A 1-bp deletion in bovine QRICH2 causes low sperm count and immotile sperm with multiple morphological abnormalities

Abstract

Background Semen quality and insemination success are monitored in artificial insemination bulls to ensure high male fertility rates. Only ejaculates that fulfill minimum quality requirements are processed and eventually used for artificial inseminations. We examined 70,990 ejaculates from 1343 Brown Swiss bulls to identify bulls from which all ejaculates were rejected due to low semen quality. This procedure identified a bull that produced 12 ejaculates with an aberrantly small number of sperm (0.2 ± 0.2 × 109 sperm per mL) which were mostly immotile due to multiple morphological abnormalities. Results The genome of this bull was sequenced at a 12× coverage to investigate a possible genetic cause. Comparing the sequence variant genotypes of this bull with those from 397 fertile bulls revealed a 1-bp deletion in the coding sequence of the QRICH2 gene which encodes the glutamine rich 2 protein, as a compelling candidate causal variant. This 1-bp deletion causes a frameshift in translation and a premature termination codon (ENSBTAP00000018337.1:p.Cys1644AlafsTer52). The analysis of testis transcriptomes from 76 bulls showed that the transcript with the premature termination codon is subject to nonsense-mediated mRNA decay. The 1-bp deletion resides in a 675-kb haplotype that includes 181 single nucleotide polymorphisms (SNPs) from the Illumina BovineHD Bead chip. This haplotype segregates at a frequency of 5% in the Brown Swiss cattle population. Our analysis also identified another bull that carried the 1-bp deletion in the homozygous state. Semen analyses from the second bull confirmed low sperm concentration and immotile sperm with multiple morphological abnormalities that primarily affect the sperm flagellum and, to a lesser extent, the sperm head. Conclusions A recessive loss-of-function allele of the bovine QRICH2 gene likely causes low sperm concentration and immotile sperm with multiple morphological abnormalities. Routine sperm analyses unambiguously identify homozygous bulls for this allele. A direct gene test can be implemented to monitor the frequency of the undesired allele in cattle populations.

Adenylate kinase 9 is essential for sperm function and male fertility in mammals

“…Reference-guided variant discovery and genotyping yielded a total of 4,616,420 and 2,588,663 variants in FR4854 that were heterozygous and homozygous for a non-reference allele, respectively. Following our previous research ( 4 , 9 – 12 ), we hypothesized that the extreme subfertility of FR4854 was due to a recessively inherited allele that is deleterious to protein function. Autozygosity mapping identified 64 runs of homozygosity that were longer than 1 Mb encompassing a total of 171.2 Mb autosomal sequence of FR4854 ( SI Appendix , Fig.…”

A Chinese indicine pangenome reveals a wealth of novel structural variants introgressed from otherBosspecies

“…We found 381 bubble breakpoints overlapping with Hereford genome coding sequences ( Supplemental Table S9 ), which indicates substantial variability in the length of amino acid sequences. These genes often contain a highly polymorphic VNTR domain, such as ALMS1 ( Liao et al 2003 ), BDP1 ( Liao et al 2003 ), RTP4 ( Boys et al 2020 ), CYLC2 ( Hess et al 1995 ), PRDM9 ( Zhou et al 2018 ), QRICH2 ( Hiltpold et al 2022 ), and mucin genes ( MUC1 , MUCL1 , MUC6 , MUC16 , MUC20 ) ( Fig. 2 D), which leads to intra- and inter-breed/species amino acid variation with the potential to affect phenotypes.…”

Structural variant-based pangenome construction has low sensitivity to variability of haplotype-resolved bovine assemblies

“…For instance, the coding sequence of QRICH2 overlapped with multiple bubbles indicating tandem duplications of a 30 bp region of the fifth exon (Figure 7a). Loss of function alleles in mammalian QRICH2 orthologs lead to multiple morphological abnormalities of the sperm flagella (Hiltpold et al, 2021; Shen et al, 2019). We find that the fifth exon of QRICH2 , which is affected by the coding sequence expansion, is transcribed in high abundance (>30 transcripts per million) in testes of mature taurine bulls (Supplementary Notes).…”