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Athena Review  Vol.2, no.2:  Recent Finds in Paleoanthropology

Molecular clockwork and related theories

Testing the basis for “Mitochondrial Eve.”

Molecular clocks, a complex topic central to current debates on human evolution, first came into prominence in paleoanthropology in the 1960’s. One well-known study by Vincent Sarich and Alan Wilson of the University of California (1967) measured the immunological reactions in primates and other animals to a control sample of the blood protein serum albumin. The differences, assumed due to a constant rate of evolution  through mutations, were then plotted on a linear scale showing time elapsed since each species diverged from a common ancestor.

On the same principle, DNA, the genetic reproductive molecule, is often used for inter-species comparison. Assuming a constant rate of mutation or random replacement of amino-acid codes in DNA, the time elapsed between descent from a common ancestor can be calculated by comparing DNA segments from many different animal populations, from sharks to chimpanzees. With access to a large genetic data base and a computer program for “best fit” distance trees, evolutionary histories or phylogenies can be constructed independently of the often problematic, gap-filled fossil record.

Increasingly, evolutionary biologists have employed the relatively simple genetic makeup of mitochondrial DNA (mtDNA) as an efficient form of molecular clock. Mitochondria, energy-producing organelles in cells, have their own DNA strands which, limited in function to mitochondrial reproduction, are significantly shorter than those in the nucleus of a cell. Mutations in the simpler mitochondrial DNA occur much faster than in nuclear DNA, compressing more evolutionary generations into less time. Adding to the appeal of mtDNA for tracking evolutionary history has been the wide consensus that, after conception, only the egg’s mitochondria survive, and mtDNA is therefore inherited only through the maternal line.

During the past 15 years, extensive searches have been made through genetic records to find a “Mitochondrial Eve” of all modern humans. A widely-publicized 1987 study by Cann, Stoneking, and Wilson (the latter, also an author of the 1967 serum albumin study) used mtDNA comparisons of 147 people from Europe, Africa, Asia, Australia, and new Guinea to show all present human mtDNA is descended from a single African woman of about 200,000 years ago.  

This has caused considerable controversy over issues beginning with the chancy workings of population genetics. Famines and other catastrophic events about 200,000 years ago could have caused genetic bottlenecks or constrictions, eliminating older human ancestral lines. Today’s retrospective survey of mtDNA would then show only surviving types, misleadingly suggesting the human species evolved at that later time (Weiss and Mann 1990). Also involved is the independent nature of mtDNA itself, evolving distinctly in each individual from the nuclear DNA which is the criteria of speciation. Comparisons based on nuclear DNA, for example, reveal chimps and humans to be closer than does mtDNA, which shows more similarities between chimps and gorillas. Finally, recent evidence (discussed below) suggests the assumption that mtDNA is only passed through the female line may itself be faulty.

The Mitochondrial Eve theory also seems to many researchers to be at variance with the fossil record, which shows widespread hominid migrations and variation after 2 million years ago (myr), well documented for Homo erectus in China, Java, and the Black Sea by 1.8-1.6 myr, and Archaic Homo sapiens and Neanderthals after 0.6 myr. According to the Mitochondrial Eve theory, all non-African H. erectus and H. neanderthalensis populations are unrelated to the evolution of anatomically modern humans (H. s. sapiens). This directly contradicts the “Regional Continuity” model used by many paleoanthropologists. In spite of such controversies, the Mitochondrial Eve theory has considerable scientific adherence and popular recognition. A new study by South African researchers, for example, proposes the most ancient mtDNA belongs to “Bushwomen” or Khoisan people. Recent genetic studies in China, meanwhile, lend support to “out of Africa” theories.

As masses of data accumulate from the statistically-oriented studies of mitochondrial biology, it is becoming apparent that the required methodology of studying mtDNA is anything but straightforward. Currently under fire is the once-canonical view that mtDNA is inherited only through the mother, now challenged by a set of studies reported in Proceedings of the Royal Society (7 March 1999) by Erika Hagelberg of Cambridge University, and Adam Eyre-Walker, Noel Smith and John Maynard Smith of Sussex University. It has long been known that paternal mitochondria can sometimes penetrate the human egg and survive for several hours. While studies of mice and other organisms  have actually shown recombination between male and female mtDNA, evidence of mtDNA recombination in human populations has been very elusive.

Now such evidence appears to have been found in a mtDNA research project led by Erika Hagelberg on the tiny island of Nguna, in the archipelago of Vanuatu in Melanesia (west of Polynesia including the Solomon Islands and Fiji). Studying human migrations, Hagelberg and her colleagues were analyzing hundreds of people from Papua-New Guinea and Melanesia. MtDNA samples on Nguna Island showed, as expected, three main population groups from colonizations over thousands of years. But in all three there also occurred a single mutation previously only known from one northern European. Hagenberg and her colleagues (1999) think it highly improbable for such a rare mutation event to occur repeatedly in such an isolated location. A more likely explanation would be recombination between different mitochondrial DNA types.

Similar conclusions were drawn by Adam Eyre-Walker and his colleagues at Sussex University, from statistical analysis of “homeoplasies,” common mutations in mitochondrial proteins that occur in seemingly distinct lineages around the world. Assuming maternal inheritance only of mtDNA, these were thought to be “hypervariable” sites where mutations occurred with high frequency. Review of some European and African mtDNA sequences by Eyre-Walker et al., however, show no evidence that these sites are particularly variable over all lineages. Most of these mutations were found in only a limited geographic area, suggesting they occurred rarely and then spread locally by recombination, which appears a far more likely cause of the homeoplasies.

Such findings, if upheld, seriously complicate the basis of using mtDNA to provide straightforward genetic lines, such as assumed in the Mitochondrial Eve hypothesis. The surprising homogeneity in the mtDNA of modern humans interpreted, in the Mitochondrial Eve hypothesis, as resulting from a recent common ancestor, may simply show the dilution of mutations caused by the recombination of mtDNA.

Even occasional mixing of maternal and paternal genes would make it uncertain whether new traits in two different human lineages are due to two independent mutations or to the transfer of a mutation from one lineage to another by recombination. Recombinations could also add to or erase changes from mutations, thus blurring, as Hagelberg's team points out, the differences between mtDNA lineages. This would make any past evaluations of human history using mtDNA, including the Mitochondrial Eve theory, subject to cautious reinterpretation. This most directly impacts the time scale of Mitochondrial Eve, and seriously weakens the value mtDNA mutation rates as a molecular clock. Recombination with paternal mtDNA causing some variation in mtDNA would make its mutation rate much lower than biologists thought. Eyre-Walker notes Eve may have lived twice as long ago as current estimates.

The controversial recombination factor is providing new directions for research and interpretation. In 1997, Svante Pääbo of the Max Planck Institute of Evolutionary Anthropology in Leipzig retrieved Neanderthal DNA over 50,000 years old, which he determined to have not contributed in any way to the mtDNA of modern humans. But the possibility of recombination suggests to Erika Hagelberg that Neanderthals might be more closely related to modern humans than Pääbo’s mtDNA data shows. Pääbo partially agrees, but feels recombination has not yet been effectively proven. MtDNA shows Neanderthals equally distant from both modern Europeans, whom they may be ancestral to, and unrelated populations.

Further research on mtDNA evolution should serve to identify and eliminate the specific genes which mutate at abnormally fast or slow rates. Jody Hey and Eugene Harris of Rutgers University suggest that future work should increasingly concentrate on the more complex nuclear genes. A recent study by Hey and Harris (1999) on the mutation rate of  PDHA1 genes in the X Chromosome, thought to have a steady rate of mutation, has identified two populations at least 200,000 years old ancestral to modern humans. To determine the mutation rate of the gene, these were compared to the differences between human and chimpanzee PDHA1 genes, diverging at least 5-6 million years ago. They found that prior to 200,000 years ago, one form of this gene existed only in Africa and led to types only in modern Africans. Another existed only outside of Africa with one variant found in some modern Africans and another which split ca. 200,000 years ago into two haplotypes found in non-Africans.

Milford Wolpoff of the University of Michigan, a long-time opponent of the oversimplified use of molecular clocks (1988), supports the recent findings of Hey and Harris. If this evidence is not to make “Out-of-Africa II” theories obsolete, they may nevertheless need to evolve significantly themselves, to accommodate Asian and European populations originating in Africa but leaving considerably earlier than 100,000 to 200,000 years ago.

[References: Cann, R.L., M. Stoneking and A.C. Wilson, Nature 325, 1987; Eyre-Walker, A., N.H. Smith, and J. Maynard Smith, Proc. Royal Society B, 1999, Vol.266, pp.477-483. Hagelberg, E. et al., Proc.Royal Society B, 1999 (vol 266, p. 485), Hey, J. and E. Harris, Proc. Natl. Academy of Sciences, 16 Mar. 1999; Ji et al., Nature 398, 1999; Kumar, S. and S.B. Hedges, Nature 392,1998; Merriweather, D.A. and F.A. Kaestle, Science 285, 1999; Sarich, V.M. and A.C. Wilson, Proc. Natl. Academy of Sciences 58, 1967; Weiss, M.L. and A.E. Mann, 1990, Human Biology and Behavior, Scott, Foresman; Wolpoff, M.H., et al, Science 241, 1988]

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