An endogenous retrovirus insertion disrupting bovine ALKBH8 causes a failure-to-thrive syndrome with immunodeficiency associated with juvenile mortality in Brown Swiss cattle

Abstract

The Brown Swiss (BS) cattle breed is one of the major Swiss dairy breeds. Intensive selection and the widespread use of few elite sires in artificial insemination have increased inbreeding and the occurrence of deleterious recessive alleles in the homozygous state. Analyzing life trajectories in large, genotyped cohorts can identify hidden recessive disorders that are difficult to detect using traditional case-control association testing. Long-read DNA sequencing enables precise detection of causal alleles, including structural variants. This study aimed to (1) identify cryptic recessive loci affecting rearing performance in Swiss BS cattle, (2) evaluate their impact on survival, (3) characterize the associated phenotype, (4) identify the causal variant using long-read whole-genome sequencing, and (5) assess its functional impact. Using Homozygous Haplotype Enrichment/Depletion (HHED) mapping, we identified a risk haplotype (BH39) on chromosome 15 spanning from 16,276,819 bp to 16,446,984 bp that was associated with increased juvenile mortality within the first 180 days of life when present in the homozygous state. The BH39 occurred at a frequency of approximately 4.5% in Swiss BS cattle and 5.3% in German and Austrian BS cattle, and homozygous carriers exhibited a significantly reduced first-year survival rate. Five females homozygous for BH39 underwent clinical examination. They all showed recurrent respiratory disease, impaired growth, poor body condition, rough hair coat, and brown-discolored teeth. Pathological examination revealed bronchopneumonia and eosinophilic enteritis. Clinicopathological findings indicated failure to thrive and immunodeficiency. Long-read WGS of two BH39 homozygous calves revealed a private homozygous coding variant that was in high linkage disequilibrium with BH39. The identified structural variant was an insertion of a large transposable element (10.4 kb ERVK[2-1-LTR]) into the third exon of ALKBH8 (NM_001080341.2 c.267_268indel). Full-length RNA sequencing of cerebellum and liver from a homozygous calf revealed that the endogenous retrovirus (ERV) insertion introduces a cryptic transcription termination signal, truncating ALKBH8 mRNA. This study demonstrates that exploring population-scale genomic data and mining thousands of life-history records, followed by veterinary follow-up evaluations and molecular genetic analyses, provides an effective strategy for identifying cryptic recessive disorders that shorten the lifespan of cattle. The findings provide strong evidence that the ERV insertion into the coding sequence of ALKBH8 represents a loss-of-function variant that causes a previously undescribed recessive disorder that results in increased rearing loss. Interpretive summary We identified a recessive disorder in Brown Swiss cattle that causes retarded growth, recurrent infections, immunodeficiency, and increased mortality during the first year of life. Using population-scale genomic data, clinical investigations, and long-read sequencing, we linked the disorder to an exonic transposable element insertion disrupting ALKBH8. The identification of the causal variant now enables direct genetic testing and the implementation of genome-based mating strategies to avoid carrier-by-carrier matings and, consequently, prevent the birth of affected homozygous offspring. We demonstrate the utility of integrating large-scale breeding records, veterinary phenotyping, and advanced genomics to identify hidden defects affecting livestock health and productivity.