Convergent evolution of somatic escape variants in SERPINA1 in the liver in alpha-1 anti-trypsin deficiency

Abstract

Somatic variants accumulate in non-malignant tissues with age1,2. Functional variants leading to clonal advantage of hepatocytes accumulate in the liver from patients with acquired chronic liver disease (CLD)3-5. Whether these somatic variants are common to CLD from differing aetiologies is unknown. We analysed somatic variants in the liver from patients with genetic CLD from alpha-1 anti-trypsin (A1AT) deficiency or haemochromatosis. We show that somatic variants in SERPINA1, the gene encoding A1AT, are strongly selected for in A1AT deficiency, with evidence of convergent evolution. Acquired variants cluster at the 3 end of SERPINA1 leading to C-terminal missense or truncation variants of A1AT. In vitro, C-terminal truncation variants abrogate disease-associated A1AT polymerisation and retention in the endoplasmic reticulum, supporting the C-terminal domain swap mechanism. Therefore, somatic escape variants from a deleterious germline variant are selected for in A1AT deficiency, suggesting adaptive functional somatic variants are disease-specific in CLD and point to disease-associated mechanisms.