Trends in Cell Biology
Volume 27, Issue 1, January 2017, Pages 55-68
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Review
Special Issue: Cell Cycle
Mechanisms of Aneuploidy in Human Eggs

https://doi.org/10.1016/j.tcb.2016.09.002Get rights and content

Trends

Fertility steadily decreases as women age and, by mid-life, women fail to produce healthy eggs. Meiotic chromosomes experience age-related structural changes that may contribute to increasing rates of chromosome segregation errors.

Novel error-causing pathways are reported in human oocytes that might explain how a previously undetected alternative segregation pattern arises. Emerging studies provide a better understanding of why oocytes are frequently defective and lead to age-related infertility.

Recent studies have found that meiosis in mammalian females is intrinsically error prone, causing high rates of aneuploidy and infertility. Cellular mechanisms responsible for segregating chromosomes are inefficient, affecting females of all ages.

Eggs and sperm develop through a specialized cell division called meiosis. During meiosis, the number of chromosomes is reduced by two sequential divisions in preparation for fertilization. In human female meiosis, chromosomes frequently segregate incorrectly, resulting in eggs with an abnormal number of chromosomes. When fertilized, these eggs give rise to aneuploid embryos that usually fail to develop. As women become older, errors in meiosis occur more frequently, resulting in increased risks of infertility, miscarriage, and congenital syndromes, such as Down's syndrome. Here, we review recent studies that identify the mechanisms causing aneuploidy in female meiosis, with a particular emphasis on studies in humans.

Section snippets

Aneuploidy in Human Oocytes: A Topic of Growing Relevance in Society

Over the past century, greater medical knowledge and technological advances have improved the quality and duration of human lives. By contrast, the span of female fertility remains unchanged. A limited reserve of oocytes (see Glossary) is formed before birth, but gradually declines in quality with age, resulting in reduced fertility and an age-related increase in eggs with an abnormal number of chromosomes, termed ‘aneuploidy’. Despite this concern, women more frequently delay having their

Meiosis in Human Oocytes

Meiosis involves two successive cell divisions, in which first homologous chromosomes (meiosis I) and then sister chromatids (meiosis II) separate. The segregation of homologous chromosomes during the first meiotic division requires that the homologous chromosomes become linked with each other. These links are established in the early stages of oocyte development during growth of the female fetus in a process called homologous recombination [3] (Figure 1). The maternal and paternal chromosomes

Types of Aneuploidy in Human Oocytes

Recent technological developments have increased the ability to detect aneuploidy in eggs or during the early stages of embryonic development (See Outstanding Questions). During preimplantation genetic diagnostics, cells of an embryo can sometimes be biopsied and screened for genetic abnormalities to select healthy embryos for implantation [21]. Testing of oocytes can be helpful and may minimize the need to test embryos. In particular, polar bodies can be used to determine the cytology of an

Age-Related Causes of Aneuploidy

Women experience a gradual loss in the ability to become pregnant as they become older. Infertility is often reached from the age of 35 to about 10 years later. Meiotic chromosome segregation errors increase sharply in this age window. A comprehensive cytogenetic analysis examining more than 20 000 human oocytes by FISH reported that aneuploidy occurs in 20% of oocytes from 35-year-old women and increases to nearly 60% of oocytes from women over 43 years of age [39]. Recent studies utilizing

Age-Independent Causes of Aneuploidy

Aneuploidy affects not only eggs from older women, but also those from younger women since eggs produced by young women in the prime years of reproductive potential are still frequently defective. Eggs donated by young women for IVF often produce embryos with aneuploidy 43, 71 and many individuals with Down's syndrome are born to mothers under the age of 35 72, 73. Depending on the study, 3–61% of oocytes from women younger than 30 years of age are affected by aneuploidy 74, 75, 76, suggesting

Concluding Remarks

Human oocytes frequently experience chromosome segregation errors in meiosis that result in aneuploidy. As women become older, their oocytes lose the potential to give rise to viable embryos. Several pathways contribute to errors in meiosis. Age-related changes to the structure of chromosomes in oocytes promote incorrect attachments of chromosomes to the meiotic spindle and the premature splitting of bivalents before cell division. What is the cause of these age-related structural changes? In

Acknowledgments

It was the authors’ intention to write an article accessible to a wide audience while also including as many new and exciting studies as possible. We would like to apologize for any omissions, because these were unintentional or due to space limitations imposed by the journal. We thank Agata Zielinska and other members of the Schuh lab for critical review of this article. M.S. and A.W. have received financial support from the Max Planck Society, the European Research Council under grant

Glossary

Anaphase
the stage of cell division when the spindle segregates chromosomes by pulling them to opposite spindle poles.
Blastocyst
a stage in early embryo development that forms before implantation into the uterus.
Centromere
the region of a chromosome where the kinetochore is assembled and microtubules attach.
Homologous recombination
an event specific to meiosis where DNA of homologous chromosomes is covalently exchanged to produce chromosomes with new allele combinations and that links homologous

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