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BMC genomics2026; doi: 10.1186/s12864-026-12728-5

Deficiency in homozygous haplotypes reveals recessive lethal variants affecting fertility and viability in the Friesian horse.

Abstract: BACKGROUND: Recessive lethal alleles causing pre- or postnatal death in homozygous mutant animals, could lead to reduced fertility success. The Friesian horse breed has signs of reduced fertility and has faced high inbreeding rates in the past (∆F > 1%). Consequently, by genetic drift lethal alleles may have reached moderate to high frequencies in the population. Our aim was to identify lethal recessive alleles that — when homozygous — may cause pre- or postnatal death in the Friesian horse. RESULTS: We analyzed genotypes (70 K SNP) of over 8,000 Friesian horses, looking for haplotypes with a homozygous deficiency, and used available sequence data of 50 Friesian sires to pinpoint the likely causal variant. A deficit in homozygous animals suggests a lethal allele, because individuals inheriting two copies of such an allele likely die before birth or die before being genotyped, creating a detectable imbalance in genotype frequencies. We found ten candidate haplotypes in the Friesian horse with carrier frequencies ranging from 8.0 to 22.1%. We identified candidate causal variants of six haplotypes, of which two were associated with the already known genetic disorders dwarfism and hydrocephalus. The other candidate variants were a 261-kilobase-pair deletion affecting several non-coding RNA’s, and a 14-base-pair frameshift deletion in the MET gene. Three haplotypes in LD comprised the deletion in MET and were associated with a 25% reduction (P < 0.001) in insemination success in risk matings, likely caused by early embryonic lethality. CONCLUSIONS: In general, considering the population characteristics of domestic horse breeds, we strongly recommend performing such analyses in other horse breeds using the increasingly available genotype data. Such analyses could provide important contribution to the improvement of fertility rates in horse populations.
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Publication Date: 2026-03-11 PubMed ID: 41808016DOI: 10.1186/s12864-026-12728-5Google Scholar: Lookup
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Summary

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The researchers scanned DNA from over 8,000 Friesian horses to find hidden recessive mutations that cause death when inherited from both parents, helping explain the breed’s reduced fertility. They discovered ten risk haplotypes, pinpointed likely causal mutations for six (including a MET gene frameshift and a large deletion), and showed that carrier-by-carrier matings tied to MET have about 25% lower insemination success, consistent with early embryonic loss.

What problem the study addresses

  • Friesian horses show reduced fertility and have a history of high inbreeding (∆F > 1%), conditions that can allow recessive lethal alleles to rise in frequency by genetic drift.
  • Recessive lethal variants cause death of homozygous embryos or foals; because these individuals never survive to be sampled, they create detectable deficits of homozygotes in population genotype data.
  • The goal was to systematically detect such lethal recessive variants by identifying haplotypes with fewer homozygotes than expected and then to pinpoint likely causal mutations.

Study design and analytic strategy

  • Genotyping: Used a ~70K SNP array on more than 8,000 Friesian horses to reconstruct haplotypes across the genome.
  • Screen for homozygous deficiency: For each common haplotype, compared the observed number of homozygous individuals to the number expected under Hardy–Weinberg equilibrium; a significant deficit suggests lethality when homozygous.
  • Variant discovery: Leveraged whole-genome sequence data from 50 Friesian sires to search, within the implicated haplotype blocks, for candidate causal variants (e.g., frameshifts, nonsense mutations, large deletions) that are rare or absent in homozygous state.
  • Validation by phenotype and fertility: Related candidate variants/haplotypes to known disorders (dwarfism, hydrocephalus) and evaluated mating outcomes; specifically assessed “risk matings” (carrier × carrier) for reduced insemination success indicative of early embryonic lethality.

Key findings

  • Identified ten haplotypes with strong homozygous deficiency, with carrier frequencies between 8.0% and 22.1%—high enough to meaningfully affect population fertility.
  • Pinpointed likely causal variants for six of these haplotypes:
    • Two map to already known Friesian disorders: dwarfism and hydrocephalus, corroborating the approach.
    • A 261-kilobase deletion affecting several non-coding RNAs.
    • A 14-base-pair frameshift deletion in the MET gene, predicted to disrupt protein function.
  • Three haplotypes in strong linkage disequilibrium tagged the MET frameshift and were associated with a 25% reduction in insemination success in carrier-by-carrier matings (P < 0.001), consistent with early embryonic death of homozygotes.

Why a deficit of homozygotes signals recessive lethality

  • Under random mating, the frequency of homozygotes for a given haplotype should follow Hardy–Weinberg expectations (frequency squared).
  • If a haplotype carries a recessive lethal mutation, embryos inheriting two copies typically die before birth (or before genotyping age), removing homozygotes from the sampled population.
  • This selective loss manifests as a statistical deficit of homozygous individuals, which can be detected when sample sizes are large and genotyping is accurate.

Biological interpretation of the candidate variants

  • MET frameshift (14-bp deletion):
    • MET encodes a receptor tyrosine kinase involved in development, cell survival, and morphogenesis; frameshift indicates likely loss of function.
    • The observed 25% drop in insemination success in risk matings strongly supports early embryonic lethality of MET homozygotes.
  • 261-kb deletion affecting non-coding RNAs:
    • Although non-coding, long deletions can disrupt regulatory elements and RNA genes with essential developmental roles.
    • The homozygous deficiency implies that deletion homozygosity is incompatible with survival to sampling.
  • Known disease loci (dwarfism, hydrocephalus):
    • Rediscovery of these loci validates the strategy and confirms their substantial contribution to reduced viability when homozygous in Friesians.

Evidence linking haplotypes to reduced fertility

  • Carrier frequency estimates (8.0–22.1%) suggest that carrier × carrier matings occur non-trivially in the breed, even under moderate selection.
  • For the MET-associated haplotypes, risk matings showed ~25% lower insemination success (P < 0.001), a direct population-level fertility impact consistent with loss of homozygous embryos.
  • The congruence of homozygote deficits and reduced pregnancy outcomes strengthens causal inference beyond statistical deficiency alone.

Implications for breeding and population management

  • Routine haplotype-based carrier screening can prevent risk matings (carrier × carrier), improving conception rates and reducing embryonic loss.
  • Managing matings to avoid homozygous lethality enables simultaneous maintenance of genetic diversity (important in inbred breeds) while minimizing fitness costs.
  • The approach is readily transferable to other horse breeds as genotyping becomes commonplace, offering a path to breed-wide fertility improvements.

Strengths and limitations

  • Strengths:
    • Large sample size (>8,000 genotyped horses) provides statistical power to detect deficits.
    • Integration of SNP-array haplotypes with whole-genome sequence data in founders (50 sires) enables biologically plausible candidate variant discovery.
    • Use of mating outcome data links genotype to a concrete fertility phenotype.
  • Limitations:
    • Haplotype tags may capture multiple linked variants; fine-mapping to a single causal mutation can be challenging in regions of high linkage disequilibrium.
    • Non-coding or structural variants (e.g., the 261-kb deletion) may require functional assays to establish mechanisms.
    • Ascertainment and phasing errors, if present, could mimic deficits; cross-validation and replication in independent cohorts would strengthen conclusions.

Recommendations and next steps

  • Implement breed-wide carrier testing for the identified haplotypes/variants, especially those tagging the MET frameshift and known disease loci.
  • In studbook management software, automatically flag and avoid carrier × carrier matings to improve insemination success rates.
  • Extend homozygous-deficiency scans to other breeds to uncover hidden recessive lethals and enhance fertility across horse populations.
  • Pursue functional validation (e.g., transcript/protein assays, embryo studies) for the MET frameshift and the 261-kb deletion to confirm pathogenicity and mechanism.

Take-home messages

  • Ten haplotypes with marked homozygous deficiency exist in Friesians, several with identified likely causal mutations.
  • A MET gene frameshift is strongly associated with a ~25% reduction in insemination success in carrier-by-carrier matings, pointing to early embryonic lethality.
  • Systematic detection and management of such recessive lethals can materially improve fertility and viability in horse breeding programs.

Cite This Article

APA
(2026). Deficiency in homozygous haplotypes reveals recessive lethal variants affecting fertility and viability in the Friesian horse. BMC Genomics. https://doi.org/10.1186/s12864-026-12728-5

Publication

BMC genomics
ISSN: 1471-2164
NlmUniqueID: 100965258
Country: England
Language: English

Researcher Affiliations

Grant Funding

  • 4164023400 / Topconsortium voor Kennis en Innovatie

Conflict of Interest Statement

Declarations. Ethics approval and consent to participate: The biological material used in this study was collected as part of routine data collection from the KFPS, and not specifically for the purpose of this project. Therefore, approval of an ethics committee was not mandatory. Blood sample collection was done by a licensed vet following the “Code of Good Veterinary Practice”. No animals were euthanized/sacrificed or anaesthetized for this study. Sample collection was conducted strictly in line with Dutch law on the protection of animals (Wet Dieren). Informed consent was obtained by the owners of the animals to collect blood samples for DNA extraction. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

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