The Complete Vindija 33.16 Neandertal Mitochondrial Genome Announced in Cell

Tomorrow’s issue of the high impact & widly cited journal Cell hosts this paper, “A Complete Neandertal Mitochondrial Genome Sequence Determined by High-Throughput Sequencing (DOI:10.1016/j.cell.2008.06.021)” First author, Richard Green, says that this genome is essentially without error. The genome comes from the Vindija 33.16 specimen, a 38,000 year old Neandertal from Croatia, of which around 0.3 grams of bone was extracted and mtDNA isolated.

Vindija Cave, Croatia
Vindija Cave, Croatia

Serre et. al. sequenced the HVR1 region of the mtDNA of the Vindija 33.16 sample in 2004, and Richard Green et al. sequenced 2414 bp of mtDNA sequence from this sample in the famous 2006 paper, “Analysis of one million base pairs of Neanderthal DNA.” Like the 2006 paper, 454 sequencing was used in the current paper because it doesn’t rely on cloning, and yet provides 34.9 fold coverage.

I won’t get into the nitty gritty details of the sequencing protocol, but here’s some of the conclusions of the mitochondrial genome analysis. Comparing the assembled 16,565 base pair Neandertal mtDNA sequence to the 16,568 base pair Cambridge reference mtDNA sequence (rCRS) showed that there are 206 differences, of which 195 are transitions and 11 are transversions).

To assess the evolutionary relationship between modern humans and this Neandertal, the authors compared this Neandertal mitochondrial genome to 53 different mtDNAs of extant humans as well as a bonobo and chimpanzee. They estimated the divergence time of the Neandertal mitochondrial genome by using the 6-8 million year old divergence time of chimpanzees. They estimate a 660,000 year old divergence time between humans and Neandertals, with a 95% credibility interval of 520,000–800,000 years ago.

COX2 Protein Sequence Differences between Neandertal and Modern Humans in Structural Context
COX2 Protein Sequence Differences between Neandertal and Modern Humans in Structural Context

The subunit 2 of cytochrome c oxidase (COX2), an enzyme that functions in the electron transport chain, of modern humans exhibits four amino acid substitutions compared to the Neandertals. While the authors don’t know the implications of these subsitutions, they do consider this interesting,

“…because mtDNA is inherited without recombination, and because the Neandertal mtDNA falls outside the variation of modern human mtDNA, this single modern human observation represents a reversion to the ancestral state seen in Neandertals and chimpanzees. Thus, these four amino acid substitutions occurred in the relatively short period after the divergence of Neandertal and extant human mtDNAs and before the most recent common ancestor of current human mtDNAs. The observation of four nonsynonymous substitutions on the modern human lineage, and no amino acid changes on the Neandertal lineage, stands in contrast to the overall trend of more nonsynonymous evolution in Neandertal protein-coding genes, and deserves consideration.”

How does Green know that the genome is without error? In other words, how do we know contamination ain’t an issue? 454 sequencing generates,

“a high average coverage of the random sequence reads in combination with amplification and sequencing of positions where coverage is low, or where longer nucleotide homopolymers may cause base calling problems, make us confident that the error rates from both these sources are low.”

The authors estimate at most, modern DNA contamination is 0.5%.

I’d be really interested to see the sequences of Neandertals prior to the last Ice Age, when population sizes were relatively larger and the genetic diversity would be larger. DNA from Neandertals that were around 110,000 years ago would be great, because, what we have now, is from few individuals that were around glaciation would affect the observed mutations. Some of you may point me 2006 Current Biology paper by Orlando et al. where the authors were able retrieve 123 bp of the mtDNA HVR-1 from the molar of a 10-12 year-old Neandertal child from Scladina cave, Belgium… but that’s a very short region piece of DNA from an individual well inside the glaciation period… But I don’t know of any 110,000 year old Neandertal specimens off the top of my head.

11 thoughts on “The Complete Vindija 33.16 Neandertal Mitochondrial Genome Announced in Cell

  1. Do you have any links to studies that have been done tracing the roots of South American people both present day and ancient civ’s? Thank you.

  2. FreeToThink,

    Please don’t abuse the comment system for this sort of inquiry. Your question is unrelated to Neandertal genome sequencing. If you have another request in the future, ask by sending an email using this comment form, and I’ll be more than happy to help.

    Kambiz

  3. Using the 6-8 million year old divergence time of chimpanzees. They estimated a 660,000 year old divergence time between humans and Neandertals – with a 95% credibility interval of 520,000–800,000 years ago? I wonder where the the 5oo,ooo years ago Neanderthals laid down there bones to rest? Also, I wonder about the 6-8 million year estimation of the divergence – I hear of a fossilized ape that walked upright 10 or more million years ago – seems to me last common ancestor would be beyond the 6-8 and therefore the divergence would be considerably older, after all, neaanderthals are extremely differnent!

  4. I wonder where the the 5oo,ooo years ago Neanderthals laid down there bones to rest?

    I think that means H. antecessor. Neanderthals as such are only like 200,000 years old.

    Also, I wonder about the 6-8 million year estimation of the divergence – I hear of a fossilized ape that walked upright 10 or more million years ago – seems to me last common ancestor would be beyond the 6-8 and therefore the divergence would be considerably older, after all, neaanderthals are extremely differnent!

    I haven’t read about that walking ape you mention nor I know if it’s our ancestor (and therefore Neanderthal’s too). But I am also concerned about the 7 million years Pan-Homo divergence estimate (based only on fossil record) being too recent and therefore not realistic.

    The hominins once known generally as H. erectus (and now subdivided in several species) colonized Eurasia some 1 billion/900,000 years ago and that is probably the actual age of Neander-Sapiens split. Also the formation of the Congo river, most likely cause of the Chimpanzee-Bonobo split is quite older than the MC estimate for the same event. To me this strongly suggests that the best MC estimates should be corrected towards older dates by a factor of 20-30%.

  5. “H. erectus … colonized Eurasia some 1 billion/900,000 years ago and that is probably the actual age of Neander-Sapiens split”. I presume it’s a mispront and you meant 1 million years.

    But there’s absolutely no reason we can’t accept a half million years separation between modern humans and Neanderthals as being roughly correct. Because there’s no need to believe there have been just two genetic expansions during our evolution: an original H. erectus expansion and a much more recent expansion that spread modern human mtDNA haplogroups around the world.

    There’s also no need to assume that the mtDNA split between Neanderthals and modern humans happened when Neanderthals’ ancestors moved out of Africa. It is just as possible, in fact I believe more likely, that the split occurred when Adam and Eve’s ancestors moved into Africa from Asia.

    In fact the evidence demonstrates that our evolution has been no different to that of any other species: various genes spread through populations altering phenotype. And genetic change is most likely to first become fixed as a result of inbreeding, usually in a geographical extremity of a species’ distribution.

    Regarding the chimp/human split. Research has shown, and common sense tells us, that this split was not instantaneous. It may have taken 4 million years, with several periods of hybridisation. Therefore it is quite possible that humans descend from an ape that walked upright 10 or more million years ago but their mtDNA divergence goes back just to 6-8 million years.

  6. I presume it’s a mispront and you meant 1 million years

    Sure, sorry.

    Because there’s no need to believe there have been just two genetic expansions during our evolution: an original H. erectus expansion and a much more recent expansion that spread modern human mtDNA haplogroups around the world.

    That’s what I gather from the archaeological record.

    There’s also no need to assume that the mtDNA split between Neanderthals and modern humans happened when Neanderthals’ ancestors moved out of Africa. It is just as possible, in fact I believe more likely, that the split occurred when Adam and Eve’s ancestors moved into Africa from Asia.

    Sounds weird. Partly for the use of the Biblical terms “Adam and Eve” without contextualization but specially because the most complete archaeological record of Homo spp. is in Africa, where it probably evolved from local variants H. erectus.

    You were just suggesting at Leherensuge that my hypothesis of a pre-Toba OOA scenario could be realistic. That also implies that MRCA estimates should be moved backwards in time, what would perfectly account for an older Neander-Sapiens divergence (as well as for geological indications of earlier Chimp-Bonobo split than currently assumed commonly).

    In fact the evidence demonstrates that our evolution has been no different to that of any other species: various genes spread through populations altering phenotype.

    As we have already discussed elsewhere, the main engine of speciation is isolation, not introgression. Introgression can happen but has nothing to do with speciation actually.

    Research has shown, and common sense tells us, that this split was not instantaneous. It may have taken 4 million years, with several periods of hybridisation.

    Hybridation or introgression? Hybridization would mean that the proto-species were in continuous contact (and contact of sexual nature) but considering the very different habitat types of our respective branches (we specialized in open terrain, chimps in the jungle) I find massive hybridation most unlikely.

    Therefore it is quite possible that humans descend from an ape that walked upright 10 or more million years ago but their mtDNA divergence goes back just to 6-8 million years.

    But based on the formation of Congo river basin, which was the most likely cause of Bonobo-Chimp split (they do not have different ecological niches, just different geography) , the actual divergence date should be at least 8 million years old, possibly even older.

    Therefore I tend to think that all MRCA estimates demand a correction of maybe +30% and at least +15%.

  7. Several problems here Maju.

    “That’s what I gather from the archaeological record”. It’s quite on the cards that Homo in Africa owes part of its ancestry to something like Homo heidelbergensis who moved into that continent from outside. This would easily fit a half million year split between modern and Neanderthal. And after all other animals have been moving in and out of Africa over the same time period.

    “Sounds weird. Partly for the use of the Biblical terms ‘Adam and Eve’ ”. I think we can safely say that anyone who believes we descend from just two ancestors has been heavily influenced by biblical mythology.

    “a pre-Toba OOA scenario could be realistic. That also implies that MRCA estimates should be moved backwards in time”. It could just mean that modern humans moved out of Africa before the modern Y- and mtDNA haplogroups appeared. The modern haplogroups followed, rather than led, the out of Africa movement.

    “the main engine of speciation is isolation, not introgression”. I doubt it. Isolation leads rapidly to inbreeding which is usually fatal for a small population.

    “Hybridization would mean that the proto-species were in continuous contact”. Not necessarily, periodic would do. I’d suggest it’s quite common for subspecies to make contact as their respective ranges expand and contract over time. There’s no reason at all to believe speciation is an instantaneous phenomenon. After all an individual with an advantageous mutation must be able to breed with other members of its population, otherwise the mutation has no chance at all of surviving.

    “the most likely cause of Bonobo-Chimp split” is not necessarily the formation of the Congo River. An extremely dry period would be sufficient to let a sub-population across, separating the species. Rivers do dry up at times. The world hasn’t always been as it has been during our individual lifetimes.

  8. The paper confirmed my earlier paper on neanderthals, dinosaurs, and mastodons.

    “Ancient Fossil Specimens of Extinct Species Are Genetically More Distant to an Outgroup than Extant Sister Species Are”
    Rev. Biol. 2008, 101: 93-108

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