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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 121; no. 33; p. e2405636121
• Main Authors: Lawson, Jessica M, Salem, Shebl E, Miller, Donald, Kahler, Anne, van den Boer, Wilhelmina J, Shilton, Charlotte A, Sever, Tia, Mouncey, Rebecca R, Ward, Jenna, Hampshire, Daniel J, Foote, Alastair K, Bryan, Jill S, Juras, Rytis, Pynn, Oliver D, Davis, Brian W, Bellone, Rebecca R, Raudsepp, Terje, de Mestre, Amanda M
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 13.08.2024
• Subjects: Aberration; Abnormalities; Abortion, Spontaneous - genetics; Animal models; Animals; Chromosome Aberrations; Chromosome number; Chromosomes; Copy number; Disease Models, Animal; Evolutionary conservation; Female; Fetuses; Horses; Humans; Lethality; Miscarriage; Organogenesis; Ploidy; Pregnancy; Somatic chromosomes; Synteny; Triploidy; embryo; genetics; miscarriage; chromosome; pregnancy
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2405636121

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.