disomy. Likewise, beca use of the introduction in the past decode of in vitro fertilization t echnology, a population of human oocytes suitable for aneuploidy scree ning became available. The examination of the cells of origin of aneup loidy, the sperm and oocytes, has provided data on the incidence of ch romosome aberrations and valuable insight into possible mechanisms of nondisjunction. Additionally, the recent identification of multiple, h ighly informative DNA polymorphisms on all human chromosomes has mode the determination of parental origin and the analysis of recombination a straightforward matter. We now know that the vast majority of triso mic conceptuses are maternal in origin, that increased maternal age is associated with nondisiunction, and that the amount and position of r ecombination on nondisjoined chromosomes is altered. In this review we will restrict discussions to these recent developments and to new mod els of the mechanism(s) of human nondisiunction based on the molecular cytogenetic analyses. Additionally, we will discuss the direction of future epidemiological research made possible through the development of molecular and molecular cytogenetic techniques. These technological advances have now allowed for a systematic search for genetic and env ironmental components to human nondisjunction. (C) 1995 Wiley Liss, In c.