031. THE ORIGIN OF ANEUPLOIDY IN HUMANS: WHERE WE’VE BEEN, WHERE WE’RE GOING

Abstract

With the advent of the human genome project in the 1990s, DNA markers became available, allowing us to determine the parent and meiotic stage of origin of human aneuploid conditions. This approach has been extensively used to study the origin of trisomies, with one over-arching conclusion: the vast majority of trisomies derive from errors in the development of the egg and, in particular, from nondisjunction occurring in the first maternal meiotic division (MI). However, against this general background, it has also become apparent that there is considerable chromosome-to-chromosome variation. For example, certain aneuploidies (e.g., the XXY condition, or Klinefelter syndrome) are commonly paternal in origin, while others (e.g., trisomy 16, the most common human trisomy) almost always originate from maternal MI errors. Thus, we now know that individual chromosomes behave differently with respect to mechanisms of meiotic nondisjunction. In this presentation, we will summarize results of these parental origin studies of aneuploidy and discuss the involvement of the first identified molecular correlate of nondisjunction – aberrant meiotic recombination – in the genesis of these abnormalities. We will also look forward, discussing the development of mouse models of human aneuploidy, and recent advances in molecular cytogenetics that make it possible to directly analyze human meiosis ‘as it happens’ in fetal oocytes and in spermatocytes.