The human mitochondrial genome is a small circular genome of 16,570 ± 50 bp (Rubino et al., 2012). It contains only a few genes but it is still invading the nuclear genome. The average human genome contains about 600 fragments of mitochondrial DNA ranging in size from 30 bp to almost the full size of the mitochondrial genome (Simone et al. 2011). They are called NumtS or nuclear mitochondrial sequences. 1
Some of the genome inserts are 100% identical in sequence to the standard mitochondrial genome sequence indicating a recent colonization event. Others are as little as 63% identical, the cut-off similarity. The total amount of mitochondria-derived DNA in one individual was 627,410 bp amounting to only 0.02% of the genome (Simone et al., 2011).
About 550 NumtS in the human genome are also found in the chimpanzee genome (Calabrese et al., 2012). These represent insertions that pre-date the common ancestor of humans and chimpanzees. There are only 53 human-specific NumtS in the reference genome representing insertions that occurred along the lineage leading to modern humans (Lang et al., 2012). Some (14) of the human-specific insertions are polymorphic in the human population and these are presumed to be the most recent insertions.
Only a small number of these 14 polymorphic NumtS were found in the Neanderthal and Denisovan genomes. That suggests that most of the insertions happened since the split between modern humans and our ancient ancestors. However, Lang et al. (2012) point out that the quality of the Neanderthal and Denisovan genomes is not good enough to make any definitive statements.
Three or four insertions are confined to non-African populations implying that they took place in populations that had already migrated out-of-Africa. That probably means insertions events that occurred less than 100,000 years ago.
Invasions of mitochondiral DNA have to occur in germline cells in order to show up in the databases in more than one individual. The vast majority of these insertions are in junk DNA regions of the genome so they are neutral alleles. They become fixed in the population by random genetic drift but that's a slow and improbable mechanism of evolution. The fact that there are 53 human-specific NumtS suggests that there are about 0.3 insertions every 1000 generations. That may not seem significant but keep in mind that there are billions of people so that means millions of newborn babies have new insertions every generation.
If you were to look at every cell in your body, chances are high that your mitochondria have invaded your genome in at least one cell.
Image Credit: Moran, L.A., Horton, H.R., Scrimgeour, K.G., and Perry, M.D. (2012) Principles of Biochemistry 5th ed., Pearson Education Inc. page 175 [Pearson: Principles of Biochemistry 5/E]
1. I'm told that this is pronounced "new-mites."
Calabrese, F.M., Simone, D., and Attimonelli, M. (2012) Primates and mouse NumtS in the UCSC Genome Browser. BMC bioinformatics, 13(Suppl 4), S15. [doi:10.1186/1471-2105-13-S4-S15]
Lang, M., Sazzini, M., Calabrese, F.M., Simone, D., Boattini, A., Romeo, A., Luiselli, D., Attimonelli, M. and Gasparre, G. (2012) Polymorphic NumtS trace human population relationships. Human Genetics 131: 757-771. [doi: 10.1007/s00439-011-1125-3]
Rubino, F., Piredda, R., Calabrese, F.M., Simone, D., Lang, M., Calabrese, C., Petruzella, V., Tommaseo-Ponzetta, M., Gasparre, C., and Attimonelli, M. (2012) HmtDB, a genomic resource for mitochondrion-based human variability studies. Nucleic acids research, 40: D1150-D1159. [doi: 10.1093/nar/gkr1086]
Simone, D., Calabrese, F.M., Lang, M., Gasparre, G., and Attimonelli, M. (2011) The reference human nuclear mitochondrial sequences compilation validated and implemented on the UCSC genome browser. BMC genomics, 12:517-527. [doi:10.1186/1471-2164-12-517]
21 comments :
Great stuff. My first inclination after reading this post is to try to come up with puns related to the phrase "barbarians at the gate". Instead, I will ask a question: does anybody know of a study that looks at the number of chimp-specific NumtS since the common ancestor of chimps and humans (Lang et al. 2012 does not appear to have addressed this)? I would be curious to know if the number is comparable to what is seen in humans.
Numts can be a pain if you're trying to sequence mitochondrial genes. I got around 8 cytochrome b sequences from one species of duck, and as far as I can tell all of them were numts. Different numts. But since they were all more recent than the split between that species and any others, they were as good for my purposes as real cytochrome b sequences. Better, since they split a long branch.
There are 751 NumtS in the reference chimpanzee genome. Since 550 of these are shared with humans it means approximately 200 chimp-specific NumtS. In order to determine whether these arose after the chimp-human split you would have to compare them to the rhesus macaque genome as was done with the human NumtS. Calabrese et al. (2012) don't give us that result but they do say that it's rare to lose a NumtS.
Another bizarre NUMTS factoid;
"Integration of numts not only appears as neutral polymorphism but, more rarely, is also associated with human diseases [32]; five cases are currently known (Figure 2). One involved a 41-bp mtDNA insertion at the breakpoint junction of a reciprocal translocation between chromosome 9 and 11 [33], the remaining cases involve insertion of mtDNA into genes. A splice site mutation in the human gene for plasma factor VII that causes severe plasma factor VII deficiency (bleeding disease) results from a 251-bp numt insertion [34]. A rare case of Pallister-Hall syndrome in which a 72-bp numt insertion into exon 14 of the GLI3 gene causes a premature stop codon, is associated with Chernobyl [35]. A case of mucolipidosis IV in which a 93-bp segment was inserted into exon 2 of MCOLN1, eliminated proper splicing of the gene [36]. As the last known example, a 36-bp insertion in exon 9 of the USH1C gene associated with Usher syndrome type IC [37] is a numt [32]."
Hazkani-Covo, Zeller, & Martin "Molecular Poltergeists: Mitochondrial DNA Copies (numts) in Sequenced Nuclear Genomes" PLoS Genet. 2010 6(2): e1000834
So if we assume that very few shared NumtS were lost in the human lineage, the chimp genome has acquired roughly 4 times as many sequences of mitochondrial origin than has the human genome? Very interesting!
Isn't it simply an artefact of comparison between different estimates drawn from different studies? Hazkani-Covo andd Graur (2007) identified 452 numts in humans and 469 in chimps; Ramos et al. (2011) identified 755 numts in the human genome, which squares well with the chimp count cited by Larry.
Isn't it simply an artefact of comparison between different estimates drawn from different studies?
That would make sense. I have not looked into the literature on this topic.
Does this imply, that in the distant future, our distant relatives will no longer have mitochondrion, as all the mtDNA will have migrated to the nuclear genome, and generation of ATP will occur from there, some how?
Or would the current infrastructure of cellular respiration and the krebs cycle be far too ingrained/established, to allow that to happen?
Kinda how genes can be highly conserved, if what they do is vital?
Interesting article!
Does this imply, that in the distant future, our distant relatives will no longer have mitochondrion, as all the mtDNA will have migrated to the nuclear genome, and generation of ATP will occur from there, some how?
If it was going to happen, it would have happened a long time ago.
It has actually happened many times in a number of groups -- usually anaerobic eukaryotes, which lose the mitochondrial genome and have hydrogenosomes or mitosomes instead of conventional mitochondria.
Also, the reduction of the mitochondrial genome was basically almost complete in the LECA (Last Eukaryotic Common Ancestor). The most gene-rich mitochondrial genomes are those of Jacobids, and they have 50-60 protein coding genes.
And there is a difference between reduction of the gene content and reduction of the genome -- most mitochondrial genomes are not at all as reduced in size as those of metazoans (there are some that are even more reduced, for example, apicomplexans, but those are exceptions). And they are absolutely bloated in size in other groups (plants in particular), but not necessarily in gene content. It most likely has to do with differences in mutation rates (see PMID 16556832)
Only a small number of these 14 polymorphic NumtS were found in the Neanderthal and Denisovan genomes. That suggests that most of the insertions happened since the split between modern humans and our ancient ancestors.
Is this really true? My (not terribly well educated) intuition is that a neutral allele like this will probably have spent a long time at low frequency, meaning that most of them probably originated well before we'll find any trace of them in the few individuals we manage to sequence.
(Similarly, even if we find a particular (recent) NumtS in all current samples, it seems to me there's a significant chance it hasn't completely fixed yet -- there may still be some individuals with the original NumtS-less sequence.)
If I recall correctly - from decades ago- there is a constraint on moving the remaining mito protein genes to the nucleus. Their chemical properties would make it impossible for the translocation apparatus to insert them to the proper location in the inner membrane.
Interesting stuff! Thanks for the replies guys!
That was Gunnar von Heijne's "hydrphobicity hypothesis".
http://www.sciencedirect.com/science/article/pii/0014579386811723
There are other theories, but the only one of note at the moment is that there is some local sensing required for the expression of the mitochondria - explaining why there is a core of cox1, cox3 and cytb conserved in all aerobes, but are quickly lost in anaerobes. But this hypothesis is lacking a mechanism for the "sensing" at the moment.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2447392/
1) The original post is about NUMTs
2) It's not true that such a thing is required for endosymbiosis to work
There's also a potential issue with the variant codes between nucleus and mitochondrion, which may be a problem for some transfers. But the likeliest drag on global transfer seems to be 'poise' - it's better to keep some proteins distributed to permit faster response.
Has anyone a reference to recent studies of Rhizobium-Legume gene transfer? Granted, the nitrogen-fixing root nodules don't generally associate with reproductive organs, but given the tendency towards totipotency among plant cells of many different tissues it's at least plausible that the Rhizobium-Legume symbiosis we see now could be an organellar-nuclear genome relationship develop in real time.
Codon variation is undoubtedly an issue, especially in animals and such where you have an amino acid coded in something that the nucleus reads as a stop codon would put up a wall to direct gene transfer. The problem with the general applicability of the codon-variation theory is that is organisms using the standard genetic code in the mitos (ex. plants) still maintain their mitochondria.
The second issue is were are not sure how much "gainful" transfer is actually ongoing. A surprisingly low number of the proteins that act in mitochondria have clear a-proteobacterial homology. Mike Gray has a recent article in PNAS discussing this.
http://www.ncbi.nlm.nih.gov/pubmed/25848019
This popped up in a pubmed search.
http://www.ncbi.nlm.nih.gov/pubmed/22586130
"And they are absolutely bloated in size in other groups (plants in particular), but not necessarily in gene content. "
You must mean protein-coding gene content. Nobody ever checked the functions of the non-coding part, however. In humans the non-protein coding part is known to regulate replication. I can think of many additional functions in plants.
I know that you will be surprised to hear it, but people do actually look into these things. The huge recombination rate in plant mitochondria make these regions unstable, and prone to not existing on all copies.
But they appear to be a side-effect of error-prone repair.
http://gbe.oxfordjournals.org/content/6/6/1448.full
Cue Claudiu Bandea and "insulator DNA discussion" in 3...2....1....
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