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Mitochondrial DNA

M.Tevfik Dorak, MD PhD

Mitochondrial DNA (mtDNA) of higher animals is a circular molecule of 16,569 bases. It corresponds to chloroplastic DNA of plants both of which are collectively known as cytoplasmic DNA. The mtDNA has no repetitive DNA, spacers, or introns. It encodes 13 mRNAs, 22 tRNAs for translation of mtDNA genes and two rRNAs. mtDNA is usually the only type of DNA to survive in ancient bone specimens because of its abundance; 500-1000 copies per cell instead of only two copies of most nuclear DNA. Unlike nuclear DNA which gets mixed around each generation (this is each meiosis), the only alteration to mtDNA is an accidental change caused by mutation, copying errors, or other accidents, i.e., it does not recombine. mtDNA lacks protective histones is repaired only to a limited extent. Subsequently, the mtDNA mutation rate is estimated to be 17-fold higher than that for nuclear DNA (Wallace, 1987). mtDNA is maternally inherited. All the copies in an individual are usually identical but populations may be highly polymorphic. The lack of polymorphism within individuals suggests that at some point in the germ-line, the effective number of copies must have been small.

The rate of base substitution in mtDNA is much higher than nuclear DNA. An estimate of the initial rate of sequence divergence is 20x10-9 per site per year per evolutionary line (this is 2% sequence divergence per million years between pairs of lineages; 10 times faster than the highest rates in nuclear DNA). This estimate applies only to the first 10 million years of species separation after which mtDNA sequence divergence begins to plateau as many bases are conserved and the genome becomes saturated with substitutions at variable sites. This high rate of substitution makes mtDNA particularly valuable in studying the relationships in recently diverged lineages.

The fact that the mtDNA is inherited only through the female line without crossing-over provides unique information to phylogenetic studies as it preserves information about ancestry. The only source of sequence variation is mutation at a well-worked out stochastically constant rate so that divergence times (coalescence times) can be estimated.

Among human populations, restriction maps of mtDNA reveal rather little sign of geographical structuring. This suggests that existing human populations migrated from a common center relatively recently. Based on the divergence rate of 20x10-9, the mean time of divergence of human races is of the order of 50,000 years. mtDNA data have also been used to estimate effective population size (Ne; those contributing to the next generation) in the past. The total divergence time elapsed since a single ancestral sequence (coalescent) gave rise to today’s variants is 4xNe generations (time for a neutral mutation to get fixed). mtDNA is haploid and maternally inherited; hence, the mean coalescence is 2xNf, where Nf is the number of mothers. When the total divergence is estimated within the existing human populations, based on the sequence divergence rate of 20x10-9 per year, it has been concluded that the single common ancestor for all the variant sequences in today’s human populations existed 10 to 20 thousand generations ago (200 to 400 thousand years, assuming 20 years as generation time). This means that Nf must have been about 5 to 10 thousand.

It is important to understand the claim that all existing human mitochondria are probably derived from a single female living less than half a million years ago does not mean that our ancestral lineage was ever reduced to a single pair or that only one female contributed to our nuclear genome. Surely most of the females within the effective population at the time contributed to our nuclear genome but the female all our mtDNAs trace back lived 200 to 400 thousand years ago. More technically, the extant mtDNA alleles coalesce to a single ancestral molecule extant at that time. It is a mathematical certainty that each gene will coalesce into one ancestor, the others just have not been able to make it today (similar to the extinction of surnames). Each one of our 40,000 genes can be traced back to its own ancestral gene. It is important to remember that only those females who have daughters have the chance to pass on their mtDNA to following generations. A similar calculation has been made for HLA-DRB1 genes. All extant DRB1 alleles seem to have derived from one ancestor lived more than 65 million years ago.

One study compared a long stretch of mtDNA in humans in different primate species. This study (Horai, 1992) showed that humans are closer to chimpanzee than gorillas in terms of their mtDNA genealogy. When the divergence of mtDNA is compared among populations, the initial mtDNA split was found between Africans and others, followed by progressively younger calibrated ages for specific Asian, Australian, New Guinea, European, and native American mtDNA types. This pattern has been thought to support the Out of Africa model in the origin of modern humans. This estimate is based on the concept that greater sequence variation in mtDNA on a continent is a sign of greater longevity. African populations are the oldest because they harbor the greatest mtDNA variation.

mtDNA and Human Evolution

Mitochondrial Genome in NCBI Map Viewer & mtDNA Sequence

V-MitoSNP for Visualization of Human Mitochondrial SNPs

mtDB (Human Mitochondrial Genome Database)

MITOMAP (A human mitochondrial genome database)

BBA Molecular Basis of Disease  mtDNA issue (Dec 2009)

M.Tevfik Dorak, M.D., Ph.D.

Last edited on 26 June 2011

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