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DNA sequence variation has been widely reported as the genetic basis for adaptation, in both humans and other animals, to the hypoxic environment experienced at high altitudes.However, little is known about the patterns of gene expression underlying such hypoxic adaptations.In this study, we examined differences in the transcriptomes of four organs (heart, kidney, liver and lung) between yak and cattle, a pair of closely related species distributed at high and low altitudes, respectively.Of the four organs examined, heart shows the greatest differentiation between the two species in terms of gene expression profiles.Detailed analyses demonstrated that adaptive alterations in genome-wide gene expression have provided yak with an enhanced oxygen supply system as well as an increase in the defense system that responds to threats of hypoxia.In addition, genes with significantly differentiated patterns of expression in all organs exhibited an unexpected uniformity of regulation along with an elevated frequency of nonsynonymous substitutions.This co-evolution of protein sequences and gene expression patterns, which is reported here for the first time, is likely to be correlated with the optimization of the yak metabolic system to resist hypoxia.