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Structural evolution of trypsinogen gene redundancy confers risk for pancreas diseases

Trypsin is an important enzyme secreted by the pancreas for digesting proteins. The precursors of major human trypsin are encoded by trypsinogen genes PRSS1 and PRSS2. Here, we leveraged multi-omic data to study their evolutionary and functional impact. We estimated that the primate trypsinogen gene was duplicated from a single copy to multiple-copy 24-34 million years ago (Mya). Compared to six protein-coding genes in non-human great apes, the human ancestral state was a 5-copy with three being pseudogenized. Interestingly, a derived 3-copy form emerged in Africans ~260 Kya and dominated in non-Africans as one of the two major haplotypes. Although no longer encoding proteins, the pseudogene enhancers still function on pancreatic PRSS2 expression, leading to ~15% up-regulation for the 5-copy than the 3-copy haplotype. Notably, the 3-copy structure was under positive selection in East Asians, where lower trypsin might be adaptive during high-starch diet shift for protecting the pancreas from autodigestion, as also supported by the identified causality of the haplotype structure to pancreatitis risk. Our efforts in elucidating the structural evolution of trypsinogen genes advance our understanding of the genetic basis and molecular mechanism of human pancreas diseases.