PhyloTree Build 17: Growing the human mitochondrial DNA tree

All current mitochondrial haplogroup classification tools require variants to be detected from an alignment with the reference sequence and to be properly named according to the canonical nomenclature standards for describing mitochondrial variants, before they can be compared with the haplogroup determining polymorphisms. With the emergence of high-throughput sequencing technologies and hence greater availability of mitochondrial genome sequences, there is a strong need for an automated haplogroup classification tool that is alignment-free and agnostic to reference sequence.

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.

Agriculture resulted in extensive population growths and human activities. However, whether major human expansions started after Neolithic Time still remained controversial. With the benefit of 1000 Genome Project, we were able to analyze a total of 910 samples from 11 populations in Africa, Europe and Americas. From these random samples, we identified the expansion lineages and reconstructed the historical demographic variations. In all the three continents, we found that most major lineage expansions (11 out of 15 star lineages in Africa, all autochthonous lineages in Europe and America) coalesced before the first appearance of agriculture. Furthermore, major population expansions were estimated after Last Glacial Maximum but before Neolithic Time, also corresponding to the result of major lineage expansions. Considering results in current and previous study, global mtDNA evidence showed that rising temperature after Last Glacial Maximum offered amiable environments and might be the most important factor for prehistorical human expansions.