New evidence of a mitochondrial genetic background paradox: impact of the J haplogroup on the A3243G mutation

Abstract

Background: The A3243G mutation in the tRNALeu gene (UUR), is one of the most common pathogenic mitochondrial DNA (mtDNA) mutations in France, and is associated with highly variable and heterogeneous disease phenotypes. To define the relationships between the A3243G mutation and mtDNA backgrounds, we determined the haplogroup affiliation of 142 unrelated French patients - diagnosed as carriers of the A3243G mutation - by control-region sequencing and RFLP survey of their mtDNAs.

Results: The analysis revealed 111 different haplotypes encompassing all European haplogroups, indicating that the 3243 site might be a mutational hot spot. However, contrary to previous findings, we observed a statistically significant underepresentation of the A3243G mutation on haplogroup J in patients (p = 0.01, OR = 0.26, C.I. 95%: 0.08-0.83), suggesting that might be due to a strong negative selection at the embryo or germ line stages.

Conclusion: Thus, our study supports the existence of mutational hotspot on mtDNA and a "haplogroup J paradox," a haplogroup that may increase the expression of mtDNA pathogenic mutations, but also be beneficial in certain environmental contexts.

Figure 1

Phylogenical repartition of the 111 different haplotypes observed in the 142 A3243G carriers. The phylogenic tree was based on recent total sequencing studies of mitochondrial DNA [33]; the new haplogroup nomenclature is used [5]. The different polymorphisms used for haplogroup determination in this study are indicated in blue. The red crosses indicate the number of individuals per haplogroup.

Figure 2

Hypothetical mechanism of the "J paradox". The impact of J polymorphisms can differed toward the mitochondrial environment. This figure summarizes these impacts on the OXPHOS level, their implications on an individual level, and their impact on the distribution of populations studied within the phylogeny.