Complex spatio-temporal distribution and genomic ancestry of mitochondrial DNA haplogroups in 24,216 Danes

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.

Fig 1. Phylogenetic tree of mtDNA sequences, modified from (http://www.phylotree.org).

Approximate geographic origins of the haplogroups are represented by colored blocks. MRCA: Most recent common ancestor.

Fig 2. Map of Denmark with major administrative regions and metropolitan areas.

The population of each region or area, as well as the number of samples, is given on the map. Based on birth-locations with ≥ 20 included individuals.

Fig 3. PCA of the macro-haplogroups L, M, N and R.

PC1: First principal component. PC2: Second principal component.

Fig 4. PCA of the macro-haplogroup R (the major European haplogroups).

PC1: First principal component. PC3: Third principal component.

Fig 5. Median-joining (M-J) network of the macro-haplogroup R mtDNA sequences (2000 chosen at random).

Fig 6. Genomic ancestry of samples as a function of mtDNA hg.

(See Materials and Methods for details).

Fig 7. The proportion of haplogroup L, M and U as a function of birth year.