Journal
GENOME RESEARCH
Volume 29, Issue 3, Pages 367-382Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gr.239830.118
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Funding
- NIH/ODONPRC [P51 OD011092]
- Auxogyn
- P.E.O. Scholar Award
- N.L. Tartar Research Fellowship
- T32 Reproductive Biology NIH Training Grant [T32 HD007133]
- Collins Medical Trust Foundation
- Glenn/AFAR Scholarship for Research in the Biology of Aging
- NIH/NICHD [F31HD094472, R01HD086073-A1]
- National Library of Medicine Biomedical Informatics Training Grant [T15LM007088]
- National Centers for Translational Research in Reproduction and Infertility (NCTRI) pilot funds (NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development) [P50 HD071836]
- Howard & Georgeanna Jones Foundation for Reproductive Medicine
- Medical Research Foundation of Oregon
- Collins Medical Trust
- [S10 RR024585]
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Aneuploidy that arises during meiosis and/or mitosis is a major contributor to early embryo loss. We previously showed that human preimplantation embryos encapsulate missegregated chromosomes into micronuclei while undergoing cellular fragmentation and that fragments can contain chromosomal material, but the source of this DNA was unknown. Here, we leveraged the use of a nonhuman primate model and single-cell DNA-sequencing (scDNA-seq) to examine the chromosomal content of 471 individual samples comprising 254 blastomeres, 42 polar bodies, and 175 cellular fragments from a large number (N = 50) of disassembled rhesus cleavage-stage embryos. Our analysis revealed that the aneuploidy and micronucleation frequency is conserved between humans and macaques, and that fragments encapsulate whole and/or partial chromosomes lost from blastomeres. Single-cell/fragment genotyping showed that these chromosome-containing cellular fragments (CCFs) can be maternally or paternally derived and display double-stranded DNA breaks. DNA breakage was further indicated by reciprocal subchromosomal losses/gains between blastomeres and large segmental errors primarily detected at the terminal ends of chromosomes. By combining time-lapse imaging with scDNA-seq, we determined that multipolar divisions at the zygote or two-cell stage were associated with CCFs and generated a random mixture of chromosomally normal and abnormal blastomeres with uniparental or biparental origins. Despite frequent chromosome missegregation at the cleavage-stage, we show that CCFs and nondividing aneuploid blastomeres showing extensive DNA damage are prevented from incorporation into blastocysts. These findings suggest that embryos respond to chromosomal errors by encapsulation into micronuclei, elimination via cellular fragmentation, and selection against highly aneuploid blastomeres to overcome chromosome instability during preimplantation development.
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