Molecular History Research Center

The Mitochondrial Eve and the Clock Vrs. Homo erectus:

Is there a Creationary model that would allow the data to fit together?

On the Mitochondrial update page, we saw that the mitochondrial DNA is still thought to follow the laws of maternal inheritance. In addition, both the Medical community and the forensic community continue to embrace the concept of maternal inheritance in their cases. So we can continue to look at the Genetic Data of early man and assume that the Mitochondrial DNA follows maternal inheritance, and that the Y chromosome follows paternal inheritance, as was assumed earlier.

  1. How long ago did the mitochondrial Eve live?
  2. Evolutionists have assumed that the mitochondrial clock rate is fairly constant. They assumed that mutations occur every 6000 to 12,000 years (that would be one mutation in every 300 to 600 generations). However, their assumptions on DNA's rate of change are based on the comparison of different species, the existence of a common ancestor, and long periods of time, which depend upon the evolutionary process to be relevant.

    So, because it is thought that the oldest primates, much like the lemur, were living around 60 million years ago; Wilson and Sarich, in the 1960s, used this idea as a calibration point to measure how long ago man had branched away from chimpanzees. In a much heated debate, the branching of human and chimp was finally hammered out to be around 5 million years ago.

    Later, in the same lab, Cann, Stoneking, and Wilson then used the 5 million year date to calibrate how long ago the original mother of today's human population had lived. She was initially thought to have lived 200,000 years ago. The date was later adjusted to be around 150,000 years ago. They called her Eve, the mitochondrial Eve.

    If there never was a common ancestor of humans and chimpanzees, then these evolutionary comparisons mean nothing.

    As a creationary scientist, I would not expect that the present mitochondrial clock rate would need to match the rate as predicted by evolutionary studies of different taxonomic groups, such as chimpanzees and humans. It is only an assumption that a comparison of different species will show how long ago different species diverged. If evolution has never occurred, if chimpanzees and humans never had a common ancestor, then a comparison study of different species would not be a measure of relatedness through the evolutionary process; But rather, it would be a measure of how similar the two species are in their physiology and their molecular biology.

    When scientists started measuring the mitochondrial DNA rate of change within a single population over time, it was shocking for the evolutionist to discover that mutations are occurring much faster than expected in some populations.

    I believe that this much faster rate of change is a better predictor of time indicating how fast DNA changes rather than the comparison of man with other species. It is only when evolutionary assumptions are held that the faster rate is held in suspect. When a different set of assumptions are taken, the faster rate of human mitochondrial genetics becomes a distinct possibility to consider.

    Initially, one of the reasons why it was thought that mitochondrial DNA might have a constant clock rate is that it would not be affected by Natural Selection. But since the actual non-coding regions of the mitochondrial DNA can be extremely fast changing regions, the push for studying DNA that is free from Natural Selection seems to have been abandoned. Now it is the slower rate of change that occurs within the coding regions for protein, of the mitochondria DNA, that Evolutionists now prefer because it matches their evolutionary expectations. Yet, they are using the numbers as if their results are still not affected by Natural Selection.

    Belief in Evolution

    Many people do not believe that it would be profitable to even entertain the idea that short ages are possible; Because, they believe that there is a broad range of supporting data in all the areas of science that serves to solidify the position that Evolution is an established fact, or at least, the only viable option.

    So, they try to say something like: "The weight of evidence proves evolution"; or, "all the data supports evolution". But this is not true, the weight of evidence does not prove anything. We do not have an issue involving the weight of evidence. Rather, what we have is the weight of interpretation!

    It is the weight of interpretations that Evolutionary theory is based. It is not based solely on data alone.

    When you ask someone why they are taking the position that they are taking, or when you start pinning someone down concerning specific supporting data, asking what the database is for this idea or that idea; it starts breaking down. The idea that: "the data supports evolution as an established fact", or that: "the data supports evolution and not creationism", is not true.

    This controversy is not over data. The data can go either way. Very intelligent people believe in the long history of the earth and they have good data to support them. There is no question about it. However, I look at that same data and I come to very different conclusions. This process is legitimate! There is such a thing as multiple interpretation to the data base. There is no proof for either position.

    All science, especially in those areas that deal with historical data, is dependent upon assumptions or presuppositions to simplify the problem. Without these assumptions, Science would literally grind to a halt. The assumptions that scientists take are assumed to be true yet because of their nature, they can not be tested. That is why they remain today as assumptions, we do not have the ability to test them.

    If it were found that one or more of the major assumptions supporting Evolution were in error, Evolution would no longer be a viable theory. Of course, the same would be true for any paradigm used to explain data, be that Creation or Evolution. Both are dependent upon assumptions for their validity.

    What is really amazing to me is that when I listen to mainstream sources that promote Evolution, I see that they do not want to acknowledge their assumptions at all.

  1. There is no deadlock between the two groups of data when viewed from a Creationary perspective.

  2. The Problem From an Evolutionary Perspective

    From an Evolutionary perspective, the out-of-Africa theory clashes against the continuous genetic change of man in different areas of the world at the same time because one set of data denies the other set of data.

    The Mitochondrial Eve is now thought to have lived 150,000 years ago and 100,000 years ago, her descendants is thought to have started migrating out of Africa. When that happened, they say the older man types vanished from the earth without a trace in our genetic record! The invading descendants of Eve just did not interbreed with the older man types.

    Most paleoanthropologists know that this out-of-Africa theory presents a major problem. They know that there is a continuity of genetic traits from the Homo erectus fossils to the more modern forms of man. There is a direct genetic link that can be seen by comparing the various features of the fossils.

    The Chinese and other Asians of today resemble the old erectus populations with the flat faces of the oriental people. So, while the mitochondrial DNA data says the Asian erectus are extinct with no genetic link to modern oriental people; The comparative studies of the two say the opposite! The characteristics of modern oriental man are indeed similar to the old erectus populations. So the fossils say there is indeed a genetic link!

    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.

    When studying the initial problems concerning the mitochondria DNA studies, it is no wonder why Paleoanthropologists Milford Wolpoff thought "It's over for Eve". The genetic study just did not agree with the fossils in the field.

    However the Mitochondrial Eve Hypothesis refused to die. Further studies such as was done by Maryellen Ruvolo, from Harvard U., helped substantiate the Eve Hypothesis by using more modern techniques such as actually sequencing the DNA rather than just using restriction analysis as part of the study. And the date for Eve was recalculated to be around 150,000 rather than 200,000 years ago.

    As is reported on the Mitochondrial Eve page, there are two irreconcilable scientific camps concerning the history of man:

    1. The mitochondrial Eve data, that supports the "out-of-Africa" theory where Eve's descendants, 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.
    1. 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 multi-regional evolutionary process. if Eve's descendants overtook the whole world supplanting 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.

    There presently seems to be no way for all the data to fit together within an evolutionary context. Both camps have good substantiated data. Wolpoff thinks that the controversy will continue until they are all dead. Then the next generation, he says, will have to decide.

    See the Mitochondrial Eve page for more details on this controversy of the two irreconcilable scientific camps.

    Now, A Look From a Creationary Perspective

  1. The original Biblical Eve or Bottleneck?
  2. Using the mitochondrial DNA data from a sampling of people from various people groups, we are able to trace back, in the past, to find that there is one mother who is the mother of us all. Everyone who is now living on the earth inherits his or her mitochondrial DNA from that mother. She has been called the Mitochondrial Eve.

    Since this mitochondrial Eve is now thought to live 150,000 years ago, much later than the earliest man types discovered; She is not thought to be the first human mother. Rather, the mitochondrial Eve is thought to have lived in a time when the human population was experiencing a bottleneck. A bottleneck is a time when only a small number of individuals are living. This increases the chance that one mother's mitochondrial DNA might survive while all others are lost.

    However, the mitochondrial data does not stipulate that Eve must live in a bottleneck or that she lived in a sub-population that survived when all others did not. The reason why bottlenecks are introduced into the model is because evolutionists think that man must have been on the earth for a much longer period of time than 150,000 years. They do not think the mitochondrial Eve could have been the first mother. So, according to their evolutionary ideas, there must have been a bottleneck to allow only one woman, who lived only a couple of thousand years ago, to be the mother of all living humans that are living on the earth today.

    As a creationary scientist, I would not expect that the present mitochondrial clock rate would match the rate as predicted by evolutionary studies of different taxonomic groups, such as chimpanzees and humans. It is only an assumption that a comparison of different species will show how long ago different species diverged. If evolution has never occurred, if chimpanzees and humans never had a common ancestor, then a comparison study of different species would not be a measure of relatedness through the evolutionary process; But rather, it would be a measure of how similar the two species are in their physiology and their molecular biology. On the Mitochondrial clock page, we saw that the mutation rate could be much faster than what is predicted by the comparison of different taxonomic groups.

    If only the mitochondrial genetic data is considered, so we do not consider the time aspect of the evolutionary paradigm; Then we should be able to consider the possibility that the mitochondrial Eve, indeed, could have been the very first mother in existence in the human family. The genetic data supports that very possibility. She does not have to be living in a bottleneck. The genetic data itself cannot distinguish between these two possibilities (the first human mother in existence, versus. a bottleneck condition where her DNA survived while all other DNA was lost). The mitochondrial genetic data can only say that the mitochondrial Eve is the most recent common ancestor of all mothers. That is all the data can suggest, that she is the most recent mother of us all.

    The same points can be made for the Y Chromosome Adam. The data can only say that he is the most recent father of us all.

  1. Adam never did met Eve

    Using the Biblical creation/flood model, we find that the genetic data fits very well with the Biblical account. The mitochondrial Eve was indeed the Biblical Eve. She is the mother of the human race. On the other hand, the Biblical creation/flood model suggests that the Y Chromosome Adam lived through a bottleneck some time later.

    According to the genetic data, the "Y Chromosomal Adam" did not live when the "Mitochondrial Eve" lived out her life. They were living at different times. The "Mitochondrial Eve" is thought to have lived in a bottleneck 150,000 years ago while the "Y Chromosomal Adam" is thought to have lived in a more recent bottleneck 60,000 years ago.

    Looking at the chart at the right (or above) we see that Eve is the suggested most recent mother of us all. We see that during the flood, the female population was not reduced to a single woman. Instead, we find that there were three or possibly four women from different families that survived (There is no Biblical evidence suggesting that Noah and his wife had children after the flood. But, since girls are not usually mentioned in the Bible, it is still a possibility.) So Eve is still the suggested most recent mother of us all.

    It is a different story for the male population. We see that during the flood, It is only Noah's Y Chromosome DNA that survives the bottleneck. All the other males were destroyed from the face of the earth. So, Noah is the sole source of the Y Chromosome in today's human population. He and his sons are the only males to come out of the storm alive! Only Noah, his wife, and his three sons and their wives were saved. So, the most recent father of us all, is Noah, not Adam. Noah's sons, which inherited their father's Y Chromosome then repopulated the earth.

    So, rather than having two bottlenecks, the Creation/Flood model suggests that only one bottleneck occurred. The Bible suggests that a great Global Flood that covered the whole surface of the planet. This is what produced the bottleneck for the human population.

    The "mitochondrial Eve" in the creation/flood model is the Biblical Eve. She lived before the Y Chromosome Adam, at the very beginning, when the Earth was created. It is interesting that some researchers see evidence of an additional bottleneck within the mitochondrial DNA itself. We are not talking about the Y Chromosome males, this bottleneck occurred since the time of the "Mitochondrial Eve" in the female human population. The affects of the flood which allow Noah to be the most recent common ancestor of the "Y Chromosome" is also the suggested cause for the bottleneck evidence in the mitochondrial DNA data.

  1. Different People Groups of Today Developed because of Language.
  2. How did the different people groups that we find in the world today originate? Evolutionists believe that there has been a Cluster of Bottlenecks. A multitude of bottlenecks that gave rise to the formation of the different races and people groups of the world.

    Within the evolutionary theory, it seems that the existence of the different human races has been caused by having small populations. To keep these populations small, the human population is thought to have experienced many bottlenecks.

    Actually, there are papers on different peoples of the world that say the same thing. do research on this.!!!!!!!!!!!!!!!!!!!!!

    Bryan Sykes in Oxford, identified at least 33 clusters of mitochondrial DNA in modern European human populations. Because bottlenecks are thought to be the process that has caused distinct people groups to form; the research suggests that each of the 33 clusters has been produced by a separate bottleneck!

    Some who are able to stand back from the data and to ascertain the reasonableness of the model, have realize that there is a real problem.

    In this site:
    Michael Furguson executive director of the American Polymath Institute says:

    "It is beginning to appear that large modern populations having their genetic roots in small original populations is a recurring theme with us humans. This renders the more improbable explanations mentioned above untenable. An asteroid might wipe out nearly all of humanity once -- maybe. But, over and over again? No."

    The Bible suggests that it was language which produced all the people groups of the world. Initially, after the flood, people did not want to separate throughout the world. So they created a big center that would help keep them together as a civilization. But God confused their language. In the confusion, the people found those who spoke the same language and each language group then began to move from that place to some where new. So all these groups separated and migrated to all parts of the world. The language itself was the isolating feature that helped to keep all the initial groups of people separate and distinct.

    The Creation/flood model then gives a very simple explanation that fits very well with the genetic data. It does not need to have a highly improbable series of bottlenecks in order to develop the different races of man in the world.

    So we see that people after the flood remained in small groups as they separated because of the language barrier. This model fits very well with conditions that produce rapid change and speciation such as Island Speciation.

    Island Speciation: a scene for rapid speciation
    The production of random mutations in the DNA of organisms is a very slow process. 4500 or even 6000 years is an extremely short time to produce the mutations that we think we are seeing in nature. Creationists need faster change than Evolutionists.

    In the simple story of the Bible we have the elements that actually fit the evidence as seen in today's human populations. When populations are small or extremely small, a sampling error occurs. This allows for a rapid loss of variability. Each human group because they are separate and distinct from each other looses a different set of genes, thus producing the different human races. See the link above: Speciation and Origins an alternate to the Biological Revolution for details. It explores Island Speciation within the context of the global flood. The formation of the human races easily fits within this phenomenon.

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Interesting Journal Articles with abstracts if available

African origin of modern humans in East Asia: a tale of 12,000 Y chromosomes. Ke Y, Su B, Song X, Lu D, Chen L, Li H, Qi C, Marzuki S, Deka R, Underhill P, Xiao C, Shriver M, Lell J, Wallace D, Wells RS, Seielstad M, Oefner P, Zhu D, Jin J, Huang W, Chakraborty R, Chen Z, Jin L.
Science. 2001 May 11;292(5519):1151-3.
State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, 220 Handan Road, Shanghai, China.

To test the hypotheses of modern human origin in East Asia, we sampled 12,127 male individuals from 163 populations and typed for three Y chromosome biallelic markers (YAP, M89, and M130). All the individuals carried a mutation at one of the three sites. These three mutations (YAP+, M89T, and M130T) coalesce to another mutation (M168T), which originated in Africa about 35,000 to 89,000 years ago. Therefore, the data do not support even a minimal in situ hominid contribution in the origin of anatomically modern humans in East Asia.
Comment on:Science. 2001 Jul 27;293(5530):567.

Y chromosome DNA haplotyping suggests that most European and Asian men are descended from one of two males. Oakey R, Tyler-Smith C.
Genomics. 1990 Jul;7(3):325-30.
CRC Chromosome Molecular Biology Group, Department of Biochemistry, University of Oxford, United Kingdom.

Three hypervariable Y chromosome DNA loci have been analyzed in human males. The haplotypes defined allow paternal lineages to be identified. Most of these lineages fall into two groups. This indicates that the ancestry of a large proportion of the men studied can be traced back to one of two males.

Three major lineages of Asian Y chromosomes: implications for the peopling of east and southeast Asia. Tajima A, Pan IH, Fucharoen G, Fucharoen S, Matsuo M, Tokunaga K, Juji T, Hayami M, Omoto K, Horai S.
Hum Genet. 2002 Jan;110(1):80-8. Epub 2001 Nov 28.
Department of Biosystems Science, The Graduate University for Advanced Studies (Sokendai), Hayama, Kanagawa 240-0193, Japan.

DNA variation on the non-recombining portion of the Y chromosome was examined in 610 male samples from 14 global populations in north, east, and southeast Asia, and other regions of the world. Eight haplotypes were observed by analyses of seven biallelic polymorphic markers ( DYS257(108), DYS287, SRY(4064), SRY(10831), RPS4Y(711), M9, and M15) and were unevenly distributed among the populations. Maximum parsimony tree for the eight haplotypes showed that these haplotypes could be classified into four distinct lineages characterized by three key mutations: an insertion of the Y Alu polymorphic (YAP) element at DYS287, a C-to-G transversion at M9, and a C-to-T transition at RPS4Y(711). Of the four lineages, three major lineages (defined by the allele of YAP(+), M9-G, and RPS4Y-T, respectively) accounted for 98.6% of the Asian populations studied, indicating that these three paternal lineages have contributed to the formation of modern Asian populations. Moreover, phylogenetic analysis revealed three monophyletic Asian clusters, which consisted of north Asian, Japanese, and Han Chinese/southeast Asian populations, respectively. Coalescence analysis in the haplotype tree showed that the estimated ages for three key mutations ranged from 53,000 to 95,000 years, suggesting that the three lineages were separated from one another during early stages of human evolutionary history. The distribution patterns of the Y-haplotypes and mutational ages for the key markers suggest that three major groups with different paternal ancestries separately migrated to prehistoric east and southeast Asia.

The making of the African mtDNA landscape. Salas A, Richards M, De la Fe T, Lareu MV, Sobrino B, Sanchez-Diz P, Macaulay V, Carracedo A.
Am J Hum Genet. 2002 Nov;71(5):1082-111. Epub 2002 Oct 22.
Unidad de Genetica Forense, Universidad de Santiago de Compostela, Santiago de Compostela, Galicia, Spain.

Africa presents the most complex genetic picture of any continent, with a time depth for mitochondrial DNA (mtDNA) lineages >100,000 years. The most recent widespread demographic shift within the continent was most probably the Bantu dispersals, which archaeological and linguistic evidence suggest originated in West Africa 3,000-4,000 years ago, spreading both east and south. Here, we have carried out a thorough phylogeographic analysis of mtDNA variation in a total of 2,847 samples from throughout the continent, including 307 new sequences from southeast African Bantu speakers. The results suggest that the southeast Bantu speakers have a composite origin on the maternal line of descent, with approximately 44% of lineages deriving from West Africa, approximately 21% from either West or Central Africa, approximately 30% from East Africa, and approximately 5% from southern African Khoisan-speaking groups. The ages of the major founder types of both West and East African origin are consistent with the likely timing of Bantu dispersals, with those from the west somewhat predating those from the east. Despite this composite picture, the southeastern African Bantu groups are indistinguishable from each other with respect to their mtDNA, suggesting that they either had a common origin at the point of entry into southeastern Africa or have undergone very extensive gene flow since.

Paternal and maternal DNA lineages reveal a bottleneck in the founding of the Finnish population. Sajantila A, Salem AH, Savolainen P, Bauer K, Gierig C, Paabo S.
Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):12035-9.
Zoological Institute, University of Munich, Germany.

An analysis of Y-chromosomal haplotypes in several European populations reveals an almost monomorphic pattern in the Finns, whereas Y-chromosomal diversity is significantly higher in other populations. Furthermore, analyses of nucleotide positions in the mitochondrial control region that evolve slowly show a decrease in genetic diversity in Finns. Thus, relatively few men and women have contributed the genetic lineages that today survive in the Finnish population. This is likely to have caused the so-called "Finnish disease heritage"-i.e., the occurrence of several genetic diseases in the Finnish population that are rare elsewhere. A preliminary analysis of the mitochondrial mutations that have accumulated subsequent to the bottleneck suggests that it occurred about 4000 years ago, presumably when populations using agriculture and animal husbandry arrived in Finland.

Multiple origins of Tibetan Y chromosomes. Qian Y, Qian B, Su B, Yu J, Ke Y, Chu Z, Shi L, Lu D, Chu J, Jin L.
Hum Genet. 2000 Apr;106(4):453-4.
Institute of Medical Biology, The Chinese Academy of Medical Sciences, Kunming, Yunnan, China.

The genetic origin of Tibetans was investigated using Y chromosome markers. A total of three populations were studied, two from central Tibet speaking central Tibetan and one from Yunnan speaking Kham. Two dominant paternal lineages (>80%) were identified in all three populations with one possibly from central Asia (YAP+) and the other from east Asia (M122C). We conclude that Tibetan Y chromosomes may have been derived from two different gene pools, given the virtual absence of M122C in central Asia and YAP+ in east Asia, with drift an unlikely mechanism accounting for these observations

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.

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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