PARENT SESSION
PLATFORM SESSION 4. GAMETE BIOLOGY AND GAMETOGENESIS I

Sunday, August 1, 2004
3:00 PM–5:00 PM
Buchanan A104
Chairs: Leslie Heckert Co-Chair: Jason Swain

(29) CHROMOSOMAL ABNORMALITIES IN IMMATURE, PRIMARY, HUMAN OOCYTES.

Hardy, Kate¹, Iatropoulou, Aikaterini¹, Margara, Raul¹, Roberts, Ruth¹, Franks, Stephen¹, ¹ Imperial College, London, UK

ABSTRACT- Aneuploidy is a major cause of human pregnancy loss and its incidence increases with maternal age. Aneuploidy originates mainly in the oocyte, resulting from aberrant chromosome segregation during meiosis. However, it has been argued that oocytes could be abnormal at the outset and that aneuploidy could also arise during mitosis of germ cells, a hypothesis which is not inconceivable in light of the high incidence of mitotic non-disjunction in preimplantation human embryos. The chromosomal constitution of oocytes arrested in prophase I of meiosis will reflect the fidelity of chromosomal segregation during germ cell mitosis. We have used fluorescent in situ hybridization to examine the number of copies of chromosomes X, 13 and 21 in 459 immature, diploid oocytes from 37 pre-menopausal women (age range 25 to 42 years). Oocytes were dissected from primordial and primary follicles isolated from ovarian biopsies taken, with informed consent, during investigative laparoscopy. The majority of oocytes had two signals for each chromosome analysed, confirming that they were diploid. However, 49/459 (11%) oocytes had 3 well separated clear signals of equal size, suggesting that these oocytes were trisomic. Trisomy 21 was the most common trisomy (6% of oocytes) and was significantly more common in older women (p=0.03). There was also strong evidence of premature chromatid separation; 32% of the oocytes had pairs of small signals (considered to result from labelling of individual chromatids) for one or more chromosomes, instead of the expected single signal. The most commonly affected chromosome was chromosome 21 and the frequency of chromatid separation for chromosomes 21 and 13 was significantly related to increasing age (p=0.0002), becoming more common in older women. This study provides the first experimental evidence that aneuploidy can arise during mitosis of primordial germ cells during fetal life. Trisomic oocytes were more common in older women, indicating that they accumulate in the ovary. Furthermore, individual chromatids, which are normally tightly held together by cohesins at this stage of meiosis, were more commonly separated in oocytes from older women. Decreased chromatid cohesion could predispose chromosomes to non-disjunction during meiosis, accounting for the age-related increase in aneuploidy.

KEY WORDS: Aneuploidy, Non-disjunction, Meiosis, Trisomy 21