Common variants spanning PLK4 are associated with mitotic-origin aneuploidy in human embryos

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Science  10 Apr 2015:
Vol. 348, Issue 6231, pp. 235-238
DOI: 10.1126/science.aaa3337

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Chromosome number varies in humans

Pregnancy loss is often associated with a loss of chromosome number, a condition known as aneuploidy. When examining aneuploid embryos during in vitro fertilization cycles, McCoy et al. found a large genomic region associated with defects in maternal chromosome number (see the Perspective by Vohr and Green). This region contains a gene, Polo-like Kinase 4 (PLK4), that is known to affect chromosome segregation and has variants that correlate with an increased rate of maternal aneuploidy. Surprisingly, such variants occur at relatively high levels in human populations and may be under positive selection.

Science, this issue p. 235; see also p. 180


Aneuploidy, the inheritance of an atypical chromosome complement, is common in early human development and is the primary cause of pregnancy loss. By screening day-3 embryos during in vitro fertilization cycles, we identified an association between aneuploidy of putative mitotic origin and linked genetic variants on chromosome 4 of maternal genomes. This associated region contains a candidate gene, Polo-like kinase 4 (PLK4), that plays a well-characterized role in centriole duplication and has the ability to alter mitotic fidelity upon minor dysregulation. Mothers with the high-risk genotypes contributed fewer embryos for testing at day 5, suggesting that their embryos are less likely to survive to blastocyst formation. The associated region coincides with a signature of a selective sweep in ancient humans, suggesting that the causal variant was either the target of selection or hitchhiked to substantial frequency.

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