ABSTRACT
After 30 years of widely held belief that humans had 48 chromosomes, the refinement of karyotyping techniques in the 1950s facilitated the discovery that humans have 46 chromosomes, including the XY sex chromosomes [1]. Using improved cytogenetic techniques, Jacobs and Strong [2] reported that Klinefelter syndrome in males was caused by an extra X chromosome [2]. In the same year, Jejeune, Gauthier, and Turpin [3,4] and the Jacobs group [5] independently discovered that Down syndrome was caused by an extra chromosome 21. Ford and colleagues [6] found that Turner syndrome was caused by the loss of an X chromosomes (45,X) in females and also reported the first mosaic individual (XXY/XX) [7]. These studies, reported in 1959, led to an explosion in the investigations into aneuploidy [8-12] and initiated epidemiological and extensive cohort studies of both spontaneous miscarriages as well as live births (Figure 5.1). Of spontaneous miscarriages, nearly 50% are chromosomally abnormal, mainly due to aneuploidy (one in
Introduction ...............................................................................................................................................41 A Historical Context for Human Aneuploidy ......................................................................................41 The J-Shaped Curve of Human Aneuploidies ..................................................................................... 42 Chromosome-Specific Effects and Equal Contributions from Monosomies and Trisomies in
Human Oocytes and Preimplantation Embryos .............................................................................. 44 Features Influencing the J Curve in Oocytes and Preimplantation Embryos ...................................... 44 The Origins of Maternal Chromosome Errors .................................................................................... 48 Errors in Meiosis I Are Predominantly Due to Pre-Division in ART Oocytes ................................... 48 Reverse Segregation: A Novel Segregation Pattern ............................................................................ 49 Time-Lapse Imaging Reveals Chromosomal “Aging” Defects May Precede Errors
in Segregation ............................................................................................................................ 50 Recombination Affects Chromosome Segregation in Human Females .............................................. 52 Recombination Rates Are Established during Fetal Life and Affect Chromosome Segregation
in Adult Oocytes .............................................................................................................................. 52 Meiotic Spindles Are Inherently Error-Prone in Human Female Meiosis .......................................... 54 General Aging Features of Human Oocytes ....................................................................................... 54 Mitotic Chromosome Errors in Preimplantation Embryos ................................................................. 54 Genome-Wide Association Study to Map Variants That Affect Chaotic Mitotic Aneuploidies ......... 55 Aneuploidy and Embryonic Arrest ..................................................................................................... 56 Future Directions ................................................................................................................................ 56
Acknowledgments .................................................................................................................................... 57 References ................................................................................................................................................ 57
three), but triploid conceptions are also common [13]. To date, the most comprehensive cohort study is the U.S. National Down Syndrome Project, which was initiated by Terry Hassold and Stephanie Sherman [14].
