Mitochondrial DNA sequence characteristics modulate the size of the genetic bottleneck.
Hum Mol Genet
; 25(5): 1031-41, 2016 Mar 01.
Article
em En
| MEDLINE
| ID: mdl-26740552
ABSTRACT
With a combined carrier frequency of 1200, heteroplasmic mitochondrial DNA (mtDNA) mutations cause human disease in â¼15000 of the population. Rapid shifts in the level of heteroplasmy seen within a single generation contribute to the wide range in the severity of clinical phenotypes seen in families transmitting mtDNA disease, consistent with a genetic bottleneck during transmission. Although preliminary evidence from human pedigrees points towards a random drift process underlying the shifting heteroplasmy, some reports describe differences in segregation pattern between different mtDNA mutations. However, based on limited observations and with no direct comparisons, it is not clear whether these observations simply reflect pedigree ascertainment and publication bias. To address this issue, we studied 577 mother-child pairs transmitting the m.11778G>A, m.3460G>A, m.8344A>G, m.8993T>G/C and m.3243A>G mtDNA mutations. Our analysis controlled for inter-assay differences, inter-laboratory variation and ascertainment bias. We found no evidence of selection during transmission but show that different mtDNA mutations segregate at different rates in human pedigrees. m.8993T>G/C segregated significantly faster than m.11778G>A, m.8344A>G and m.3243A>G, consistent with a tighter mtDNA genetic bottleneck in m.8993T>G/C pedigrees. Our observations support the existence of different genetic bottlenecks primarily determined by the underlying mtDNA mutation, explaining the different inheritance patterns observed in human pedigrees transmitting pathogenic mtDNA mutations.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
DNA Mitocondrial
/
Mutação Puntual
/
Doenças Mitocondriais
/
Padrões de Herança
/
Modelos Genéticos
Tipo de estudo:
Prognostic_studies
Limite:
Child
/
Female
/
Humans
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article