Human chromosome nondisjunction leads to an extraordinary frequency of aneuploidy: an estimated 10- 25% of all human conceptions have too many or too few chromosomes. This chromosome error is the leading cause of pregnancy loss, mental retardation and birth defects. Despite this clinical significance, little is known about the causes and associated risk factors for nondisjunction. For the past 15 years, we have investigated trisomy 21, the leading cause of Down syndrome (DS), as a model to understand nondisjunction. We have built an unprecedented resource of infants with DS and their parents, including biological samples, epidemiological and clinical data. We have shown that altered recombination patterns along the nondisjoined chromosome are a risk for nondisjunction, and for the first time, have shown that the position of susceptible recombinants differ by the age of the oocyte. In this proposal, we will focus on the characteristics of altered recombination to address the following critical points: 1) Our preliminary evidence suggests that maternal-age related patterns of recombination differ between Ml and MIl errors. As evidence suggests that both errors are initiated in Ml, can we develop a unifying hypothesis to explain these conflicting patterns? In addition, is there a subset of recombination profiles that are, of themselves, sufficient to cause nondisjunction? If so, are these """"""""stand-alone"""""""" profiles more frequent among the nondisjoined chromosomes of younger oocytes? 2) Absence of recombination is a hallmark of nondisjunction, both in humans and model systems. What is the extent of this reduced recombination: is the altered/reduced recombination limited to the nondisjoining bivalent, or are there genome-wide """"""""disturbances"""""""" in recombination among oocytes bound for nondisjunction? 3) In the presence of a specific environmental influence, can the risk for nondisjunction be altered by individual exchange patterns? In other words, are there unique pairings of recombination and environment that increase the risk for nondisjunction or are environmental influences and recombination patterns unrelated? Our multidisciplinary strategy will ensure progress toward understanding nondisjunction and its significant impact on humans.
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