Molecular History Research Center


The Mitochondrial Clock Update:

Is the idea of maternal mitochondrial inheritance correct?


Initially I became interested in this topic because of the projected 6000 years that the mitochondrial Eve was recalculated to have lived in the past, using the faster mutation rate that was discovered for mitochondrial DNA. However, since then, the faster rate has been dismissed for all sorts of reasons. Because these anomalous mutation patterns go against the established phylogenetic assumptions of evolution, the mutations of the D loop have been dismissed as sequencing errors, or mutation hotspots. The truth is that no one knows the mechanism behind the mutation rate heterogeneity of mitochondrial DNA. There is presently no good satisfactory explanation from an evolutionary view, to explain the apparent mutation rate heterogeneity.

In addition to the mutation rate problem, many were against the "African Eve" or the "mitochondrial Eve" concept that the data seemed to suggest. So, many started to look for possible reasons for the increased rate of mutation. The one mechanism that seems to hold the greatest promise is recombination. Is there any paternal (from the father) mitochondrial DNA to recombine with the maternal mitochondrial DNA of the egg?

Initially, it was thought that when the sperm came to the egg, only the head with its DNA was taken into the egg (this is what I was taught concerning humans when I took embryology in college) However, on further investigation, it was found that pretty much the whole sperm was taken into the egg. Actual pictures have now been taken showing the mid section of the sperm inside the egg. Now it is known that the sperm DNA along with most of the remains of the sperm are specifically degraded by enzymes of the ubiquitin system. So while the door is open for possible recombination, apparently, it normally does not happen.

A few specific cases of patients have now been found to have mitochondrial DNA that was recombined from both their mother and father! So many are now saying that the mitochondrial genetics is more complex than we first thought. Sometimes, recombination does occur.

Other researchers have come back attacking the possibility of recombination as having any real influence in mitochondrial genetics over long periods of time. One group, even came out saying that the finding of patients with both maternal and paternal mitochondrial DNA can only be explained by human error, contamination and sample mix-up.

Many or most of these people who have recombined mitochondrial DNA are so sick that they will never have offspring. Apparently, something seriously major must have occurred to these unfortunate patients producing massive changes to their DNA and the recombination will never enter the human population.

I believe that when actual populations are studied, as they have in the scientific community, that the maternal inheritance will continue to be the rule. This view is backed up by the forensic community who continue to see maternal inheritance in their cases, and the Medical community, who keep using maternal inheritance as the source of their genetic advice to families.

View the journal articles below to see some of the actual ideas being expressed in the field.

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Interesting Journal Articles with abstracts if available


Misconceptions about mitochondria and mammalian fertilization: implications for theories on human evolution. Ankel-Simons F, Cummins JM.
Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13859-63.
Duke University Primate Center, Durham, NC 27705, USA.

In vertebrates, inheritance of mitochondria is thought to be predominantly maternal, and mitochondrial DNA analysis has become a standard taxonomic tool. In accordance with the prevailing view of strict maternal inheritance, many sources assert that during fertilization, the sperm tail, with its mitochondria, gets excluded from the embryo. This is incorrect. In the majority of mammals-including humans-the midpiece mitochondria can be identified in the embryo even though their ultimate fate is unknown. The "missing mitochondria" story seems to have survived--and proliferated-unchallenged in a time of contention between hypotheses of human origins, because it supports the "African Eve" model of recent radiation of Homo sapiens out of Africa. We will discuss the infiltration of this mistake into concepts of mitochondrial inheritance and human evolution.


Active digestion of sperm mitochondrial DNA in single living sperm revealed by optical tweezers. Nishimura Y, Yoshinari T, Naruse K, Yamada T, Sumi K, Mitani H, Higashiyama T, Kuroiwa T.
Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1382-7. Epub 2006 Jan 23.
Department of Biological Sciences, Graduate School of Science, University of Tokyo, Hongo 7-3-1, Tokyo 113-0033, Japan. yn37@cornell.edu

In almost all eukaryotes, mitochondrial (mt) genes are transmitted to progeny mainly from the maternal parent. The most popular explanation for this phenomenon is simple dilution of paternal mtDNA, because the paternal gametes (sperm) are much smaller than maternal gametes (egg) and contribute a limited amount of mitochondria to the progeny. Recently, this simple explanation has been challenged in several reports that describe the active digestion of sperm mtDNA, down-regulation of mtDNA replication in sperm, and proteolysis of mitochondria triggered by ubiquitination. In this investigation, we visualized mt nucleoids in living sperm by using highly sensitive SYBR green I vital staining. The ability to visualize mt nucleoids allowed us to clarify that the elimination of sperm mtDNA upon fertilization is achieved through two steps: (i) gradual decrease of mt nucleoid numbers during spermatogenesis and (ii) rapid digestion of sperm mtDNA just after fertilization. One notable point is that the digestion of mtDNA is achieved before the complete destruction of mitochondrial structures, which may be necessary to avoid the diffusion and transmission of potentially deleterious sperm mtDNA to the progeny.


The sperm mitochondria-specific translocator has a key role in maternal mitochondrial inheritance. Hayashida K, Omagari K, Masuda JI, Hazama H, Kadokawa Y, Ohba K, Kohno S.
Cell Biol Int. 2005 Jun 23; [Epub ahead of print]
Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki 852-8501, Japan.

The mechanism of maternal mitochondrial inheritance in animals involves the selective elimination of sperm mitochondria by the elimination factor of the egg and the sperm mitochondria-specific factor. In vitro fertilization using sperm from isogenic mice incorporating heterospecific mitochondrial DNA (mtDNA) showed that the number of PCR positives of sperm mtDNA in two-cell embryos was significantly increased following sperm incubation with anti-tetratricopeptide repeat-containing protein involved in spermatogenesis (tpis) protein, anti-translocator of mitochondrial outer membrane (Tom) 22 and anti-Tom40 antibodies. The treatment of fertilized eggs with EGTA and other endonuclease inhibitors increased the sperm mtDNA levels. We conclude that the elimination factor, which is probably an endonuclease, is selectively received by the tpis protein of the sperm mitochondrial outer membrane within the egg. It is then transported into the sperm mitochondria by Tom22 and Tom40, where it destroys the sperm mtDNA, establishing the maternal inheritance of mtDNA.


Evolutionary genetics. Clonal inheritance of avian mitochondrial DNA. Berlin S, Ellegren H.
Nature. 2001 Sep 6;413(6851):37-8.
Department of Evolutionary Biology, Evolutionary Biology Centre, Uppsala University, Norbyvagen 18D, SE-752 36, Uppsala, Sweden.

We have taken a new approach to test the commonly accepted, but recently questioned, principle of clonal inheritance of vertebrate mitochondrial DNA (mtDNA) by relating its inheritance to a female-specific marker of nuclear DNA. Whereas this is impossible in organisms with male heterogamy (such as mammals), we show here that genealogies of mtDNA and the female-specific W chromosome of a bird species are completely concordant. Our results indicate that inheritance of mtDNA is free of detectable recombination effects over an evolutionary timescale.


The incomplete natural history of mitochondria. Ballard JW, Whitlock MC.
Mol Ecol. 2004 Apr;13(4):729-44.
Department of Biological Sciences, University of Iowa, Iowa City, Iowa 52242, USA.

Mitochondrial DNA (mtDNA) has been used to study molecular ecology and phylogeography for 25 years. Much important information has been gained in this way, but it is time to reflect on the biology of the mitochondrion itself and consider opportunities for evolutionary studies of the organelle itself and its ecology, biochemistry and physiology. This review has four sections. First, we review aspects of the natural history of mitochondria and their DNA to show that it is a unique molecule with specific characteristics that differ from nuclear DNA. We do not attempt to cover the plethora of differences between mitochondrial and nuclear DNA; rather we spotlight differences that can cause significant bias when inferring demographic properties of populations and/or the evolutionary history of species. We focus on recombination, effective population size and mutation rate. Second, we explore some of the difficulties in interpreting phylogeographical data from mtDNA data alone and suggest a broader use of multiple nuclear markers. We argue that mtDNA is not a sufficient marker for phylogeographical studies if the focus of the investigation is the species and not the organelle. We focus on the potential bias caused by introgression. Third, we show that it is not safe to assume a priori that mtDNA evolves as a strictly neutral marker because both direct and indirect selection influence mitochondria. We outline some of the statistical tests of neutrality that can, and should, be applied to mtDNA sequence data prior to making any global statements concerning the history of the organism. We conclude with a critical examination of the neglected biology of mitochondria and point out several surprising gaps in the state of our knowledge about this important organelle. Here we limelight mitochondrial ecology, sexually antagonistic selection, life-history evolution including ageing and disease, and the evolution of mitochondrial inheritance.


Do avian mitochondria recombine? Berlin S, Smith NG, Ellegren H.
J Mol Evol. 2004 Feb;58(2):163-7.
Department of Evolutionary Biology, Evolutionary Biology Centre, Uppsala University, Norbyvagen 18D, 752 36 Uppsala, Sweden. Sofia.Berlin@ebc.uu.se

The dogma of strict maternal inheritance of mitochondria is now being tested with population genetics methods on sequence data from many species. In this study we investigated whether recombination occurs in the mitochondria of the blue tit ( Parus caeruleus) by studying polymorphisms in the mitochondrial control region and in a recently identified (A)(n) microsatellite on the W chromosome. The female heterogamety of avian sex chromosomes allows a test of whether mitochondrial recombination affects genealogical inference by comparison of mitochondrial and W-linked sequence variation. There is no discrepancy between mitochondrial and W-linked genealogies in blue tits, consistent with no recombination. We also analyzed mitochondrial sequence variation in both blue tits and peregrine falcons ( Falco peregrinus) using a coalescent-based approach which accounts for recurrent mutation; in neither bird species did we find evidence of recombination. We conclude that it is unlikely that mitochondrial recombination has large effects on mitochondrial genetic variability in birds.


Degradation of paternal mitochondria after fertilization: implications for heteroplasmy, assisted reproductive technologies and mtDNA inheritance. Sutovsky P, Van Leyen K, McCauley T, Day BN, Sutovsky M.
Reprod Biomed Online. 2004 Jan;8(1):24-33.
Department of Animal Science, University of Missouri-Columbia, MO, USA. SutovskyP@missouri.edu

Maternal inheritance of mitochondrial DNA has long been regarded as a major paradox in developmental biology. While some confusion may still persist in popular science, research data clearly document that the paternal sperm-borne mitochondria of most mammalian species enter the ooplasm at fertilization and are specifically targeted for degradation by the resident ubiquitin system. Ubiquitin is a proteolytic chaperone that forms covalently linked polyubiquitin chains on the targeted proteinaceous substrates. The polyubiquitin tag redirects the substrate proteins to a 26-S proteasome, a multi-subunit proteolytic organelle. Thus, specific proteasomal inhibitors reversibly block sperm mitochondrial degradation in ooplasm. Lysosomal degradation and the activity of membrane-lipoperoxidating enzyme 15-lipoxygenase (15-LOX) may also contribute to sperm mitochondrial degradation in the ooplasm, but probably is not crucial. Prohibitin, the major protein of the inner mitochondrial membrane, appears to be ubiquitinated in the sperm mitochondria. Occasional occurrence of paternal inheritance of mtDNA has been suggested in mammals including humans. While most such evidence has been widely disputed, it warrants further examination. Of particular concern is the documented heteroplasmy, i.e. mixed mtDNA inheritance after ooplasmic transplantation. Intracytoplasmic sperm injection (ICSI) has inherent potential for delaying the degradation of sperm mitochondria. However, paternal mtDNA inheritance after ICSI has not been documented so far.


Paternal transmission of mitochondrial DNA is (fortunately) rare. Johns DR.
Ann Neurol. 2003 Oct;54(4):422-4.
Comment Editorial Comment on: Next two papers:


Genotypes from patients indicate no paternal mitochondrial DNA contribution. Taylor RW, McDonnell MT, Blakely EL, Chinnery PF, Taylor GA, Howell N, Zeviani M, Briem E, Carrara F, Turnbull DM.
Ann Neurol. 2003 Oct;54(4):521-4.
School of Neurology, Neurobiology and Psychiatry, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom.

A cornerstone of mitochondrial genetics, strict maternal inheritance, has been challenged recently by the study of a patient with mitochondrial myopathy due to a sporadic 2bp deletion. The mitochondrial DNA (mtDNA) harboring the mutation was paternal in origin, whereas the patient's blood was identical to the maternal genotype. To determine whether this is a common phenomenon, we studied mtDNA sequence variation between muscle and blood from 35 patients with sporadic mitochondrial myopathies, but detected no evidence of paternal mtDNA transmission. Our findings suggest that paternal transmission of mtDNA is rare and should not alter our genetic advice to families.


Lack of paternal inheritance of muscle mitochondrial DNA in sporadic mitochondrial myopathies. Filosto M, Mancuso M, Vives-Bauza C, Vila MR, Shanske S, Hirano M, Andreu AL, DiMauro S.
Ann Neurol. 2003 Oct;54(4):524-6.
Department of Neurology, Columbia University College of Physicians and Surgeons, New York, NY, USA.

In 2002, paternal inheritance of muscle mitochondrial DNA (mtDNA) was reported in a patient with exercise intolerance and a mitochondrial DNA (mtDNA) mutation restricted to skeletal muscle. To evaluate whether paternal inheritance is a common phenomenon, we studied 10 sporadic patients with skeletal muscle-restricted mtDNA mutations: five harbored mtDNA point mutations in protein-coding genes and five had single mtDNA deletions. We performed haplotype analysis and direct sequencing of the hypervariable regions 1 and 2 of the D-loop in muscle and blood from the patients and, when available, in blood from their parents. We did not observe paternal inheritance in any of our patients.


Death to sperm mitochondria. Hopkin K.
Sci Am. 1999 Mar;280(3):21.
News


Can mitochondrial clocks keep time? Strauss E.
Science. 1999 Mar 5;283(5407):1435, 1437-8.
News


Recombination or mutation rate heterogeneity? Implications for Mitochondrial Eve. Hagelberg E.
Trends Genet. 2003 Feb;19(2):84-90.
Biology Dept, University of Oslo, PO Box 1050 Blindern, N-0316, Oslo, Norway. erika.hagelberg@bio.uio.no

The study of mitochondrial DNA (mtDNA) has helped to demonstrate the African origin of our species and the relationship between living humans and the Neanderthals. mtDNA data have also been used to establish the time and route of major events in human history, such as the expansion of Neolithic farmers into Europe, and the settlement of the Pacific and the New World. However, it is becoming apparent that mtDNA evolution is more complex than previously believed. Anomalous mutation patterns perturb phylogenetic assumptions based on mtDNA data. Although they are frequently dismissed as sequencing errors or mutation hotspots, some of the anomalies have no satisfactory explanation. The mechanisms behind apparent mutation rate heterogeneity, or even possible mtDNA recombination, remain unknown. These issues need to be addressed, as they have profound consequences for the interpretation of mtDNA data.


More evidence for non-maternal inheritance of mitochondrial DNA? Bandelt HJ, Kong QP, Parson W, Salas A.
J Med Genet. 2005 May 27; [Epub ahead of print]
Dept. of Mathematics, University of Hamburg, Germany.

A single case of paternal co-transmission of mitochondrial DNA (mtDNA) in humans has been reported so far. METHODS: To find potential instances of non-maternal inheritance of mtDNA we searched published medical case studies (of single patients) for irregular mtDNA patterns by contrasting the given haplotype information for different clones or tissues to the worldwide mtDNA database as known to date - a method that has proven to be robust and reliable for the detection of flawed mtDNA sequence data. RESULTS: We found more than 20 studies reporting clear-cut instances with mtDNAs of different ancestries in single individuals. By way of example, we reviewed here a few cases from the recent medical literature, which, at face value, might therefore be taken as evidence for paternal inheritance of mtDNA or recombination. CONCLUSIONS: Multiple types (or recombinant types) of quite dissimilar mitochondrial DNA, from different parts of the known mtDNA phylogeny, are frequently reported in single individuals. In view of re-analyses and corrigenda of forensic mtDNA data, however, we assert that the phenomenon of mixed or mosaic mtDNA can solely be ascribed to contamination and sample mix-up.


Recombination of human mitochondrial DNA. Kraytsberg Y, Schwartz M, Brown TA, Ebralidse K, Kunz WS, Clayton DA, Vissing J, Khrapko K.
Science. 2004 May 14;304(5673):981.
Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.


New patterns of inheritance in mitochondrial disease. Review Schwartz M, Vissing J.
Biochem Biophys Res Commun. 2003 Oct 17;310(2):247-51.
Department of Clinical Genetics, National University Hospital, Rigshospitalet, Copenhagen, Denmark. schwartz@rh.dk

With the identification of a patient with mutated mitochondrial DNA (mtDNA) of paternal origin, it has been unequivocally proven that not only does paternal mtDNA survive in the zygote, but it can also contribute substantially to the mtDNA pool of adult, human skeletal muscle. The questions are: how often does paternal mtDNA inheritance occur and what mechanisms are involved? In this paper, we will review current knowledge on the fate of sperm mitochondria after fertilization and discuss the impact paternal inheritance may have on our understanding of mitochondrial biology.


Paternal inheritance of mitochondrial DNA. Schwartz M, Vissing J.
N Engl J Med. 2002 Aug 22;347(8):576-80.
Department of Clinical Genetics, University Hospital Rigshospitalet, Copenhagen, Denmark. schwartz@rh.dk.

Mammalian mitochondrial DNA (mtDNA) is thought to be strictly maternally inherited. Sperm mitochondria disappear in early embryogenesis by selective destruction, inactivation, or simple dilution by the vast surplus of oocyte mitochondria. Very small amounts of paternally inherited mtDNA have been detected by the polymerase chain reaction (PCR) in mice after several generations of interspecific backcrosses. Studies of such hybrids and of mouse oocytes microinjected with sperm support the hypothesis that sperm mitochondria are targeted for destruction by nuclear-encoded proteins. We report the case of a 28-year-old man with mitochondrial myopathy . . .
Comment in: Next three papers


Another surprise from the mitochondrial genome. Williams RS.
N Engl J Med. 2002 Aug 22;347(8):609-12.

Advances in the field of mitochondrial genetics have challenged the general principles of molecular biology on several occasions. The universality of the genetic code that relates triplet-nucleotide sequences in DNA to specific amino acids in proteins was overturned by the discovery that the translation of mitochondrial proteins involves different coding rules.1 Studies of mitochondria led to the surprising discoveries of autocatalytic RNA (RNA with enzymatic activity in the absence of proteins), RNA editing (post-transcriptional modification of the nucleotide sequence in messenger RNA [mRNA]), and trans-splicing (the joining of two separate primary RNA transcripts to form a single mRNA molecule).. . .


Paternal inheritance of mitochondrial DNA. Heckerling PS.
N Engl J Med. 2002 Dec 19;347(25):2081-2; author reply 2081-2.


Paternal inheritance of mitochondrial DNA. Gustafson AW.
N Engl J Med. 2002 Dec 19;347(25):2081-2; author reply 2081-2.


Recombination in animal mitochondrial DNA. Smith JM, Smith NH.
Mol Biol Evol. 2002 Dec;19(12):2330-2.

Previous attempts to demonstrate, or refute, the occurrence of recombination in mitochondria have used tests designed to measure relatively frequent recombination between rather similar sequences: for example, the homoplasy test (Maynard Smith and Smith 1998 ) and the regression of linkage disequilibrium between pairs of loci with distance along the chromosome (Awadalla, Eyre-Walker, and Maynard Smith 1999 ). Recently, Ladoukakis and Zouros (2001 ; subsequently LZ) have attempted to demonstrate rare recombination events between sequences differing at 10% or more of nucleotides. The aim of this note is, first, to evaluate the statistical support for their conclusion and, second, briefly to discuss its significance.


Do mitochondria recombine in humans? Eyre-Walker A.
Philos Trans R Soc Lond B Biol Sci. 2000 Nov 29;355(1403):1573-80.
Centre for the Study of Evolution and School of Biological Sciences, University of Sussex, Brighton, UK. a.c.eyre-walker@sussex.ac.uk

Until very recently, mitochondria were thought to be clonally inherited through the maternal line in most higher animals. However, three papers published in 2000 claimed population-genetic evidence of recombination in human mitochondrial DNA. Here I review the current state of the debate. I review the evidence for the two main pathways by which recombination might occur: through paternal leakage and via a mitochondrial DNA sequence in the nuclear genome. There is no strong evidence for either pathway, although paternal leakage seems a definite possibility. However, the population-genetic evidence, although not conclusive, is strongly suggestive of recombination in mitochondrial DNA. The implications of non-clonality for our understanding of human and mitochondrial evolution are discussed.
Review, Tutorial


Human mitochondrial DNA recombination: can it be true? Hey J.
Trends Ecol Evol. 2000 May;15(5):181-182.
Dept of Genetics, Rutgers University, Nelson Biological Labs, 604 Allison Road, Piscataway, NJ 08854-8082, USA.


Can paternal mtDNA be inherited? Morris AA, Lightowlers RN.
Lancet. 2000 Apr 15;355(9212):1290-1.
Department of Child Health, Royal Victoria Infirmary, University of Newcastle upon Tyne, UK.


Failure of elimination of paternal mitochondrial DNA in abnormal embryos. St John J, Sakkas D, Dimitriadi K, Barnes A, Maclin V, Ramey J, Barratt C, De Jonge C.
Lancet. 2000 Jan 15;355(9199):200.

Paternal mitochondrial DNA is normally eliminated from mammalian embryos. We have shown the presence of paternal mtDNA at the blastocyst stage in some abnormal human embryos.
Letter


Human genetics. mtDNA shows signs of paternal influence Strauss E.
Science. 1999 Dec 24;286(5449):2436.
Comment - News


Linkage disequilibrium and recombination in hominid mitochondrial DNA. Awadalla P, Eyre-Walker A, Smith JM.
Science. 1999 Dec 24;286(5449):2524-5.
Institute of Cell, Animal and Population Biology, University of Edinburgh, Edinburgh EH9 1JT, UK.

The assumption that human mitochondrial DNA is inherited from one parent only and therefore does not recombine is questionable. Linkage disequilibrium in human and chimpanzee mitochondrial DNA declines as a function of the distance between sites. This pattern can be attributed to one mechanism only: recombination.
Comment


Mitochondrial recombination? Arctander P.
Science. 1999 Jun 25;284(5423):2090-1.
Comment - Letter


Mitochondrial DNA inheritance. Zouros E, Ball AO, Saavedra C, Freeman KR.
Nature. 1994 Apr 28;368(6474):818.
Letter


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Officially posted August 22, 2005
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