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

Somatic variants accumulate in non-malignant tissues with age 1,2 . 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.