Lineage-Specific Selection in Human mtDNA: Lack of Polymorphisms in a Segment of MTND5 Gene in Haplogroup J

Abstract

Human mitochondrial DNA (mtDNA) is a nonrecombining genome that codes for 13 subunits of the mitochondrial oxidative phosphorylation system, 2 rRNAs, and 22 tRNAs. Mutations have accumulated sequentially in mtDNA lineages that diverged tens of thousands of years ago. The genes in mtDNA are subject to different functional constraints and are therefore expected to evolve at different rates, but the rank order of these rates should be the same in all lineages of a phylogeny. Previous studies have indicated, however, that specific regions of mtDNA may have experienced different histories of selection in different lineages, possibly because of lineage-specific interactions or environmental factors such as climate. We report here on a survey for lineage-specific patterns of nucleotide polymorphism in human mtDNA. We calculated molecular polymorphism indices and neutrality tests for classes of functional sites and genes in 837 human mtDNA sequences, compared the results between continent-specific mtDNA lineages, and used two sliding window methods to identify differences in the patterns of polymorphism between haplogroups. A general correlation between nucleotide position and the level of nucleotide polymorphism was identified in the coding region of the mitochondrial genome. Nucleotide diversity in the protein-coding sequence of mtDNA was generally not much higher than that found for many genes in nuclear DNA. A comparison of nonsynonymous/synonymous rate ratios in the 13 protein-coding genes suggested differences in the relative levels of selection between haplogroups, including the European haplogroup clusters. Interestingly, a segment of the MTND5 gene was found to be almost void of segregating sites and nonsynonymous mutations in haplogroup J, which has been associated with susceptibility to certain complex diseases. Our results suggest that there are haplogroup-specific differences in the intensity of selection against particular regions of the mitochondrial genome, indicating that some mutations may be non-neutral within specific phylogenetic lineages but neutral within others.

Mitochondrial DNA and ACTN3 genotypes in Finnish elite endurance and sprint athletes

“…14,34 Indeed, neutrality tests have revealed lineage-specific differences between the various European mtDNA haplogroups and haplogroup clusters, suggesting that mtDNA has evolved in a lineage-specific manner. 13 We suggest that subhaplogroup J2 and haplogroup K are 'uncoupling genomes.' There are no previous studies on biochemical properties of cells harbouring different mtDNA lineages, but, interestingly, sperm cells harbouring mtDNA haplogroup T have been found to be slower in motility than cells harbouring haplogroup H. 35 …”

“…Endurance runners should have highly efficient ATP production by OXPHOS, whereas sprinters may rely more on anaerobic glycolysis. Despite the crucial role of mitochondrial function in endurance performance, and despite the recent data on lineagespecific differences in mtDNA, 13,14 differences in mtDNA haplogroups between sprinters and endurance runners have not previously been reported. We therefore set out to study mtDNA haplogroup and subhaplogroup frequencies in Finnish track and field athletes competing at the top level in endurance or sprint events.…”

A combination of three common inherited mitochondrial DNA polymorphisms promotes longevity in Finnish and Japanese subjects

“…The association between a combination of these three mtDNA variants and longevity provides the first epidemiological support for the assumption that the pathogenic or adaptive nature of a variant is influenced by interactions with other loci in mtDNA. 19 Our previous study on Finnish nonagenarians has suggested an association between haplogroups J and U and longevity, respectively, and a negative association between haplogroup H and longevity. 11 The absence of 150T in haplogroup H coincides with the lower frequency of this haplogroup among the very old and, similarly, the higher frequency of haplogroup J among the very old coincides with the presence of 150T within haplogroup J2.…”

Mitochondrial DNA haplogroup diversity in Basques: A reassessment based on HVI and HVII polymorphisms

“…Given the paucity of data on the hypervariable region II, and to maximize the number of sequences available for comparative analysis of the mtDNA diversity, the HVII data employed to compute diversity parameters were restricted to the 255 nucleotides encompassed between positions 66 and 320, both inclusive. The reference populations considered in the sequence diversity analyses were Austria, France, Egypt, Spain (Madrid), Spain (Saragossa), US Caucasoids (Budowle et al, 1999), NE Spain (Crespillo et al, 2000), Galicia (Salas et al, 1998(Salas et al, , 2000, Portugal (Pereira et al, 2000), Finland (Moilanen et al, 2003), Balkan (GenBank, accession nos. AY005485-AY005795), Russia (GenBank, accession nos.…”