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  • What is the human mutation rate?

    Thu, 2010-11-04 01:33 -- John Hawks

    Last spring I wrote about a study that used whole-genome comparisons between parents and offspring to estimate the rate of per-genome mutation in humans ("A low human mutation rate may throw everything out of whack").

    The study was by Jared Roach and colleagues [1], and as you might guess from my post title, the result was surprising. Previous work had suggested a human mutation rate around 2.5 x 10-8 per site per generation. The new study found less than half the expected number of mutations between these parents and offspring, an estimated rate of only 1.1 x 10-8 per site.

    If this lower rate of mutation were to hold up, it would affect much of our understanding of the chronology of human evolution. Fossils and archaeological sites would not change in date, but some hypotheses about their relationships would be challenged. For example, the higher rate of 2.5 x 10-8 per site suggests a chimpanzee-human population divergence around 4 million years ago. A new rate of 1.1 x 10-8 would not have a linear effect on this divergence time -- the genes don't have genealogical roots at the same instant as the population divergence. But the human-chimpanzee divergence time would be radically higher than in many recent estimates.

    The same might be true for other primate divergences, and for genealogical relations within human populations today. Basically any times that are estimated from genetic differences may be affected by our knowledge of the per-generation rate of mutations.

    What does this mean? Open below the fold to read more.

    What mutations are we counting?

    Human genomes differ from each other in many ways. There are single base-pair changes in sequences, insertions and deletions, repeat polymorphisms, and larger-scale rearrangements such as inversions and gene duplications. Recent work suggests that some of these larger-scale effects may be very important to phenotypic variation among people. So why should we be talking about only the first of these kinds of variation?

    Single nucleotide mutations have been the focus of most attention about mutation rates because they are relatively easy and quantify. In high-quality sequence data, a single nucleotide change is relatively unambiguous. Reversals are fairly unlikely, although at a small fraction of "hotspot" sites, recurrent mutations can make a big difference.

    It is somewhat misleading to refer to "a" rate of single nucleotide mutations, because some kinds of sites (e.g., CpG nucleotides) have had a much higher probability of mutations than others. This affects the apparent rate of mutations in noncoding versus synonymous sites [2]. Also, the germline in males has been estimated to be as much as 6 times more likely to suffer mutations than the germline in females (discussed by Crow [3]). The idea of a genome-wide rate assumes that when we bin all the single nucleotide mutations together, across large amounts of sequence, we do arrive at a relatively stable rate that can be applied to similarly broad extents of sequence data. Or at least that we can identify sequence regions with compatible rates (e.g., noncoding DNA or synonymous sites).

    At the moment, technical issues make it hard to find and quantify many other kinds of variation. The current generation of sequencing devices tend to generate short reads, which make it difficult to assess the presence of insertions or deletions of more than a few base pairs. Duplications and other rearrangements require special treatment such as higher coverage or longer sequence reads. By contrast, a single nucleotide mutation will typically align in the proper location and be quite evident in a read. In principle, we can just run down the genome and count them.

    Still, finding novel mutations is not without its problems. Recent sequencing projects have yielded a very high rate of false positives. The rate of false negatives is really not yet known. We have a good reason to suspect that the false negative rate will be high. In a low-coverage genome, many short segments of the genome will have very low read numbers, making it likely that the sequence reads represent only one of the two copies of the genome present at that location. Any novel mutations in that area have a 50-50 chance of being missed by our sequencing efforts. This false negative risk can be reduced by adding higher sequence coverage, but we're not yet at the point where we have a lot of genomes sequenced at the 10x or higher coverage that we would really want.

    So while sequencing a parent and offspring genome is the most direct way to estimate the per-generation mutation rate, it is not yet ideal.

    Where did the high rate come from?

    That means we need to look very closely at other sources of data, to see if they may provide some independent confirmation of a lower per-generation mutation rate. In the process, we should ask, why did the higher rate, around 2.5 x 10-8 per generation, become so widely accepted?

    The source cited by Roach and colleagues for the higher rate, 2.5 x 10-8 per site, is a paper by Michael Nachman and Susan Crowell [4]. Nachman and Crowell examined processed pseudogenes in humans and chimpanzees, under the assumption that mutations in these pseudogenes would be neutral to selection in the human and chimpanzee lineages.

    The average mutation rate was calculated from the average autosomal rate of evolution assuming a generation time of 20 years (Table 3). Recent estimates of the time since humans and chimpanzees diverged (T) include 4.5 mya (TAKAHATA and SATTA 1997 ), 5.5 mya (KUMAR and HEDGES 1998 ), and 6.0 mya (GOODMAN et al. 1998 ). ARNASON et al. 1998 estimated the Homo-Pan divergence at 10–13 mya; however, their estimate is based on a calibration using distant, nonprimate species and is at odds with most other recent estimates. Mutation rates were calculated for a range of different human-chimpanzee divergence times and for two different ancestral population sizes. Mutation rate estimates vary from 1.3 x 10-8 (assuming T = 6 mya and Ne = 105) to 2.7 x 10-8 (assuming T = 4.5 mya and Ne = 104). If the average generation time is assumed to be 25 years (e.g., EYRE-WALKER and KEIGHTLEY 1999 ), then mutation rates are estimated to be between 1.6 x 10-8 and 3.4 x 10-8.

    Wait a minute. There's no independent estimate of mutation rate here at all!

    What they did was to assume values for the human-chimpanzee divergence and ancestral (chuman) effective size, and then provide an estimate of mutation rate consistent with those assumptions. That's perfectly reasonable as a way of quantifying the genetic divergence that they observed. If our goal is to predict the per-generation mutation rate from interspecific divergence, that's more or less the kind of estimate that we want.

    But many, many other studies have instead used a citation to the Nachman and Crowell rate as a justification for their own estimates of the human-chimpanzee divergence time! That's not perfectly reasonable, in fact, it's perfectly circular. It's turtles all the way down!

    Worse, those citations tend to cite the midpoint of Nachman and Crowell's range of estimates (2.5 x 10-8) as if it were a true value measured with little error. Reading the original reference, you can plainly see that Nachman and Crowell reported estimates that varied over a factor of three, corresponding to a wide range of chuman population histories. From their discussion:

    Mutation rates estimated for a range of divergence times and ancestral population sizes fall between 1.3 x 10-8 and 2.7 x 10-8 assuming a generation time of 20 years (Table 3) or between 1.6 x 10-8 and 3.4 x 10-8 assuming a generation time of 25 years. We suggest that 2.5 x 10-8 is a reasonable estimate of the average mutation rate per nucleotide site (but caution that the actual rate may be between 1.3 x 10-8 and 3.4 x 10-8).

    That 2.5 x 10-8 is simply the midpoint of their range of estimates with the 25-year generation time.

    What would be more reasonable? For hominins and chimpanzees, we probably want to apply a shorter generation length, a larger ancestral effective size, and a higher time of divergence. All of these would have yielded a lower rate for the Nachman and Crowell data. But we don't want to just assume these values, we should try to test whether they are valid based on other data.

    Other mutation rates from phylogenetic comparisions

    Nachman and Crowell have not been alone in their ultimate reliance on fossil evidence as an assumption underlying the per-generation mutation rate. But several other studies came to a slower mutation rate. Mostly, these studies have assumed that the human-chimpanzee divergence happened significantly earlier than 5 million years ago. Necessarily, then, the human per-generation mutation rate would have to be lower, as long as the sequence divergence remained the same.

    These estimates are ultimately rooted in the date of one or more fossils, among which the generation time certainly varied. The resulting per-site mutation rates are often reported as per-year instead of per-generation. For example, Yi and colleagues [5] yielded a rate of 0.99 x 10-9 per year for the human-chimpanzee comparison, which would multiply to 1.98 x 10-8 per 20-year generation. They propose this as a maximal rate, assuming that Sahelanthropus at a minimum date of 6 million years ago is a hominin. With an older divergence date, they propose a correspondingly lower rate (e.g., 0.79 x 10-9 per year, not accounting for ancestral population polymorphism).

    Similarly, Steiper and Young [6] considered a long (1.9 Mb) alignment of sequence from 19 primate species. In their model to estimate relative rates on different branches of the primate phylogeny, they incorporated the assumption that Sahelanthropus is on the hominin clade. A divergence date of 6 million years gave rise to a human per-site mutation rate of 0.65 x 10-9 per year (1.3 x 10-8 per 20-year generation). A divergence date of 7 million years lowered the mutation rate to 0.57 x 10-9 per year.

    Low mutation rates do not always result from these studies. Several have arrived at either a high human mutation rate or a recent human-chimpanzee divergence time. Sometimes a recent human-chimpanzee divergence emerges simply by assuming the rate given by Nachman and Crowell. Yang [7] provides an example of this -- a paper that very thoroughly explores the relationship of divergence time and ancestral effective population size, but ultimately roots the estimates on a single value for mutation rate. This rate we have already seen was itself based on an assumption about divergence time.

    Kumar and colleagues [8] came to a much lower estimate for the human-chimpanzee divergence time, based on an Old World monkey-hominoid divergence at 23.8 million years ago. This estimate did not consider the effect of ancestral polymorphism on the mean genetic divergence time, and so should -- in the language of computer software -- be deprecated.

    I should reiterate that none of these estimates are suitable for testing the times of phylogenetic divergences, because they all assume that the date of some particular fossil (or set of fossils, by fitting a model) is the minimum divergence time for a clade.

    So much of the literature in this area is ultimately circular, I'm pulling out my sparse hair reading through it. By the time we get back to the mid-1990's, the sequence data are even sparser than my hair by today's standards -- only a few hundred base pairs, or a sampling of restriction sites. But the divergence time estimates have propagated forward from that time to today, recycled through the assumptions of papers in the intervening time. It's like the genetic equivalent of money laundering!

    Evidence from parent-offspring sequence differences

    There is another way besides phylogenetic comparison: Simply look at living people and see how many new mutations they have.

    But this is tricky because we are rarely in a position to know which mutations are new. Most variations that we see between two people have persisted in the population for hundreds of generations or more. It takes a special kind of mutation to make its newness evident.

    Up until the advent of large-scale sequencing, the most important source of information about the mutation rate came from the rates of spontaneous Mendelian diseases. When a person has a dominant genetic disorder not carried by either of his parents, you know that the mutation must be new. Disease rates have long been tracked as standard public health data.

    However, the per-genome or per-locus rate of Mendelian disorders can estimate the per-site rate of mutations only by adding well-resolved information about the target size of functional genes. For example, if we know the average gene length and the proportion of different amino acids in functional proteins we can make some estimate of the ratio of synonymous to nonsynonymous sites. But we would still lack information about the fraction of nonsynonymous mutations that cause deleterious effects on protein function. For this reason, it was possible for very early workers (e.g., Haldane) to come within the ballpark of per-locus mutation rates even before the genetic code was available. Yet such estimates are not strictly useful for understanding per-site rates of mutation.

    By 2000, widespread sequencing had begun to identify disease-causing mutations at the sequence level. When exons are known, it is possible to determine the "target size" -- the number of sites at which loss-of-function mutations may occur. These two values provide the numerator and denominator for an estimate of the per-site mutation rate.

    Kondrashov [9] applied this method to estimate the per-site mutation rate across 20 human genes. He surveyed the literature for genes where more than 100 patients had been sequenced completely for the causative locus, finding the causal mutations. Using this value and the disease incidence allowed an estimate of the per-site rate of mutation for different categories of transitions and transversions. There was some variation among loci, with an average rate of per-site mutation equal to 1.8 x 10-8 per generation.

    Kondrashov observed a few hotspots in these genes, with substitution or deletion rates as much as a hundred times the average site. He also observed that the per-gene rate of mutation varies according to the number of CpG sites. The rate of short deletions was on the order of 5 x 10-10, insertions were even less frequent.

    The rate estimate by Kondrashov is within the range considered by Nachman and Crowell, but only 3/4 of the value 2.4 x 10-8 widely cited as the long-term estimate. If this rate were applied to Nachman and Crowell's pseudogene data, it would predict a human-chimpanzee divergence time around 6 million years.

    This year, Lynch [10] performed a more extensive comparison using similar methods as Kondrashov. Including more genes, and considering a broader range of mutational effects (including missense as well as nonsense coding mutations), Lynch found an even lower estimate of mutation rate per generation -- only 1.28 x 10-8 per site.

    These estimates are not precisely the same as comparing parent-offspring pairs, but they are exceedingly powerful because the data on disease rates encompass very large populations of people.

    We should keep in mind the result of Subramanian and Kumar [2], which showed that exons have a higher effective rate of substitution than do noncoding regions. That result implies that the genome-wide rate of change should be lower than estimated by Lynch, because his estimate encompasses only coding mutations. Also, any effect of purifying selection on these mutations will tend to decrease the long-term rate of substitutions per site to a lower value than the rate of mutations. The rate estimated by Lynch should then be an overestimate of the substitution rate that would be applicable to hominoid phylogenetic relationships.

    A slower rate

    These estimates of the per-generation mutation rate are all low compared to the commonly-cited 2.5 x 10-8. They are not quite as low as the rate estimated by Roach and colleagues [1], but the Lynch estimate is very close: 1.28 x 10-8 compared to 1.1 x 10-8 per site.

    The lower estimate from Roach and colleagues is a direct comparison of parent and offspring. In my earlier discussion of that rate, I suggested that false negatives in the sequence comparisons might have lowered the apparent rate of mutations. I still think we can't rule out that possibility. But the rate is not alone, and so it is less surprising than it may have seemed.

    My post last week on the 1000 Genomes Project results ("Now for anthropological genomics") mentioned that the 1000 Genomes comparisions have arrived at essentially the same rate as Roach and colleagues. Comparison of one family trio led to a rate of 1.0 x 10-8 per site per generation; the other family trio gave rise to an estimate of 1.2 x 10-8 per site per generation. These bracket the estimate given by Roach and colleagues.

    My basic observation about the human-chimpanzee divergence time is still sound:

    If this mutation rate is accurate, then the average human-chimpanzee gene divergence has to be up around 11 million years ago. That can be accommodated with a 7-million-year-old species divergence only if we assume a very large ancestral population -- on the order of 50,000 or higher. Or, the ancestral effective size could be lower -- but that would make the species divergence substantially older -- 9 million years or more.

    As we go further back in time, this lower human mutation rate may be less and less relevant, because different primate lineages may have higher (or lower) rates. When some of the kinks have been worked out of whole-genome sequencing, it would be tremendously useful to sequence parent-offspring pairs in other primate species. With those data, rate heterogeneity could be tested directly.

    For events within the hominins, the parent-offspring rate of mutations ought to be better than a rate estimated from phylogenetic distance. Phylogenetic distances are estimated with even more error than mutations, increasingly so as our methods for comparing genomes improve. But some fraction of new mutations will ultimately be lost to purifying selection. That implies, again, that the longer term rate of substitutions will be lower than the rate of mutations measured from parent-offspring comparisons.

    A rate of 1.1 x 10-8 would have no effect on the number of genetic differences observed between people, because these differences are just counted, not estimated by genealogical relationships that are known. It is the unknown genealogical relationships, which are estimated from genetic differences, that may change substantially.

    Let's consider an example. Harris and Hey [11] sequenced 4200 bp of the gene PDHA1, an X-linked gene whose product is part of a mitochondrial enzyme complex. At the time of their study (1999), their result was one of the oldest coalescence times estimated for non-African populations based on sequence data; they estimated the root of the PDHA1 genealogy was 1.8 million years old. This estimate was based on the assumption that human and chimpanzee copies, which differed by an average of 40.42 substitutions, had diverged at 5 million years ago. That would imply that the average genetic difference between humans across the deepest root of the genealogy, 15.05 mutational differences, corresponds to 1.86 million years of time. If we instead assert a per-generation rate of 1.1 x 10-8 per site, these data would generate an estimate of 163,000 generations for the root of the genealogy, roughly 3.3 million years.

    In other words, a coalescence that appeared to have happened in early Homo now looks rooted at the age of A. afarensis. The chimpanzee-human genetic root would be around 8.7 million years for these data.

    These estimates would likely be biased too low, because the X chromosome has a lower rate of mutation than the autosomes by some extent. That issue was addressed by Lynch [10], due to the fact that X chromosomes are in males (with their higher rate of mutations) only 1/3 of the time compared to 1/2 the time for autosomes. Any purifying selection would also bias the estimate too low. If these 4200 bp have a higher-than-average CpG content, that is one factor that might require a higher per-generation rate.

    Is any of this a problem? I don't think we know yet. A lower rate must readjust the apparent correspondence of some molecular time estimates with the archaeological record. But to be honest, most of the apparent correspondences of such dates have been illusory, because genealogical relationships among genes have such large expected variance under any realistic human population model. It is really the availability of whole-genome comparisons that has a chance of improving these population models.

    References

    1. Roach JC, Glusman G, Smit AFA, Huff CD, Hubley R, Shannon PT, Rowen L, Pant KP, Goodman N, Bamshad M, et al. Analysis of Genetic Inheritance in a Family Quartet by Whole-Genome Sequencing. Science [Internet]. 2010;328:636–639. Available from: http://dx.doi.org/10.1126/science.1186802
    2. Subramanian S, Kumar S. Neutral Substitutions Occur at a Faster Rate in Exons Than in Noncoding DNA in Primate Genomes. Genome Research [Internet]. 2003;13:838–844. Available from: http://dx.doi.org/10.1101/gr.1152803
    3. Crow JF. The origins, patterns and implications of human spontaneous mutation. Nature Reviews Genetics [Internet]. 2000;1:40–47. Available from: http://dx.doi.org/10.1038/35049558
    4. Nachman MW, Crowell SL. Estimate of the Mutation Rate per Nucleotide in Humans. Genetics [Internet]. 2000;156:297–304. Available from: http://www.genetics.org/cgi/content/abstract/156/1/297
    5. Yi S, Ellsworth DL, wen-Hsiung Li. Slow Molecular Clocks in {Old World} Monkeys, Apes, and Humans. Molecular Biology and Evolution. 2002;19:2191–2198.
    6. Steiper ME, Young NM. Primate molecular divergence dates. Molecular Phylogenetics and Evolution [Internet]. 2006;41:384–394. Available from: http://dx.doi.org/10.1016/j.ympev.2006.05.021
    7. Yang Z. Likelihood and Bayes Estimation of Ancestral Population Sizes in Hominoids Using Data From Multiple Loci. Genetics [Internet]. 2002;162:1811–1823. Available from: http://www.genetics.org/cgi/content/abstract/162/4/1811
    8. Kumar S, Filipski A, Swarna V, Walker A, Hedges BS. Placing Confidence Limits on the Molecular Age of the Human-Chimpanzee Divergence. Proceedings of the National Academy of Sciences, U. S. A. [Internet]. 2005;102:18842–18847. Available from: http://dx.doi.org/10.1073/pnas.0509585102
    9. Kondrashov AS. Direct estimates of human per nucleotide mutation rates at 20 loci causing mendelian diseases. Hum. Mutat. [Internet]. 2003;21:12–27. Available from: http://dx.doi.org/10.1002/humu.10147
    10. Lynch M. Rate, molecular spectrum, and consequences of human mutation. Proceedings of the National Academy of Sciences [Internet]. 2010;107:961–968. Available from: http://dx.doi.org/10.1073/pnas.0912629107
    11. Harris EE, Hey J. X chromosome evidence for ancient human histories. Proceedings of the National Academy of Sciences, U. S. A. 1999;96:3320–3324.
    Tags: 
    mutation rate
    mutation
    1000 Genomes Project
    chimpanzees
    genetic divergence
    population genetics
    chumans
    Synopsis: 
    The 1000 Genomes Project is finding that the mutation rate is half the value usually assumed.

  • Ardipithecus challenge explication: the molecular clock

    Sat, 2010-05-29 18:28 -- John Hawks

    I've had a chance to mull over the exchange between Esteban Sarmiento and Tim White and colleagues in Science this week (Sarmiento 2010, White et al. 2010). It is not really fair to rely on brief technical comments to straighten out the meaning of a fossil skeleton. Each set of authors had less than 1000 words to put forth their arguments, which means that there were doubtless many pieces of support that they had no space to include.

    But when I write a technical comment, I spend a lot of time and effort to make the important points in that small space. If we can't agree on the basic outlines of the issues in a thousand words, I expect that ten thousand wouldn't settle anything, either.

    I have a wide array of reactions to the points in these comments, but I think it will be most useful for me to focus on just three issues. I'm going to include a lot more text than I would for a technical comment, both so that I can include the direct quotes from Sarmiento and White and colleagues, and so that readers with less direct knowledge of the issues can follow along. And I'll divide each issue into its own post, so that it doesn't take a week to get something posted.

    Let's start with the molecular clock argument. Sarmiento puts it briefly, depending on citations to do the lifting:

    Over the past 40 years, a multitude of independent biomolecular studies based on different methods, some analyzing millions of DNA base-pair sequences, have arrived at a minimum human/African ape divergence date of ~3 to 5 million years before the present (19–26)—a date that accords well with those based on comparative anatomical studies of living and fossil hominoids (15). With a 4.4-million-year geologic age (1), Ar. ramidus probably predates the human and African ape divergence.

    As I mentioned earlier this week, I discussed the issue in some depth last fall. The same argument originally was made by Vince Sarich, when the biomolecular evidence was based on antibody reactions to blood albumin, and the question was whether Ramapithecus was too old to be a hominin. Sarich (1971:76) memorably wrote:

    [O]ne no longer has the option of considering a fossil specimen older than about eight million years a hominid no matter what it looks like.

    David Pilbeam and others had claimed Ramapithecus as a hominid mostly because of its dental similarities to Australopithecus. Later, it became clear (especially thanks to David Frayer and Leonard Greenfield) that Ramapithecus wasn't even a valid taxon; the remains were females of Sivapithecus. Later it was shown that Sivapithecus itself had the forelimb of an arboreal quadruped; it apparently did not have a locomotor strategy like that of living great apes.

    Sound familiar?

    Sarmiento is correct. Over the past ten years, the human-chimpanzee divergence time has usually been put around 4 million years ago. Two things make this a deeper problem than it may appear. This estimate refers to the population divergence, and is a function both of the average genetic divergence and the variance among genetic loci in that divergence. That means that a simple recalibration to a lower mutation rate may not be enough to raise the estimate substantially.

    Second, the date of Ardipithecus isn't 4.4 million years -- it's 5.5 million, the time assigned to Ardipithecus kadabba. Unless they want to sunder the genus, White and colleagues really need a much higher population divergence time than the range most studies have been reporting.

    It's a complicated issue. So I was very interested to see which parts of this problem White and colleagues were especially focused on. How would they respond to the Sarich argument?

    [Sarmiento] argues that biomolecular studies accurately converge on a divergence date of approximately 3 to 5 million years ago, concluding that Ar. ramidus "probably predates the human and African ape divergence." However, his cited estimates vary widely and all rely on inadequate calibration. Indeed, the strongest calibration is now from hominids themselves: Late Miocene fossils from Chad, Kenya, and Ethiopia whose derived characters effectively falsify late divergence estimates (2).

    I found this really disappointing. There's no attempt here at any sensible critique of the molecular divergence time. Why is the calibration inadequate? What is the maximum human-chimpanzee divergence date we get by assuming that Chororapithecus is on the gorilla clade? Do they have a candidate for a significantly earlier pongine than Sivapithecus indicus? Do White and colleagues advocate an Eocene divergence of hominoids and cercopithecoids? Do they claim a mutation rate slowdown in humans, or in hominoids?

    Instead of giving a sensible response, White and colleagues resort to circular logic. In their description, molecular comparisons can never show that Ardipithecus is too early to be a hominin, because we can never accept a calibration that shows Ardipithecus is too early to be a hominin.

    References:

    Frayer DW. 1976. A reappraisal of Ramapithecus Yearbook Phys Anthropol 18:19-30.

    Greenfield LO. 1979. On the adaptive pattern of "Ramapithecus". Am J Phys Anthropol 50:526-548.

    Sarich VM. 1971. A molecular approach to the question of human origins. In (P. Dohlinow & V.M. Sarich, Eds.) Background for Man: Readings in Physical Anthropology, pp. 60‐81. Boston: Little, Brown.

    Sarmiento EE. 2010. Comment on the paleobiology and classification of Ardipithecus ramidus. Science 328:1105. doi:10.1126/science.1184148

    White TD, Suwa G, Lovejoy CO. 2010. Response to Comment on the paleobiology and classification of Ardipithecus ramidus. Science 328:1105. doi:10.1126/science.1185462

    Tags: 
    chumans
    Tim White
    Ardipithecus
    genetic divergence
    Aramis

  • A low human mutation rate may throw everything out of whack

    Thu, 2010-03-18 16:30 -- John Hawks

    Last week, a paper looking for the genetic causes of Miller syndrome reported the whole genomes of four members of a single family: two siblings with the disorder and their two parents without. The idea was that they would simply compare the affected and unaffected genomes. They would then find candidate loci that might account for Miller syndrome in the affected siblings. By exploiting some other sources of information, they found what they were looking for. Daniel MacArthur covered the story in his post, "Disease hunting with whole genome sequences: the good news, and the bad news".

    I got interested in another aspect of the story. With whole-genome sequences of parents and offspring, it becomes possible to directly determine the rate of mutations in each generation. The paper by Roach and colleagues did just that -- they counted 28 in the 2.3 billion bases of sequence they included in their comparison. That makes a per-site mutation rate of 1.1 x 10-8 per generation.

    Which is a pretty interesting number. You see, it's less than half what it ought to be:

    [O]ur estimated human mutation rate is lower than previous estimates, the most widely cited of which is 2.5 x 10-8 per generation (10) based on three parameters: a human-chimpanzee nucleotide divergence per site (Kt) of 0.013, a species divergence time of five million years ago, and an ancestral effective population size of 10,000. More recent estimates indicate a nucleotide divergence of 0.012 (9), species divergence time between six and seven million years ago (11–15), and ancestral effective population size between 40,000 and 148,000 (16–19). With these parameter ranges and a generation length of 15 to 25 years, the mutation rate estimate is between 7.6 x 10-9 and 2.2 x 10-8 per generation, which is consistent with our intergenerational estimate of 1.1 x 10-8. Our estimate is within one standard deviation (SD) of an earlier estimate of 1.7 x 10-8 (SD: 9 x 10-9) based on 20 disease-causing loci (20). The rate we report is for autosomes, and should be several-fold lower than that of the Y chromosome, as in the male germline more cell divisions occur per generation. Though our rate differs approximately as expected from the recently reported estimate of 3.0 x 10-8 (95% CI: 8.9 x 10-9 – 7.0 x 10-8) for the Y chromosome, the error rates make this difference not significant (21).

    You can see the obvious implication: If this mutation rate is accurate, then the average human-chimpanzee gene divergence has to be up around 11 million years ago. That can be accommodated with a 7-million-year-old species divergence only if we assume a very large ancestral population -- on the order of 50,000 or higher. Or, the ancestral effective size could be lower -- but that would make the species divergence substantially older -- 9 million years or more.

    There is a second implication. Most studies of human genetic variation have assumed that 5-million-year-old human-chimpanzee divergence and the high associated rate of mutations. If the true rate is less than half that, then the coalescence times of human genes are more than double most estimates. That would include our estimates of human-Neandertal genetic differences.

    Well, that's a fine pickle.

    I'm not quite ready to believe the very low rate estimate. The analysis in this paper uncovered tens of thousands of false positives, and had to filter through those to arrive at 28 true mutations. The filtering involved resequencing all the positives to determine which were true and which were false, but maybe there's room in there for a substantial number of false negatives, too.

    If this low estimate were true of the human-chimpanzee divergence, it would imply vastly higher ages for other primate divergences, or a much lower rate on the human lineage specifically. So that allows another check on the process.

    But generally, I'll be looking at whole-genome family comparisons with great interest, because they will give us a much more precise understanding of the rate of mutations and recombinations across the genome.

    References:

    Roach JC and 14 others. 2010. Analysis of Genetic Inheritance in a Family Quartet by Whole-Genome Sequencing. Science (early online) doi:10.1126/science.1186802

    Tags: 
    mutation rate
    mutation
    1000 Genomes Project
    genomics
    sequencing
    chumans
    genetic divergence
    coalescent
    Synopsis: 
    Whole genome sequencing of a family finds a very low number of mutations, suggesting evolution doesn't have the timescale we thought.

  • Unbelievable Y chromosome differences between humans and chimpanzees

    Thu, 2010-01-14 00:11 -- John Hawks

    Holy crap!

    Indeed, at 6 million years of separation, the difference in MSY gene content in chimpanzee and human is more comparable to the difference in autosomal gene content in chicken and human, at 310 million years of separation.

    So much for 98 percent. Let me just repeat part of that: humans and chimpanzees, "comparable to the difference ... in chicken and human".

    This is from a new paper that's just shown up in the Nature advance publication zone. The authors are Jennifer Hughes and colleagues, and the subject is the first complete sequencing of the chimpanzee Y chromosome. "MSY" stands for "male-specific region of the Y chromosome" -- it's most of the Y, aside from a small fraction that recombines with the X chromosome.

    The Y chromosome was part of the initial chimpanzee genome draft, and was recognized then as a "clear outlier" in showing low human-chimpanzee sequence similarity (Chimpanzee Genome Consortium 2005). But it wasn't obvious just how different it was because the relatively short sequencing reads aligned fairly well with the human draft. That comparison also seems not to have included the missing genes (they might have just been missed during sequencing), or duplications. Moreover, the Y chromosome includes a high fraction of repetitive sequence, including long front-to-back, or "palindromic" passages. Only with very long reads with long overlaps is it possible to straighten out the large-scale sequence, and thereby detect sequence reorganizations and large copy number variants. This kind of intensive sequencing has so far been completed only for chromosome 21 and now the Y chromosome.

    I can't believe how sedated the reaction to this paper has been so far. The outcome of the sequencing is really, really weird. More than thirty percent of the chimpanzee Y chromosome has no homolog in humans, and likewise for the human Y in chimpanzees.

    I mean, really -- here's a map:

    Chimpanzee compared to human Y chromosome

    Just glancing at the ideograms, they don't even look like homologous chromosomes!

    Obviously they are; there's a whole lot of homologous sequence in there including functional genes. But the structure of both human and chimpanzee Y chromosomes has evolved incredibly fast compared to the rest of the genome.

    The central question: beyond its interest for Y chromosome structural evolution, what does this result say about the evolution of human (and chimpanzee) phenotypes?

    Option 1: Maybe nothing. The main mechanism for the rapid structural evolution was probably autologous recombination. Imagine that the Y chromosome wriggles around and different copies of repetitive sequences get together with each other.

    The molecular mechanisms that enabled this wholesale remodelling of ampliconic regions merit consideration. Although the chimpanzee and human MSYs do not normally participate in meiotic exchange with a partner chromosome, the mirroring of sequences in the ampliconic regions provides ample opportunity for ectopic homologous recombination within the MSY. This recombinational proclivity is well documented in the human MSY, where it has repeatedly given rise to large-scale structural polymorphisms during the past 100,000 years of human history as well as to Y-chromosomal anomalies that cause spermatogenic failure and sex reversal in current generations. We suggest that ectopic homologous recombination between MSY amplicons has similarly accelerated structural remodelling of the MSY in the chimpanzee and human lineages during the past 6 million years.

    That leads to rapid structural evolution, but not necessarily any functional changes.

    Option 2: Massive changes in gene regulation. Then again, widespread relocations of genes have a way of stripping them apart from upstream (or downstream) elements that may regulate their expression. Besides that, chimpanzees have lost several genes entirely, while humans have picked up a few that weren't in the common ancestor. So there's a potential for phenotypic evolution from these changes, possibly reverberating through the genome.

    In aggregate, the consequence of gene loss and gain in the chimpanzee and human lineages, respectively, is that the chimpanzee MSY contains only two-thirds as many distinct genes or gene families as the human MSY, and only half as many protein-coding transcription units.

    That's pretty amazing. They speculate that the most important phenotypic correlates of these genetic changes may be related to sperm or testicular function, which certainly is a target of rapid evolution elsewhere in the chimpanzee and human genomes.

    Option 3: Hitchhiking. OK, this isn't different or mutually exclusive from the above, but it's worth remembering that it only takes a single advantageous mutation to fix the entire Y chromosome in the population. That event carries with it whatever strange mutations might be on the same copy as the initial advantageous change. This kind of event may have happened dozens or even hundreds of times on the chimpanzee and human lineages. Indeed, if it was common enough, hitchhiking can drive its own dynamic, since it tends to fix lots of slightly deleterious variations that later have to be repaired or accommodated.

    An interesting possibility: Maybe the extreme evolution of the Y chromosome in the emerging human and chimpanzee lineages explains the unusual similarity of their X chromosomes.

    I'm thinking back to the story about chumans and the divergence of chimpanzee and human lineages ("The dawn chumans"). Patterson and colleagues (2006) suggested that the two lineages had undergone some kind of hybridization event long after they began to diverge. This surprising hypothesis was meant to explain why the X chromosome shows a substantially lower level of genetic difference between humans and chimpanzees, compared to the average autosomal locus. I don't think that a late hybridization is necessary to account for X chromosome similarity. A large ancestral effective population size implies a wide variance in coalescence times in the ancestral population; the average on the X will be lower than the autosomes, and if there was any hitchhiking the X would be lower still.

    But...that X chromosome similarity might have a different explanation. A fraction of the human Y chromosome continues to recombine with the X. Imagine an initially rapid divergence of Y chromosomes within the chuman population. For a while, there might have been a strong selection pressure on the ancestral X to equip it for the structural diversity of the Y. Possibly an inverse relation would have emerged: the as the Y becomes variable (possibly in partially isolated subpopulations), the X adapts to that variation until reproductive isolation finally occurs.

    Could this have been the proximate cause of human-chimpanzee reproductive isolation? The sex chromosomes are often implicated in speciation through Haldane's rule. It's a bit of speculation, but not too far from some discussion within the paper, particularly the relation between Y chromosome variations and infertility.

    References:

    Hughes JF and 16 others. 2010. Chimpanzee and human Y chromosomes are remarkably divergent in structure and gene content. Nature (early online) doi:10.1038/nature08700

    Tags: 
    Y chromosome
    chumans
    genetic divergence
    X chromosome
    copy number variants
    genomics

  • Chumans not chimps

    Sat, 2010-01-02 14:34 -- John Hawks

    Found in Nature's year-end Research Highlights:

    Palaeontology: Not from chimps

    ...

    Analysis of the remains by Tim White at the University of California, Berkeley, and a large team of collaborators revealed that humans did not evolve from ancient chimpanzees, as has long been believed. Humans instead evolved along a separate lineage from the last common ancestor shared by early hominids and extinct apes.

    Good grief! Didn't anybody proofreading this realize the problem? This is Biology 101 stuff.

    Meanwhile, this reminds us of one problem of the "Ardi was not like chimpanzees" storyline. It's quite an important aspect of the discovery, but it should reaffirm the prediction that the chumans weren't living chimpanzees. White and Lovejoy handled this relatively well with their "as Darwin told us" schtick, even if the "Darwin" quotes didn't come from Darwin.

    Tags: 
    Ardipithecus
    creationism
    chumans

  • Reviewing the clock, and phylogenomics

    Tue, 2009-11-17 18:27 -- John Hawks

    After reading yesterday's penguin post, one of my readers thought I'd given up the ghost on the molecular clock.

    But notice the bottom line of that message: those ancient penguins didn't tell us any thing new about the rate of mitochondrial changes over 10s of thousands of years. The rate, over at that time period, is pretty much what you would expect from comparing humans, or comparing Neandertals. Considering that the generation-to-generation rate of mutations of the mitochondrial DNA is maybe an order of magnitude higher, I'd say that consistency is pretty impressive.

    Much more important, when it comes to comparing humans and chimps, we've come billions of base pairs beyond the mitochondrial DNA alone. We have drafts of the complete the numbers of humans and chimpanzees, macaques, and working drafts for gorillas, orangutans, and a handful of other primates. We have a better ability than ever to reconstruct the phylogenetic relationships of those species, the times that they diverged from each other, and even something about the number of individuals and structure of their ancient populations.

    For the past five years, almost every study including more than a single gene has agreed on one central fact: humans and chimpanzees last exchanged genes less than 6 million years ago. Most of them place the date much younger -- an average of less than four and a half-million years ago.

    Still, these kinds of comparisons can be quite complicated, and many -- maybe most -- of my paleoanthropology colleagues would prefer to remain ignorant of the details.

    I can kind of sympathize. If somebody is willing to say it could be 6 million years, well, that doesn't sound so different from seven. And Sahelanthropus is only seven. What's the problem anyway?

    I've got to say, though, that attitude is a fundamental lack of seriousness about the data. It's like if I said about Lucy, "Hey it's just a pelvis, right, what's the big deal?"

    Well, it's the evidence, that's what. A. afarensis is a large and substantial sample with dozens of shared homologous features with humans and other hominins. If the genetics told us that humans and chimpanzees diverged less than 2 million years ago that would be a substantial conflict. Either that estimate would be wrong, or much of what we thought we knew about the pattern of hominin evolution would be.

    We are in fact at that point in genetics. If the human-chimpanzee divergence really were much older than 5 million years ago, then much of what we think we know about population genetics of primates must be wrong.

    I understand that many of my readers might welcome that suggestion. I, on the other hand, am having a hard time figuring out just how I'm supposed to make the divergence date much older than the current best estimates. In the 1990's, it was fashionable to just say that the clock was wrong, because our estimates of mutation rate were wrong, and leave it at that. People even did silly things like provide "confidence intervals" based on different assumptions about the human-orangutan divergence. If it was 12 million years ago, you'd get one (low) answer; if it were 16 million years ago, you'd get another (high) answer. Report the low and high ends, there's your "confidence" interval. Human-chimpanzee divergence: 4 to 6 million years.

    It was a joke, but that's where things stood.

    Nowadays, we know an awful lot more about the relations of these populations. I'm going to point everybody to a recent review paper -- it was released the same week as Ardipithecus was -- by Adam Siepel, in Genome Research. It's a very good review of the recent literature on the human-chimpanzee divergence, and by implication the human-gorilla and other primate divergences. It is not about building a phylogenetic tree -- it's about how we use sequence data from many genes to put together a phylogenomic tree, one that involves the divergences of populations and also their inbreeding and selection characteristics.

    The time we estimate for a population divergence depends on the size of the ancestral population, as well as the pattern of selection within it. These factors also affect the sorting of gene variants of the ancestors into the descendant populations. As Siepel points out, these effects have led to two different methods of examining the demography and divergence times of ancient species:

    Two simple, but ingenious, approaches were proposed early on, both of which exploited the fact that, with sparse sampling across the genome, the loci under study were likely to be unlinked, and their genealogies could be assumed to be statistically independent. The first method, by Takahata (1986), derived information about ancestral population sizes from the variance in the estimated divergence times for pairs of orthologous sequences. The second, by Wu (1991) (see also Hudson 1983a; Nei 1987), made use of the variance in tree topologies estimated from three or more orthologous sequences. Takahata's method essentially estimated [population divergence time] and [effective size] from the variance in estimates of [genetic divergence time] at multiple loci (in the notation above), while Wu's method estimated [effective size] from the relative frequency of topological inconsistency in reconstructed gene trees.

    Those topological inconsistencies began to show up during the 80's and 90's, when people would publish sequences that favored human-gorilla or chimpanzee-gorilla clades. These were genes in which humans really were more closely related to gorillas, because the human-chimpanzee (chuman) ancestral population was large enough to retain two divergent alleles for the two million or so years that chumans existed.

    Siepel goes on to review the literature using variants of these two approaches during the last seven or eight years. The Nature chimp-human hybridization paper by Patterson and colleagues (2006, which I reviewed here) forms a central part in the discussion, as people have reacted to that paper and the major issue it raised.

    Reading the review, one cannot help but notice the low age estimates that keep coming up again and again. Most of them are under 4.5 million years. Patterson and colleagues had one of the highest recent estimates, putting the speciation at less than 5.4 million years. That's because they assume a smaller effective size in the ancestral lineages -- pushing the date higher. The more that demography fiddles with the assortment of ancestral genes before a population divergence, the younger the resulting estimate of divergence date will be.

    To make the date older, you need to assume there was no demography -- an extreme chuman bottleneck. But that would be inconsistent with the evidence of incomplete lineage sorting -- those gorilla genes that we share. And it would take some magical rate discontinuities among genetic loci to get them the amount of interlocus variability that they have.

    The review mentions some recent work suggesting that background selection may have reduced the site diversity in the ancestral species -- work to explain why the human X chromosome is even more similar to chimpanzees than the autosomes. Taken to an extreme, background selection or massive hitchhiking could raise the divergence estimate a bit, but it doesn't overcome the issue of incomplete lineage sorting, either.

    You could push the human-orangutan divergence higher, or the human-macaque divergence, both of which help to calibrate the mutation rate. But that's not going to make 4 million years into 8 million, not unless orangutans diverged from us in the Oligocene.

    You could propose a massive slowdown in mutations in the chuman lineage. But why? How? Like I said earlier, you'd have to change something pretty fundamental about our understanding of primate genetics.

    No, it's very hard to see how these dates are going to get much older. What I'm saying is that you can't just wave them away; these are serious estimates and I don't see any simple way to get a better one.

    Now, the question is, do the geneticists insufficiently appreciate the hominins? Do they just not care about the havoc this wreaks in paleoanthropology-land?

    In fact, Siepel addresses this issue. The review mentions that Patterson and colleagues (2006) offered their hybridization idea in part to explain the early "hominin", Sahelanthropus. With the revelation of Ardipithecus' postcranial anatomy, I don't think we need to resort to chuman hybrids.

    I think it's more parsimonious to imagine a widespread population of chumans, a large-bodied, basically Ardipithecus-like primate, structured into regional populations in much the way that today's chimpanzees and gorillas are. This population was numerous and stable, and it gave rise over time to many more arboreally adapted branches -- first the gorillas and later the chimpanzees. The remainders, as it were, became the hominins.

    There are various hangups with this scenario that make me hesitate. I do take Orrorin seriously, for example -- it is hard to accommodate a 6-million-year old hominin under the large-population recent-divergence hypothesis.

    And on the genetic side, the substitution rate in the nuclear genome is affected by positive selection, background selection, duplications and unequal crossing over. It's quite possible that some odd demographic scenario might reduce the genetic divergence date yet further, or increase it to some extent.

    What's encouraging is that today's dense genetic data and fast modeling give us the chance to test these scenarios. We can model selection and demography directly and comparing results to observed genetic patterns.

    OK, it's bedtime. More on this later...

    References:

    Siepel A. 2009. Phylogenomics of primates and their ancestral populations. Genome Res 19:1929-1941. doi:10.1101/gr.084228.108

    Tags: 
    chumans
    phylogenomics
    genomics
    genetic divergence
    speciation

  • Beneath the dawn chumans

    Thu, 2009-08-27 08:30 -- John Hawks

    Thomas Mailund covers some recent modeling of the human-chimpanzee divergence: "Doubts about complex speciation between humans and chimpanzees". Here's the bottom line:

    Voilà! No more need for a complex speciation history!

    I wrote about the initial suggestion of a "complex speciation" when it came out in 2006: "The Dawn Chumans" I didn't buy it then, I don't now. This is an important issue to work out, because all our estimates of the human-chimpanzee divergence time depend on the importance of lineage-sorting in the ancestral (chuman) population.

    (via Evolving Thoughts)

    Tags: 
    Miocene
    chumans
    lineage sorting
    genetic divergence

  • Late Miocene fossil apes from Africa

    Tue, 2009-08-25 22:42 -- John Hawks

    Time for some attention to the Miocene apes. I've neglected them for the last few years, and there have been some interesting finds. I don't mean the stuff that most people find interesting -- near-complete skeletons, or discovery of rare postcranial elements. There've been some of those, but they're European. No, I mean interesting as in African, which means potential ancestors of humans, gorillas or chimpanzees. Or all three.

    This is a part of the fossil record that potentially can confirm (or disconfirm) details of the genetic comparisons between living apes. We have an increasingly detailed model for the speciation of humans and chimpanzees from their chuman ancestors. That model has been built from the complete genomes of humans, chimpanzees and macaques, and the partial genomes of the other apes. But there are potential reasons for uncertainty in the timing and duration of speciations among these living hominoids. What we need is a fossil record.

    And now we have just a tiny bit of one.

    Chororapithecus

    I wrote about Chororapithecus two years ago on its announcement ("Did Gen Suwa just save paleoanthropology?", "More on Chororapithecus"). It's a small set of 10-million-year-old teeth from Ethiopia that look a lot like you'd expect an early gorilla to look. I don't have any new news about it, but I was reading back through the paper by Gen Suwa and colleagues (2007) and once again ran across this shocking paragraph:

    Acceptance of Chororapithecus as a basal member of the gorilla clade would push back the gorilla species split to >10.5 Myr ago. Because this is a minimum date established from a meagre fossil record, the actual divergence would have predated this by an unknown time gap. From the currently available evidence, we consider that a species split of ~20 Myr ago for Pongo, 12 Myr ago for Gorilla, and 9 Myr ago for Pan are all probable estimates (see Supplementary Information). We consider that the early divergence hypothesis is congruent with both fossil and molecular data, and should be further evaluated using both sides of the evidence (Suwa et al. 2007:924).

    I found that so astounding when reading it this time, that I had to go back and check what I'd written two years ago. And, blog be praised, I took good notes on it. After quoting from their online supplement (once again, grumbling that the essential details are hidden online where nobody reads them!), I concluded:

    Well, that's a tricky bit of argument. We might believe that African apes never left Africa and that all the dryopithecines are therefore on the orangutan line. At least, that makes some biogeographic sense. But it's hard to argue that any of these dates are "congruent" with genetic evidence as we currently understand it. Many of the recent methods don't make any prior assumptions about "calibrated" divergence times like the orangutan-human divergence. Worse, Hobolth et al. (2007) found a human-chimp speciation time of 4 million years even considering an orangutan-human divergence of 18 million years.

    The "shorter generation lengths" explanation doesn't help much -- after all, if we infer that the current great ape lineages existed as early as 20 million years ago, then almost all of the divergence time is occupied by long-generation-length species. Much faster evolution in Old World monkeys should show a strong signal of acceleration in that lineage (with a higher number of derived substitutions), and we don't see it.

    If we believe these interpretations of the genes, a 10-million-year-old gorilla did not exist. Chororapithecus was something else.

    Many years ago, I got used to the fact that paleontologists and geneticists live in separate realities. But this one is a real mind-bender. How somebody can blithely write that a date could be consistent with genetic estimates when the date is actually twice as old as any genetic estimate -- it's just astounding. And that we have to push all of this around for three teeth.

    OK, so why am I re-reading this now? Well, Chororapithecus no longer has the only three teeth. So, it's time for a little review of the rest of the fossil record of African Late Miocene apes.

    Nakalipithecus

    The most substantial sample belongs to Nakalipithecus, reported by Yutaka Kunimatsu and colleagues in 2007. I didn't review that paper at the time, because it came out at the same time as our acceleration paper, so I was a little busy. The Nakalipithecus and Chororapithecus papers came out too close together for there to have been systematic comparisons of the two apes. Based on the papers -- and the brief account by Kunimatsu et al. (2007) -- the Nakalipithecus dentition is more comparable to Ouranopithecus than to gorillas.

    In addition, Kunimatsu and colleagues mentioned a "large mystery ape" (my phrase, not theirs) represented by a single premolar. They wrote that this ape is more primitive and very different from Nakalipithecus or hominins. From an upper premolar, I find this idea hard to interpret -- maybe it looks like a Proconsul? They don't picture it or give measurements, so I'd say it's a genuine mystery. Maybe they are hoping to turn up more examples before they publish.

    A mixed bag from Kenya and Niger

    Martin Pickford and Brigitte Senut (2005) reported four ape teeth from three sites in Kenya. Three of the teeth, dating to around the same age as Orrorin, 5.9 million years ago, represent a gorilla-sized ape whose teeth look quite a bit like you'd expect an early gorilla to look, if a bit smaller.

    Strangely, neither Suwa and colleagues (2007) nor Kunimatsu and colleagues (2007) mentioned these ancient gorilla-like teeth. You'd think somebody would have pointed this out. The upper molar fragment from Kapsomin looks an awful lot like the Chororapithecus holotype -- the two papers show the anatomy in profile, and the break in the Kapsomin specimen allows comparison of the enamel thickness, which is very comparable. The lower molar from Cheboit, on the other hand, doesn't look very much like the Chororapithecus lower molar, even though both are supposed to be M3. The Chororapithecus specimen looks more like a gorilla M3 -- elongated and narrower at the distal end, looking triangular in occlusal view. But the three examples of Nakalipithecus lower M3 do look like the Cheboit tooth -- all are more rectangular in occlusal shape than the triangular Chororapithecus example, two of them have a slightly lingually displaced hypoconulid. The difference is size -- the Nakalipithecus teeth are bigger, well within the gorilla range, while the Cheboit and Kapsomin teeth are at the bottom end or below that range.

    Pickford and Senut (2005) also described an older molar from Ngarora, some 12.5 million years old. I think you could probably find a reasonable match for this tooth among samples of Dryopithecus -- it's the size of a chimpanzee molar but doesn't share any derived features. The authors suggest that the specimen may be an early member of the chimpanzee clade, which would require pushing the Pan-Homo divergence back before 12.5 million years ago. That's the same argument we saw above from Suwa and colleagues (2007).

    Part of the reason I'm bringing this up now is a new paper by Martin Pickford and colleagues (2009), describing an ape mandible fragment from Niger. This is not the first publication on the fossil; they previously presented it in the South African Journal of Science (2008). It is a museum specimen collected in 1964 by oil geologists, and the precise locality was not recorded. The associated faunal collection allowed Pickford and colleagues to place it in the Late Miocene, but only broadly between 11 and 5 million years ago. The mandible only preserves a segment of the body around and including the roots of a first molar -- it's the right size and robustness to be a chimpanzee, but again there are no derived features, not even any occlusal anatomy on the molar. Perhaps it's Sahelanthropus' sinister twin.

    I'll just mention Samburupithecus, another element of the Late Miocene African fossil ape inventory. Pickford and Ishida (1998) interpreted it as relatively derived compared to Kenyapithecus, and possibly an ancestor or outgroup to the African ape-hominin clade. At 9.5 million years old, it would predate the divergence of gorillas from the chimp-human clade, on the current molecular chronology.

    Where do they fit?

    OK, so after all these ape dental and mandibular remains, we come back to the question that got me started. Do any of these apes compel us to revisit the current DNA chronology?

    Let's review the problem: DNA comparisons suggest that humans and chimpanzees diverged less than 5 million years ago, and gorillas a shade before that, within the last 7 million years. Against that chronology, we have three samples of fossils that are arguably hominins, from earlier than 5 million years ago (Sahelanthropus, Orrorin, and Ardipithecus kadabba), two large fossil East African apes, known from teeth, which have been compared with gorillas, and several specimens that may belong either to a gorilla-sized or chimpanzee-sized ape.

    It is tempting to play "what-if" games with the chronology -- what if we changed the date of the human-chimp ancestor, for example; would the large hominoids work as members of a gorilla clade? But that's really very misleading. The genealogy of a single gene locus can be pushed around on the assumption of a different rate calibration. Models for multiple loci involving lineage sorting -- the models that we now test using genome-wide data -- involve trade-offs between speciation time, population history, rate heterogeneity, and branch lengths.

    I think before I can answer the question, I will need to review two more issues:

    1. What are the real constraints and confidence intervals on the genetic estimates? Just how far is it fair to push them?

    2. Do we face any similar problems with the Asian apes? What about the cercopithecoids? If a single chronology works for these other lineages, the argument is less credible for a special chronological exception for the African ape-hominin (that would be hominine) clade.

    So, the next post in this series will cover genetic estimates of human-chimpanzee divergence times.

    References:

    Bernor RL. 2007. New apes fill the gap. Proc Nat Acad Sci USA 104:19661-19662. doi:10.1073/pnas.0710109105

    Kunimatsu Y and 13 others. 2007. A new Late Miocene great ape from Kenya and its implications for the origins of African great apes and humans. Proc Nat Acad Sci USA 104:19220-19225. doi:10.1073/pnas.0706190104

    Suwa G, Kono RT, Katoh S, Asfaw B, Beyene Y. 2007. A new species of great ape from the late Miocene epoch in Ethiopia. Nature 448:921-924. doi:10.1038/nature06113

    Pickford M, Ishida H. 1998. Interpretation of Samburupithecus, an Upper Miocene hominoid from Kenya. C R Acad Sci Paris 326:299-306.

    Pickford M, Senut B. 2005. Hominoid teeth with chimpanzee- and gorilla-like features from the Miocene of Kenya: Implications for the chronology of ape-human divergence and biogeography of Miocene hominoids. Anthropol Sci 113:95-102. doi:10.1537/ase.04S014

    Pickford M, Senut B, Morales J, Braga J. 2008. First hominoid from the Miocene of Niger. S Afr J Sci 104:337-339.

    Pickford M, Coppens Y, Senut S, Morales J, Braga J. 2009. Late Miocene hominoid from Niger. C R Palevol 8:413-425. doi:10.1016/j.crpv.2008.11.003

    Tags: 
    Samburupithecus
    Chororapithecus
    apes
    genetic divergence
    Nakalipithecus
    Miocene
    chumans

  • Did Gen Suwa just save paleoanthropology?

    Thu, 2007-08-23 08:21 -- John Hawks

    That depends on whether these teeth are really from a gorilla, I suppose.

    Chororapithecus teeth compared to gorilla mandible

    Chororapithecus abyssinicus teeth compared to gorilla mandible. Photo credit: Gen Suwa/University of Tokyo.

    Oh yeah, sure, "saved paleoanthropology" is overdramatic. But what am I supposed to write? Over four years, we have had a series of genomic comparisons narrowing down the age of the human-chimp common ancestor to something like 2/3 the age of Sahelanthropus. I said it was a crisis, and it is: these data sources must agree. Either we have to cast out a bunch of hominids, or we have to wrench the genes by around a factor of two.

    Now, Suwa and colleagues show up with a 10-million-year-old gorilla. A 10-million-year-old gorilla works just fine with 7-million-year-old hominids. It doesn't work at all with a 7-million-year-old human-gorilla common ancestor. So there's no doubt about the centrality of this particular ancient gorilla -- if it is one.

    So far, all the articles I've seen have someone on the record expressing some reluctance to accept the teeth belonged to the gorilla lineage. Reuters has Peter Andrews; Nature has Jay Kelley; National Geographic has Richard Potts.

    Should we be skeptical? Well, there are lots of convergences among Miocene apes. Many of the dental convergences are detailed in our paper about Sahelanthropus, available open-access from PaleoAnthropology. These convergences make it difficult to identify hominids based on the teeth alone. They also make it hard to say that any particular big-toothed, leaf-eating ape is definitely a gorilla. After all, if it eats like a gorilla, why shouldn't it have teeth like a gorilla?

    Suwa and colleagues go to some pains to demonstrate that the dental similarities with gorillas are more than enamel-deep. Their strongest argument is that the tooth morphology exhibits a derived gorilla-like condition well below the surface, at the enamel-dentine junction. That is, while the tooth was forming, the initial growth surface took on a distinctive shape which was then reflected by the form that the growing enamel took.

    The most distinctive features of the Chororapithecus dentition are the derived shearing structures seen in portions of its molars (Fig. 2), despite a generally low cuspal topography (the latter is apparently a primitive retention).

    Examination of internal morphology by micro-computed tomography (micro-CT) demonstrates that these occlusal features were underlain by distinct enamel-dentine junction (EDJ) structure (Fig. 2). In particular, the straight to weakly concave mesial protocone crest seen in the EDJ of CHO-BT 4, -BT 5 and -BT 6 is gorilla-like, and is formed by a mesiobucally located junction of the mesial protocone crest and mesial marginal ridge. Such spatial placements are best considered to be regulated by enamel-knot-related signalling patterns during early morphogenesis [23, 24], and may be one of the underlying causes of the mesiodistally elongate upper molar shape generally characteristic of folivorous primate species. In the lower molars, the most distinctive EDJ topography occurs at the trigonid crest, the structural counterpart that occludes with the upper molar mesial protocone crest. The high trigonid EDJ crest is continuous between the metaconid and protoconid cusp tips (Fig. 2). Because recent experimental and quantitative genetic studies suggest significant degrees of morphogenetic independence between corresponding upper and lower molar structures [25, 26], the presence of a functionally integral inter-jaw pattern of morphological expression, as seen in the Chororapithecus molars, suggests adaptation by natural selection, as opposed to chance emergence of neutral morphological minutia.

    Still, "minutia" is a loaded term. Why shouldn't an ape that evolves the same shear characteristics as a gorilla molar use the same developmental process to achieve them? The more that development of the teeth are constrained by these genes, the more likely it is that different lineages will evolve in parallel.

    Nor is it entirely obvious that Chororapithecus is actually gorilla-like in these characters. The paper compares two ratios involving cusp dimensions measured internally beneath the enamel cap. That's high-tech, but the ratios do not sort out gorillas from chimpanzees, don't sort Chororapithecus from either of those apes or early hominids, and -- even worse -- it's not even clear how these ratios may vary with size. Does Chororapithecus look sort-of like a gorilla on these ratios because it's a sort-of gorilla? Or because it's big? The enamel is relatively thicker than gorillas, like other Miocene apes and orangutans. Clearly the specimen is much less derived than gorillas, but could that be because it isn't a gorilla?

    Well, there's the problem: there's not too much to go on with these teeth. I think Suwa et al. laid out as good a case as there is. A 10-million-year-old gorilla can't be expected to look just like gorillas today. It's not like the teeth look more like something else besides a gorilla. Gorillas really are far more derived in these dental characters than the Chororapithecus dentition, which makes the comparison more difficult. And so, the conclusion of the paper is equivocal:

    The similarities seen between the two genera raise the possibility that Chororapithecus is a Miocene member of the Gorilla clade. Alternatively, with its combination of thick enamel and distinct molar cresting pattern, Chororapithecus may represent a unique adaptation that is convergent with gorillas in molar structure and function. Although the evidence for phylogenetic affinity between Chororapithecus and Gorilla is inconclusive, it may be that the basal members of the gorilla clade shared large tooth size and incipiently enhanced molar shear as a part of an herbivorous diet that accompanied (presumed) larger body size. Chororapithecus may then represent one example of adaptational (and perhaps phyletic) differentiation within that clade.

    I don't know about anybody else, but I don't think this helps us with our little problem very much. Here's what I think: the problem is not so much the 10-million-year-old gorilla, as it is the 17-million-year-old orangutan that it necessitates. Here's the very next paragraph of the paper:

    Acceptance of Chororapithecus as a basal member of the gorilla clade would push back the gorilla species split to >10.5 Myr ago. Because this is a minimum date established from a meagre fossil record, the actual divergence would have predated this by an unknown time gap. From the currently available evidence, we consider that a species split of 20 Myr ago for Pongo, 12 Myr ago for Gorilla, and 9 Myr ago for Pan are all probable estimates (see Supplementary Information). We consider that the early divergence hypothesis is congruent with both fossil and molecular data, and should be further evaluated using both sides of the evidence.

    I think those dates don't really need to be so old. A 10.5-million-year gorilla divergence could easily correspond to a 17-million-year orangutan divergence. Still, for those of us who have gotten used to the idea that Dryopithecus might have something to do with the origin of African apes, this idea might seem a little troubling. So, let's look at the part of the Supporting Information that, well, supports their assertion that all these dates are "congruent":

    The above summarized molecular predictions are in concert with the notion that the Pongo lineage existed in Africa prior hominoid migration to the Eurasian continent, the earliest such opportunity for dispersal (barring significant rafting) being at circa 17 Ma (44). If in fact the Gorilla split was 12 Ma, then the OWM split estimate (33.6-43 Ma) largely predates the earliest known definitive occurrence of catarrhines (Propliopithecus and Aegyptopithecus) (45), and many would consider this to be somewhat outside an acceptable boundary condition. However, it may be indicative of variable molecular rates of evolution across lineages (46, 47), with higher mutation rates in the OWMs (48) (and early hominoids) because of their shorter generation lengths (48, 49) and/or higher metabolic rate in relation to smaller body mass (50).

    Well, that's a tricky bit of argument. We might believe that African apes never left Africa and that all the dryopithecines are therefore on the orangutan line. At least, that makes some biogeographic sense. But it's hard to argue that any of these dates are "congruent" with genetic evidence as we currently understand it. Many of the recent methods don't make any prior assumptions about "calibrated" divergence times like the orangutan-human divergence. Worse, Hobolth et al. (2007) found a human-chimp speciation time of 4 million years even considering an orangutan-human divergence of 18 million years.

    The "shorter generation lengths" explanation doesn't help much -- after all, if we infer that the current great ape lineages existed as early as 20 million years ago, then almost all of the divergence time is occupied by long-generation-length species. Much faster evolution in Old World monkeys should show a strong signal of acceleration in that lineage (with a higher number of derived substitutions), and we don't see it.

    If we believe these interpretations of the genes, a 10-million-year-old gorilla did not exist. Chororapithecus was something else.

    If we believe that Chororapithecus was a gorilla, then these genetic interpretations are simply wrong. And Dryopithecus was on the orangutan lineage. And hominoids diverged from Old World monkeys in the Eocene.

    And Sahelanthropus could have been a hominid.

    References:

    Suwa G, Kono RT, Katoh S, Asfaw B, Beyene Y. 2007. A new species of great ape from the late Miocene epoch in Ethiopia. Nature 448:921-924. doi:10.1038/nature06113

    Hobolth A, Christensen OF, Mailund T, Schierup MH. 2007. Genomic Relationships and Speciation Times of Human, Chimpanzee, and Gorilla Inferred from a Coalescent Hidden Markov Model. PLoS Genet 3(2): e7. doi:10.1371/journal.pgen.0030007

    Tags: 
    gorillas
    Miocene
    Sahelanthropus
    Ethiopia
    chimpanzees
    Chororapithecus
    Africa
    chumans
    Synopsis: 
    The discovery of a gorilla-like primate may demand a recalibration of the molecular clock
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