john hawks weblog

paleoanthropology, genetics and evolution

X chromosome

  • 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

  • More on the X variation conundrum

    Sun, 2009-05-17 13:30 -- John Hawks

    Last winter I noted the contradiction between two papers that each attempted to explain variation on the X chromosome compared to the autosomes. They had come to opposite conclusions, based on discrepancies in their data. I noticed that they had used different methods of determining mutation rates for X chromosome loci:

    So, for their current paper, Keinan and colleagues (2008) try to correct for the recent divergence of human and chimpanzee X chromosomes. Simple enough -- rescale all X chromosome mutation events by the some ratio proportional to the human-chimp divergence discrepancies. In this case, they attempt to rescale to the human-macaque divergence. Since that divergence happened in the Oligocene, the discrepancies among chromosomes should slight compared to the overall divergence. I'd feel better if they actually tested this idea.

    Meanwhile, Mike Hammer and colleagues scaled X chromosome diversity to the human-orangutan divergence. They claimed that this gave the same results as the human-chimpanzee divergence. Which, if true, would obviously give a different outcome than the procedure followed by Keinan and colleagues, which was predicated on the idea that the human-chimpanzee X divergence is the wrong number to use.

    I had sort of forgotten about this (which drove me crazy at the time), but another question led me to revisit it late this week. In the intervening time, I see that Carlos Bustamante and Sohini Ramachandran (2009) happened across the same explanation that I had offered:

    It appears that the rest of the discrepancy is explained by different normalizations for background mutation rate differences between the X chromosome and autosomes (Hammer et al.10 used human-orangutan divergence and Keinan et al.9 used human-macaque divergence).

    So you read it here first. Which I suppose means that I should submit letters to journals more often. I don't because it seems to me that all I'm doing is reading and trying to understand papers, which sometimes takes more work than it should. On the other hand, I wonder how many people are really putting much effort into their reading...

    Meanwhile, Bustamante and Ramachandran add an additional explanation -- the different means of ascertainment, since Mike Hammer's group used resequencing to find variation, while Keinan and colleagues (2008) had used HapMap SNPs under a specific ascertainment model. They end their short piece by pointing out the value of further resequencing data:

    In order to address continuing questions on the nature of sex-biased processes, full genome sequencing of large numbers of individuals sampled from diverse populations will be needed. The upcoming 1,000 Genomes Project (http://www.1000genomes.org/), for example, will provide orders of magnitude more data for these types of analyses. We share the enthusiasm of the population genetics community that this will bring the potential for resolving continuing questions regarding how human history and cultural practices have shaped global patterns of genomic diversity.

    Ascertainment is a serious issue with the existing SNP data, because different SNPs were ascertained in different, non-commensurable ways. That's how I was led into reconsidering this issue this week, another set of data seem to have features that are partially explained by ascertainment, but partially not. It's hard to use existing data for some kinds of population genetics analysis, although others are less affected by ascertainment biases.

    So the 1000 Genomes effort will make some kinds of analyses simpler to accomplish. I suppose if ascertainment becomes less of a problem, we may see people focus more effort into understanding non-genetic sources of information, too!

    References:

    Bustamante CD, Ramachandran S. 2009. Evaluating signatures of sex-specific processes in the human genome. Nat Genet 41:8-10. doi:10.1038/ng0109-8

    Tags: 
    X chromosome
    mutation rate
    genetic drift
    bottlenecks

  • Data supplements driving me crazy

    Mon, 2008-12-22 23:58 -- John Hawks

    I'm about to pull out my hair reading "supplementary information" for papers.

    Two recent papers (by Mike Hammer's group and David Reich's group) attempt estimates of the diversity level of the X chromosome versus the autosomes. As discussed on Gene Expression this week, the two papers came to completely opposite results.

    In the olden days, ten years ago, I would simply put the two papers side by side and find the discrepancies. But nooooo, we can't do that any more. Now, all the relevant parameters from one of the papers (you guessed it, the one published by the Nature Publishing Group) are hidden away in a supplement.

    You'd think that might not be so bad, since I have the supplement. But I have to keep tracking the cross references to the paper to find out where the methods apply. It's a pain in the neck. Nobody else ever seems to complain. But that's because they simply don't read the papers! AAARGGGH!

    So what's the discrepancy in this case? I'm still working through these darned things.

    My first impression is that both papers use different methods to estimate the mutation rate on the X chromosome. It was Reich's group, after all, who claimed that the human-chimp divergence was followed by extended hybridization, a process that took over 4 million years in their estimation. The evidence was the X chromosome.

    So, for their current paper, Keinan and colleagues (2008) try to correct for the recent divergence of human and chimpanzee X chromosomes. Simple enough -- rescale all X chromosome mutation events by the some ratio proportional to the human-chimp divergence discrepancies. In this case, they attempt to rescale to the human-macaque divergence. Since that divergence happened in the Oligocene, the discrepancies among chromosomes should slight compared to the overall divergence. I'd feel better if they actually tested this idea.

    Meanwhile, Mike Hammer and colleagues scaled X chromosome diversity to the human-orangutan divergence. They claimed that this gave the same results as the human-chimpanzee divergence. Which, if true, would obviously give a different outcome than the procedure followed by Keinan and colleagues, which was predicated on the idea that the human-chimpanzee X divergence is the wrong number to use.

    The human-chimpanzee divergence discrepancy, if it exists to the extent claimed by Patterson et al. (2006), is probably enough to explain the discrepancies in the results of these two papers, and clearly in the correct direction. By assuming a low divergence date for the human-chimp X chromosome comparison, Keinan et al. have assumed a low mutation rate for the X. That means that the X variation in humans represents relatively less time, and therefore lower genealogical diversity and a lower effective size, than estimated by Hammer et al.

    But I don't think that's the end of the story. In fact, I think there are quite a few strange aspects of the results of both papers. Even though both papers explain their results in terms of demography, I don't think that avenue is very promising. The kinds of demographic changes that happened in the Late Pleistocene just don't look very much like those coming out of these papers. More on that later...

    What the Keinan et al. paper is showing is some substantial differences in the derived/ancestral ratio between populations, and large discrepancies in X diversity across different regions of the X. Large discrepancies would be expected between small regions due to the intrinsic variability of the coalescent process. But these large discrepancies exist between regions 3 centimorgans in length -- large enough regions that there ought to be less dispersion among them. The Asian and European samples have a strong deficit of derived alleles at frequencies lower than 30 percent, but the African sample has a slight excess.

    We'll apply some more simpleminded analysis to these data and see if anything interesting pops out. As they say, garbage in, garbage out -- but when the garbage consistently looks like banana peels, you can guess there's a monkey somewhere.

    UPDATE (2008/12/21): More craziness -- this article from New Scientist includes a quote from David Reich:

    However, the chance of finding archaeological evidence for these migrants is slim. "You're looking for a population that was there only a short period of time, perhaps only 10 generations, so the physical impact of that population in that environment wouldn't be enough to detect," Reich says.

    Surely he's not talking about a bottleneck 10 generations long, which by the estimate in the paper would mean an effective size of around 50 individuals. Surely not. No. It's just a quote in an article.

    Oh, heck. I think the point of all these recent papers that use "inbreeding ratio" instead of effective size and time as bottleneck parameters is to hide these kind of crazy numbers from peer review. We've got people out there who are talking about biblical models of human migration, like Noah-and-the-Flood level bottlenecks.

    And archaeology makes no difference. All those archaeological sites you've got? Well, they're not the ones who founded the world's population. Our actual ancestors made no impact on the environment that we can detect today. They were invisible.

    And hey, if results contradict each other? No worries. It's not like this is a refutationist science, after all:

    Their analysis also challenges a study published earlier this year, which found that all humans descend from fewer numbers of males than females. The researchers suggested that polygyny, where few men procreate with many women, accounts for this result.

    "It's possible, in principle, that both are true in some level," says Reich.

    Polygyny that occurred over the last million years of human evolution could have left an imprint in our genomes, says Michael Hammer, a geneticist at the University of Arizona, who led that study.

    Reich and Keinan, on the other hand, focused their analysis on the period when anatomically modern humans left Africa.

    "We'll have to figure out this issue in future work," Reich says.

    GAAAAAAAAHHHHHH! And you thought I was silly to be driven crazy by these papers! "It's possible, in principle, that both are true in some level."

    Pfui.

    Tags: 
    bottlenecks
    metascience
    journals
    X chromosome
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