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

Denis Pierron¹^,2^,3 , Christophe Rocher³ , Patricia Amati-Bonneau⁴ , Pascal Reynier⁴ , Marie-Laure Martin-Négrier⁵ , Stéphane Allouche⁶ , Cécile Batandier⁷ , Benedicte Mousson de Camaret⁸ , Catherine Godinot⁹ , Agnes Rotig¹⁰ , Delphine Feldmann¹¹ , Christine Bellanne-Chantelot¹² , Benoit Arveiler¹³ , Erwann Pennarun¹⁴ , Rodrigue Rossignol³ , Marc Crouzet² , Pascal Murail¹ , Didier Thoraval² and Thierry Letellier³

¹Université Bordeaux 1, Laboratoire d'Anthropologie des Populations du Passé, UMR 5199 PACEA, 33400 Talence, France

²Institut de Biochimie et Génétique Cellulaires, UMR 5095, CNRS, Université Victor Segalen-Bordeaux 2, 33076 Bordeaux, France

³INSERM, U688 Laboratoire de Physiopathologie Mitochondriale; Université Victor Segalen-Bordeaux 2, 33076 Bordeaux, France

⁴INSERM, U694, Angers, F-49033 France; Departement de Biochimie et Génétique, Centre Hospitalier Universitaire, Angers, F-49033 France

⁵Laboratoire d'Anatomie Pathologique, Centre Hospitalier Universitaire, Laboratoire d'Histologie-Embryologie, UFRII, Université Victor Segalen Bordeaux 2, 33076 Bordeaux, France

⁶Laboratoire de Biologie cellulaire et moléculaire de la signalisation, UPRES-EA 3919, Université de Caen, 14033 Caen, France

⁷Laboratoire de Biochimie et Génétique Moléculaire, Centre Hospitalier Universitaire de Grenoble, 38054 Grenoble, France

⁸Laboratoire de Biochimie Pédiatrique, Hôpital Debrousse, 69322 Lyon, France

⁹Centre de Génétique Moléculaire et Cellulaire, UMR 5534, CNRS, Université Claude Bernard de Lyon 1, 69622 Villeurbanne, France

¹⁰Department of Genetics, INSERM U781 Hôpital Necker-Enfants Malades, 75743 Paris, France

¹¹Service de Biochimie et de Biologie Moléculaire, INSERM U587 Hôpital d'Enfants Armand-Trousseau, AP-HP, 75571 Paris, France

¹²Department of Cytogenetics, Hôpital Saint-Antoine-AP-HP, 75012 Paris, France

¹³Pôle Génotypage-Séquençage, Université Victor Segalen Bordeaux 2, 33076 Bordeaux, France

¹⁴Department of Evolutionary Biology, Institute of Molecular and Cell Biology, University of Tartu and Estonian Biocentre, Tartu, Estonia

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BMC Medical Genetics 2008, 9:41doi:10.1186/1471-2350-9-41


Published:	7 May 2008

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.