Efficiency of haplotype-based methods to fine-map QTLs and embryonic lethal variants affecting fertility: Illustration with a deletion segregating in Nordic Red cattle

Despite its importance, fertility has been declining in many cattle populations. In dairy cattle, this decline is often attributed to the negative correlation between fertility and productions traits. Recent studies showed that embryonic lethal variants might also account for a non-negligible fraction of the fertility decline. Therefore identification of such embryonic lethal variants is essential to improve fertility. We herein illustrate, with an example of a large recessive lethal deletion recently identified in Nordic Red cattle, that haplotype-based method are particularly efficient to identify such embryonic lethal variants. We first show that haplotypes can be used in traditional QTL mapping approaches and that they present very high linkage disequilibrium with underlying variants. Haplotypes can also be used in scan for lack of homozygosity. Indeed, if a haplotype is associated to a recessive lethal variant, significantly fewer living individuals will be homozygote for that haplotype than expected. For both approaches, haplotype-based methods were particularly efficient. The lack of homozygosity approach achieved higher significance than the QTL approach. Only frequent variants can be detected with both approaches unless huge genotyped cohorts are available. An alternative approach would rely on identifying potential harmful variants in next-generation sequencing data followed by the genotyping of a larger population for these variants.