Abstract
BackgroundConception is a fundamental trait for successful cattle reproduction. However, conception rates in Japanese Black cattle have been gradually declining over the last two decades. Although conception failures are mainly caused by embryonic mortality, the role of maternal genetic factors in the process remains unknown. Copy number variation (CNV), defined as large-scale genomic structural variants, contributes to several genetic disorders. To identify CNV associated with embryonic mortality in Japanese Black cattle, we evaluated embryonic mortality as a categorical trait with a threshold model and conducted a genome-wide CNV association study for embryonic mortality using 791 animals.ResultsWe identified a deleted-type CNV ranging from 378,127 to 412,061 bp on bovine chromosome 8, which was associated with embryonic mortality at 30–60 days after artificial insemination (AI). The CNV harbors exon 2 to 6 of ANNEXIN A10 (ANXA10). Analysis of sequence traces from the CNV identified that 63 bp reads bridging the breakpoint were present on both sides of the CNV, indicating that the CNV was generated by non-allelic homologous recombination using the 63 bp homologous sequences. Western blot analysis showed that the CNV results in a null allele of ANXA10. This association was replicated using a sample population size of 2552 animals. To elucidate the function of ANXA10 in vivo, we generated Anxa10 null mice using the CRISPR/Cas9 system. Crossbreeding experiments showed that litter size from crosses of both Anxa10 -/- and Anxa10 +/- females had fewer pups than did Anxa10 +/+ females, and embryos of Anxa10 -/- females died between implantation stages E4.5 and E12.5. These results indicate that loss of maternal Anxa10 causes embryonic mortality.ConclusionsThis study identified a deleted-type CNV encompassing ANXA10 in cows that was associated with embryonic mortality at 30–60 days after AI. Using a mouse model, we confirmed that litter sizes were smaller in crosses of both Anxa10 -/- and Anxa10 +/- females relative to those of wild females. These results indicate that ANXA10 is a maternal factor that is critical for embryo development.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3312-z) contains supplementary material, which is available to authorized users.
Highlights
Conception is a fundamental trait for successful cattle reproduction
We identified a deleted-type Copy number variation (CNV), encompassing ANNEXIN A10 (ANXA10), which was associated with embryonic mortality at 30–60 days after artificial insemination (AI)
Embryonic mortality was evaluated as a categorical trait with a threshold model in Japanese Black cattle Embryonic mortality was defined in cows that received a second round of AI (2nd AI) at 18–29 days (D), 30–60 D, 61–90 D, 91–140 D, and 141 D–parturition after the first AI (1st AI) (Fig. 1a)
Summary
Conception is a fundamental trait for successful cattle reproduction. conception rates in Japanese Black cattle have been gradually declining over the last two decades. Over the past two decades, conception rates for artificial insemination (AI) breeding programs in Japanese Black cattle have been gradually declining (e.g., first-AI conception rates have decreased from 67.4 to 56% between 1992 and 2012 in Japan) [1]. This trend has been observed in dairy cattle [1, 2]. Copy number variation (CNV) is defined as deleted or duplicated segments of genome that range from 1 kb to several Mb, reviewed in [5].
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