Abundance of the POLG disease mutations in Europe, Australia, New Zealand, and the United States explained by single ancient European founders

Abstract

We reported previously that the DNA polymerase gamma (POLG) W748S mutation, a common cause of mitochondrial recessive ataxia syndrome (MIRAS), has a common ancient founder for all the disease chromosomes in Finland, Norway, United Kingdom, and Belgium. Here, we present results showing that the same ancestral chromosome underlies MIRAS and Alpers syndrome in Australia and New Zealand. Furthermore, we show that a second common POLG mutation, A467T, also shows common European ancestry: patients from Australia, New Zealand, and the United States share a common haplotype with the previously reported European patients. These data of ancestral haplotypes indicate that the POLG locus is quite stable and that the recessive W748S and A467T mutations, and probably also G848S, have occurred once in history. They have effectively spread to populations of European descent with carrier frequencies up to 1% in several populations. Our data predict that these mutations are common causes of ataxia and Alpers disease in the Western world.