

Mitochondrial Eve

In 1987, A world wide survey of human mitochondrial DNA (mtDNA) was published by Cann, Stoneking, and Wilson in Nature magazine. Its main point was that "all mitochondrial DNAs stem from one woman" and that she probably lived around 200,000 years ago in Africa. When the media picked up from Wilson, one of the authors of the paper, that they had found the "Mitochondrial Eve" or "African Eve", the story became a sensation. Have scientists found "the mother of us all"? Most people know about the nuclei of cells and that the genetic inheritance from both parents are found in the nucleus. Humans have 46 chromosomes which they inherit from both their parents. Parts of both the DNA from the mother and father are put together in a recombination process that allows the children to have traits from both their mother and their Father. However, there is DNA located in other parts of the cell. In the cytoplasm, organelles called mitochondria, which provide energy for the cell in the form of ATP, also have DNA. This DNA, however, does not seem to come from both parents. Instead, it comes only from the mother and not from the Father (There seems to be some rare exceptions to the rule that only the mother contributes the mitochondrial DNA. See the mitochondrial Clock Update: Is maternal mitochondrial inheritance still thought to be true?). Initially, it was thought that for humans, most of the sperm remained outside of the egg. Only the head with the nuclear DNA and the centrosome, were thought to enter the egg. But that view has changed. Now it has been determined that the whole sperm enters the egg. However, virtually all of the sperm is broken down by enzymes. Only the chromosomes found in the head of the sperm in crystalline form are preserved and used in the recombination process to produce the final version of the new egg cell DNA. The sperm mitochondria and its DNA are broken down by enzymes made for that purpose. See the mitochondrial Clock Update: for details. However, the end result is still the same. The mitochondria and its DNA from the sperm are not used. Only the mitochondria from the egg are used for the newly developing person. So, our mitochondrial DNA is essentially identical to that of our mother. Mitochondrial DNA is transfered from mother to daughter, generation after generation. The mitochondrial DNA in the son, which he got from his mother, is a dead end street, since his mitochondrial DNA will not be used in his children. Nuclear DNA changes a lot since it undergoes recombination in every generation. However, the mitochondrial DNA gets transfered from generation to generation without any recombination. Only the normal mutation rate that occurs when DNA is replicated allows the mitochondrial DNA to change. This is why the world wide survey was able to determine that all people are related via some original mother which they called the "mitochondrial Eve". They produced ancestral trees that depended on the slow mutation rate of mitochondrial DNA to estimate how the whole human population came from a single woman. After the initial discovery of the "mitochondrial Eve", Wilson felt uneasy about using the term "Eve" because it caused many to think that she was the only woman living at that time, much like what is written in Genesis of the Bible concerning Adam and Eve in the Garden of Eden. Also, the usual evolutionary time-scale for man did not allow such a short time as 200,000 years. Rather, it is believed that man has been around for a much longer period of time. Java man is thought to be 800,000 years old. Homo erectus specimens are found all throughout the world. Over forty specimens of Asian Homo erectus which have been found in China, have been dated 220,000 to 500,000 years of age. Lucy, and the earliest remains of specimens that are thought to be of the first to stand upright, are thought to be at least 1 to 4 million years of age. So, because the presence of man is thought to have been around for a much longer period of time than just 200,000 years, it was concluded that the mitochondrial Eve must not have been the first human female nor would she have been the only female alive at the time. Evolutionists have come to believe that Eve must have been one of many women of her time, in a genetic bottleneck. A time when there were a tiny population of people alive. It is not known why the human population would became so depleted in a bottleneck. Some suggests that environmental pressures could have brought the human population almost to extinction. It has even been suggested, that the ability to speak languages was a reason why only one group survived over all others. All sorts of reasons have been offered to explain why bottlenecks would exist: a continuous plaque, asteroid impact, or a climate change are just a few of the many ideas. Many suggest that Eve must have had some vast superiority because her offspring are thought to have conquered the whole world without any evidence of any interbreeding. Others state that selection had nothing to do with the takeover of the human population. They inject that it was a purely statistical process.

Paleoanthropologists Attack the Mitochondrial Eve Story The story of the mitochondrial Eve is not what paleoanthropologists wanted to hear. They did believe that man came from Africa, but they believed it happened one million years ago. If Eve had lived a million years ago, most of the paleoanthropologists would have accepted the idea with open arms because the mitochondrial Eve data would have fit into the data they had. Now it seemed that there were several waves of humans that left Africa. Each wave seems to have taken over the world. Eve must have lived in Africa, 200,000 years ago, and then her descendants started migrating out of Africa, maybe 100,000 years ago to take over all the earth and all the older man types vanished from the earth without a trace in our genetic record! In addition, there is no evidence from the mitochondrial DNA data that Eve's descendants interbreeded with the older man types at all. The overtaking of the world's population by Eve's descendants in the last wave, a mere 100,000 years ago, is a point of contention because many of the paleoanthropologists saw a continuity of genetic traits between Homo erectus (the older type of man that Eve's descendants are thought to have killed off) and modern man. A continuity of genetic traits of the fossil remains suggests that Homo erectus actually had a direct genetic link to the more modern form of man. So, the modern chinese would be the decendants of Chinese erectus. Paleoanthropologists see this continuity as happening in separate parts of the world at the same time, in a parallel evolutionary process. What they see in the field is: African erectus evolving into modern africans, Chinese erectus evolving into modern chinese, European erectus evolving into Neandertals then modern Europeans, etc. So, the mitochondrial data seems to be at odds with fossils found in the field. The idea that Eve's children had conquered the whole world without any interbreeding at all, goes against the evidence showing that Homo erectus in various places of the world like China and Africa, look like the modern people of those same regions. Why do the chinese have traits associated with Asian erectus if all the Asian erectus had been wiped out when Eve's descendants arrived in Asia with no interbreeding at all? One paleoanthropologist, Milford Wolpoff, made the point that the out-of-Africa hypothesis was "Wacko"! When Eve's descendants left Africa, they left as Africans, but when they arrived in Asia, they were Asians! The Chinese and other Asians of today resemble the old erectus populations with the flat faces of the oriental people. The mitochondrial DNA data says the Asian erectus are extinct but the characteristics of modern man says they are not. The same phenomenon occurs in other regions of the world such as Europe where modern Europeans are actually closer to classic Neandertal than they are to any living human population with such features as a prominent nose and the shape of the rear end of the cranium. These kinds of arguments were countered by Chris Stringer who said: "Your fossils are not ancestors of modern men. What you have done for the last ten, twenty years was a complete waste of time". Rebeca Cann, one of the original authors of the study (mentioned above) had also said that paleoanthropologists could never tell for certain if a specific fossil actually left any descendants. On the other hand, there was "100 percent certainty that genes in modern populations have a history that can be examined and will trace back in absolute time to real ancestors". It is easy to tell that feelings were running high over this fight between the "out-of-Africa" theory and the "multi-regional continuity" theory that modern man arose from various place on the earth at the same time. The critics of the Eve story, who saw that the mitochondrial data did not fit with the fossils in the field that show a multi-regional continuity, so they started voicing several complaints against the mitochondrial data: The mitochondrial data was determined using restriction analysis rather than DNA sequencing. Restriction analysis is an enzymeatic method which can give false results at times. They used African Americans rather than Africans from Africa to represent native Africans in their study. So they did not get a proper sampling of the African population. They used an inferior method to build a phylogenetic tree. They used a program called PAUP which had been written to determine evolutionary relationships. However, the program gave different results when you entered the data in a different order. The answer was dependant upon the order that the data was entered into the computer. A big problem! Blair Hedges and his group in Penn State, found that when the data was entered in different orders, that sometimes some other part of the world was indicated as the place where Eve lived, rather than Africa. Newslines Headings in 1992 and 1993 such as: "Mitochondrial Eve: Wounded, But Not Dead Yet" and "Mitochondrial Eve Refuses to Die" are indications that the Mitochondrial Eve Hypothesis was in real trouble. At the 1993 AAAS (American Association for the Advancement of Science) meeting, Milford Wolpoff anounced: "It's over for Eve". Ever since it was admitted that there were serious problems with the statistics that supports the Eve idea, Wolpoff had wanted to give her last rites. However, in the very same meeting, Maryellen Ruvolo, from Harvard U. presented new data that used DNA sequencing rather than restriction analysis to study a part of the cytochrome oxidase gene found in the mitochondrial genome. The original work was criticized because it was based on a rapidly evolving part of the mitochondria. Ruvolo's work was based on a slowly evolving portion of the mitochondrial genome and he got the same answer as is found in the original work. What his work shows is that the short time for Eve is essentially correct. The "multi-regional continuity" people were hoping for an older date, like maybe 1 million years. That would have allowed the mitochondrial Eve data to fit with the "multi-regional continuity" theory. However that did not happen. Currently the battle is still raging over the history of Modern Human Origins and we still have the same two irreconcilable scientific camps: The mitochondrial Eve data, that supports the "out-of-Africa" theory where Eve's decendents, on coming out of Africa, are seen as taking over the whole world and overcoming all the other man types with no sign of interbreeding, only 100,000 years ago. The continuous genetic change of fossil data in many places on the globe seems to suggest to many that mankind has been advancing across the globe in a parallel multiregional evolutionary process. if Eve's descendants overtook the whole world suplanting all other peoples, there would be a break in the type of fossils seen in the field. The older fossils would not relate to the newer fossils that descend from Eve. There would be no way to explain the continuous change of fossil remains that is seen around the world, using the mitochondrial Eve data. So, there seems to be no way for all the data to presently fit together. It is true, as "Kip" Thorne from Australian National University, mentioned: "The fossil evidence is really scrappy. There just isn't enough of it." However, it does not look like the situation will change anytime soon. Wolpoff thinks that the controversy will continue until they are all dead. Then the next generation, he says, will have to decide.

Interesting Journal Articles with abstracts if available

Mitochondrial DNA and human evolution. Cann RL, Stoneking M, Wilson AC.

Nature. 1987 Jan 1-7;325(6099):31-6.

Department of Biochemistry, University of California, Berkeley, California 94720, USA Mitochondrial DNAs from 147 people, drawn from five geographic populations have been analysed by restriction mapping. All these mitochondrial DNAs stem from one woman who is postulated to have lived about 200,000 years ago, probably in Africa. All the populations examined except the African population have multiple origins, implying that each area was colonised repeatedly.

Mitochondrial COII sequences and modern human origins. Ruvolo M, Zehr S, von Dornum M, Pan D, Chang B, Lin J.

Mol Biol Evol. 1993 Nov;10(6):1115-35.

The aim of this study is to measure human mitochondrial sequence variability in the relatively slowly evolving mitochondrial gene cytochrome oxidase subunit II (COII) and to estimate when the human common ancestral mitochondrial type existed. New COII gene sequences were determined for five humans (Homo sapiens), including some of the most mitochondrially divergent humans known; for two pygmy chimpanzees (Pan paniscus); and for a common chimpanzee (P. troglodytes). COII sequences were analyzed with those from another relatively slowly evolving mitochondrial region (ND4-5). From class 1 (third codon position) sequence data, a relative divergence date for the human mitochondrial ancestor is estimated as 1/27 th of the human-chimpanzee divergence time. If it is assumed that humans and chimpanzees diverged 6 Mya, this places a human mitochondrial ancestor at 222,000 years, significantly different from 1 Myr (the presumed time of an H. erectus emergence from Africa). The mean coalescent time estimated from all 1,580 sites of combined mitochondrial data, when a 6-Mya human-chimpanzee divergence is assumed, is 298,000 years, with 95% confidence interval of 129,000-536,000 years. Neither estimate is compatible with a 1-Myr-old human mitochondrial ancestor. The mitochondrial DNA sequence data from COII and ND4-5 regions therefore do not support this multiregional hypothesis for the emergence of modern humans.

Erratum in: Mol Biol Evol 1994 May;11(3):552.

Identification of the remains of the Romanov family by DNA analysis. Gill P, Ivanov PL, Kimpton C, Piercy R, Benson N, Tully G, Evett I, Hagelberg E, Sullivan K

Nat Genet 1994 Feb;6(2):130-5

Central Research and Support Establishment, Forensic Science Service, Aldermaston, Reading, Berkshire, UK.

Comment in: Nat Genet 1994 Feb;6(2):113-4 Nine skeletons found in a shallow grave in Ekaterinburg, Russia, in July 1991, were tentatively identified by Russian forensic authorities as the remains of the last Tsar, Tsarina, three of their five children, the Royal Physician and three servants. We have performed DNA based sex testing and short tandem repeat (STR) analysis and confirm that a family group was present in the grave. Analysis of mitochondrial (mt) DNA reveals an exact sequence match between the putative Tsarina and the three children with a living maternal relative. Amplified mtDNA extracted from the remains of the putative Tsar has been cloned to demonstrate heteroplasmy at a single base within the mtDNA control region. One of these sequences matches two living maternal relatives of the Tsar. We conclude that the DNA evidence supports the hypothesis that the remains are those of the Romanov family.

Mitochondrial DNA sequence heteroplasmy in the Grand Duke of Russia Georgij Romanov establishes the authenticity of the remains of Tsar Nicholas II. Ivanov PL, Wadhams MJ, Roby RK, Holland MM, Weedn VW, Parsons TJ

Nat Genet 1996 Apr;12(4):417-20

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow. In 1991, nine sets of skeletal remains were excavated from a mass grave near Yekaterinburg, Russia which were believed to include the Russian Tsar Nicholas II, the Tsarina Alexandra, and three of their daughters. Nuclear DNA testing of the remains verified such a family group, and mitochondrial DNA (mtDNA) sequences of the presumed Tsarina matched a known maternal relative, Prince Philip. mtDNA sequences from bone of the presumed Tsar matched two living maternal relatives except at a single position, where the bone sample had a mixture of matching (T) and mismatching (C) bases. Cloning experiments indicated that this mixture was due to heteroplasmy within the Tsar; nevertheless, the 'mismatch' fueled a lingering controversy concerning the authenticity of these remains. As a result, the official final report on the fate of the last Russian Royals has been postponed by Russian authorities pending additional, convincing DNA evidence. At the request of the Russian Federation government, we analysed the skeletal remains of the Tsar's brother Georgij Romanov in order to gain further insight into the occurrence and segregation of heteroplasmic mtDNA variants in the Tsar's maternal lineage. The mtDNA sequence of Georgij Romanov, matched that of the putative Tsar, and was heteroplasmic at the same position. This confirms heteroplasmy in the Tsar's lineage, and is powerful evidence supporting the identification of Tsar Nicholas II. The rapid intergenerational shift from heteroplasmy to homoplasmy, and the different heteroplasmic ratios in the brothers, is consistent with a 'bottleneck' mechanism of mtDNA segregation.

How rapidly does the human mitochondrial genome evolve? Howell N, Kubacka I, Mackey DA

Am J Hum Genet 1996 Sep;59(3):501-9

Department of Radiation Therapy, University of Texas Medical Branch, Galveston 77555-0656, USA. nhowell@mspo3.med.utmb.edu The results of an empirical nucleotide-sequencing approach indicate that the evolution of the human mitochondrial noncoding D-loop is both more rapid and more complex than is revealed by standard phylogenetic approaches. The nucleotide sequence of the D-loop region of the mitochondrial genome was determined for 45 members of a large matrilineal Leber hereditary optic neuropathy pedigree. Two germ-line mutations have arisen in members of one branch of the family, thereby leading to triplasmic descendants with three mitochondrial genotypes. Segregation toward the homoplasmic state can occur within a single generation in some of these descendants, a result that suggests rapid fixation of mitochondrial mutations as a result of developmental bottlenecking. However, slow segregation was observed in other offspring, and therefore no single or simple pattern of segregation can be generalized from the available data. Evidence for rare mtDNA recombination within the D-loop was obtained for one family member. In addition to these germ-line mutations, a somatic mutation was found in the D-loop of one family member. When this genealogical approach was applied to the nucleotide sequences of mitochondrial coding regions, the results again indicated a very rapid rate of evolution .

The mutation rate of the human mtDNA deletion mtDNA4977. Shenkar R, Navi di W, Tavare S, Dang MH, Chomyn A, Attardi G, Cortopassi G, Arnheim N

Am J Hum Genet 1996 Oct;59(4):772-80

Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Science Center, Denver, USA.

Comment in: Am J Hum Genet 1996 Oct;59(4):749-55 The human mitochondrial mutation mtDNA4977 is a 4,977-bp deletion that originates between two 13-bp direct repeats. We grew 220 colonies of cells, each from a single human cell. For each colony, we counted the number of cells and amplified the DNA by PCR to test for the presence of a deletion. To estimate the mutation fate, we used a model that describes the relationship between the mutation rate and the probability that a colony of a given size will contain no mutants, taking into account such factors as possible mitochondrial turnover and mistyping due to PCR error. We estimate that the mutation rate for mtDNA4977 in cultured human cells is 5.95 x 10(-8) per mitochondrial genome replication. This method can be applied to specific chromosomal, as well as mitochondrial, mutations.

Mutational analysis of the human mitochondrial genome branches into the realm of bacterial genetics. Howell N

Am J Hum Genet 1996 Oct;59(4):749-55

Comment on: Am J Hum Genet 1996 Oct;59(4):772-80

Comment in: Am J Hum Genet 1997 Oct;61(4):983-90

mtDNA mutation rates--no need to panic. Macaulay VA, Richards MB, Forster P, Bendall KE, Watson E, Sykes B, Bandelt HJ

Am J Hum Genet 1997 Oct;61(4):983-90

As part of this letter to the editor, a reply to Macaulay et al. by Neil Howel and David Mackey is included.

Comment on: Am J Hum Genet 1996 Oct;59(4):749-55

A high observed substitution rate in the human mitochondrial DNA control region. Parsons TJ, Muniec DS, Sullivan K, Woodyatt N, Alliston-Greiner R, Wilson MR, Berry DL, Holland KA, Weedn VW, Gill P, Holland MM

Nat Genet 1997 Apr;15(4):363-8

Armed Forces DNA Identification Laboratory, Armed Forces Institute of Pathology, Rockville, Maryland 20850, USA. The rate and pattern of sequence substitutions in the mitochondrial DNA (mtDNA) control region (CR) is of central importance to studies of human evolution and to forensic identity testing. Here, we report a direct measurement of the intergenerational substitution rate in the human CR. We compared DNA sequences of two CR hypervariable segments from close maternal relatives, from 134 independent mtDNA lineages spanning 327 generational events. Ten substitutions were observed, resulting in an empirical rate of 1/33 generations, or 2.5/site/Myr. This is roughly twenty-fold higher than estimates derived from phylogenetic analyses . This disparity cannot be accounted for simply by substitutions at mutational hot spots, suggesting additional factors that produce the discrepancy between very near-term and long-term apparent rates of sequence divergence . The data also indicate that extremely rapid segregation of CR sequence variants between generations is common in humans, with a very small mtDNA bottleneck. These results have implications for forensic applications and studies of human evolution.

Intraspecific nucleotide sequence variability surrounding the origin of replication in human mitochondrial DNA. Greenberg BD, Newbold JE, Sugino A.

Gene. 1983 Jan-Feb;21(1-2):33-49. We have cloned the major noncoding region of human mitochondrial DNA (mtDNA) from 11 human placentas. Partial nucleotide sequences of five of these clones have been determined and they share a maximum of 900 bp around the origin of H-strand replication. Alignment of these sequences with others previously determined has revealed a striking pattern of nucleotide substitutions and insertion/deletion events. The level of sequence divergence significantly exceeds the reported estimates of divergence in coding regions. Two particularly hypervariable regions have also been defined. More than 96% of the base changes are transitions, and length alterations have occurred exclusively by addition or deletion of mono-or dinucleotide segments within serially repeating stretches. This region of the mitochondrial genome, which contains the initiation sites for replication and transcription, is the least conserved among species with respect to both sequence and length (Anderson et al., 1981; Walberg and Clayton, 1981). Despite this overall lack of primary sequence conservation, several consistencies appear among the available mammalian mtDNA sequences within this region. Between species, a conserved linear array of characteristic stretches exists which nonetheless differ in primary sequence. Among humans, several conserved blocks of nucleotides appear within domains deleted from the mtDNA of other species. These observations are consistent with both a species-specificity of nucleotide sequence, and a preservation of the necessary genetic functions among species. This provides a model for the evolution of protein-nucleic acid interactions in mammalian mitochondria.

The mutation rate in the human mtDNA control region. Sigurgardottir S, Helgason A, Gulcher JR, Stefansson K, Donnelly P.

Am J Hum Genet. 2000 May;66(5):1599-609. Epub 2000 Apr 7.

deCODE Genetics, Inc., Reykjavik, Iceland 110. The mutation rate of the mitochondrial control region has been widely used to calibrate human population history. However, estimates of the mutation rate in this region have spanned two orders of magnitude. To readdress this rate, we sequenced the mtDNA control region in 272 individuals, who were related by a total of 705 mtDNA transmission events, from 26 large Icelandic pedigrees. Three base substitutions were observed, and the mutation rate across the two hypervariable regions was estimated to be 3/705 =.0043 per generation (95% confidence interval [CI].00088-.013), or.32/site/1 million years (95% CI.065-.97). This study is substantially larger than others published, which have directly assessed mtDNA mutation rates on the basis of pedigrees, and the estimated mutation rate is intermediate among those derived from pedigree-based studies. Our estimated rate remains higher than those based on phylogenetic comparisons. We discuss possible reasons for-and consequences of-this discrepancy. The present study also provides information on rates of insertion/deletion mutations, rates of heteroplasmy, and the reliability of maternal links in the Icelandic genealogy database.

Mitochondrial mutation rate revisited: hot spots and polymorphism. Jazin E, Soodyall H, Jalonen P, Lindholm E, Stoneking M, Gyllensten U

Nat Genet 1998 Feb;18(2):109-10

As part of this correspondence, Parsons and Holland respond

Comment on: Nat Genet 1997 Apr;15(4):363-8

Mitochondrial genome variation and the origin of modern humans. Ingman M, Kaessmann H, Paabo S, Gyllensten U.

Nature. 2000 Dec 7;408(6813):708-13.

Department of Genetics and Pathology, Section of Medical Genetics, University of Uppsala, Sweden.

The analysis of mitochondrial DNA (mtDNA) has been a potent tool in our understanding of human evolution, owing to characteristics such as high copy number, apparent lack of recombination, high substitution rate and maternal mode of inheritance. However, almost all studies of human evolution based on mtDNA sequencing have been confined to the control region, which constitutes less than 7% of the mitochondrial genome. These studies are complicated by the extreme variation in substitution rate between sites, and the consequence of parallel mutations causing difficulties in the estimation of genetic distance and making phylogenetic inferences questionable. Most comprehensive studies of the human mitochondrial molecule have been carried out through restriction-fragment length polymorphism analysis, providing data that are ill suited to estimations of mutation rate and therefore the timing of evolutionary events. Here, to improve the information obtained from the mitochondrial molecule for studies of human evolution, we describe the global mtDNA diversity in humans based on analyses of the complete mtDNA sequence of 53 humans of diverse origins. Our mtDNA data, in comparison with those of a parallel study of the Xq13.3 region in the same individuals, provide a concurrent view on human evolution with respect to the age of modern humans.

Erratum in: Nature 2001 Mar 29;410(6828):611.

Comment in: Nature. 2000 Dec 7;408(6813):652-3.

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