Abstract
Mitochondrial DNA (mtDNA) haplogroups (hgs) are evolutionarily conserved sets of mtDNA SNP-haplotypes with characteristic geographical distribution. Associations of hgs with disease and physiological characteristics have been reported, but have frequently not been reproducible. Using 418 mtDNA SNPs on the PsychChip (Illumina), we assessed the spatio-temporal distribution of mtDNA hgs in Denmark from DNA isolated from 24,642 geographically un-biased dried blood spots (DBS), collected from 1981 to 2005 through the Danish National Neonatal Screening program. ADMIXTURE was used to establish the genomic ancestry of all samples using a reference of 100K+ autosomal SNPs in 2,248 individuals from nine populations. Median-joining analysis determined that the hgs were highly variable, despite being typically Northern European in origin, suggesting multiple founder events. Furthermore, considerable heterogeneity and variation in nuclear genomic ancestry was observed. Thus, individuals with hg H exhibited 95%, and U hgs 38.2% - 92.5%, Danish ancestry. Significant clines between geographical regions and rural and metropolitan populations were found. Over 25 years, macro-hg L increased from 0.2% to 1.2% (p = 1.1*E-10), and M from 1% to 2.4% (p = 3.7*E-8). Hg U increased among the R macro-hg from 14.1% to 16.5% (p = 1.9*E-3). Genomic ancestry, geographical skewedness, and sub-hg distribution suggested that the L, M and U increases are due to immigration. The complex spatio-temporal dynamics and genomic ancestry of mtDNA in the Danish population reflect repeated migratory events and, in later years, net immigration. Such complexity may explain the often contradictory and population-specific reports of mito-genomic association with disease.
Highlights
Mitochondria are subcellular organelles responsible for oxidative phosphorylation (OXPHOS), producing ~ 80% of the ATP in eukaryotic cells[1], apoptosis and cell-cycle regulation[2], redox- and calcium homeostasis[3] as well as intracellular signaling[4]
Thirteen genes code for proteins in the five enzyme complexes conducting OXPHOS, whereas twenty-two genes code for tRNAs and two for rRNAs, all involved in intra-mitochondrial translation[6]
The Mitochondrial DNA (mtDNA) macro-hg distribution pattern is typically northern European[39] with > 90% belonging to the R macro-hg, 7.0% belonging to N and 1.6% to M of likely Near Eastern or Asian origin[39] and 0.7% belonging to the combined L macro-hgs (L0-L6) of a likely African origin[40] (Table 1)
Summary
Mitochondria are subcellular organelles responsible for oxidative phosphorylation (OXPHOS), producing ~ 80% of the ATP in eukaryotic cells[1], apoptosis and cell-cycle regulation[2], redox- and calcium homeostasis[3] as well as intracellular signaling[4]. Each mitochondrion contains 2–10 copies of a 16.6 kb double-stranded mtDNA containing 37 genes[5]. Thirteen genes code for proteins in the five enzyme complexes conducting OXPHOS, whereas twenty-two genes code for tRNAs and two for rRNAs, all involved in intra-mitochondrial translation[6]. The mitochondrial proteome comprises approximately 1200 proteins[7, 8], of which mtDNA genes encode ~ 1%. The mtDNA is maternally inherited[9], exhibits a high mutation rate[10], and does not undergo recombination[5]. Genetic variants in mtDNA–as well as variants in the nuclear genes encoding the mitochondrial proteome—have been associated with disease[11,12,13]. Over 150 mitochondrial syndromes[14] have been associated with over 300 variants[7, 15]
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