Defining "mutation" and "polymorphism" in the era of personal genomics

Abstract

Background: The growing advances in DNA sequencing tools have made analyzing the human genome cheaper and faster. While such analyses are intended to identify complex variants, related to disease susceptibility and efficacy of drug responses, they have blurred the definitions of mutation and polymorphism.

Discussion: In the era of personal genomics, it is critical to establish clear guidelines regarding the use of a reference genome. Nowadays DNA variants are called as differences in comparison to a reference. In a sequencing project Single Nucleotide Polymorphisms (SNPs) and DNA mutations are defined as DNA variants detectable in >1 % or <1 % of the population, respectively. The alternative use of the two terms mutation or polymorphism for the same event (a difference as compared with a reference) can lead to problems of classification. These problems can impact the accuracy of the interpretation and the functional relationship between a disease state and a genomic sequence. We propose to solve this nomenclature dilemma by defining mutations as DNA variants obtained in a paired sequencing project including the germline DNA of the same individual as a reference. Moreover, the term mutation should be accompanied by a qualifying prefix indicating whether the mutation occurs only in somatic cells (somatic mutation) or also in the germline (germline mutation). We believe this distinction in definition will help avoid confusion among researchers and support the practice of sequencing the germline and somatic tissues in parallel to classify the DNA variants thus defined as mutations.

Fig. 1

Nomenclature of variants according to sequencing design. In a paired approach (a), diseased (tumor) DNA and DNA from the germline (blood, saliva, or other non-diseased tissue) have been extracted and individually sequenced and mapped against a human genome reference assembly. If there are common variants found in both the tumor and germline DNA, they should be called germline mutations. If there are variants found only in tumor DNA, they should be called somatic mutations. In a non-paired approach of variant detection (b), only diseased DNA is extracted from the tissue of interest. The extracted DNA has been sequenced and mapped against a human genome reference assembly and differences as compared with the reference will be labeled as variants