Mitochondrial DNA variant associated with Leber hereditary optic neuropathy and high-altitude Tibetans

Abstract

The distinction between mild pathogenic mtDNA mutations and population polymorphisms can be ambiguous because both are homoplasmic, alter conserved functions, and correlate with disease. One possible explanation for this ambiguity is that the same variant may have different consequences in different contexts. The NADH dehydrogenase subunit 1 (ND1) nucleotide 3394 T > C (Y30H) variant is such a case. This variant has been associated with Leber hereditary optic neuropathy and it reduces complex I activity and cellular respiration between 7% and 28% on the Asian B4c and F1 haplogroup backgrounds. However, complex I activity between B4c and F1 mtDNAs, which harbor the common 3394T allele, can also differ by 30%. In Asia, the 3394C variant is most commonly associated with the M9 haplogroup, which is rare at low elevations but increases in frequency with elevation to an average of 25% of the Tibetan mtDNAs (odds ratio = 23.7). In high-altitude Tibetan and Indian populations, the 3394C variant occurs on five different macrohaplogroup M haplogroup backgrounds and is enriched on the M9 background in Tibet and the C4a4 background on the Indian Deccan Plateau (odds ratio = 21.9). When present on the M9 background, the 3394C variant is associated with a complex I activity that is equal to or higher than that of the 3394T variant on the B4c and F1 backgrounds. Hence, the 3394C variant can either be deleterious or beneficial depending on its haplogroup and environmental context. Thus, this mtDNA variant fulfills the criteria for a common variant that predisposes to a "complex" disease.

A mitochondrial bioenergetic etiology of disease

“…Haplogroup M9 mtDNA with the ND1 T3394C (Y30H) variant is present at less than 2% at sea level, but increases to about 35% of the mtDNAs in the highest Tibetan villages (ref. 20 and Figure 3).…”

“…Even more surprising, the 3394C allele, when present in the M9 haplogroup mtDNA, is associated with complex I activity equal to or greater than any of the macrohaplogroup N mt DNAs with the wild-type T3394 (Y30) variant (ref. 20 and Figure 3). Similar physiological differences have been documented between European haplogroup H and Uk mtDNAs (11,21).…”

“…For example, haplogroup F mtDNAs are associated with low complex I activity (20) and predilection to diabetes (23). Hence, ancient mtDNA variants and haplogroups are likely the long-sought common variants that predispose to common diseases.…”

“…Both M9 and 3394C mtDNAs increase in frequency with altitude in Tibet. Finally, M9 complex I activity is equal to or greater than that of any of the N haplogroups with the wild-type T3394 allele (20). Asterisks indicate that the stated complex I activity is predicted, based on the known genotype and complex I activities determined for cell lines harboring ND1 T3394C (Y30H)-containing mtDNAs.…”

Severity of cardiomyopathy associated with adenine nucleotide translocator-1 deficiency correlates with mtDNA haplogroup

“…Both recent deleterious and ancient evolutionarily adaptive mtDNA variants can affect human clinical phenotypes; the latter are associated with region-specific clusters of related mtDNA haplotypes, termed haplogroups (19)(20)(21). Haplogroups can differ substantially in their mitochondrial biochemistry, as shown by comparison of cybrids harboring European mtDNA haplogroups H and Uk (22).…”