Similarly, Lenzi et al [17] observed a ten-fold difference in the number of MLH1 foci in individual oocytes, and suggested that as many as 30% of human oocytes might be predisposed to nondisjunction because of events occurring in fetal oogenesis. in the dictyate oocyte, during the 1050 12 months period of meiotic arrest; or during the final stages of oocyte growth and maturation, when meiosis resumes and the meiotic divisions take place. Recent evidence from studies of human oocytes and trisomic conceptions and from studies in model organisms implicates errors at each of these stages == Summary == It seems likely that there are multiple causes of human age-related nondisjunction, complicating our Pozanicline efforts to understand and, ultimately, to provide preventative measures for errors associated with increasing maternal age. Keywords:trisomy, maternal age, recombination == Introduction == The association between advancing maternal age and trisomy is one of the best-known and longest acknowledged risk factors for any human genetic defect. As early as 1933 a quarter century before the identification of trisomy 21 by Lejeune et al [1] Penrose acknowledged that Down syndrome was more common in older women [2]. Studies in the 19601980s confirmed and extended these observations, and it is now clear that increasing age of the women increases the likelihood of trisomy Pozanicline for most, if not all, human chromosomes [3,4]. However, our understanding of the basis of the age effect has not matched our understanding of the clinical importance of the effect; indeed, we Pozanicline know little more about the underlying causes of the age effect than did either Penrose or Lejeune. Fortunately, this situation may finally be changing. Large-scale analyses of the origin of trisomy 21, new approaches to the study of human gametes, and mutational analyses of model organisms have begun to shed light on processes that mediate nondisjunctional risks. In this review, we summarize these observations in four actions: first, reviewing Pozanicline the stages of oocyte development; second, summarizing recent analyses of human trisomies; third, critiquing recent studies of meiosis in human oocytes; and finally, discussing recent improvements in our understanding of nondisjunction from meiotic analyses of model organisms. == The life cycle of the human oocyte: a complicated journey == It is perhaps not amazing Pozanicline that most human trisomies are maternally-derived, since the life cycle of the oocyte is usually long and complicated. In both the fetal ovary and testis the germ cells undergo a period of mitotic proliferation, but the two pathways soon diverge. Shortly after the onset of testis differentiation, male germ cells cease proliferating and enter into a protracted arrest phase. In contrast, in the ovary female germ cells enter meiotic prophase during the first trimester of pregnancy in response to meiosis-specific inducers such asStra8(e.g., [5]) (Physique 1). Over the next several weeks a complicated series of chromosomal events occur, with homologous chromosomes first obtaining and synapsing with one another and ultimately exchanging genetic material, or recombining. Shortly thereafter, the process grinds to a halt, and oocytes enter an arrest phase, termed dictyate. The prophase-arrested oocyte remains in a state of meiotic suspended animation until it is eliminated by atresia or, following the onset of menses, is usually recruited into the pool of growing oocytes. On average, one oocyte per ovarian cycle completes the first meiotic division (MI) and proceeds to metaphase of meiosis II (MII); if fertilized by a sperm, it completes the second division and embryonic development ensues. Thus, over the approximate 30 12 months reproductive lifetime of a human female, only a few hundred oocytes total the first meiotic division and few if any total the second. == Physique 1. == Life cycle of the human oocyte. There are several different timepoints at which events may occur that increase the likelihood of meiotic nondisjunction in older women; examples of some of these events (and the recommendations supporting their importance) are provided. Because the oocyte remains in prophase arrest for Rabbit Polyclonal to OR5A2 most of its lifetime, abnormalities arising during this stage seem the most obvious candidates for the genesis of the age effect. However, as detailed below, there is growing evidence that this pre-meiotic.