Concept for estimating mitochondrial DNA haplogroups using a maximum likelihood approach (EMMA).
The assignment of haplogroups to mitochondrial DNA haplotypes contributes substantial value for quality control, not only in forensic genetics but also in population and medical genetics. The availability of Phylotree, a widely accepted phylogenetic tree of human mitochondrial DNA lineages, led to the development of several (semi-)automated software solutions for haplogrouping. However, currently existing haplogrouping tools only make use of haplogroup-defining mutations, whereas private mutations (beyond the haplogroup level) can be additionally informative allowing for enhanced haplogroup assignment. This is especially relevant in the case of (partial) control region sequences, which are mainly used in forensics. The present study makes three major contributions toward a more reliable, semi-automated estimation of mitochondrial haplogroups. First, a quality-controlled database consisting of 14,990 full mtGenomes downloaded from GenBank was compiled. Together with Phylotree, these mtGenomes serve as a reference database for haplogroup estimates. Second, the concept of fluctuation rates, i.e. a maximum likelihood estimation of the stability of mutations based on 19,171 full control region haplotypes for which raw lane data is available, is presented. Finally, an algorithm for estimating the haplogroup of an mtDNA sequence based on the combined database of full mtGenomes and Phylotree, which also incorporates the empirically determined fluctuation rates, is brought forward. On the basis of examples from the literature and EMPOP, the algorithm is not only validated, but both the strength of this approach and its utility for quality control of mitochondrial haplotypes is also demonstrated.
Institute of Legal Medicine, Innsbruck Medical University, Innsbruck, Austria.
Alexander W
AW
Röck
Institute of Mathematics, University of Innsbruck, Innsbruck, Austria.
Arne
A
Dür
Department of Forensic Molecular Biology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
Mannis
M
van Oven
Institute of Legal Medicine, Innsbruck Medical University, Innsbruck, Austria; Penn State Eberly College of Science, University Park, PA, USA. Electronic address: walther.parson@i-med.ac.at.
Walther
W
Parson
D004272:DNA, Mitochondrial / Q000235:genetics*; D030541:Databases, Genetic; D006239:Haplotypes; D006801:Humans; D010802:Phylogeny
D004272:DNA, Mitochondrial
EMPOP; Fluctuation rates; Haplogroup; Phylotree; mtDNA