Whole genome analysis reveals aneuploidies in early pregnancy loss in the horse

Chromosome abnormalities are well documented in human spontaneous abortion studies, yet rarely reported in domesticated animals. Rodent models have previously been used to study the effects of maternal ageing on oocyte quality and ultimately aneuploidy, however the differing endocrine profiles, oocyte characteristics and the polytocous nature of rodents are limitations for translation into human medicine. Early Pregnancy Loss (EPL) occurs in 5-10% of confirmed equine pregnancies and has no diagnosis in over 80% of cases. Aneuploidy has never been described in equine pregnancy loss, thus the objectives of this study were to quantify the frequency and characteristics of aneuploidy associated with equine EPL. EPL conceptuses were submitted from clinical cases of spontaneous pregnancy loss (14-65 days of gestation) between 2013 and 2018. Age matched control conceptuses were obtained from terminated clinically normal pregnancies (CNP). Aneuploidy was detected in 12/55 EPLs (21.8%), 0/10 CNP, 0/5 healthy term chorioallantois, and 0/5 healthy adult mares via genotyping. Whole genome sequencing (30X) and ddPCR validated results. Aneuploidies involved 10/32 equine chromosomes, consisting of nine trisomies and three monosomies. Autosomal aneuploidies were detected in both placental and fetal compartments in all samples tested. Aneuploid types (7/9) were mostly unique to EPL, supporting their embryonic/fetal lethality. Presenting the first evidence of aneuploidies in failed equine pregnancies not only provides the initial step in identifying genetic causes for these early losses, but also offers the horse as a new model for studying naturally occurring aneuploidy. We also demonstrate that SNP arrays provide a simple, cost effective way to screen aneuploidies across a large population. Author SummaryThe first 8 weeks of pregnancy is a critical time in both humans and horses, as the majority of pregnancy losses occur during this period. Despite such high prevalence, many cases do not have a known cause. Abnormal chromosome number (aneuploidy) is the most common finding in human pregnancy loss studies, but to date no equivalent study has been performed in domesticated animals, including the horse. We studied the genetics of naturally occurring pregnancy losses from Thoroughbred horses and found a similar level of aneuploidy to that observed in women. As humans and horses share similarities in their reproductive biology (ageing eggs, increased pregnancy loss in older mothers, similar key hormones), we suggest that by comparing the genetics of these two species, greater advances in identifying causes of aneuploidy pregnancy can be reached. Thoroughbred horses also tend to be more inbred than humans, facilitating the identification of mutations that increase the chance of aneuploidy, and this knowledge could potentially be applied in human medicine, as well as in species conservation.