September 11, 2012

A slower mutation rate has implications... and here they are

I've talked about the implications of a slower mutation rate in a few posts in August, and now an Opinion by Scally and Durbin has appeared in Nature Reviews Genetics that spell these implications out.

First, a reminder of what this is all about: researchers have long used an autosomal mutation rate for humans that was based on a calibration of the split between humans and chimps (actually, other assumptions regarding effective population size were involved, but, in any case, a 2.5x10-8/bp/gen rate came to be widely used). More recently, a variety of studies using a variety of techniques (latest one from ASHG 2012) all came up with a rate that is about half that value.

A smaller mutation rate implies more time to accumulate an observed level of sequence difference. We obtain age estimates by dividing sequence difference by mutation rate, and halving the latter means doubling age estimates.

Scally and Durbin work out precisely these implications. From their summary:

The four key points may be summarized as follows. First, the divergence between modern humans and both Neanderthals and Denisovans, which was originally estimated to be 272,000–435,000 years ago, is revised to 400,000–600,000 years ago. This is in better agreement with the range of estimated split times from mtDNA and also with the idea that the ancestral population of these groups may have been H. heidelbergensis. Second, for the split between the Khoe–San and other modern humans, revised estimates from nuclear genomic data suggest a divergence 250,000–300,000 years ago, older than single locus estimates for the root of the human tree. Third, revised estimates of the separation time between Africans and non-Africans suggest that this predates the appearance of modern humans in Europe and Asia by up to 60,000 years. We have suggested a scenario of exodus from Africa via an intermediate population in East Africa and the Middle East, which may fit better with growing evidence for modern human occupation of the latter region before the wider colonization of Eurasia and may provide a longer interval for Neanderthal admixture with non-African populations. Finally, revised split times of 40,000–80,000 years ago for Europeans and Asians agree better with the palaeoanthropological record and with estimates from mtDNA. 
The authors compare autosomal with mitocondrial dates in their paper. But, mitochondrial dates are not independent: the state of the art time-dependent mtDNA clock used in the most recent studies has been indirectly calibrated with a young Human-Chimp split, and, subsequently the mtDNA clock may need updating itself. So, both mtDNA Eve and L3 itself may become older, although it is not clear whether this will be "enough":  mtDNA exhibits a non-linear mutation rate (saturation), so the mitochondrial clock needs to be examined anew, but I think that older dates are a certainty. How much older will depend on a potentially older human-chimp divergence, as well as where on the saturation curve an age estimate is.

Second, if divergence is pushed to ~300 thousand years, then we're either (a) underestimating the appearance of modern humans in Africa, or (b) the higher divergence dates may be driven, in part, by archaic admixture, if some African populations with shallow divergence times mixed with other African populations with very deep divergence times (archaic admixture). I am fairly convinced on the basis of population-specific SNPs that some such admixture has taken place. Some of the remarkable excess of polymorphism and rare haplotype clusters in Africans may be a legacy of such events.

Finally, a pre-100ka divergence of Africans and Eurasians agrees well with the first appearance of modern humans in Asia (the Qafzeh/Skhul hominins from the Levant), as well as the appearance of the Nubian complex in south Arabia. I have proposed a theory that seems to match the evidence: the "two deserts" theory that derives Eurasians from an Out-of-Sahara/North Africa migration prior to 100 thousand years when modern humans first settled in the Levant and Arabia. However, they remained "bottled up" there by the Nearndertals to their north before eventually venturing out to populate the rest of  Eurasia.

At c. 70ka, the drying up of the Sahara and Arabia and/or the Toba eruption, became responsible for the Great  Eurasian Bottleneck that is so often detected in genetic data. This event led some modern humans (Y-haplogroup: CF) to expand north Out-of-Arabia, where they intermixed with Neandertals and eventually "broke through" the Neandertal barrier to populate the rest of Eurasia. A second group of humans (Y-haplogroup: DE) expanded southwest (back-migrants into Africa, carrying Y-haplogroup E), or southeast (Y-haplogroup D, now having a relic distribution in Asia).

In conclusion, I think we are at the beginnings of a new synthesis that will see a lot of dates multiplied by two, and a few human evolution textbooks re-written.

UPDATE (12 Sep 2012): Co-author Aylwyn Scally communicated the following with respect to the need to re-calibrate mtDNA ages in view of the new autosomal rate (and hence Human-Chimp speciation):

mtDNA studies have tended to use 6-6.5 Mya as a value for the human-chimp TMRCA at the mtDNA locus. As you know, the TMRCA or sequence divergence time predates the speciation time by an amount which is proportional to the ancestral effective population size. (And in fact the mtDNA calibrations were already at odds with the previous nuclear genomic estimates, which had a low speciation time of 4 Mya, but I guess they didn't believe such low estimates!) Now with a revised nuclear mutation rate we estimate a human-chimp speciation around 6-7 Mya. The ancestral human-chimp effective population size seems to have been much larger than that of modern humans, so whereas two modern humans typically have a common mtDNA ancestor perhaps 150,000 years ago, for two individuals back then it might have been as long as 0.5 Mya. But even so it means we expect a the human-chimp mtDNA TMRCA to be only 0.5 My earler than the human-chimp speciation, i.e. 6.5-7.5 Mya. If the old calibration point was 6 Mya, the new one might be as much as 25% more, but not double. 
In other words, the calibration point for mtDNA isn't changed much, because they were already implicitly using an older human-chimpanzee speciation date. If the mtDNA dates remain discordant with nuclear ones even after we analyse more whole genome data, we should probably consider other possible explanations, some of which we discuss in the paper.



Nature Reviews Genetics, advance online publication, Published online 11 September 2012 | doi:10.1038/nrg3295

Revising the human mutation rate: implications for understanding human evolution

Aylwyn Scally & Richard Durbin

Abstract

It is now possible to make direct measurements of the mutation rate in modern humans using next-generation sequencing. These measurements reveal a value that is approximately half of that previously derived from fossil calibration, and this has implications for our understanding of demographic events in human evolution and other aspects of population genetics. Here, we discuss the implications of a lower-than-expected mutation rate in relation to the timescale of human evolution.

Link

19 comments:

Africa Gómez said...

Thank you for sharing this, a really timely paper. I wonder what sense there is in estimating times of diverging between European and Asian, especially if most of the genetic substrate of Europeans is of Asian origin. Are these estimates taking into account massive gene flow from Asia to Europe?

Ponto said...

I am wondering what happened to the divide Y chromosome haplogroup subclades formation date by 3? Sorry, I never accepted that divide by 3 idea.

A lot of those haplogroup dates were formed by incorrect hypotheses like for example, that R1b was formed in Europe and in the Pleistocene. The dates are a crock.

terryt said...

"This event led some modern humans (Y-haplogroup: CF) to expand north Out-of-Arabia, where they intermixed with Neandertals and eventually 'broke through' the Neandertal barrier to populate the rest of Eurasia. A second group of humans (Y-haplogroup: DE) expanded southwest (back-migrants into Africa, carrying Y-haplogroup E), or southeast (Y-haplogroup D, now having a relic distribution in Asia)".

I agree to a considerable extent, but I have explained elsewhere why I believe it is very difficult to claim a movement SE through South Asia for Y-DNA D. To me the Y-DNA haplogroup that moves through South Asia is obviously F.

Teo. said...

@terryt

But D seems to be associated with M* mtDNA in some of the SE Asian relic and isolated populations (Andamanese islanders, some Thai-speaking groups), and the earliest layer of Indian mtDNA seems to be M* (unlike Australasia, which is C/F and N*), and possibly Andamanese-like. So the pattern would seem suggest that D was indeed present in India before being displaced by subsequent waves of F (L,H,R), and that C/F is instead associated with N. IMO, that pattern is not unusual. In many areas of South America, for example, you won't find Q Y-DNA hgs around in the non-Amerindian population (as if it had left no trace), but the mtDNA distribution is mostly Amerindian/African. If we didn't know the history of the Americas, we might as well say that R1b moved in with A/B/C/D/L mtDNA haplogroups, which would be a little absurd.

Teo. said...

On the update: interestingly, the nuclear genomic calculation might be cosistent with my speculation (arrived at from entirely different data) that the dates should be 1/3 YOUNGER than current estimates. I have shown elsehwhere in this blog forum (http://dienekes.blogspot.com.br/2012/07/estimating-age-of-y-chromosome-adam_30.html)
that this 2/3 proportion fits perfectly with geological and possibly linguistic data. Yes, yes, I could be spectacularly wrong on this point, but it's nice to see that at least one important piece of genetic evidence points to a similar scenario (even though it's contradicted by other evidence, of course).

MOCKBA said...

Some of the clustering haplotypes / excessively common rare polymorphisms might be intraspecific in origin? E.g. caused by pseudogene conversion events, or by repair of multiple synchronous DNA damage events from the spurs of ionizing radiation. How common should be these clusters to make a conclusion of their interspecific origin inevitable?

terryt said...

"But D seems to be associated with M* mtDNA in some of the SE Asian relic and isolated populations (Andamanese islanders, some Thai-speaking groups)"

But haplogroups swap partners, as we know from the Polynesian expansion into the Pacific. Just because D and M are associated in some populations doesn't mean at all that they must have arrived at the original expansion point within all those separate regions together.

"and the earliest layer of Indian mtDNA seems to be M* (unlike Australasia, which is C/F and N*)"

D is certainly not associated with M in India. In fact it is quite rare, and almost entirely confined (if not actually 'entirely confined') to Sino-Tibetan-speaking groups, so presumably entered India with those groups.

"So the pattern would seem suggest that D was indeed present in India before being displaced by subsequent waves of F (L,H,R)"

I agree that haplogroup replacement has occurred, and quite frequently. But I think such replacement in India is unlikely. After all any number of F-derived haplogroups survive there as well as (apparently) two C-derived haplogroups. Strange that just D should have disappeared there. D is actually spread in an arc from Japan in the northeast to Tibet, Mongolia, and down into SE Asia, specifically the Andaman Islands, with basically a separate haplogroup in each region.

"and that C/F is instead associated with N".

I'll grant that C is quite closely associated with N, but it is difficult to make a case for F being so. On the other hand F-derived MNOPS is closely associated with R-derived mt-DNA haplogroups. But that seems to be yet another example of partner swapping.

Teo. said...

@terry

Okay, but just how common is that "swapping", and under what circumstances?

In the scenario you proposed, a relic hunter-gatherer population such as the Andamanese would have to have acquired the female lineages from the incoming F population while totally replacing its own, which doesn't seem any more likely than total replacement of D, IMO.

terryt said...

"Okay, but just how common is that 'swapping', and under what circumstances?"

The 'classic' example is the Austronesian expansion west, where Y-DNA C2 (most likely from Southern Wallacea) joined up with mt-DNA B4a (most likely from Taiwan or the Philippines). Some Y-DNA O1 and O3 was carried some of the way. As for the circumstances: it seems that the Austronesians developed as a result of a mix of populations in island and mainland SE Asia. Presumably other examples of 'swapping' would also be the result of mixing in particular regions.

"In the scenario you proposed, a relic hunter-gatherer population such as the Andamanese would have to have acquired the female lineages from the incoming F population while totally replacing its own, which doesn't seem any more likely than total replacement of D, IMO".

I suggest that the 'swapping' did not take place on the Andamans, but on the nearby mainland. To me it looks as though D moved south from somewhere near the Tibet/China border region (as it has continued to do in recent prehistory) where it met up with a pre-existing mainland population containing mt-DNA M and probably some sort of F- or F-derived Y-DNA. The moving Y-DNA population wave picked up the women as it moved past, leaving the indigenous male line behind. It looks to me very much as though the human movement into America was much the same. An eastward moving population containing Y-DNA Q (and possibly mt-DNA X) moved slightly to the north of a population containing mt-DNA C and D, and possible A and B as well. Once more it left the male line in that population behind although American Y-DNA C3 may have been carried along. Another probable example is in SE Asia where an incoming population containing Y-DNA MNOPS mixed with a pre-existing population containing mt-DNA R (with Y-DNA C). From that mixture Y-DNA P moved west and NO moved north, each carrying members of mt-DNA R. Some C* also looks to have been carried along as far as Eastern India.

There is surely no need to always assume an intimated connection between particular mt-DNAs and Y-DNAs. It is not only married men who move on.

Valikhan said...

"I agree to a considerable extent, but I have explained elsewhere why I believe it is very difficult to claim a movement SE through South Asia for Y-DNA D. To me the Y-DNA haplogroup that moves through South Asia is obviously F."
Agree. I think hg D appeared in Asia about 6,000 with Sino-Tibetan speakers. And movement took place through modern Central Asia rather coastal.

Teo. said...

"I think hg D appeared in Asia about 6,000 with Sino-Tibetan speakers"

Alas, that'd be too good to be true in terms of linguistic paleoanthropology.

It would be great if we could explain D in Southeast Asia as resulting from the earliest Chinese Neolithic or something similar (an élite from the Himalayan slopes).

That could promptly explain the apparent similarities
between Sino-Tibetan-Austronesian-Andamanese. But the division between the D clades there seems to be way too deep for that, or so anthropologists tell us, and therefore that is unlikely.

terryt said...

"I think hg D appeared in Asia about 6,000 with Sino-Tibetan speakers".

I'm sure that D had been in East Asia long before the Sino-Tibetan language had even developed. The situation is simply that its expansion through much of SE Asia and into India is no more than 6000 years old. Even its arrival in the Andamans is unlikely to be much more than about 12,000 years ago. It is certainly not a remnant of any original 'great southern coastal migration'.

"And movement took place through modern Central Asia rather coastal".

I agree 100% with that.

terryt said...

"It would be great if we could explain D in Southeast Asia as resulting from the earliest Chinese Neolithic or something similar (an élite from the Himalayan slopes)".

I think Y-DNA O, especially O3, fits that scenario better than does D. In fact I strongly suspect O3 was responsible for the expansion of Sino-Tibetan. D just got carried along into some regions. However as far as I'm aware the Andaman Islanders did not have a Neolithic culture, although it is possible their arrival is associated with the early Hoabinhian.

"That could promptly explain the apparent similarities
between Sino-Tibetan-Austronesian-Andamanese".

I think the connection goes this way: O3-Sino/Tibetan, O1-Austonesian/Thai and O2-Austro-Asiatic. The similarity (?) between Austronesian and some Andaman island languages appears to be independent of any genetic connection.

Lathdrinor said...

Not independent - Great Andamanese do possess Haplogroup O, K, L, and P, among others, and seeing that the Andamanese are said to have ASI admixture, there are a variety of potential links between them and their mainland neighbors.

J Humphreys said...

Dienekes et al,
We at Open Genomes Foundation (see our non-profit Mission Statement link at bottom), believe in making all genomic data open for the advancement of science and bettering of public health.

To that end, also attached are Google files that give Y-chromosome data that we believe argues for a human Y-chromosome origin in Cameroon.

Question:
Dienekes, in light of a slower human autosomal mutation rate and given the potential origin of AMH in Cameroon, how does the following 400kbp WTY sequencing data, and SMGF data showing matches between a mid-19th century African in America and Cameroonians, influence your opinion about the age of the Y chromosome?

http://goo.gl/cDJMv (SNP’s potentially at the ROOT of the Y phylogenic tree)

http://goo.gl/M40x3 (Y chromosomes for African in America mid-19th century and Cameroonians)

OGF Mission Statement (http://goo.gl/kI2cO)

Open Genomes Foundation said...

We are all curious about the implications of Y0 in Cameroon about the overall age of AMH. It seems that the MDS plots of Africans in fact center on Cameroon geographically as a center of diversity.

We invite everyone to weigh in on this.
The above data, as links, to make it easier to access:
Y0, A0, and A1a-T basal Y SNPs
Y0 STR haplotypes including the full set of STRs (new) along with the palindromic STRs.

Y0 appears to be 129x as old as A0. If the Cruciani date for A0 is correct at 142,000 years, then Y0 will be approximately 183,000 years, and this correlates almost perfectly with both the calculated mtDNA L0-L1'6 basal split of 176,689.4 years and the earliest AMH remains of Homo sapiens "idaltu".

An important point:
No one has ever found a terminal SNP below Y M222, in spite of the fact that is seems to have diverged about 1360 years ago. (The origin is much earlier.) This is quite an anomaly if in fact there is 1 SNP about every 4 generations on the Y. This corresponds to what we are seeing about the slower mutation rates.

Given that Y0 is based on resequencing of a single sample, perhaps someone can list the Reference Sequence (RP11 L2 contigs) and M222 SNPs in the exact same regions as a "terminal" haplotype measure of the overall relative Y mutation rate, and post these here. Hypothetically there should be an equal number of SNPs between Y0 and L2 and M222. We can then use this to arrive at relative Y calibrations based on different slow or fast mutation rates. We can then list these on the spreadsheet (with credit given, of course).

Who would like to try it? Dienekes?

Here are the 1000 Genomes Y SNPs not on the Y tree:

1000 Genomes Y SNP Analysis

Let's see what we come up with.

Open Genomes Foundation Mission Statement

terryt said...

"Not independent - Great Andamanese do possess Haplogroup O, K, L, and P, among others, and seeing that the Andamanese are said to have ASI admixture, there are a variety of potential links between them and their mainland neighbors".

Thanks for that information.

"given the potential origin of AMH in Cameroon"

Interesting. Makes sense.

terryt said...

"Great Andamanese do possess Haplogroup O, K, L, and P"

Any information as to what branch of O? K and L are not surprising, but what branches of P have been tested for? If it really is 'P' it would strengthen the case for P having first appeared somewhere in SE Asia, from MNOPS.

Teo. said...

@terryt, @lathdrinor

Actually, the Great Andamanese intermarried with Burmese male settlers during much of British colonial rule and with Indians afterwards, so we can't be sure if those hgs really represent a pre-contact situation (most certainly don't).

Fortunately, there are many Andamanese samples from the beginning stages of contact held in museums which could be studied to settle the issue.