Updating the East Asian mtDNA phylogeny: a prerequisite for the identification of pathogenic mutations

Abstract

Knowledge about the world phylogeny of human mitochondrial DNA (mtDNA) is essential not only for evaluating the pathogenic role of specific mtDNA mutations but also for performing reliable association studies between mtDNA haplogroups and complex disorders. In the past few years, the main features of the East Asian portion of the mtDNA phylogeny have been determined on the basis of complete sequencing efforts, but representatives of several basal lineages were still lacking. Moreover, some recently published complete mtDNA sequences did apparently not fit into the known phylogenetic tree and conflicted with the established nomenclature. To refine the East Asian mtDNA tree and resolve data conflicts, we first completely sequenced 20 carefully selected mtDNAs--likely representatives of novel sub-haplogroups--and then, in order to distinguish diagnostic mutations of novel haplogroups from private variants, we applied a 'motif-search' procedure to a large sample collection. The novel information was incorporated into an updated East Asian mtDNA tree encompassing more than 1000 (near-) complete mtDNA sequences. A reassessment of the mtDNA data from a series of disease studies testified to the usefulness of such a refined mtDNA tree in evaluating the pathogenicity of mtDNA mutations. In particular, the claimed pathogenic role of mutations G3316A, T3394C, A4833G and G15497A appears to be most questionable as those initial claims were derived from anecdotal findings rather than e.g. appropriate association studies. Following a guideline based on the phylogenetic knowledge as proposed here could help avoiding similar problems in the future.

Revisiting the role of the Himalayas in peopling Nepal: insights from mitochondrial genomes

“…43 The ages of the lineages G2a2 (further defined by mutation 16193 and named G2a2 tentatively) and M9a1a2a (characterized by mutations 16145, 16316 and a back mutation at site 16362, and designated as M9a1a2a) (Table 4) were estimated by using the r statistic 44,45 with the suggested calibration rates. 44,46 RESULTS AND DISCUSSION On the basis of the combined information from control-region and partial coding-region segments, the majority (96.34%; 237/246) of the Nepalese mtDNAs could unambiguously be allocated into the defined haplogroups of East Eurasian (36.59%; 90/246), 1,[20][21][22][23][24][25] Table S1, Supplementary Material online), 5 and this pattern remains almost stable for both the East Eurasian (45.11%; 189/419) and South Asian (47.49%; 199/419) components after taking into account the recently reported Nepalese mtDNA data. 5 As for the 21 samples with ambiguously phylogenetic status, completely sequencing their mtDNA genomes revealed that virtually all of these samples in fact belong to the already defined haplogroups, such as M3, M5, M18, M30, M35, M43, D4, R8 and M60.…”

Population increase and environmental deterioration correspond with microlithic innovations in South Asia ca. 35,000 years ago

“…The analyses of mtDNA haplogroup age distributions were based on the published complete mtDNA coding region sequences from South Asia, East Asia, and Oceania (8,40,41). Coalescent time estimates with standard errors for clades defined by at least 2 sequences were obtained by rho statistic (42) by using a molecular clock calibrated for synonymous substitutions (43).…”

Mitochondrial DNA haplogroup associated with sperm motility in the Han population

“…16 Statistical analysis A univariate comparison was performed to compare variables between the two groups by using the unpaired t-test for continuous variables and Fisher's exact test for categorical variables. For all comparisons, P,0.05 was considered to be statistically significant.…”