NOTE: This is a revision of our original post, because a mistake on our part was pointed out by a commenter, to whom we offer thanks. Our main point hasn't changed....unless there are still misperceptions on our part.
BBC Earth headline: "Inbreeding Makes Mountain Gorillas Genetically Healthy." We are so tempted to add an exclamation point to that, but we won't. Anyway, you know it's there, whether we add it or not. Everyone 'knows' that inbreeding is bad; what a juicy story!
And, to summarize, the story is this: Mountain gorillas are an endangered species, surviving now in just two small groups in central Africa, a total population of only about 800 individuals. Their numbers had fallen to just under 300 in the 1980's, for multiple reasons including poaching and loss of habitat, but Diane Fossey made their conservation her life's work, and the population more than doubled since its lowest point.
But, their small numbers led to extensive inbreeding, which is always worrisome to conservationists because it may reduce a population's ability to adapt to changing environments. But, the BBC writes:
Now scientists have discovered inbreeding has actually benefitted mountain gorillas by removing many harmful genetic variations. They are also genetically adapted to living in small populations.And,
Fewer harmful genetic mutations, which stop genes functioning and can cause serious health conditions, were found in the mountain gorilla population than in the western gorilla populations.Ok, let's step over to the actual paper ("Mountain gorilla genomes reveal the impact of long-term population decline and inbreeding," Xue et al.), in Science last week, to get the story without the go-between. So, the investigators sequenced the whole genomes of 13 eastern gorillas, including seven mountain gorillas and six eastern lowland gorillas. They compared these sequences with published sequences of lowland gorillas further west, and found lower genetic diversity in both the mountain and lowland gorillas from the east, which they report as consistent with the smaller population sizes there. Their analysis, they report, confirms that the eastern lowland and mountain gorillas are two genetically distinct populations. Genome wide linkage disequilibrium was higher in the eastern gorillas than the western, evidence of different demographic histories of these populations, and suggesting a recent population bottleneck in the eastern gorillas.
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| Foraging gorilla, Congo; Wikipedia, Pierre Fidenci |
In eastern gorillas, chromosomes were found to be homozygous across 34 to 38% of their length, while in western lowland gorillas, they were 13% homozygous, indicating that the eastern gorillas have a recent history of several generations of close inbreeding. Xue et al. also report that the eastern and western populations diverged perhaps 150,000 years ago, with no mating history in the last 20,000 years or so. And, overall, it seems that gorilla population sizes have been small for thousands of years, and thus probably have been inbreeding for all of that time.
Again comparing mountain with lowland gorillas, Xue et al found no evidence for natural selection or adaptation favoring functional genes in either group.
Such adaptation might be expected from the fact that mountain gorillas range over high altitudes (1500 to 4000 m), with consequences for diet, morphology, and physiology. However, we found no significant enrichment in any functional category of genes, although there are interesting examples related to nervous system morphology, immunoglobulin quantity, and red blood cell morphology. Mountain gorillas carry a significant excess of variants in genes associated with blood coagulation in humans (fig. S21), perhaps linked to high-altitude living. We also identified variants associated with cardiomyopathy, including in one deceased individual (Kaboko) in whom post mortem analysis revealed evidence of muscular hypertrophy. Cardiovascular disease has been identified as a notable cause of death in captive western lowland gorillas.With respect to unfavorable effects of inbreeding, the authors report the opposite, saying that inbreeding seems to have purged deleterious mutations from the genome. They suggest that gorillas have found workarounds for inbreeding effects, as well, such as by "natal dispersal and gene flow between isolated populations."
Xue told the BBC that gorillas have been coping with small populations for thousands of years, and,
"While comparable levels of inbreeding contributed to the extinction of our relatives, the Neanderthals, mountain gorillas may be more resilient. There is no reason why they should not flourish for thousands of years to come."No reason?
But, we can think of a number of reasons. The Ebola virus has been devastating to chimps and gorillas, wiping out 95% of some groups of gorillas in which it has spread. And, there's always the possibility that other infectious diseases may emerge, or reach these animals, and be equally, or even more devastating.
And, poaching continues to be a problem, and hunting for bushmeat. Loss of habitat continues to be a problem. Climate change will surely have consequences for these animals. As with any other animal, including humans, environmental change and its consequences are unpredictable. Whether or not any species has the genetic wherewithal to adapt to that change is unpredictable; it's impossible to know what any single gene will do in every possible environment, never mind what every gene, and every genetic interaction will do. This is, of course, true with respect to predicting our own futures from our genomes as well.
What is 'inbreeding' and what does it mean?
There are several things about this paper aside from the apparent obliviousness of the research report to the real threat to gorilla 'fitness', namely that they're widely projected to become extinct because of human incursion and predation, in addition to disease. We might also ask, if the western gorillas have so little relative homozygosity, why they aren't plagued with the sorts of defects that the easterners have already purged, and on the verge of collapse -- or long gone?
The answer is that both populations (not just the eastern) did well enough to be here today. Both low and high homozygosity are obviously good enough, because neither wiped out either population structure in their past. So why tell the story as if one way's better? It seems to be the tired old evolutionary trope that we cannot seem to escape: To be different from is to be better than, to evolve away from is because it's a better way. But, mutation is always happening, genetic drift is always happening, and if a variant works, it works. It isn't necessarily selected because it's better, or more adaptive, than anything that came before.
This paper is in a sense an exaggeration of, and in a way confusion about inbreeding and its effects. There are several meanings of 'inbreeding' that are relevant here** . The classical meaning refers to mating with close relatives relative to random-mating. The issue there is the classical one of increased incidence of recessive disorders with inbreeding. In that context, the probability of an allele being homozygous more than just by chance: if the latter is p^2 when there is random mating, the former is p^2 + Fp(1-p), where p is the frequency of the variant in question, and F is the excess probability of being homozygous due to non-random mating. That may be because of socially constructed preferential kin-mating or just a deviation from random mating. In many, if not historically most, human populations, mating was prescribed as to be between cousins of various types. If variants are harmful but recessive so that their harm is only seen in homozygotes (both copies in a person being defective), then mating between close relatives can increase the frequency of such events, and the loss of the harmful variant from the population, but of course only at the expense of the carriers of those harmful genotypes. One can argue that if something like close-relative mating were so dangerous it would never have evolved to be, in a sense, the ancestral human way as it has. Or, one can note that the reason for local group endogamy or exogamy (how mates are chosen in any population, human or otherwise) has to do with social structure, resource distribution, and control of internecine and intergroup strife--not because of disease genes.
The authors appear not to have done this kind of calculation, however, and samples would have been too small for it to make sense. Instead, they looked along the genome to see what fraction was homozygous (that is, variant sites along the region in the sequenced animals). This reflects a different use of the term 'inbreeding', and we think what this paper is referring to, is the rise in homozygosity due to genetic drift in small populations. In a small population, rarer alleles (genetic variants) are lost more rapidly from the population, mainly just by chance. Homozygosity at a given site is an inevitable reflector of population size, and in a small population the region of a chromosome that is homozygous (not varying) would be larger than in a large outbred population. That is not an automatic indicator of a history of loss of harmful mutations, recessive or otherwise. In any population harmful variants have a shorter staying time than helpful ones, but their duration depends on many different factors that can't be inferred from the stretches of homozygosity alone.
Do western lowland gorillas, with their lack of a history of 'inbreeding' as presented by this story, show some detectable load of sub-par individuals? If so, that would be relevant news. In fact, both groups have coefficients higher than human cousins relative to each other, as a commentary on this paper notes. But so what? In fact, and perhaps to the contrary, being too inbred in the small-population sense could, as far as just-so stories go, mean there would not be enough variation in the population to respond to environmental challenges.
What the study does no doubt actually show is that the two gorilla populations have had different demographic histories. That is ecologically interesting and perhaps useful for understanding wildlife conservation issues. But in itself it says basically nothing about purging harmful variation except that it would be somewhat faster, on average, in one group than the other -- but only slightly so, because if that were not the case the burden of loss could have threatened the very survival of the group in the past so that it never made it to the present, which obviously isn't the case. 'Inbreeding' in headlines may have a juicy sound and catch the lascivious eye, and that's why the news media go for it so readily.
It should also be noted that extensive, detailed, biomedically documented studies in human isolate populations have found each to have particular instances of elevated recessive diseases or other traits due to inbreeding effects, but the overall burden of genetic disease has not been particularly increased, if at all.
***The often and perhaps still confusing issue of inbreeding have been clarified long ago, e.g., by Albert Jacquard in 1975, in J. Theoretical Biology, "Inbreeding: one word, several meanings", by various wrtiting of Warren Ewens back in the 70s, or see Templeton and Read, Conservation Genetics, 1994; they are discussed in any good population genetics text.
9 comments:
So, perhaps I have misunderstood something, but I think there is a bit of confusion here about what quantities the authors are reporting, and how they relate to the Hardy-Weinberg relation.
Xue et al report, for multiple different populations, the fraction of the genome that you would expect to be found bound up in runs of homozygosity 2.5cM or greater in length within a single individual randomly chosen from that population.This is not a measurement of any particular genotype frequency in the population, nor does it measure the average or typical frequency of recessive genotypes within the population, as is implied by the procedure of taking the square root and calling it the "typical recessive allele frequency".
This appears to have been a mistake on my part, by not reading carefully enough. Thanks for pointing it out. We have revised the post.
I think it doesn't change our main points about 'inbreeding' and in a sense (based on the authors' measure) whether they should have used the term at all.
The long stretches of homozygosity would, however, in the tenor of the authors' usage in the paper, really only reflect population size and drift effects. Variants both good and harmful, recessive or dominant or otherwise, would be affected in different ways, and making the kinds of harmfulness conclusions they did is unwarranted.
Thanks for writing about our research. You raise some interesting points. However I do think it's important to distinguish between media headlines about a paper and the paper itself. With regard to the the outlook for gorillas and the threats they face, here's what the paper said:
'An increased burden of deleterious mutation and low genetic diversity - including at the major histocompatibility locus, of central importance to the immune system (fig. S22) - have likely reduced their resilience to environmental change and pathogen evolution. However, the origins of this condition extend far into their history, because both eastern subspecies have experienced a long decline over tens of millennia. Indeed, the demographic histories of mountain and eastern lowland gorillas (Fig. 3A) bear unhappy resemblance to similar histories inferred from Neandertals before their disappearance.'
Earlier we highlighted the risks from habitat loss and diseases such as ebola, so it's not clear why you think the paper is oblivious to those!
I don't think we have argued anywhere that inbreeding was a net positive. In fact it's important to note that the signal of purging we detected only detected for loss-of-function mutations, not mutations at other protein-changing (missense) sites, of which there are many more in the genome. The latter are still moderately deleterious, and indeed we show that the overall burden of missense mutation is increased in eastern gorillas compared to western lowlands. We certainly haven't argued that homozygosity is 'an automatic indicator of a history of loss of harmful recessive mutations'!
So for example your question 'We might also ask, if the western gorillas have so little relative homozygosity, why they aren't plagued with the sorts of defects that the easterners have already purged, and on the verge of collapse -- or long gone?' Well – they do have them, but they are rare and probably mostly recessive, so they survive in the population without causing a major problem.
With regard to supposed distinctions between different types of inbreeding, I think people are sometimes confused about this - really they are just different aspects of the same process, namely the impact of demography and relatedness on genetic ancestry. If you focus on long tracts of homozygosity then you are sensitive to recent coalescent events, whereas low genome-wide heterozygosity, e.g. at single sites, is a function of demography on a longer timescale. When population sizes are very low for a long time, as seems to have happened here, you will get both signals. I don't see why you think we are confused about this or exaggerating – perhaps you can clarify what you mean?
One other point, as to why some media reports went with headlines (and sometimes stories) along the lines of 'inbreeding is good for mountain gorillas'. All I can say is it's very hard to control how journalists – most of whom you don't get to interact with and are picking up the story second hand – will report your work. With hindsight we could have tried to ensure that no such interpretation was possible, but then we were equally worried that the story would be 'mountain gorillas doomed due to severe inbreeding'. Indeed, some places did report just that!
I'm happy that at least we got across the message that mountain gorillas are not a lost cause – which is a pervasive meme about small low-diversity populations. Also it's fair to say that inbreeding purging is a small positive – call it a silver lining – on a net negative. And I think it is fair to suggest that the fact mountain gorilas have existed for a long time at low levels suggests they might be better adapted to that condition than if this was a sudden collapse from recent large population numbers. But this is just a conjecture and presented as such.
I'm not aware of good evidence for predicting extinction or survival based on the level of inbreeding in a population – or indeed based on any particular genetic evidence, given then limits of our understanding, but I'd be very interested to learn more if there is such evidence. I don't think genetic factors are the major issue, albeit low diversity almost certainly increases the risks, as we point out. If it was, mountain gorillas would probably already be gone. Almolst certainly the biggest predictor of extinction is having low census population size; attracting the attention of humans is usually bad news too.
Thanks for your clarifications, Aylwyn. We have already revised the post, as noted, because of a mistake on our part about the nature of the homozygosity being reported. That is irrelevant to your comments, but was in part a problem due to news media splash, and when it is major media it is fair to raise the point because most people won't even read the original.
We did not intend to criticize your population genetics, and I don't think we did. However, our original discussion of the subtleties of inbreeding was given because many people, maybe most, have very different ideas of what the word means, and we think that the sensationalizing overshadowed the more simple point about population history. We did rewrite that part of the post because we'd originally carelessly misread your paper.
Both populations have survived to the present, and we don't see how homozygosity stretches account for that, one way or the other, since each population has had its own history of dealing with harmful (and helpful) variants.
Our comment about ebola etc was intended to point out that the implied better health of the one population (attributed to homozygosity) compared to the other seems to us to be unjustified.
You did raise the issue of continued threats from infectious diseases and so on in the paper. It's possible that the first author of the paper was misquoted saying that sequencing indicates that there's no reason gorillas won't flourish for thousands of years to come. If so, we apologize for assuming this represents the views of at least one of the authors of the paper.
Your own comments here raised the issue of recessivity in inbreeding, too big a subject for a comment or blog post, except to say that it's somewhat beside the point of the kind of inbreeding you describe. That's because as you well know, even advantageous mutations have substantial chances to go extinct in small populations. And then one can debate the extent to which harmful, or really any, mutations are recessive. One can argue whether your idea that homozygosity is helpful or 'adaptive' as a general rule, and bodes for a better future in one of the populations relative to the other. In any case, our point, relative to the splash of the story, was that inbreeding of any sort is totally trivial compared to what is the real threat to these animals.
A larger population is bound to have more variants and hence more that may have harmful effects, but they may have more 'good' alleles, too. But both populations have survived to date, with more and less homozygosity, and there's no reason to think the homozygosity story is directly related to that, rather than to the many other ominous aspects of rarified populations.
Finally, one cannot say that higher homozygosity is a boon for a population, because variation is itself adaptive. What the balance is between variation enabling a population to respond to environmental conditions, and removal of harmful variation, is entirely context-dependent and we could debate that endlessly. Finally, the difference you found was quantitative, and whether it's enough to matter given the chaos of fitness, and the demographic dynamics, is certainly debatable.
Of course, if we misrepresented your story in any serious way, we're sorry and apologize. But we were writing about the 'event', the paper and its publicity. We didn't suggest that you hadn't found differences in variability, and this possibly could have some relevance in principle to conservation efforts and the future of the gorillas.
Thanks Ken. Perhaps we could have said more explicitly: we are not arguing that genetic processes are the major factor in determining mountain gorillas' survival, compared to non-genetic factors such as poaching and habitat loss. But the reason we didn't say this explicitly is that it is not a finding, or even a conjecture, of the paper.
Yali's quote 'there's no reason gorillas won't flourish...' should probably be reworded 'no genetic reason'; I guess she assumed the context would indicate this. It should also be more clear that this is conjectural – obviously perhaps, since it's a prediction about the future, but better to be explicit.
Personally I'm not sure that genetic factors are actually unimportant - it may be that disease immunity or lack thereof is crucial. Who knows. It turns out however that for the public, or at least for much of the press, genetic diversity is assumed to be a big factor determining a species' chances of extinction. I'd be interested in any insights into why this might be so.
I still don't understand what you mean by 'our idea that homozygosity is helpful or 'adaptive' as a general rule' or that 'higher homozygosity is a boon for a population'. Where do you think we say this? Pointing out that mountain gorillas have survived for a long time despite low Ne and with extensive homozygosity on all scales is not an argument that homozygosity has been beneficial! Rather it suggests that low diversity does not spell certain doom, at least not in the short term. I think this, coupled with the prior assumption that inbreeding is extinction's calling card, seemed to some people like a more optimistic message than we perhaps expected.
Having said that, some kinds of homozygosity can certainly be adaptive - e.g. the loss of diversity due to a selective sweep. I'm not sure we can say anything about homozygosity as a general rule, except insofar as it may be a symptom of low Ne or inbreeding, which is almost certainly negative overall. The purging of severely deleterious mutations is probably a silver lining at best, but may play some small positive role.
Aylwyn,
Thanks again for your clarifications. I will leave responding to the inbreeding issues to Ken, but I did want to make a point or two.
The paper was certainly treated recklessly by the media, always a problem. The conclusions that you yourselves are drawing from the study aren't strongly stated in the paper -- you were indeed cautious. But it's hard not to assume, given your co-author's statement to the press, that one of your conclusions is that because gorillas have survived this long in small groups, with inbreeding, they are genetically adapted to their habitat, and that's the reason they will survive for thousands of years to come.
We can't agree with that, for several reasons. First, it's true that Ken and I often prefer to allow for the possibility of chance and drift where others see adaptation and selection. Still, the idea that high homozygosity would be protective in one group, when the group with lower homozygosity has been equally successful (or, in a way, given such small populations, unsuccessful), to us, points to a less adaptive explanation.
And second, coming so soon after the announcement in the US that 'precision medicine' is now what we're calling the promise that we'll be able to predict our futures from our genomes, which there are many reasons to think is just not going to be possible, the idea that it's possible to predict the gorilla's future from their genes rubbed us the wrong way. Environments change, variants that are harmless in one environment are harmful in others, gorillas live in a dangerous world, and so on.
So, perhaps we were reacting to unspoken assumptions as much as to the paper itself. Fair or not!
THIS REVISES A RESPONSE FROM EARLIER THAT HAD A BAD TYPO IN IT (A 'NOT' THAT DIDN'T BELONG).
Aylwyn,
These exchanges could go on forever, and are largely if not strictly semantic and/or relate to the combined effect of the paper and its news coverage (by the popular as well as scientific press). I basically agree with Anne's response. The media show is not one resisted by these particular journals, and generally not resisted enough by authors or commenters being interviewed. There have been many criticisms about how things are done these days, but it's the landscape we've collectively created, for many reasons.
In this case, I think that if a more circumspect terminology, like 'bottleneck' or 'population history' had been used, and not 'inbreeding', a lot of issues might have been avoided. Part of our blog was intended for the many, professionals and otherwise, who have unclear understanding of that word, something that's long been true.
Anyway, rather than worrying about the details of the paper or the reporting, probably everyone with a conservation bent would agree that the bottom line is that gorillas have had a tough time of it, for whatever length of time, and a severe time recently. There are geographic genetic as well as environmental differences among them, as you showed, but it seems from what we read that gorillas are all facing a high probability of imminent doom, from the encroaching outside world.
Hopefully that won't happen, but if it does I think everyone agrees that it's unlikely to be due to specific genes. To me, homozygosity cuts in different ways under different circumstances, and no strong generalizations about future prospects or even causal past events can be read from such current values and samples.
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