Phylogenetic analysis of the mitochondrial genomes from Leber hereditary optic neuropathy pedigrees

N. Howell, I. Kubacka, S. Halvorson, B. Howell, D. A. McCullough, D. Mackey

Research output: Contribution to journalArticle

90 Citations (Scopus)

Abstract

The nucleotide sequences of the mitochondrial genomes from patients with Leber hereditary optic neuropathy (LHON) were used for phylogenetic analysis to study the origin and population history of pathogenic mitochondrial mutations. Sequences of both the coding region (8300 bp) and the more rapidly evolving noncoding control region (1300 bp) were analyzed. Patients with the primary LHON mutations at nucleotides 3460, 11,778, and 14,484 were included in this study, as were LHON patients and non-LHON controls that lacked these primary mutations; some of the subjects also carried secondary LHON mutations. The phylogenetic analyses demonstrate that primary LHON mutations arose and were fixed multiple times within the population, even for the small set of LHON patients that was analyzed in these initial studies. In contrast, the secondary LHON mutations at nucleotides 4216, 4917, and 13,708 arose once: the mitochondrial genomes that carried these secondary mutations formed a well-supported phylogenetic cluster that apparently arose 60,000 to 100,000 years's ago. Previous studies found secondary LHON mutations at a higher frequency among LHON patients than among control subjects. However, this finding does not prove a pathogenetic role of these mutations in LHON. Instead, the increased frequency is more likely to reflect the population genetic history of secondary mutations relative to that of primary LHON mutations.

Original languageEnglish
Pages (from-to)285-302
Number of pages18
JournalGenetics
Volume140
Issue number1
Publication statusPublished - 1 Jan 1995
Externally publishedYes

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Leber's Hereditary Optic Atrophy
Mitochondrial Genome
Pedigree
Mutation
Nucleotides
Optic Nerve Diseases
Population Genetics
Population

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Howell, N., Kubacka, I., Halvorson, S., Howell, B., McCullough, D. A., & Mackey, D. (1995). Phylogenetic analysis of the mitochondrial genomes from Leber hereditary optic neuropathy pedigrees. Genetics, 140(1), 285-302.
Howell, N. ; Kubacka, I. ; Halvorson, S. ; Howell, B. ; McCullough, D. A. ; Mackey, D. / Phylogenetic analysis of the mitochondrial genomes from Leber hereditary optic neuropathy pedigrees. In: Genetics. 1995 ; Vol. 140, No. 1. pp. 285-302.
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Howell, N, Kubacka, I, Halvorson, S, Howell, B, McCullough, DA & Mackey, D 1995, 'Phylogenetic analysis of the mitochondrial genomes from Leber hereditary optic neuropathy pedigrees' Genetics, vol. 140, no. 1, pp. 285-302.

Phylogenetic analysis of the mitochondrial genomes from Leber hereditary optic neuropathy pedigrees. / Howell, N.; Kubacka, I.; Halvorson, S.; Howell, B.; McCullough, D. A.; Mackey, D.

In: Genetics, Vol. 140, No. 1, 01.01.1995, p. 285-302.

Research output: Contribution to journalArticle

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AB - The nucleotide sequences of the mitochondrial genomes from patients with Leber hereditary optic neuropathy (LHON) were used for phylogenetic analysis to study the origin and population history of pathogenic mitochondrial mutations. Sequences of both the coding region (8300 bp) and the more rapidly evolving noncoding control region (1300 bp) were analyzed. Patients with the primary LHON mutations at nucleotides 3460, 11,778, and 14,484 were included in this study, as were LHON patients and non-LHON controls that lacked these primary mutations; some of the subjects also carried secondary LHON mutations. The phylogenetic analyses demonstrate that primary LHON mutations arose and were fixed multiple times within the population, even for the small set of LHON patients that was analyzed in these initial studies. In contrast, the secondary LHON mutations at nucleotides 4216, 4917, and 13,708 arose once: the mitochondrial genomes that carried these secondary mutations formed a well-supported phylogenetic cluster that apparently arose 60,000 to 100,000 years's ago. Previous studies found secondary LHON mutations at a higher frequency among LHON patients than among control subjects. However, this finding does not prove a pathogenetic role of these mutations in LHON. Instead, the increased frequency is more likely to reflect the population genetic history of secondary mutations relative to that of primary LHON mutations.

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Howell N, Kubacka I, Halvorson S, Howell B, McCullough DA, Mackey D. Phylogenetic analysis of the mitochondrial genomes from Leber hereditary optic neuropathy pedigrees. Genetics. 1995 Jan 1;140(1):285-302.