Evidence for Variable Selective Pressures at a Large Secondary Structure of the Human Mitochondrial DNA Control Region

Filipe Pereira, Pedro Soares, João Carneiro, Luísa Pereira, Martin B. Richards, David C. Samuels, António Amorim

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

A combined effect of functional constraints and random mutational events is responsible for the sequence evolution of the human mitochondrial DNA (mtDNA) control region. Most studies targeting this noncoding segment usually focus on its primary sequence information disregarding other informative levels such as secondary or tertiary DNA conformations. In this work, we combined the most recent developments in DNA folding calculations with a phylogenetic comparative approach in order to investigate the formation of intrastrand secondary structures in the human mtDNA control region. Our most striking results are those regarding a new cloverleaf-like secondary structure predicted for a 93-bp stretch of the control region 5′-peripheral domain. Randomized sequences indicated that this structure has a more negative folding energy than the average of random sequences with the same nucleotide composition. In addition, a sliding window scan across the complete mitochondrial genome revealed that it stands out as having one of the highest folding potential. Moreover, we detected several lines of evidence of both negative and positive selection on this structure with high levels of conservation at the structure-relevant stem regions and the occurrence of compensatory base changes in the primate lineage. In the light of previous data, we discuss the possible involvement of this structure in mtDNA replication and/or transcription. We conclude that maintenance of this structure is responsible for the observed heterogeneity in the rate of substitution among sites in part of the human hypervariable region I and that it is a hot spot for the 3′ end of human mtDNA deletions.

LanguageEnglish
Pages2759-2770
Number of pages12
JournalMolecular Biology and Evolution
Volume25
Issue number12
Early online date9 Oct 2008
DOIs
Publication statusPublished - 1 Dec 2008
Externally publishedYes

Fingerprint

secondary structure
Mitochondrial DNA
mitochondrial DNA
folding
DNA conformation
Nucleic Acid Conformation
DNA
Mitochondrial Genome
DNA replication
DNA Replication
primate
Primates
targeting
sliding
substitution
Nucleotides
genome
transcription (genetics)
nucleotides
Maintenance

Cite this

Pereira, Filipe ; Soares, Pedro ; Carneiro, João ; Pereira, Luísa ; Richards, Martin B. ; Samuels, David C. ; Amorim, António. / Evidence for Variable Selective Pressures at a Large Secondary Structure of the Human Mitochondrial DNA Control Region. In: Molecular Biology and Evolution. 2008 ; Vol. 25, No. 12. pp. 2759-2770.
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abstract = "A combined effect of functional constraints and random mutational events is responsible for the sequence evolution of the human mitochondrial DNA (mtDNA) control region. Most studies targeting this noncoding segment usually focus on its primary sequence information disregarding other informative levels such as secondary or tertiary DNA conformations. In this work, we combined the most recent developments in DNA folding calculations with a phylogenetic comparative approach in order to investigate the formation of intrastrand secondary structures in the human mtDNA control region. Our most striking results are those regarding a new cloverleaf-like secondary structure predicted for a 93-bp stretch of the control region 5′-peripheral domain. Randomized sequences indicated that this structure has a more negative folding energy than the average of random sequences with the same nucleotide composition. In addition, a sliding window scan across the complete mitochondrial genome revealed that it stands out as having one of the highest folding potential. Moreover, we detected several lines of evidence of both negative and positive selection on this structure with high levels of conservation at the structure-relevant stem regions and the occurrence of compensatory base changes in the primate lineage. In the light of previous data, we discuss the possible involvement of this structure in mtDNA replication and/or transcription. We conclude that maintenance of this structure is responsible for the observed heterogeneity in the rate of substitution among sites in part of the human hypervariable region I and that it is a hot spot for the 3′ end of human mtDNA deletions.",
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Evidence for Variable Selective Pressures at a Large Secondary Structure of the Human Mitochondrial DNA Control Region. / Pereira, Filipe; Soares, Pedro; Carneiro, João; Pereira, Luísa; Richards, Martin B.; Samuels, David C.; Amorim, António.

In: Molecular Biology and Evolution, Vol. 25, No. 12, 01.12.2008, p. 2759-2770.

Research output: Contribution to journalArticle

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