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


CONCLUSIONS
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.
Pierron
Denis
D
1Université Bordeaux 1, Laboratoire d'Anthropologie des Populations du Passé, UMR 5199 PACEA, 33400 Talence, France. d.pierron@anthropologie.u-bordeaux1.fr
Rocher
Christophe
C
Amati-Bonneau
Patricia
P
Reynier
Pascal
P
Martin-Négrier
Marie-Laure
ML
Allouche
Stéphane
S
Batandier
Cécile
C
Mousson de Camaret
Benedicte
B
Godinot
Catherine
C
Rotig
Agnes
A
Feldmann
Delphine
D
Bellanne-Chantelot
Christine
C
Arveiler
Benoit
B
Pennarun
Erwann
E
Rossignol
Rodrigue
R
Crouzet
Marc
M
Murail
Pascal
P
Thoraval
Didier
D
Letellier
Thierry
T
D015331:Cohort Studies; D004247:DNA / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D004272:DNA, Mitochondrial / Q000235:genetics*; D005602:France; D006239:Haplotypes; D006801:Humans; D028361:Mitochondrial Diseases / Q000235:genetics; D009154:Mutation; D010802:Phylogeny; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D012356:RNA, Transfer, Leu / Q000235:genetics*; D044465:White People / Q000235:genetics
D004272:DNA, Mitochondrial; D012356:RNA, Transfer, Leu; D004247:DNA