Why Study Meiosis?

Why Should We Study Meiosis in Mammalian Eggs?

Understanding the fundamental mechanisms of chromosome segregation during meiosis has immense clinical relevance in the treatment of human infertility and congenital disorders. Chromosome segregation errors during meiosis very frequently give rise to aneuploidy in eggs, a chromosomal abnormality where too many or too few chromosomes are present in the egg.

Incidence of aneuploidy in human embryos is astonishingly high, occurring in at least 5% of pregnancies (1). Importantly, because most chromosomally abnormal human embryos die before birth, aneuploidy is the most frequent cause of pregnancy failure. Underlining this very fact, only ~0.3% of liveborns are aneuploid (2) whereas incidence of aneuploidy significantly increases to nearly 4% in stillbirths (embryo deaths that occur after 20 weeks of pregnancy) (2). This statistic further increases in spontaneous abortions where ~35% of embryos are aneuploid (2). A common form of aneuploidy is trisomy, where three copies of a specific chromosome are present instead of two. In spontaneous abortions, trisomies of chromosomes 16, 21 and 22 account for nearly ~50% of all trisomies (1).

Aneuploidy in embryos does not always lead to pregnancy failure and some chromosomal abnormalities are compatible with life. However, most of these often lead to debilitating developmental defects such as mental retardation. The most common forms of life-compatible aneuploidies are trisomies of chromosome 21 and sex chromosomes. In particular, trisomy 21 causes a genetic disorder known as Down syndrome which is associated with intellectual disability, visual and hearing defects as well as several other health problems.     

Importantly, aneuploidy in human embryos is mainly attributed to chromosomally abnormal eggs but not sperm. Karyotyping and Fluorescence In Situ Hybridization (FISH) assays estimate 1-4% of sperm are aneuploid (3-5). In contrast, these assays and recent cytogenetic analyses have revealed 10-70% of human eggs are chromosomally abnormal (6-11).  While differences in the method of analyses may result in varying estimates of aneuploidy in eggs, studies spanning decades have clearly established very high incidence of aneuploidy in human eggs but not sperm. One major difference in the way eggs and sperm undergo meiosis may explain why eggs but not sperm are prone to high rates of aneuploidy. During spermatogenesis, sperm proceed through meiosis without delay. However, during oogenesis, oocytes are typically arrested in prophase of meiosis I for many years before homologous chromosomes are segregated. It is generally thought that this prolonged arrest in meiosis contributes to high incidence of chromosome segregation errors in oocytes. Indeed, the accuracy of chromosome segregation during meiosis declines even further with increasing maternal age, a phenomenon often referred to as ”maternal age effect”. Since the early discovery that the incidence of Down syndrome increases with maternal age (12), several studies have demonstrated similar correlation for most other trisomies.

Despite the clinical implication of erroneous meiosis, we still know very little about the mechanisms that ensure accurate chromosome segregation in oocytes. Although recent advances in live imaging technologies and cytogenetics have allowed us to study meiosis at unprecedented details, much more is needed if we are to clinically intervene with human embryo deaths, infertility and congenital birth defects that arise from aneuploidy. In the lab, we combine advanced microscopy with molecular cell biology and biochemical techniques to study the intricate mechanisms of meiotic chromosome segregation in mammalian oocytes.

References

  1. T. Hassold, P. Hunt, To err (meiotically) is human: the genesis of human aneuploidy. Nat Rev Genet 2, 280-291 (2001).
  2. T. Hassold et al., Human aneuploidy: incidence, origin, and etiology. Environ Mol Mutagen 28, 167-175 (1996).
  3. R. H. Martin, A. Rademaker, The frequency of aneuploidy among individual chromosomes in 6,821 human sperm chromosome complements. Cytogenet Cell Genet 53, 103-107 (1990).
  4. R. H. Martin, E. Ko, A. Rademaker, Distribution of aneuploidy in human gametes: comparison between human sperm and oocytes. Am J Med Genet 39, 321-331 (1991).
  5. C. Templado, F. Vidal, A. Estop, Aneuploidy in human spermatozoa. Cytogenet Genome Res 133, 91-99 (2011).
  6. F. Pellestor, B. Andreo, T. Anahory, S. Hamamah, The occurrence of aneuploidy in human: lessons from the cytogenetic studies of human oocytes. Eur J Med Genet 49, 103-116 (2006).
  7. F. Pacchierotti, I. D. Adler, U. Eichenlaub-Ritter, J. B. Mailhes, Gender effects on the incidence of aneuploidy in mammalian germ cells. Environ Res 104, 46-69 (2007).
  8. E. Fragouli et al., The cytogenetics of polar bodies: insights into female meiosis and the diagnosis of aneuploidy. Mol Hum Reprod 17, 286-295 (2011).
  9. A. S. Gabriel et al., Array comparative genomic hybridisation on first polar bodies suggests that non-disjunction is not the predominant mechanism leading to aneuploidy in humans. J Med Genet 48, 433-437 (2011).
  10. J. Geraedts et al., Polar body array CGH for prediction of the status of the corresponding oocyte. Part I: clinical results. Hum Reprod 26, 3173-3180 (2011).
  11. A. Obradors et al., Whole-chromosome aneuploidy analysis in human oocytes: focus on comparative genomic hybridization. Cytogenet Genome Res 133, 119-126 (2011).
  12. L. S. Penrose, The relative effects of paternal and maternal age in mongolism. 1933. J Genet 88, 9-14 (2009).