Common Variants Spanning PLK4 Are Associated With Mitotic-Origin Aneuploidy in Human Embryos. Issue 7 (July 2015)

• Record Type: Journal Article
• Authors: McCoy, Rajiv C.; Demko, Zachary; Ryan, Allison; Banjevic, Milena; Hill, Matthew; Sigurjonsson, Styrmir; Rabinowitz, Matthew; Fraser, Hunter B.; Petrov, Dmitri A.
• Is Part Of: Obstetrical & gynecological survey. Volume 70:Issue 7(2015)
• Publication Date: 2015-07
• Subjects: Obstetrics -- Periodicals; Gynecology -- Periodicals; Generative organs, Female -- Surgery -- Periodicals; 618
• DOI: 10.1097/OGX.0000000000000223
• Languages: English
• ISSNs: 0029-7828

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>ABSTRACT</title> <p>Aneuploidy—the incorrect number of chromosomes in a cell—is extremely common in early embryos and is the primary cause of miscarriage and congenital birth defects. Errors can be introduced in the egg (meiotic-origin aneuploidy) and early embryo development (mitotic-origin aneuploidy). The likelihood of meiotic-origin aneuploidy increases with maternal age, especially after age 35 years. Rates of mitotic-origin aneuploidy vary in women of the same age undergoing in vitro fertilization (IVF). The factors responsible for mitotic-origin aneuploidy are largely unknown.</p> <p>The authors hypothesized that that variation in paternal gene products may contribute to variation in rates of mitotic-origin aneuploidy. The hypothesis was tested by performing a genome-wide association study of aneuploidy risk in patients undergoing preimplantation genetic screening of embryos collected from IVF cycles.</p> <p>Screening day-3 embryos during IVF cycles identified an association between putative mitotic-origin aneuploidy and a single-nucleotide variant (SNP rs2305957) on chromosome 4 of maternal genomes. The genetic region of this variant included a candidate gene, Polo-like kinase 4 (<italic>PLK4</italic>), which is responsible for spindle formation and chromosome segregation in mitotic cell division. Fewer embryos for testing were contributed at day 5 by mothers with high-risk genotypes, suggesting that their embryos are less likely to survive to blastocyst formation.</p> <p>The high frequency of the rs2305957 variant in modern populations and its absence from Neanderthal genomes suggest that it has been under positive selection during human evolution. This apparently deleterious allele either hitchhiked to substantial frequency during evolution or was a target of selection. Positive selection during evolution of a genetic variant that decreases viability of the embryo is paradoxical. Some possible benefits of maintenance of this variant are discussed.</p> </sec> </abstract>