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Home / Equine Research Bank / Proc Natl Acad Sci U S A / Naturally occurring horse model of miscarriage reveals tempo...
Proceedings of the National Academy of Sciences of the United States of America2024; 121(33); e2405636121; doi: 10.1073/pnas.2405636121

Naturally occurring horse model of miscarriage reveals temporal relationship between chromosomal aberration type and point of lethality.

Abstract: Chromosomal abnormalities are a common cause of human miscarriage but rarely reported in any other species. As a result, there are currently inadequate animal models available to study this condition. Horses present one potential model since mares receive intense gynecological care. This allowed us to investigate the prevalence of chromosomal copy number aberrations in 256 products of conception (POC) in a naturally occurring model of pregnancy loss (PL). Triploidy (three haploid sets of chromosomes) was the most common aberration, found in 42% of POCs following PL over the embryonic period. Over the same period, trisomies and monosomies were identified in 11.6% of POCs and subchromosomal aberrations in 4.2%. Whole and subchromosomal aberrations involved 17 autosomes, with chromosomes 3, 4, and 20 having the highest number of aberrations. Triploid fetuses had clear gross developmental anomalies of the brain. Collectively, data demonstrate that alterations in chromosome number contribute to PL similarly in women and mares, with triploidy the dominant ploidy type over the key period of organogenesis. These findings, along with highly conserved synteny between human and horse chromosomes, similar gestation lengths, and the shared single greatest risk for PL being advancing maternal age, provide strong evidence for the first animal model to truly recapitulate many key features of human miscarriage arising due to chromosomal aberrations, with shared benefits for humans and equids.
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Publication Date: 2024-08-05 PubMed ID: 39102548PubMed Central: PMC11331123DOI: 10.1073/pnas.2405636121Google Scholar: Lookup
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  • Journal Article

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

Overview

  • This study examines chromosomal abnormalities in horse miscarriages to explore the horse as a natural animal model for understanding human miscarriage caused by chromosomal aberrations.
  • The researchers analyzed pregnancy losses in horses, identifying specific chromosomal changes and their relationship to the timing and severity of fetal lethality, highlighting similarities to human miscarriage.

Background and Importance

  • Chromosomal abnormalities are a leading cause of miscarriage in humans but are rarely documented in other species, limiting the ability to study these conditions in animal models.
  • Horses (mares) are considered a potential model because they receive detailed veterinary care during pregnancy, allowing for precise observation and collection of pregnancy loss samples.
  • The study leverages the naturally occurring pregnancy loss in horses to investigate chromosomal aberrations in products of conception (POCs) collected over the embryonic development period.

Methods and Sample

  • The study analyzed 256 POCs from mares experiencing pregnancy loss during early embryonic stages.
  • They used genetic techniques to identify chromosomal copy number aberrations, including triploidy, trisomies, monosomies, and subchromosomal changes.

Key Findings on Chromosomal Aberrations

  • Triploidy, which means having three copies of each chromosome set instead of the normal two, was the most prevalent abnormality, found in 42% of the POCs.
  • Other aberrations detected included trisomies and monosomies in 11.6% and subchromosomal abnormalities in 4.2% of POCs.
  • The aberrations involved 17 different autosomes (non-sex chromosomes), with chromosomes 3, 4, and 20 frequently affected.
  • Triploid fetuses exhibited significant developmental issues, particularly noticeable brain anomalies.

Biological and Comparative Significance

  • The pattern of chromosomal abnormalities causing pregnancy loss in horses closely mirrors that seen in humans, particularly the dominance of triploidy during organ development phases.
  • Horses and humans share highly conserved synteny—a similarity in chromosome structure and gene content—between their genomes, enhancing the validity of the horse as a model species.
  • Gestational lengths and risk factors, notably advancing maternal age being the greatest shared risk for miscarriage, align between the two species.

Conclusions and Implications

  • These findings position the horse as the first natural animal model that accurately replicates key features of human miscarriage related to chromosomal aberrations.
  • This model can help in understanding the timing and nature of chromosomal abnormalities leading to pregnancy loss.
  • Research benefits include improved insight into miscarriage causes for humans and horses alike, important for veterinary care and reproductive health management.

Cite This Article

APA
Lawson JM, Salem SE, Miller D, Kahler A, van den Boer WJ, Shilton CA, Sever T, Mouncey RR, Ward J, Hampshire DJ, Foote AK, Bryan JS, Juras R, Pynn OD, Davis BW, Bellone RR, Raudsepp T, de Mestre AM. (2024). Naturally occurring horse model of miscarriage reveals temporal relationship between chromosomal aberration type and point of lethality. Proc Natl Acad Sci U S A, 121(33), e2405636121. https://doi.org/10.1073/pnas.2405636121

Publication

Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
NlmUniqueID: 7505876
Country: United States
Language: English
Volume: 121
Issue: 33
Pages: e2405636121
PII: e2405636121

Researcher Affiliations

Lawson, Jessica M
  • Department of Pathobiology and Population Sciences, Royal Veterinary College, London AL9 7TA, UK.
Salem, Shebl E
  • Department of Biomedical Sciences, Baker Institute for Animal Health, Cornell University, Ithaca, NY 14853.
Miller, Donald
  • Department of Biomedical Sciences, Baker Institute for Animal Health, Cornell University, Ithaca, NY 14853.
Kahler, Anne
  • Department of Pathobiology and Population Sciences, Royal Veterinary College, London AL9 7TA, UK.
van den Boer, Wilhelmina J
  • Department of Biomedical Sciences, Baker Institute for Animal Health, Cornell University, Ithaca, NY 14853.
Shilton, Charlotte A
  • Department of Pathobiology and Population Sciences, Royal Veterinary College, London AL9 7TA, UK.
Sever, Tia
  • Department of Biomedical Sciences, Baker Institute for Animal Health, Cornell University, Ithaca, NY 14853.
Mouncey, Rebecca R
  • Department of Pathobiology and Population Sciences, Royal Veterinary College, London AL9 7TA, UK.
Ward, Jenna
  • Department of Biomedical Sciences, Baker Institute for Animal Health, Cornell University, Ithaca, NY 14853.
Hampshire, Daniel J
  • Department of Pathobiology and Population Sciences, Royal Veterinary College, London AL9 7TA, UK.
Foote, Alastair K
  • Rossdales Laboratories, Rossdales Ltd, Beaufort Cottages Stables, Newmarket CB8 8JS, UK.
Bryan, Jill S
  • Rossdales Laboratories, Rossdales Ltd, Beaufort Cottages Stables, Newmarket CB8 8JS, UK.
Juras, Rytis
  • Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843.
Pynn, Oliver D
  • Rossdales Veterinary Surgeons, Rossdales Ltd, Beaufort Cottages Stables, Newmarket CB8 8JS, UK.
Davis, Brian W
  • Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843.
Bellone, Rebecca R
  • Department of Population Health and Reproduction, Veterinary Genetics Laboratory, School of Veterinary Medicine, University of California, Davis, CA 95617.
  • Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95617.
Raudsepp, Terje
  • Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843.
de Mestre, Amanda M
  • Department of Biomedical Sciences, Baker Institute for Animal Health, Cornell University, Ithaca, NY 14853.

MeSH Terms

  • Animals
  • Horses
  • Female
  • Chromosome Aberrations
  • Abortion, Spontaneous / genetics
  • Pregnancy
  • Disease Models, Animal
  • Humans
  • Triploidy

Grant Funding

  • SPrj046 / Horserace Betting Levy Board (HBLB)
  • TBA2019 / Thoroughbred Breeders Association

Conflict of Interest Statement

Competing interests statement:The authors declare no competing interest.

References

This article includes 42 references
  1. Quenby S.. Miscarriage matters: The epidemiological, physical, psychological, and economic costs of early pregnancy loss. Lancet 397, 1658–1667 (2021).
    pubmed: 33915094
  2. Essers R.. Prevalence of chromosomal alterations in first-trimester spontaneous pregnancy loss. Nat. Med. 29, 3233–3242 (2023).
    pmc: PMC10719097pubmed: 37996709
  3. Fan L.. Analysis of chromosomal copy number in first-trimester pregnancy loss using next-generation sequencing. Front. Genet. 11, 545856 (2020).
    pmc: PMC7606984pubmed: 33193619
  4. Charalambous C., Webster A., Schuh M.. Aneuploidy in mammalian oocytes and the impact of maternal ageing. Nat. Rev. Mol. Cell Biol. 24, 27–44 (2023).
    pubmed: 36068367
  5. Hassold T., Hall H., Hunt P.. The origin of human aneuploidy: Where we have been, where we are going. Hum. Mol. Genet. 16, R203–R208 (2007).
    pubmed: 17911163
  6. Schmutz S. M., Moker J. S., Clark E. G., Orr J. P.. Chromosomal aneuploidy associated with spontaneous abortions and neonatal losses in cattle. J. VET Diagn. Invest. 8, 91–95 (1996).
    pubmed: 9026087
  7. Shilton C. A.. Whole genome analysis reveals aneuploidies in early pregnancy loss in the horse. Sci. Rep. 10, 13314 (2020).
    pmc: PMC7415156pubmed: 32769994
  8. Esteki M. Z.. The effect of embryonic genome imbalances on pregnancy. Nat. Med. 29, 3014–3015 (2023).
    pubmed: 38012316
  9. Lipták N., Gál Z., Biró B., Hiripi L., Hoffmann O. I.. Rescuing lethal phenotypes induced by disruption of genes in mice: A review of novel strategies. Physiol. Res. 70, 3–12 (2021).
    pmc: PMC8820508pubmed: 33453719
  10. Tosh J., Tybulewicz V., Fisher E. M. C.. Mouse models of aneuploidy to understand chromosome disorders. Mamm Genome 33, 157–168 (2022).
    pmc: PMC8913467pubmed: 34719726
  11. Shilton C. A., Kahler A., Roach J. M., Raudsepp T., de Mestre A. M.. Lethal variants of equine pregnancy: Is it the placenta or foetus leading the conceptus in the wrong direction?. Reprod. Fertil. Dev. 35, 51–69 (2022).
    pubmed: 36592981
  12. Rose B. V.. A method for isolating and culturing placental cells from failed early equine pregnancies. Placenta 38, 107–111 (2016).
    pubmed: 26907389
  13. Halley A. C.. The tempo of mammalian embryogenesis: Variation in the pace of brain and body development. Brain Behav. Evol. 97, 96–107 (2022).
    pmc: PMC9187598pubmed: 35189619
  14. Ozawa N.. Maternal age, history of miscarriage, and embryonic/fetal size are associated with cytogenetic results of spontaneous early miscarriages. J. Assist. Reprod. Genet. 36, 749–757 (2019).
    pmc: PMC6505004pubmed: 30739229
  15. Kahler A.. Fetal morphological features and abnormalities associated with equine early pregnancy loss. Equine Vet. J. 53, 530–541 (2021).
    pubmed: 32869365
  16. Vázquez-Diez C, Paim LMG, FitzHarris G. Cell-size-independent spindle checkpoint failure underlies chromosome segregation error in mouse embryos.. Curr. Biol. 29, 865–873.e3 (2019).
    pubmed: 30773364
  17. Bugno-Poniewierska M, Raudsepp T. Horse clinical cytogenetics: Recurrent themes and novel findings.. Animals 11, 831 (2021).
    pmc: PMC8001954pubmed: 33809432
  18. Kubien EM, Tischner M. Reproductive success of a mare with a mosaic karyotype: 64, XX/65, XX, +30.. Equine Vet. J. 34, 99–100 (2002).
    pubmed: 11817560
  19. Holl HM, Lear TL, Nolen-Walston RD, Slack J, Brooks SA. Detection of two equine trisomies using SNP-CGH.. Mamm Genome 24, 252–256 (2013).
    pubmed: 23515943
  20. Klunder LR, McFeely RA, Beech J, McClune W, Bilinski WF. Autosomal trisomy in a standardbred colt.. Equine Vet. J. 21, 69–70 (1989).
    pubmed: 2920704
  21. Lear TL, Cox JH, Kennedy GA. Autosomal trisomy in a Thoroughbred colt: 65, XY, +31.. Equine Vet. J. 31, 85–88 (1999).
    pubmed: 9952335
  22. Buoen LC. Arthrogryposis in the foal and its possible relation to autosomal trisomy.. Equine Vet. J. 29, 60–62 (1997).
    pubmed: 9031866
  23. Rizzo M. The horse as a natural model to study reproductive aging-induced aneuploidy and weakened centromeric cohesion in oocytes.. Aging 12, 22220–22232 (2020).
    pmc: PMC7695376pubmed: 33139583
  24. Nybo Andersen A-M, Hansen KD, Andersen PK, Davey Smith G. Advanced paternal age and risk of fetal death: A cohort study.. Am. J. Epidemiol. 160, 1214–1222 (2004).
    pubmed: 15583374
  25. Munisha M, Schimenti JC. Genome maintenance during embryogenesis.. DNA Repair 106, 103195 (2021).
    pubmed: 34358805
  26. Gruhn JR. Chromosome errors in human eggs shape natural fertility over reproductive life span.. Science 365, 1466–1469 (2019).
    pmc: PMC7212007pubmed: 31604276
  27. Allais A, FitzHarris G. Absence of a robust mitotic timer mechanism in early preimplantation mouse embryos leads to chromosome instability.. Development 149, dev200391 (2022).
    pubmed: 35771634
  28. De Coster T. Genome-wide equine preimplantation genetic testing enabled by simultaneous haplotyping and copy number detection.. Sci. Rep. 14, 2003 (2024).
    pmc: PMC10805710pubmed: 38263320
  29. McFadden DE. Phenotype of triploid embryos.. J. Med. Genet. 43, 609–612 (2005).
    pmc: PMC2564556pubmed: 16236813
  30. Gabriel AS. An algorithm for determining the origin of trisomy and the positions of chiasmata from SNP genotype data.. Chromosome Res. 19, 155–163 (2011).
    pubmed: 21225334
  31. Massalska D. Triploid pregnancy–Clinical implications.. Clin. Genetics 100, 368–375 (2021).
    pubmed: 34031868
  32. Bergman JEH. Amniotic band syndrome and limb body wall complex in Europe 1980–2019.. Am. J. Med. Genet. A 191, 995–1006 (2023).
    pubmed: 36584346
  33. Baumer A, Balmer D, Binkert F, Schinzel A. Parental origin and mechanisms of formation of triploidy: A study of 25 cases.. Eur. J. Hum. Genet. 8, 911–917 (2000).
    pubmed: 11175278
  34. Passerini V. The presence of extra chromosomes leads to genomic instability.. Nat. Commun. 7, 10754 (2016).
    pmc: PMC4756715pubmed: 26876972
  35. Wade CM. Genome sequence, comparative analysis, and population genetics of the domestic horse.. Science 326, 865–867 (2009).
    pmc: PMC3785132pubmed: 19892987
  36. Kalbfleisch TS. Improved reference genome for the domestic horse increases assembly contiguity and composition.. Commun. Biol. 1, 197 (2018).
    pmc: PMC6240028pubmed: 30456315
  37. R Core Team. R: A language and environment for statistical computing. (R Foundation for Statistical Computing, Vienna, Austria, 2024).
  38. Gel B, Serra E. karyoploteR: An R/Bioconductor package to plot customizable genomes displaying arbitrary data.. Bioinformatics 33, 3088–3090 (2017).
    pmc: PMC5870550pubmed: 28575171
  39. Giulotto E, Raimondi E, Sullivan KF. The unique DNA sequences underlying equine centromeres.. Prog. Mol. Subcell Biol. 56, 337–354 (2017).
    pubmed: 28840244
  40. Raudsepp T. Molecular heterogeneity of XY sex reversal in horses.. Anim. Genet. 41, 41–52 (2010).
    pubmed: 21070275
  41. Lawson JM. deMestre-lab/Pregnancy-Loss-Genetics-PNAS.. Zenodo Deposited 15 July 2024.
    doi: 10.5281/zenodo.12745505google scholar: lookup
  42. Lawson JM. GGP equine intensity files.. Zenodo Deposited 15 July 2024.
    doi: 10.5281/zenodo.12746246google scholar: lookup

Citations

This article has been cited 3 times.
  1. Picchetta L, Ottolini CS, Tao X, Zhan Y, Jobanputra V, Vallejo CM, Mulas F, Paraboschi EM, Escribá Pérez MJ, Molinaro T, Whitehead C, Gill P, Mounts E, Babariya D, Rienzi LF, Ubaldi FM, Garcia-Velasco JA, Pellicer A, Carmi S, Hoffmann ER, Capalbo A. Maternal age and genome-wide failure of meiotic recombination are associated with triploid conceptions in humans.. Am J Hum Genet 2025 Nov 6;112(11):2665-2678.
    doi: 10.1016/j.ajhg.2025.09.014pubmed: 41092908google scholar: lookup
  2. Ryan CA, Berry DP, Bugno-Poniewierska M, Burke MK, Raudsepp T, Egan S, Doyle JL. Two Cases of Chromosome 27 Trisomy in Horses Detected Using Illumina BeadChip Genotyping.. Animals (Basel) 2025 Jun 22;15(13).
    doi: 10.3390/ani15131842pubmed: 40646741google scholar: lookup
  3. Lawson EF, Pickford R, Aitken RJ, Gibb Z, Grupen CG, Swegen A. Mapping the lipidomic secretome of the early equine embryo.. Front Vet Sci 2024;11:1439550.
    doi: 10.3389/fvets.2024.1439550pubmed: 39430383google scholar: lookup
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