IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v12y2021i1d10.1038_s41467-021-25028-1.html
   My bibliography  Save this article

Human MLH1/3 variants causing aneuploidy, pregnancy loss, and premature reproductive aging

Author

Listed:
  • Priti Singh

    (Cornell University College of Veterinary Medicine
    Fred Hutchinson Cancer Research Center)

  • Robert Fragoza

    (Cornell University
    Cornell University)

  • Cecilia S. Blengini

    (Rutgers University, Dept. of Genetics)

  • Tina N. Tran

    (Cornell University College of Veterinary Medicine)

  • Gianno Pannafino

    (Cornell University)

  • Najla Al-Sweel

    (Cornell University)

  • Kerry J. Schimenti

    (Cornell University College of Veterinary Medicine)

  • Karen Schindler

    (Rutgers University, Dept. of Genetics)

  • Eric A. Alani

    (Cornell University)

  • Haiyuan Yu

    (Cornell University
    Cornell University)

  • John C. Schimenti

    (Cornell University College of Veterinary Medicine
    Cornell University)

Abstract

Embryonic aneuploidy from mis-segregation of chromosomes during meiosis causes pregnancy loss. Proper disjunction of homologous chromosomes requires the mismatch repair (MMR) genes MLH1 and MLH3, essential in mice for fertility. Variants in these genes can increase colorectal cancer risk, yet the reproductive impacts are unclear. To determine if MLH1/3 single nucleotide polymorphisms (SNPs) in human populations could cause reproductive abnormalities, we use computational predictions, yeast two-hybrid assays, and MMR and recombination assays in yeast, selecting nine MLH1 and MLH3 variants to model in mice via genome editing. We identify seven alleles causing reproductive defects in mice including female subfertility and male infertility. Remarkably, in females these alleles cause age-dependent decreases in litter size and increased embryo resorption, likely a consequence of fewer chiasmata that increase univalents at meiotic metaphase I. Our data suggest that hypomorphic alleles of meiotic recombination genes can predispose females to increased incidence of pregnancy loss from gamete aneuploidy.

Suggested Citation

  • Priti Singh & Robert Fragoza & Cecilia S. Blengini & Tina N. Tran & Gianno Pannafino & Najla Al-Sweel & Kerry J. Schimenti & Karen Schindler & Eric A. Alani & Haiyuan Yu & John C. Schimenti, 2021. "Human MLH1/3 variants causing aneuploidy, pregnancy loss, and premature reproductive aging," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25028-1
    DOI: 10.1038/s41467-021-25028-1
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-021-25028-1
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-021-25028-1?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25028-1. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.