The Mitochondrial Clock:
Introduction to the Mitochondrial Eve story. Is it true that scientist have found the mother of us all? There are two opposing view points on the history of mankind. The Mitochondrial Eve story seems to support the "Out-of-Africa" viewpoint, while those who hold the "multi-regional continuity" theory, continue to point out the problems in the Eve research.
Is the Mitochondrial Clock speed faster than we thought? Some have calculated that the "mitochondrial Eve" probably lived 100,000 to 200,000 years ago in Africa. However it has been found that mtDNA can experience a much faster mutation rate. Using this faster mutation rate as a new clock speed, Eve can be calculated as living a mere 6500 or 6000 years ago.
A continuation of the Mitochondrial Eve story. Is the clock speed still faster than we thought? Is the idea of maternal mitochondrial inheritance correct? Or is the evidence for Recombination and Paternal inheritance of mitochondrial DNA a convincing argument? How dependable is the sperm mitochondria-specific translocator in destroying the sperm mitochondria DNA and establishing the maternal inheritance of mtDNA?
Is there a Creationary model that would allow the mitochondrial Eve and the mitochondrial clock data to fit and agree with the "multi-regional continuity" data involving Homo erectus?
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. email@example.com
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.
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
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