title: Common variants spanning PLK4 are associated with mitotic-origin aneuploidy in human embryos.
abstract: 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.
authors: Department of Biology, Stanford University, Stanford, CA, USA.
authors: Rajiv C
authors: RC
authors: McCoy
authors: Natera, Inc., San Carlos, CA, USA.
authors: Zachary
authors: Z
authors: Demko
authors: Natera, Inc., San Carlos, CA, USA.
authors: Allison
authors: A
authors: Ryan
authors: Natera, Inc., San Carlos, CA, USA.
authors: Milena
authors: M
authors: Banjevic
authors: Natera, Inc., San Carlos, CA, USA.
authors: Matthew
authors: M
authors: Hill
authors: Natera, Inc., San Carlos, CA, USA.
authors: Styrmir
authors: S
authors: Sigurjonsson
authors: Natera, Inc., San Carlos, CA, USA.
authors: Matthew
authors: M
authors: Rabinowitz
authors: Department of Biology, Stanford University, Stanford, CA, USA.
authors: Hunter B
authors: HB
authors: Fraser
authors: Department of Biology, Stanford University, Stanford, CA, USA.
authors: Dmitri A
authors: DA
authors: Petrov
mesh_terms: D000483:Alleles; D000782:Aneuploidy; D001757:Blastomeres; D004622:Embryo, Mammalian / Q000502:physiology*; D047108:Embryonic Development; D005220:Fathers; D005260:Female; D005307:Fertilization in Vitro; D056726:Genetic Association Studies; D005820:Genetic Testing; D006239:Haplotypes; D006801:Humans; D008297:Male; D008938:Mitosis; D009035:Mothers; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000502:physiology; D012641:Selection, Genetic; D014327:Trophoblasts
chemical_list: C490219:PLK4 protein, human; D017346:Protein Serine-Threonine Kinases