A Reduced Number of mtSNPs Saturates Mitochondrial DNA Haplotype Diversity of Worldwide Population Groups

Abstract

BackgroundThe high levels of variation characterising the mitochondrial DNA (mtDNA) molecule are due ultimately to its high average mutation rate; moreover, mtDNA variation is deeply structured in different populations and ethnic groups. There is growing interest in selecting a reduced number of mtDNA single nucleotide polymorphisms (mtSNPs) that account for the maximum level of discrimination power in a given population. Applications of the selected mtSNP panel range from anthropologic and medical studies to forensic genetic casework.Methodology/Principal FindingsThis study proposes a new simulation-based method that explores the ability of different mtSNP panels to yield the maximum levels of discrimination power. The method explores subsets of mtSNPs of different sizes randomly chosen from a preselected panel of mtSNPs based on frequency. More than 2,000 complete genomes representing three main continental human population groups (Africa, Europe, and Asia) and two admixed populations (“African-Americans” and “Hispanics”) were collected from GenBank and the literature, and were used as training sets. Haplotype diversity was measured for each combination of mtSNP and compared with existing mtSNP panels available in the literature. The data indicates that only a reduced number of mtSNPs ranging from six to 22 are needed to account for 95% of the maximum haplotype diversity of a given population sample. However, only a small proportion of the best mtSNPs are shared between populations, indicating that there is not a perfect set of “universal” mtSNPs suitable for all population contexts. The discrimination power provided by these mtSNPs is much higher than the power of the mtSNP panels proposed in the literature to date. Some mtSNP combinations also yield high diversity values in admixed populations.Conclusions/SignificanceThe proposed computational approach for exploring combinations of mtSNPs that optimise the discrimination power of a given set of mtSNPs is more efficient than previous empirical approaches. In contrast to precedent findings, the results seem to indicate that only few mtSNPs are needed to reach high levels of discrimination power in a population, independently of its ancestral background.

Haplogrouping mitochondrial DNA sequences in Legal Medicine/Forensic Genetics

“…Since control-region variation alone cannot settle the desired haplogroup assignment in many cases, the most natural approach is to gain more information from the codingregion, for instance, either by directly sequencing several fragments [17] or by SNP screening via multiplex analysis [18][19][20][21][22]; see Table 1 in [23] for a list of articles on SNP multiplex analyses. The design of a multiplex SNP array would depend on whether it is supposed to (1) be used on a (sub-)continental scale without prior sequence information (e.g., [18][19][20][21]) or (2) be restricted to a specific haplogroup (e.g., [24,25]) or (3) complement control-region information (e.g., [19,26]).…”

“…There is no realistic solution for a worldwide universal SNP design, even when only discrimination power is targeted [23], given the limitations of casework samples with respect to availability of mtDNA for such additional analyses. Neither would any worldwide SNP array be of much use even for coarse haplogrouping since there are simply too many basal branches in the Eurasian mtDNA phylogeny (especially within haplogroup M).…”

Developing a multiplex mtSNP assay for forensic application in Han Chinese based on mtDNA phylogeny and hot spot

“…However, the former was almost constructed by target mtSNPs for haplogroup assignment possessing ancestral information that might lead to low discrimination power due to lack of polymorphisms, while the latter two should be used combining HVR I and II, or the complete control region sequencing. Generally, these strategies did not necessarily optimize the discrimination power of a particular set of mtSNPs .…”

“…With the forensic applications in mind, we suggested a design, with one assay with a reduced number of SNPs from whole mitochondrial genome, as a rapid screening approach. A careful selection of mtSNPs was a key step in this study and any reasonable analysis of mitochondrial DNA (mtDNA) data could not bypass the phylogeny . Therefore, we focused on the balance of target mtSNPs for haplogroup assignment and hot‐spot mtSNPs for increasing discrimination power.…”

Biogeographical informativeness of Y-STR haplotypes

“…Research on biogeographical ancestry (BGA) is becoming of growing interest in forensic genetics and in the biomedical literature [1]. Thus, for instance, the need to predict ethnicity of an unknown suspect based on DNA profiles found at the crime scene is of maximum interest in criminalistics [2], and several autosomal SNP panels have been designed and tested for BGA investigations [3,4]. Most of these panels aim at discriminating three main continental groups (sub-Saharan Africans, Europeans, and Asians) by way of testing a number of ancestry informative markers (AIMs) that run from a few dozens to a few hundred [5] (see more background in Supplementary data online).…”