Abstract
The domestication of cattle from the now-extinct wild aurochs (Bos primigenius) involved selection for physiological and behavioral traits, with underlying genetic factors that remain largely unknown. Non-coding microRNAs have emerged as key regulators of the spatio-temporal expression of target genes controlling mammalian growth and development, including in livestock species. During the domestication process, selection of mutational changes in miRNAs and/or miRNA binding sites could have provided a mechanism to generate some of the traits that differentiate domesticated cattle from wild aurochs. To investigate this, we analyzed the open reading frame DNA sequence of 19,994 orthologous protein-coding gene pairs from extant Bos taurus genomes and a single extinct B. primigenius genome. We identified miRNA binding site polymorphisms in the 3′ UTRs of 1,620 of these orthologous genes. These 1,620 genes with altered miRNA binding sites between the B. taurus and B. primigenius lineages represent candidate domestication genes. Using a novel Score Site ratio metric we have ranked these miRNA-regulated genes according to the extent of divergence between miRNA binding site presence, frequency and copy number between the orthologous genes from B. taurus and B. primigenius. This provides an unbiased approach to identify cattle genes that have undergone the most changes in miRNA binding (i.e., regulation) between the wild aurochs and modern-day cattle breeds. In addition, we demonstrate that these 1,620 candidate domestication genes are enriched for roles in pigmentation, fertility, neurobiology, metabolism, immunity and production traits (including milk quality and feed efficiency). Our findings suggest that directional selection of miRNA regulatory variants was important in the domestication and subsequent artificial selection that gave rise to modern taurine cattle.
Highlights
MATERIALS AND METHODSSince their domestication from wild aurochs (Bos primigenius) some 10,000 years ago, cattle (Bos taurus and Bos indicus) have been continuously exposed to both natural and artificial selection (Bradley and Magee, 2006; Magee et al, 2014)
In our previous study of the B. primigenius genome, we demonstrated that the bovine phytanoyl-CoA 2-hydroxylase interacting protein gene (PHYHIP), which is involved in neurodevelopment, is targeted differentially by a miRNA gene variant that is polymorphic between aurochs and domestic cattle (Park et al, 2015)
We have identified an enrichment of genes with miRNA binding site variants belonging to the nuclear factor of activated T-cells (NFATs) pathway, which is involved in the establishment of innate immune responses to infection (Fric et al, 2012; Zanoni and Granucci, 2012)
Summary
Since their domestication from wild aurochs (Bos primigenius) some 10,000 years ago, cattle (Bos taurus and Bos indicus) have been continuously exposed to both natural and artificial selection (Bradley and Magee, 2006; Magee et al, 2014). These selection processes, coupled with mutation, genetic drift and admixture have produced the multitude of extant humpless taurine and humped zebu cattle breeds (Food and Agriculture Organization, 2015). We hypothesized that DNA sequence polymorphisms affecting miRNA-mediated gene regulation are likely associated with pre- and post-domestication differences in cattle, for traits under natural and artificial selection within the ∼10,000 year time frame of cattle domestication (Larson and Fuller, 2014; Larson et al, 2014; MacHugh et al, 2016)
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