The goals of this project are to determine by fluorescent in situ hybridization (FISH) the pairing behavior and the level of gametic aneuploidy of specific chromosomes in human female germ cells from fetal life to the menopausal period. This data, collected over the entire germ cell developmental period, will be used to establish normative data for chromosomal anomalies in oocytes throughout reproductive life and has the potential to distinguish among the various hypotheses that have been proposed to explain the high incidence of aneuploidy in female gametes and the related maternal age effect. The operation of reduced recombination in disomic 21 gametes should be reflected in unpaired chromosome 21 homologues in post pachytene gametes. If maternal age is involved in the recombination effect, the level of unpaired chromosome 21's should increase with oocyte age. The level of aneuploidy at different ages could distinguish among the models of selection that have been proposed to explain maternal age dependent trisomy. If oogonial nondisjunction followed by selection of euploid gametes in early reproduction plays a significant role in trisomy 21, then a detectable level of gametic aneuploidy should be seen in oocytes from older women. Multicolor FISH analysis will permit the detection of heterologous associations in early meiosis which could be indicative of the hypothesized """"""""searching"""""""" or """"""""trial and error"""""""" process preceding pairing. It will allow determination of possible heterologous associations between acrocentrics which are known to form Robertsonian translocations. Identification of individual chromosomes in mammalian oogonial meiosis is normally not possible. This proposal represents the first time in which molecular technique will permit the general identification of chromosome and their possible interaction in mammalian oogenesis. Aneuploidy and pairing anomalies on fetal and adult oocytes will be identified using FISH with whole chromosome probes (chromosome painting). Fetal specimens will be obtained from second trimester terminations and from all stillborns undergoing autopsy. Adult oocytes will be extracted from surgical ovarian specimens from women of all ages who are undergoing indicated gynecologic surgery. Dual color FISH will be used to evaluate for heterologous associations between acrocentrics to analyze pairing relationships and their possible role in the formation of Robertsonian translocations. Multicolor FISH will be used to evaluate for heterologous associations in early meiosis to determine their significance in the formation of structural rearrangements.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29HD033033-05
Application #
6164903
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Hanson, James W
Project Start
1996-03-01
Project End
2004-02-28
Budget Start
2000-03-01
Budget End
2004-02-28
Support Year
5
Fiscal Year
2000
Total Cost
$103,950
Indirect Cost
Name
University of Washington
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Cheng, Edith Y; Naluai-Cecchini, Theresa (2004) FISHing for acrocentric associations between chromosomes 14 and 21 in human oogenesis. Am J Obstet Gynecol 190:1781-5; discussion 1785-7
Cheng, E Y; Chen, Y J; Disteche, C M et al. (1999) Analysis of a paracentric inversion in human oocytes: nonhomologous pairing in pachytene. Hum Genet 105:191-6