Haplotype-aware inference of human chromosome abnormalities

Daniel Ariad, Stephanie M. Yan, Andrea R. Victor, Frank L. Barnes, Christo G. Zouves, Manuel Viotti, Rajiv C. McCoy

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Extra or missing chromosomes—a phenomenon termed aneuploidy—frequently arise during human meiosis and embryonic mitosis and are the leading cause of pregnancy loss, including in the context of in vitro fertilization (IVF). While meiotic aneuploidies affect all cells and are deleterious, mitotic errors generate mosaicism, which may be compatible with healthy live birth. Large-scale abnormalities such as triploidy and haploidy also contribute to adverse pregnancy outcomes, but remain hidden from standard sequencing-based approaches to preimplantation genetic testing for aneuploidy (PGT-A). The ability to reliably distinguish meiotic and mitotic aneuploidies, as well as abnormalities in genome-wide ploidy, may thus prove valuable for enhancing IVF outcomes. Here, we describe a statistical method for distinguishing these forms of aneuploidy based on analysis of low-coverage whole-genome sequencing data, which is the current standard in the field. Our approach overcomes the sparse nature of the data by leveraging allele frequencies and linkage disequilibrium (LD) measured in a population reference panel. The method, which we term LD-informed PGT-A (LD-PGTA), retains high accuracy down to coverage as low as 0.05× and at higher coverage can also distinguish between meiosis I and meiosis II errors based on signatures spanning the centromeres. LD-PGTA provides fundamental insight into the origins of human chromosome abnormalities, as well as a practical tool with the potential to improve genetic testing during IVF.

Original languageEnglish
Article numbere2109307118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number46
StatePublished - 16 Nov 2021
Externally publishedYes


  • haploidy
  • in vitro fertilization
  • mosaicism
  • triploidy
  • trisomy

ASJC Scopus subject areas

  • General


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