Biochimica et Biophysica Acta 1797 (2010) 1099–1104
Contents lists available at ScienceDirect
Biochimica et Biophysica Acta
j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / b b a b i o
Review
Evolution and disease converge in the mitochondrion
D. Mishmar ⁎, I. Zhidkov
a
b
Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
National Institute of Biotechnology in the Negev (NIBN), Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
a r t i c l e
i n f o
Article history:
Received 16 November 2009
Received in revised form 31 December 2009
Accepted 7 January 2010
Available online 13 January 2010
Keywords:
Disease
Evolution
Mitochondria
Mitochondrial DNA (mtDNA)
Mutation rate
Variant
Haplogroup
a b s t r a c t
Mitochondrial DNA (mtDNA) mutations are long known to cause diseases but also underlie tremendous
population divergence in humans. It was assumed that the two types of mutations differ in one major trait:
functionality. However, evidence from disease association studies, cell culture and animal models support
the functionality of common mtDNA genetic variants, leading to the hypothesis that disease-causing
mutations and mtDNA genetic variants share considerable common features. Here we provide evidence
showing that the two types of mutations obey the rules of evolution, including random genetic drift and
natural selection. This similarity does not only converge at the principle level; rather, disease-causing
mutations could recapitulate the ancestral DNA sequence state. Thus, the very same mutations could either
mark ancient evolutionary changes or cause disease.
© 2010 Elsevier B.V. All rights reserved.
1. Introduction
The emergence of new species is a result of interplay between
genetics and environment. Intuitively, the genetic material in the form
of nucleic acids (DNA and/or RNA) should change in reaction to this
interplay. However, concomitantly, the genetic material has to be
well-protected from changes, since it encodes multiple factors that act
in concert to ensure proper embryo development. Nevertheless,
during the past ∼ 3 billion years of life on earth, environmental
conditions changed dramatically multiple times, and many organisms
which were adapted to those ancient environments could no longer
sustain life and reproduce. If those environmental changes were not
accompanied by genetic adaptations, mass extinctions would eventually lead to the eradication of life. Since this obviously did not
happen, and since mass extinctions indeed occurred many times
during our planet's history, it is imperative to assume that new life
always emerged from the ashes like the legendary phoenix. The main
difference from the legend is that the survival of life forms despite
extinctions was most likely not due to magic, but because of the ability
to adapt to changes, that, following Charles Darwin's theory [1], lies in
the basis of the very existence of genetic diversity. Such diversity
provides a large enough repertoire of mutations to cope with multiple
possible environmental conditions, and enable the survival of the
⁎ Corresponding author. Department of Life Sciences, Building 40, Room 005, Ben-Gurion
University of the Negev, Beer-Sheva 84105, Israel. Tel.: +972 8 6461355; fax: +972
8 6461356.
E-mail address: [email protected] (D. Mishmar).
0005-2728/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.bbabio.2010.01.003
fittest. Therefore, it is only reasonable that organisms that could
survive environmental changes are those that either could cope with
a wide variety of environments, or those that had the capacity to
go through genetic alterations and adaptations. Indeed, the more
specialized the organism, the harder it is to adapt to the changing
environments. Therefore, environmental changes are likely to be
associated with the appearance of diseases in complex organisms
that did not harbor the capacity to allow well being in the new
environmental conditions.
Although the above discussion constitutes a simplistic summary of
the principles that govern the dynamic history of life on earth, one
could logically find correlations between the appearance of many
complex disorders in man today and ancient environmental changes
during human evolution. It is therefore no wonder that the emergence
of several infectious diseases correlates with the appearance of human
sedentary life-style and the increase of human population density [2].
Likewise, the appearance of age-related diseases correlates with the
two-fold extended life span in modern human populations from the
mean age of ∼35 years during the Paleolithic era [3] to over 70 today
[4].
Unlike other complex disorders, age-related disorders such as
Alzheimer's and Parkinson's diseases cannot be easily removed from
the human population by natural selection, as their onset occurs many
years after reproductive age. It may well be, that the genetic landscape
of human populations during ancient times harbored genetic variants
that allowed, and even played a role, in human survival in different
environmental conditions, but today act as disease susceptibility
factors. This is the logic that lies in the basis of the ‘common disease-
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D. Mishmar, I. Zhidkov / Biochimica et Biophysica Acta 1797 (2010) 1099–1104
common variant’ approach to investigating the genetic basis of
complex disorders [5]. An excellent example for this is the ‘thrifty
genotype’ hypothesis explaining the high prevalence of metabolic
disorders in modern times [6]. According to this hypothesis, during
ancient times when food was less available, selection acted towards
efficient energy-producing genotypes. When these genotypes encountered the prosperity and food availability of the western world
today, they conferred increased tendency towards obesity and
diabetes [6]. This led us to the hypothesis that the genetic changes
underlying fundamental evolutionary processes, such as local adaptations, natural selection and the emergence of new species, follow a
very similar scheme and obey the same rules as disease-causing
mutations. These principles could be so similar, that the very same
mutations could either cause disease or allow adaptation to certain
environmental factors, such as in the classic case of sickle cell anemia
and the resistance to malaria [7]. Moreover, while considering
disease-causing mutations, it is clear that only a subset of the genetic
alterations allow survival of the embryo to term, whereas the rest are
negatively selected and are abolished via natural miscarriages.
Similarly, mutations that comprise human genetic variation today
constitute population-fixed (and hence common) variants that
survived long term evolutionary processes, but also rare un-fixed
variants that have yet to face natural selection.
In this perspective, we discuss the similarities rather than obvious
differences between the genetic characteristics and evolutionary
schemes of disease-causing mutations versus genetic variants in
humans. We focus on a single genetic system that played central roles
both in human evolution and in various complex disorders — the
mitochondrial energy-producing system, oxidative phosphorylation
(OXPHOS).
2. The unique mitochondrial genetic system
Unlike most eukaryotic cellular systems, mitochondrial functions
are encoded by two genomes that notably differ in their mutation
rates and their mode of inheritance. Whereas most of the ∼ 1500
genes encoding mitochondrial functions are located in the nuclear
genome (nDNA), 37 are encoded by the maternally inherited
mammalian mitochondrial genome (mtDNA). Of these, seven encode
subunits of NADH ubiquinone oxidoreductase (complex I, ND1–ND6,
ND4L), one encodes a subunit of cytochrome bc1 oxidase (complex III,
cytb), three encode subunits of cytochrome c oxidase (complex IV,
CO1–3), two encode subunits of F1–F0 ATP synthase (complex V,
ATP6 and 8), 22 encode tRNAs and two rRNA genes (12S and 16S). As
previously discussed, since animal mtDNA evolves at least an order of
magnitude faster than the nDNA [8], tight co-evolution between
nDNA and mtDNA-encoded genes should occur to maintain mitochondrial structure and function (Reviewed by [9,10]). Mutations
occurring in the mtDNA are transferred to the next generation in a
haploid manner, because of its maternal mode of inheritance.
Inheritance of mtDNA mutations from generation to generation
depends on the percentage of mutant mitochondria in the fertilized
egg: at first, the mutated mtDNA is harbored by only a small portion of
cellular mitochondria (heteroplasmy). In time, however, it could
reach fixation in the germline, mostly via a severe bottleneck
involving the random unbalanced partition of the cytoplasm during
cell divisions (replicative segregation) in gamete formation, as well as
over generations. Moreover, the severe bottleneck that reduces the
effective population size of mitochondria occurs in the female
precursor germ cells, resulting in the reduction of mitochondrial
population from tens of thousands to ∼200, thus improving the odds
of low-prevalence mutations to reach fixation [11,12]. The apparently
stochastic nature of this mutation fixation process could be altered
when the mutation has an evolutionary advantage. Such is the case of
large mtDNA deletions in somatic tissues, that on the one hand reduce
essential gene content and cause disease, but on the other hand create
smaller circular mtDNA which replicates faster than the full length
mtDNA [13]. In addition, it has been suggested that the shift from
heteroplasmy to homoplasmy of mtDNA mutations in nasopharyngeal
oncocytic tumors could be due to selective advantages accompanying
the oncocytic transformation [14]. The established pathological
mtDNA mutations T8993C and T9176C, which cause Neuropathy,
Ataxia and Retinitis Pigmentosa (NARP), conferred advantage in
tumor growth in nude mice [15,16]. It is worth noting that it is not
clear whether the increase of heteroplasmy level in these mutations
over generations is due to some sort of selective advantage or just
random genetic drift [17]. Taken together, as will be discussed below,
these evidence support the hypothesis that both disease-causing
mutations and mtDNA genetic variants respond to genetic drift as well
as to negative or positive selection, thus underlining their functional
similarity.
3. Mitochondrial–nuclear interactions in disease and evolution
Mitochondrial (mito)–nuclear genetic interactions were suggested
to play a crucial role in adaptation as well as the creation of
reproductive barriers [9,10,18]. In evolutionary time scale, multiple
pieces of evidence exemplify that disruption of mito–nuclear interactions cause reduction in mitochondrial activity. Accordingly,
nuclear transfer in cattle or cytoplasmic hybrid (cybrid) experiments
in primates or rodents, which introduce the mtDNA from one species
into cells harboring the nDNA from another species of the same genus
[19–22], result in reduced mitochondrial activity. Similarly, altered
mitochondrial activity was observed in cybrid experiments in
humans, introducing mtDNAs into cells harboring the nuclear genome
from different populations [23–25] as well as in backcross experiments in Drosophila, wasps, rats and the copepod Tigriopus californicus
[26–29]. The mentioned backcross experiments also described
reduced fitness in the inter-population hybrids. Hence the tight
mito–nuclear co-evolution occurs not only at the species level, but
could also lie in the basis of reduced fitness and hybrid breakdown in
inter-population crosses [9,30–32]. It is therefore conceivable that
mito–nuclear interactions could be important in maintaining mitochondrial structure and function within the human species. Indeed,
pathological mutations causing Leber's Hereditary Optic Neuropathy
(LHON) [25], complex I-specific neurodegenerative disease [33] or
Leigh syndrome [34] affect the assembly of OXPHOS complexes by
interfering with the interaction between mtDNA and nDNA-encoded
subunits. It is therefore conceivable that mito–nuclear interactions
play a role not only in evolutionary processes but also in disease.
Despite this similarity, it is yet to be determined whether disrupting
the evolutionary scheme of co-evolving amino acid positions in
interacting mtDNA and nuclear DNA-encoded factors cause disease.
4. Disease-causing mutations and genetic variants in the mtDNA,
and their cross-talk with evolutionary forces
If the same evolutionary principles govern the dynamics of
disease-causing mutations and common mtDNA genetic variants,
several predictions emerge: (A) disease-causing mutations could be
subjected to both negative and positive selection, (B) both diseasecausing mutations and common genetic variants could respond to
genetic drift, (C) mutations defining mtDNA genetic backgrounds play
a role both in human response to different environmental conditions
and in disease susceptibility, and (D) at least a subset of the mtDNA
genetic variants should be functional. Indeed, all predictions are
supported by evidence from real life.
More than a hundred disease-causing mutations have been
described in the human mitochondrial genome [35]. Some of these
mutations result in early onset whereas others cause late onset
disorders, which are mostly systemic and thus affect many tissue
types [35]. Of these mutations, most occur in highly conserved
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nucleotide positions within the mtDNA coding region, consistent with
their functionality [36]. These mutations can be insertions, deletions
or point mutations, which cause diseases in different levels of
heteroplasmy, i.e. deletions and insertions (generally speaking)
could cause disease while inhabiting less than 60% of cellular
mitochondria, whereas many point mutations will cause diseases
only when their cellular level reaches around 100% [37]. Since
disease-causing mutations could, by definition, reduce fitness, the
apparent repertoire of disease-causing mutations is only a subset of
the actual mutation rate. Indeed this logic applies to chromosomal
aberrations, of which only a subset are found in fetuses whereas the
vast majority are found in spontaneous abortions [38]. It is yet to be
assessed whether the same logic applies to mtDNA mutations, namely
that mtDNA disease-causing mutations represent those that are
compatible with life and hence are only a subset of all generated
mtDNA mutations.
Indeed, it is only reasonable that most disease-causing mutations
are negatively selected, i.e. do not become fixed in the population.
However, the action of adaptive selection on disease-causing mutations is far less trivial, as they have to confer some sort of evolutionary
advantage. Although such an effect was not clearly demonstrated in
people carrying mtDNA disease-causing mutations, there is evidence
for differential functionality of mtDNA disease-causing mutations in
different populations. Mutations causing Leber's hereditary optic
neuropathy (LHON) result in disease with varying severity depending
on the mtDNA genetic background (haplotype, haplogroup) they
occur on [39,40]. Specifically, certain LHON-causing mtDNA mutations
may result in blindness, depending on whether they have occurred in
combination with the mtDNA haplogroup J [41]. Moreover, the 14484
LHON mutation is associated only with haplogroup J, implying
possible advantage for its survival in combination with this mtDNA
genetic background [42]. Similarly, haplogroup U patients with large
mtDNA deletions show altered phenotypic severity [43]. These data
not only imply of the existence of genetic modifiers modulating the
expression of a mitochondrial disorder, but also could reflect the
action of selective forces in favor of the survival of some mtDNA
disease-causing mutations under certain conditions. A clearer positive
selection effect for mtDNA disease-causing mutations has been
demonstrated in cancer, where the NARP-causing mtDNA mutations
C8993T and C9176T grew exceedingly faster as compared to wild type
mtDNAs, and caused faster growing tumors in nude mice [15,16].
Since cancer was previously referred to as an evolutionary process
obeying Darwinian principles [44], one could interpret the growth
advantage of the mtDNA disease-causing mutations as reflecting an
adaptive value of these mutations, namely positive selection. Thus
disease-causing mutations respond both to negative and possibly
positive selection at least at the cellular level. It is important to note,
that advantage conferred at the population level was not observed for
mtDNA disease-causing mutations. In the case of mtDNA genetic
variants, both negative and positive selection has been previously
discussed [45]. Evidence for negative selection has been reflected in
significantly reduced genetic variation within some mtDNA-encoded
genes, and in the fact that most non-synonymous mtDNA variants are
rare variants that still did not endure the effects of selection [46]. The
action of positive (adaptive) selection has been demonstrated in
human mtDNA variants [36,47,48]. Our rigorous analysis of whole
mtDNAs from all major global populations has shown that human
mtDNA genetic variation was shaped by both negative and positive
selection [36,47,48], and that mtDNA genetic variation played a role as
humans migrated from the warm climates of Africa to populate the
considerably colder northern hemisphere. In summary, natural
selection, certainly negative but possibly also positive selection, has
left its mark in the pattern of global mtDNA genetic variation and
possibly affected mtDNA disease-causing mutations.
It is widely accepted that population dynamics during the course
of time has affected allele frequencies in different populations, largely
1101
due to the effect of genetic drift [49]. Interestingly, genetic drift also
affects the prevalence of disease-causing mutations. Apparently most
mtDNA disease-causing mutations are rare, segregate among families,
and arise independently and repeatedly in combination with
phylogenetically distant genetic backgrounds. These characteristics
support strong negative selection against the fixation of these
mutations. However, disease-causing mutations are also subjected
to genetic drift. Although many of them first appear in a heteroplasmic state, they can eventually dominate the mitochondrial
population in the cell (homoplasmic state) due to replicative
segregation, namely due to the random division of the cytoplasm
during cell division [17,50]. Such replicative segregation during cell
division is frequently compared to the population-based genetic drift.
Thus, the dynamics of both mtDNA disease-causing mutations and
mtDNA genetic variants respond to random population dynamics and
founder effects (Fig. 1).
Similarly to disease-causing mutations, multiple studies support
the functionality of mtDNA genetic variants. Firstly, mtDNA genetic
backgrounds (haplogroups) have been repeatedly associated with
altered susceptibility to various complex phenotypes including
Parkinson's disease [51–56], type 2 diabetes and its complications
[57–60], endurance athletics [61–63], various cardiovascular disorders [64–67], age-related macular degeneration [68–70], altered
plasma lipid and cholesterol levels [71–73], schizophrenia [74,75],
various types of cancer [76–78], human sperm motility [79–81], and
successful aging [82–86]. It is worth noting that the high population
divergence of mtDNA [87], and its close interplay with nDNA-encoded
and environmental factors have resulted in the questioning of some of
these associations [88–90]. Careful inspection of these studies reveals
associations of certain haplogroups, such as haplogroup J and T in
Europeans and haplogroup D in Asians, with multiple phenotypes,
suggesting that these genetic backgrounds harbor functional mutations. Secondly, a comparison of cytoplasmic hybrids (cybrids)
sharing the same nucleus but differing in their mtDNA genetic
backgrounds showed differences in mitochondrial function, reflected
by calcium uptake [23], the production of reactive oxygen species
(ROS) [24] and the degree of resistance to apoptosis [91]. Thirdly, we
have shown that a genetic variant defining haplogroup J in the mtDNA
control region (C295T), which is not present in any other human
lineage, altered the rate of in vitro transcription and consistently
altered mtDNA copy number in cybrids carrying this variant as
compared to cybrids with haplogroup H [92]. Therefore, common
mtDNA variants and disease-causing mutations are not only subjected
to similar selective forces at the population level, but both lead to
functional consequences, explaining their appearance on the ‘radar
screen’ of natural selection.
5. Recurrence of mtDNA ancient variants in the wrong genetic
context could result in disease
So far we have demonstrated the similarity in the action of
evolutionary forces on disease-causing mutations and mtDNA genetic
variants. We also presented evidence from disease association studies
and cell culture experiments supporting that at least a portion of
haplogroup-defining mutations have functional properties. It follows
that the recurrence of ancient variants as de novo mutations on the
existent genetic background could be associated with disease. Indeed,
as mentioned above, since nDNA and mtDNA-encoded factors tightly
co-evolve, it is not surprising that the presence of mtDNA from a given
species in the nuclear genetic background of another species results in
altered mitochondrial function. However, what happens if mtDNA
haplogroup-defining mutations occur as de novo mutations in the
context of distantly related mtDNA genetic backgrounds? To test such
a hypothesis, we chose to use tissue samples in which the mtDNA
mutation rate is significantly increased, and many de novo mtDNA
mutations accumulate. Such is the situation in various cancer types
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D. Mishmar, I. Zhidkov / Biochimica et Biophysica Acta 1797 (2010) 1099–1104
Fig. 1. Similarity in the dynamics of mtDNA genetic variants and disease-causing mutations. The large circles represent human cells. The nucleus (N) and mitochondria (multiple
ovals) are represented. Arrow 1 — mutation occurs in a single mitochondrial DNA (mtDNA). Arrow 2 — due to bottleneck and/or selection events the mutant mtDNA molecule could
either become fixed within the cellular mitochondrial population (A), remain in only a portion of the mitochondrial population (B), or be completely eliminated from the cellular
population (C). Arrow I in the phylogenetic tree: any of the three conditions could become rare, i.e. represented by rare cells in a tested tissue or a rare individual within the human
population. Arrow II in the phylogenetic tree: alternatively, the mutant could become common, i.e. fixed in the cellular population or in a node of the human population. The latter
could occur either due to random genetic drift or positive selection whereas the former (rare) mutant could still be subjected to negative selection and will be eliminated at
subsequent stages.
[93,94]. We noticed that most of these reports sift out mutations that
have occurred in nucleotide positions harboring a genetic variant, in
order to focus on ‘real’ de novo mutations with functional (‘driver’)
potential. Fortunately for us, this was not true of all the reports. We
recently performed an analysis using a dataset of 83 whole mtDNA
pairs sequenced from normal and corresponding head and neck
squamous cell carcinoma [95], as well as 15 paired normal and
pancreatic cancer samples [96]. Our analysis revealed preferential
accumulation of de novo mutations in sites harboring ancient mtDNA
variants [97]. Such a tendency was previously implied in metaanalysis of multiple tumors [93]. When counting recurrent de novo
combinations of mutations, we noticed that they strikingly recapitulated major mtDNA haplogroups harboring combinations of up to 7
different mutations [97]. It is noteworthy that many mutational
screens for mtDNA de novo mutations in several cancer types failed to
identify any of the known mitochondrial disease-causing mutations,
suggesting some type of negative selection against these alterations in
cancer. This suggests that human evolution and the types of cancer
that were studied are likely to be under similar selective constraints.
Similarly, most mutations causing Familial Mediterranean Fever in the
protein Pyrin recapitulate the primate ancestral state [98], thus
further supporting the view that ancient variants could have
functional consequences whenever their genetic context changes.
These evidence imply that evolutionary principles not only govern the
formation and occurrence of both disease-causing mutations and
genetic variants, but that changing the genetic landscape could
transform a relatively innocent genetic variant to a disease-causing
mutation.
6. Concluding remarks
One of the worries a clinical geneticist faces is the possibility that a
disease-causing mutation found in a patient sample is confined to his
own family, and that the disease can be caused by many other
mutations in many other genes, each confined to a certain family. This
means that of the similar mutations that comprise human genetic
diversity, the mutations causing common diseases could form a
genetic repertoire of their own. Some of these mutations will be more
common than others either (A) due to drift and population expansion
owing to the degree of their expressivity in combination with the
various genetic backgrounds or (B) due to natural selection favoring
their survival in certain conditions. In this perspective, we underlined
the similarity rather than the difference between disease-causing
mutations and genetic variants, not only because both obey the
principles and rules of evolution, but because in some conditions the
very same mutations could be nearly harmless variants or cause
disease. Thus, taking into account the principles of evolution while
investigating the molecular basis of diseases could pave the path
towards the discovery of the causes of diseases not necessarily in the
form of novel mutations but also in the form of ‘Janus’-like (two faced)
genetic variants.
Acknowledgements
The authors wish to thank Naama Shani, BGU, for critical reading of
the manuscript. This work was supported by grants from the Israeli
Science Foundation (ISF), Bikurah F.I.R.S.T. Foundation and Israel
Cancer Association awarded to D.M. The authors also thank the Israeli
Ministry of Absorption for a graduate student scholarship to I.Z.
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