Rs2305957

SNP rs2305957 is identified in a genome-wide association study for mitotic origin aneuploidy in early embryo development. This association study is performed on 2362 unrelated mothers (1956 in vitro fertilization patients and 406 oocyte donors) and found that SNP rs2305957 is strongly associated (Odds Ratio 1.244, P value 8.68*10-16), with the minor allele (A is the minor allele and G is the major allele) conferring a significantly increased rate of mitotic error and thus embryonic mortality. The minor allele is present in diverse human populations at frequencies of 20 to 45%. Among the 2362 mothers, 1332 have European ancestry and 259 have East Asian ancestry. Separating analysis of the 1332 female patients with a high proportion of European ancestry has OR 1.238 and P-value 1.91*10-9, while the analysis of 259 patients with East Asian ancestry has OR 1.323 and P-value 4.58*10-4.

Aneuploidy is common in early human embryos and often leads to embryonic mortality. Understanding of aneuploidy risk may assist the future development of diagnostic or therapeutic technologies targeting certain forms of infertility. Even though aneuploidy incidence from maternal meiotic origin is maternal age related, variation in mitotic origin aneuploidy incidence can be partially explained by variation in parents’ genome.

The haplotype associated with SNP rs2305957 lies in a region of low recombination spanning more than 600 Kbp of chromosome 4. This region contains genes INTU, SLC25A31, HSPA4L, PLK4, MFSD8, LARP1B, and PGRMC2. Although other genes in the region can't be ruled out, PLK4 is the most attractive aneuploidy related candidate. It is a master regulator of centriole duplication, a key component of the centrosome cycle, and is essential for mediating bipolar spindle formation during the first cell divisions in mouse embryos. Both up- and down-regulation of PLK4 have the potential to induce chromosome instability. Altered PLK4 expression is commonly observed in several forms of cancer.