Rewiring of gene expression in circulating white blood cells is associated with pregnancy outcome in heifers (Bos taurus)

Abstract

16Infertility is a disease that affects humans and cattle in similar ways. The resemblance includes 17 complex genetic architecture, multiple etiology, low heritability of fertility related traits in females, 18 and the frequency in the female population. Here, we used cattle as a biomedical model to test 19 the hypothesis that gene expression profiles of protein-coding genes expressed in peripheral 20 white blood cells (PWBCs), and circulating micro RNAs in plasma, are associated with female 21 fertility, measured by pregnancy outcome. We drew blood samples from 17 female calves on the 22 day of artificial insemination and analyzed transcript abundance for 10496 genes in PWBCs and 23 290 circulating micro RNAs. The females were later classified as pregnant to artificial 24 insemination, pregnant to natural breeding or not pregnant. We identified 1860 genes producing 25 significant differential coexpression (eFDR<0.002) based on pregnancy outcome. Additionally, 26 237 micro RNAs and 2274 genes in PWBCs presented differential coexpression based on 27 pregnancy outcome. Furthermore, using a machine learning prediction algorithm we detected a 28 subset of genes whose abundance could be used for blind categorization of pregnancy outcome. 29Our results provide strong evidence that bloodborne transcript abundance is highly associated 30 with fertility in females. 42dissecting female fertility traits 20,21 . 43Beyond the importance as a biomedical model, cattle production systems provide 44 approximately 28% 22 of the protein supply globally. Improving cattle production efficiency is 45 essential for farmers to attain sustainable production and support the growing demand for animal 46 protein 22 . Infertility is a major factor that hinders efficiency in cattle production, and it starts with 47 limited success of pregnancy in young female calves. First breeding success greatly influences 48 the lifetime efficiency of beef replacement heifers. Heifers that calve early in their first calving 49 season experience increased productivity and longevity than their later calving herd 50 mates 23,24,25,26 . Furthermore, the genetic correlation between yearling pregnancy rate and lifetime 51 pregnancy rate is high (0.92-0.97) 27,28 . Therefore, the ability to identify heifers that experience 52 optimal fertility during the first breeding is essential to the sustainability of beef cattle production 53 systems. 54The examination of the genetic components of fertility in beef heifers have yielded several 55 genes potentially associated with fertility traits 5,6,7,8,9,10,11,12 , but the effect of these markers are 56 minimal, and there is no clear redundancy in genetic markers identified across breeds. Beyond 57 the genomic profiling, the analysis of multiple layers of an individual's molecular blueprint is likely 58 key for understanding the underlying biology of complex traits 29 . In line with this rationale, 59 expression-trait association studies have emerged as a means to better understand complex 60 traits 30,31 . Specificall...

Beef heifer fertility: importance of management practices and technological advancements

“…In an attempt to assess the predictive value of circulating miRNAs on first breeding season pregnancy outcome, we profiled small RNAs collected from plasma of 18 beef heifers on the day of fixed-time AI. One miRNA (miR-11995) was more abundant in plasma of AIpregnant heifers than not-pregnant heifers, while no differences in miRNA expression were detected between NB-pregnant and not-pregnant or AI-pregnant and NBpregnant heifers [96]. Such results indicate that expression profiles of miRNA alone may provide little indication of heifer fertility.…”

“…The data from year 2015/2016 was used to train the algorithms and the data from 2016/2017 was used for blind predictions and assessment of model accuracy. The heifers in the test data were classified with 100% of accuracy in 46.3% out of 2000 randomizations), followed by 53.1% correct classification for 10 out of 11 heifers [96]. Altogether, remarkable differences exist in the abundances of genes expressed in the PWBC of heifers of differing fertility outcomes, and there is strong indication that these differences are useful as predictive tools for pregnancy outcome.…”