Genes and pathways associated with pregnancy loss in dairy cattle

Abstract

Pregnancy loss directly impairs reproductive performance in dairy cattle. Here, we investigated genetic factors associated with pregnancy loss following detection of a viable embryo around 42 days of gestation. The objectives of this study were to perform whole-genome scans and subsequent gene-set analyses for identifying candidate genes, functional gene-sets and gene signaling pathways implicated in pregnancy loss in US Holstein cows. Data consisted of about 58,000 pregnancy/abortion records distributed over nulliparous, primiparous, and multiparous cows. Threshold models were used to assess the binary response of pregnancy loss. Whole-genome scans identified at least seven genomic regions on BTA2, BTA10, BTA14, BTA16, BTA21, BTA24 and BTA29 associated with pregnancy loss in heifers and lactating cows. These regions harbor several candidate genes that are directly implicated in pregnancy maintenance and fetal growth, such as CHST14, IGF1R, IGF2, PSEN2, SLC2A5 and WNT4. Moreover, the enrichment analysis revealed at least seven significantly enriched processes, containing genes associated with pregnancy loss, including calcium signaling, cell-cell attachment, cellular proliferation, fetal development, immunity, membrane permeability, and steroid metabolism. Additionally, the pathway analysis revealed a number of significant gene signaling pathways that regulate placental development and fetal growth, including Wnt, Hedgehog, Notch, MAPK, Hippo, mTOR and TGFβ pathways. Overall, our findings contribute to a better understanding of the genetic and biological basis of pregnancy loss in dairy cattle and points out novel strategies for improving pregnancy maintenance via marker-assisted breeding.

Figure 1

Whole-genome scans for pregnancy loss across the first three parities in Holstein dairy cows: Percentage of additive genetic variance explained by 2.0 Mb single nucleotide polymorphism (SNP)-windows across the genome. Genes directly implicated in pregnancy maintenance and fetal growth are highlighted in green.

Figure 2

Functional terms and pathways significantly enriched with genes associated with pregnancy loss. Several annotation databases were analyzed, including GO, Medical Subject Headings, InterPro, Reactome and MSigDB. The y-axis displays the names of gene-sets associated with pregnancy loss, and letters within parenthesis represent the three parities (N: Nulliparous; P: Primiparous and M: Multiparous). The size of the dots represents the significance of enrichment (− log₁₀ P-Value, Fisher’s exact test) and x-axis represents the percentage of significant genes in each functional term.

Figure 3

Heatmap plot of gene signaling pathways associated with pregnancy loss across the three parities. The y-axis displays the names of gene signaling pathways, and x-axis displays the names of genes involved in the pathways. Genes highlighted in red are recognized as bovine transcription factors.