A Report on the Genetics, Inheritance and Expression

of Mitochondrial DNA
Ben Roberts
May 4, 2019

Mitochondria play a key role in the metabolism of nearly all eukaryotic organisms. Their
peculiar evolutionary origin and independent DNA (mtDNA) make them, along with plas-
tids, useful tools for studying genetics and evolution. Most animals, humans included, inherit
their mitochondria maternally from the oocyte. Sato and Sato (2013) describe a variety of
mechanisms that ensure this is the case by eliminating paternal mtDNA or mitochondria.
Mitochondria also have a unique mechanism for initiating DNA structure and replication
using a short section of three-stranded DNA called a displacement loop; the third strand
acts as a DNA primer to initiate replication either through synchronous replication of the
strands, or a simultaneous strand-couple mechanism (Fish, 2004). The mtDNA of most
eukaryotes specifies some of the proteins necessary for oxidative phosphorylation, transcrip-
tion, and translation (although much variation exists across the domain) while the rest of the
components are specified in the host cell’s nucleus (Burger, Gray, & Lang, 2003). MtDNA’s
genetic code also shows key differences from other DNA. Loss of some tRNAs necessitates
additional degeneracy in the anticodon pairing. Bovine mitochondria have been found to
have mitoribosomes with special binding activity that’s sequence-independent of the mRNA,
suggesting that translation initiation sequences are not necessary. (Taanman, 1999) MtDNA
also provides evidence of human evolution and population migrations, such as the migration
out of Africa and to the Americas via Siberia (Wallace, 2015).

This author sought answers to a handful of seemingly unrelated questions. What are the
various structures and gene layouts of eukaryotic mitochrondria, and are there patterns?
Why are human mitochondria so compact genetically? And why do mitochondria so often
rely on a maternal inheritance pattern among animals, with paternal mtDNA excluded or
eliminated? As it happens, certain attributes in each of these areas suggest some common
mechanisms in their explanations.

Eukaryotes generally exhibit an enormous diversity in their mitochondrial DNA, with few
obvious correlations to explain the various forms. As mentioned above, many of the genes
for proteins critical to mitochondrial function can be found in nuclear DNA of at least some
eukaryotic organisms. The mitochondrial genome itself can be a single circular chromosome,
linear, or a complex of hundred of individual linear molecules akin to chromosomes as in
Amoebidium parasiticum. The size of the genome varies widely, often due to large noncoding

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regions containing repeats. And although both gene number and mtDNA size are highly
variable, there is no apparent correlation between them. Some eukaryotes even have unusual
structures within the genes, with some critical genes kept in multiple fragments on the
chromosome that must somehow be assembled together (possibly post-translation). There
are even known examples in plants of proteins that are assembled from a combination of
mtDNA and nuclear DNA in a similar manner. This suggests the ability for genetic material
that was ancestrally part of mtDNA to migrate to the nucleus of the host cell. Furthermore,
there are even a few known cases of gene transfer in the reverse direction, but only frequently
in plants. Evidence for such transfers shows that the size of the mitochondrial and nuclear
genomes do not have to experience selective pressure to grow or shrink, otherwise one would
expect them to do so in tandem. Perhaps the only remaining hypothesis after comparing
genomes is that mitochondria evolution could be driven by an organism’s demand for rapid
growth, while slowly growing organisms would place less evolutionary pressure on theirs.
(Burger et al., 2003)

Narrowing the focus to just animal mitochondria can provide some interesting insights.
Despite the large variation in nuclear genome size among animals, mtDNA is typically small
at just 15-20 kb and encodes a consistent collection of genes. Occasional large variations
in chromosome size are due to regions of non-coding repeats. Most of the genome diversity
among animals is due to gene rearrangements. (Boore, 1999) Another uniformity among
animals is uniparental inheritance of mtDNA, but how different animals achieve this varies
greatly. Some mammals exclude the sperm mitochondria from the oocyte cytoplasm at fer-
tilization, but most do not and appear instead to possess species-specific mechanisms to
degrade them. In Caenorhabditis elegans, sperm fertilization of the egg triggers autophago-
somes to form around penetrated sperm components to destroy them. In Oryzias latipes,
a small fish, part of the process involves the sperm degrading some of their own mitochon-
dria prior to fertilization. Drosophila melanogaster shows an analogous pattern, with sperm
mtDNA nucleoids degrading as part of the sperm maturation process. An exception to the
maternal inheritance pattern can be found in some mussels, wherein the males carry a differ-
ent type of mitochondria in the gonads that are used in the sperm, and are only inherited by
male offspring. (Sato & Sato, 2013) All of these various mechanisms suggest some advantage
to uniparental inheritance of mtDNA, at least among animals.

Oddly enough, humans may serve as a useful model organism for understanding some
of these patterns. Humans have a perplexingly large diversity of polymorphic alleles in
their mtDNA, some of which change amino acids on important proteins that are highly
conserved among many other species. Wallace (2015) explains how the maternal inheritance
of mtDNA and large geographic radiation of human populations has produced a number of
mtDNA lineages, each with their own unique alleles. His explanation, originally from Wallace
and Chalkia (2013), is that heteroplasmic mitochrondria in the female germ line experience
a genetic drift event with every generation as part of development. This leads to oocytes
with disproportionate ratios of normal and mutant mtDNAs. Furthermore, many mtDNA
mutations will be expressed at the cellular level within the oocyte, so many deleterious
mutations in the mitochondria will be efficiently selected against without requiring extensive

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development first. Humans have also spread to a wide range of environmental conditions
where certain mitochondrial mutations, even those which may seem detrimental, can in fact
be advantageous. For instance, a mutation in an oxidative phosphorylation pathway that
lowers the efficiency of ATP production will produce excess heat, an advantage in colder
climates. Finally, these mutations in mtDNA can lead to coevolution with nuclear DNA
to further optimize the mutation’s phenotype. A significant consequence in the extreme
case, then, is that breeding between distantly related mitochondrial haplogroups can lead
to recombination of nuclear DNA but not of mtDNA, making the host cells less adapted for
their organelles. Applied to humans, Wallace believes this process could be playing a role in
many common diseases.

All of these factors seem to provide a plausible explanation for the advantages of uni-
parental inheritance. There should be reduced viability (at least in subsequent generations)
of offspring heteroplasmic for two highly derived mtDNAs because it would be unlikely that
the host’s nuclear DNA would retain optimal alleles for both mitochondria lineages, espe-
cially if different mutations of the same gene are required. Yet recombination of nuclear DNA
alleles should still provide other advantages, so most organisms would be best suited to elim-
inate any trade-offs by ensuring that only one parent’s mtDNA is present. In a simplified
scenario, then, the first-generation offspring of a cross between two pure lines would have
mitochondria from only one lineage and be heterozygous for the nuclear alleles optimized
for them. The frequency of maternal inheritance patterns could just be due to simplicity, as
animals’ sperm could not reasonably carry enough mitochondria to supply an entire zygote.

References
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