Banner
    What Genes Did We Lose To Become Human?
    By Michael White | January 6th 2008 09:21 PM | 20 comments | Print | E-mail | Track Comments
    About Michael

    Welcome to Adaptive Complexity, where I write about genomics, systems biology, evolution, and the connection between science and literature,

    ...

    View Michael's Profile
    When we think of the genetic changes that had to take place during our evolutionary history, we typically think of changes that resulted in a gain of function, like genetic changes that resulted in a larger and more sophisticated brain, improved teeth for our changing prehistoric diet, better bone anatomy for bipedalism, better throat anatomy for speech, and so on. In many cases however, we have lost genes in our evolutionary history, and some of those losses have been beneficial. The most widely known example, found in every introductory biochemistry textbook, is the sickle-cell mutation in hemoglobin - a clear example of a mutation that damages a functional protein yet confers a beneficial effect. People with mutations in both copies of this particular gene are terribly sick, but those who have one good and one bad copy are more resistant to malaria. Another example is the CCR5 gene - people with mutations that damage this gene are more resistant to HIV. In the more distant past, a universal human mutation in a particular muscle gene that results in weaker jaw muscles may have played a role in brain evolution, by removing a constraint on skull dimensions. These few examples were found primarily by luck, but now with the availability of multiple mammalian genome sequences, researchers can systematically search for human genes that show signs of being adaptively lost at some point in our history. David Haussler's group at UC Santa Cruz, in a recent paper, looked for the genes we lost as we developed into our modern-day human species. What they found could help us better understand our evolutionary history, and possibly the human diseases that are the side-effects of that history. It's not hard to find genes that have been lost in the human genome - our genomes are littered with pseudogenes, genes which harbor inactivating mutations making them unable to produce a functional protein. But most of these damaged genes have functional copies elsewhere in the genome. Genes are frequently duplicated in the random shuffling that goes on in our chromosomes, and often the duplicate copy will be destroyed by mutations while the good copy continues to perform its original function. Another frequent phenomenon is the production of processed pseudogenes - these are genes that were produced when RNA was transcribed back into DNA and integrated into the genome. The result is a gene that looks just like a highly processed RNA molecule, often surrounded by the classic genetic residue that is left behind when a piece of DNA is integrated back into the genome. Looking for lost genes Haussler's group was not interested in these two relatively mundane classes of pseudogenes; they were searching for genes that are clearly functional in other mammals, and which have not been duplicated or reverse transcribed from RNA. In other words, the genes they were looking for would have no other functional copies hanging around somewhere else in the genome. Genes in this category are likely to be candidates for adaptive losses - genes whose function has been completely eliminated from the human genome, which may have provided some benefit to the original ancestor in which the gene was lost. These researchers performed their search by comparing functional genes in the mouse genome with genes in the human and dog genomes. Mice are more closely related to humans than dogs are; a gene that is present and functional in mice and dogs, but destroyed by mutation in humans has therefore been present in mammals for a very, very long time, but was recently lost in the human lineage. You can see how this works in the figure below (which I have marked up slightly from the original version in the paper). The mouse and human versions of our hypothetical gene line up nicely, but there is an inactivating mutation in the human version. In the dog version (not shown), that mutation is absent.

    What they found After completing their genome scan, and applying various quality control filters, Haussler's group came up with 72 candidate lost genes. They found some well-known lost genes, such as GULO, an enzyme necessary for making vitamin C that was been destroyed in primates, but is still functional in most other mammals. (If we still had a functional copy of this gene, we wouldn't get scurvy.) Thee researchers found new lost genes as well, most of which have poorly characterized functions. One gene, named ACYL3 (NM_177028 in the mouse genome, for those of you who want to check out GenBank), contains a very highly conserved enzyme structure, called an acyltransferase domain (see more here). This particular acyltransferase domain is very ancient - it is found in bacteria, archaea, plants, fungi, and animals. Many species have multiple copies of this domain (the fruitfly has over 30), but mammals have only a few copies, and humans have absolutely no functional copies. We know almost nothing about this gene: it produces a membrane protein, it is expressed in the mouse pituitary gland, and it is necessary for normal embryo development in worms and flies. Why was it lost in humans, and was that loss beneficial? We don't know yet. Do we get some diseases that mice don't get, because we lack this gene? It would be fascinating to figure out. Although we know little about ACYL3, Haussler's group was able to pinpoint the timeframe of the loss. This gene was destroyed by a nonsense mutation, a change from TGG (coding for the amino acid tryptophan) to TGA, which means stop - the protein is truncated right in the middle of a highly conserved region. This TGG to TGA change is found only in chimps and humans, not gorillas, orangutans, or any other mammals checked. The mutation therefore happened after the chimp-human lineage split off from the other great apes. Gorillas and orangutans have a functional ACYL3 gene; humans and chimps don't.

    Other lost genes found by these researchers included genes lost in only chimps, gorillas and humans, genes lost in all great apes, and genes lost in primates. Each of these losses is an example of an ancient gene that was functional for hundreds of millions of years, but then lost very recently in the lineage that led to primates, and ultimately humans. Without detailed functional studies in multiple species, it is hard to know which genes were lost adaptively, providing an immediate benefit sustained by natural selection, and which were lost simply because they were no longer necessary in a particular environment (such as the vitamin C biosynthesis enzyme). But with this list of genes in hand, we know where to start. It would be fascinating to figure if any of these lost genes are linked to human diseases (like GULO and scurvy), since the lost function could provide an important clue regarding the mechanism of the disease. It's worth noting the implications of studies like this for the creation-evolution debate. Creationists, including most of the major advocates for its latest form, Intelligent Design, have frequently expressed their disbelief in human evolution and the common ancestry of today's species. In the case of ACYL3, the only plausible explanation for the pattern of mutation that Haussler's group found is that humans and chimps shared a common ancestor. If humans and chimps had been created de novo as separate species, it would an be extremely unlikely coincidence for these identical mutations to occur by chance individually in each species. And when you factor in the distribution of dozens, hundreds, thousands of such mutations, all occurring in a similar pattern, it becomes not just unlikely but essentially impossible that such patterns of mutation would have arisen by chance in each separately created species. One could suggest that a designer just decided to arrange things this way, but that argument falls in the same class as the claim that God just made the universe and the earth appear old, after creating it all 10,000 years ago. There is simply no rationale based on evidence to question the fact of common descent, and those who continue to resist this fact can only do so for religious or psychological reasons. Figures from the original paper were annotated, cropped and posted under the PLoS Open Access License.

    Comments

    Tikum Olam
    The evolution of the human species is a dynamic shared by a system of biological factors including the human animal host and the cluster of bacteria and virus necessary for biological existence. Add to this the environment and the social circumstance and an interesting ecology emerges. Humans may be viewed as a living dynamic that balances various biological assets and liabilities within the changing shape of human beings. Human genetics is a pool rich in suggestions about past environments survived by the human species. Human biological adaptation has brought about suppression of some genes and alteration/creation of others that favor biological survival. Its possible that the greater portion of 'unused' genetic material in human genetics is actually a working 'map' of the entire survival conducts of the species during the span of its evolution. One might then consider the fair question: What genes have humans LOST that may have provided sensory capability no longer active in the human genome? How could such sets of survival capability enhancements be identified and 'resurrected' to an active mode in the human? Is it a viable concern to revivify such gene sets to enable humans to adapt most favorably to extra-terrestrial environments such as low gravity environment on the moon, or diverse climates on other worlds in our solar system? Exobiology may include the possibility of human genome modification and enhancement for space program initiatives hosted by 'volunteers'. or human variants (corporate property). Model the 'unused' portion of the human genome as 'white noise' and consider mandelbrot set patterns as probability set values that may identify clusters of traits that may lead to identifying genetic templates hosted by a particular invironment in the earth's geological past. Submit the genetic material to chemical invironments typical of geological time periods and watch for latent DNA responses triggered by the synthetic environment.
    You can spend your life anyway you want, but you can only spend it ONCE.
    adaptivecomplexity
    I should expand on the suggestion that these lost genes could shed light on the mechanism underlying some human diseases. How would we know whether one of these dead genes is connected to a disease? Take the case of ACYL3 for example - since this gene is long dead in humans, you won't find humans with disease-conferring mutants in ACYL3, which is how you typically find a gene linked to a disease. What you do is study the function of recently lost genes in mice, or say, Rhesus monkeys (who do have a functional ACYL3, for example). When you've found the biological processes that such genes are involved in, the next step is to see which diseases are connected with that particular biological process in humans, and to check whether those diseases are non-existent or different in mice. This is not easy work, but it could generate some interesting and possibly worthwhile hypotheses. In sum, this is an argument for studying certain genes that are not present in humans, something which hasn't necessarily been a priority in mouse research.
    Mike
    Scientists may eventually circle back to those long-debated traits of sophisticated language, culture, and technology, in which nurture as well as nature plays a leading role. We're in the age of the genome, but we can still recognize that it takes much more than genes to make the human.
    closet

    "One could suggest that a designer just decided to arrange things this way, but that argument falls in the same class as the claim that God just made the universe and the earth appear old, after creating it all 10,000 years ago. There is simply no rationale based on evidence to question the fact of common descent, and those who continue to resist this fact can only do so for religious or psychological reasons."One could also suggest that the earth is a lot older than 10 k years and still be "created" by "God". We have fossils of dino's that are in fact over 10 k years old. There is no denying this for the educated christian, but there is no denying that science proves itself wrong on a daily basis. so, what we held as fact yesterday will likely not be fact tomorrow.You can do the math a million times and not come up with the right solution if you are using the wrong formula, and as humans, we are prone to using the wrong formula. One simple variation change can skew the results, and this is as simple as the cooking process of foods and how different foods react to each other under different conditions.

    Although I am never very good at understanding scientific articles, reading this one did make me curious as to whether at one time in human history if our sense of smell and of hearing might have been closer to that of canines and what caused it to change if it was.

    i have read this article with fascination and i have been bought up that god was my creator but the more i look at it the less feasible it seems. i prefer the scientific road with the bacterium level. how else did our bodies procreate and adapt to the land around us ie:hunter gatherer mode

    i have read this article with fascination and i have been bought up that god was my creator but the more i look at it the less feasible it seems. i prefer the scientific road with the bacterium level. how else did our bodies procreate and adapt to the land around us ie:hunter gatherer mode

    adaptivecomplexity
    i have been bought up that god was my creator but the more i look at it the less feasible it seems.
    Personally, I'm not a religious believer, but evolution and a belief in God are not necessarily mutually exclusive Some can accept God and evolution at the same time, others can't. Everyone has to find their own path.

    Mike
    Read creation.com - It has a daily article plus heaps of other things to research when confronted by articles like this and its implications for creation.

    Now seeing the same gene in two creatures should not suprise us. Seeing the same mutation in a gene might. As the author says - what are the chances? I don't know ... I could posit that perhaps this gene's structure might mutate from state A to state B less randomly than at first we thought. Possibly a stop code TGA is not uncommon or is the kind of mutation that is more likely than others? I guess, I would want to see how many more times this occurs, I would like to see multiple mutated genes and multiple histories such as this. Frankly I don't know and let's just see where the evidence falls. No one is interested in holding a false belief.

    I certainly agree that this kind of analysis and finding and tracing genes and their mutations might bare fruit for evolution but like so much that I have seen, it's simply calling the game over too soon.

    The evidence for evolution can be overwhelming but not always compelling when you can find a counter point and contrast the two.

    adaptivecomplexity
    I could posit that perhaps this gene's structure might mutate from state A to state B less randomly than at first we thought. Possibly a stop code TGA is not uncommon or is the kind of mutation that is more likely than others?
    These are all good questions, and in fact they have been addressed for a long time.
    it's simply calling the game over too soon.
    It's really not.  You have come up with some good questions, and the answers are out there. But gaining a technical background in evolution, and learning how researchers have addressed these questions over 150 years of research takes a significant investment of time and effort. Until you've obtained that kind of background, you shouldn't assume that just because you personally haven't found the answers to your questions about evolution, scientists haven't addressed them.
    Mike
    logicman
    Read creation.com - It has a daily article plus heaps of other things to research when confronted by articles like this and its implications for creation.
    The term 'confronted' above shows emotive and agendist bias.  No rational human feels 'confronted' by a well-researched and well-written article on a scientific topic.

    The invitation from creation.com is the standard cultist invitation:
    "Confused?  Let us do your thinking for you."
    Actually, shared genetics between chimps and humans is agnostic with respect to evolution or "intelligent design".
    In software engineering, you often find shared code (or even junk code) in the source of various projects as
    it develops from "Product 1.0" to "Product 2.0" to "Product 3.0". I.e., it's a strawman argument to assume
    the "intelligent designer" started from scratch for chimps and humans. That doesn't sound intelligent at all.

    Like a software designer, the "designer" would have hacked up whatever existing code base he had to
    get him to the next milestone. So the "chimp release" and "human release" of the designer's software
    of course share the same bugs, since they are off the same code base.

    Note this is not a claim that the designer "just made things look that way" i.e. tried to trick observers;
    it's based on how things are actually done in software design were there is no intent to trick at all.
    It's simple basic engineering for large projects--you don't start from scratch each time.

    adaptivecomplexity
    It's not the shared genetics alone - it's the shared, improbable genetic events. Having the exact same highly improbable mutation in the same spot in both the chimp and human genomes (something like say, a transposable element insertion) is strong evidence of common ancestry. That's basically how paternity testing works.
    Of course you can postulate a designer intelligent enough to create chimps and humans, but sloppy enough to reuse the same buggy code. But that's one of the problems with intelligent designer - you can postulate any kind of designer you want, with any kind of bizarre motives you can come up with.  But one things is clear: this designer does not resemble a human designer. Our genomes don't resemble human software engineering.
    Mike
    Yeah the whole point of my post is that "common ancestry" i.e. common (genetic) code is agnostic with respect
    to evolution or "intelligent design".

    I'm not sure you're reading or understanding my post. I said:

    Note this is not a claim that the designer "just made things look that way" i.e. tried to trick observers;
    it's based on how things are actually done in software design were there is no intent to trick at all.
    It's simple basic engineering for large projects--you don't start from scratch each time.

    All we have to assume is a non-perfect "intelligent designer" which I don't think is a stretch. It's not
    "sloppy" at all to reuse code, it's a standard software engineering practice. As a far as "buggy," bugs
    are present in all but the smallest and most overengineered software projects. They might get
    copied into multiple releases (code streams--chimp and human) for any of a number of reasons:
    the bug is not discovered before the release, and or it's minor enough to ignore because there are
    more important issues to focus on.

    Again, I'm not invoking an "bizarre motives" here. Just standard software engineering practices.

    As far as you last point, I would think the DNA would be the object code rather than source code.
    In that case, we'd have to know or conjecture what sort of compiler and source language could
    generate that object code to evaluate whether DNA (that we see) could be the output.

    adaptivecomplexity
    I understand what you're saying, but DNA doesn't look that way - it doesn't look reused source code; instead it looks, on a large species scale, like just what you see on a smaller, family scale: descent from common ancestors. 
    This is not just an issue of an imperfect designer - it's one who would have gone to great lengths to make it look like you have genealogical relationships between species. This designer would have purposely made arbitrary, non-functional changes that have nothing to do with creating a different 'code stream.'

    Take histone proteins for example, which package up DNA into chromosomes. Histones do the same thing in all eukaryotic species - there is no reason to change them. You can take chicken histones, and use them to wrap up yeast DNA. If someone were reusing 'histone code' in each newly designed species, there would be absolutely no functional reason whatsoever to change it - you don't need one kind of histone for chimps, and another for bats, and another for humans. And yet histone sequences have changed, in arbitrary places, in a way that reflects the genealogy of species. Human and chimp histones are closer to each other than they are to chicken histones, etc.  

    There is no design explanation for this, and this pattern doesn't look anything like what you see in reused human code. It looks just like what you would expect to see when random mutations accumulate over generations.

    Mike
    Could be a time-generated "software crash," as in, there could be some outside interference with the original code. Like, for example, when you try introducing Mac software to a PC through DOS. It is bound to fail over time, though probably far less time than we can evidently tell.

    There's the chance that things could have been "coded," which would explain a lot - similarities between species, transpositions of species necessary for an efficient working environment, and a self-sufficient overall code. But, though the elements of the code may have been well-made, the other elements (other creatures, other floating elements) could have corrupted bits of code, making mutations like the ACYL3 gene change. In this case, it's neither the fault of the "designer" nor the "object code" themselves, but only of the interactions between elements. All-around weird stuff (glitches) and viruses (hacks) are the result.

    why the chimp doesn't evolute into somekind of human?
    is it because the lost genes and the mutation thing?

    I'm just curious and want to pose a question regarding gene mutations. Why is it that somewhere along the line humans evolved out of the chimp? Why aren't the chimps changing?

    Brian,

    I'll pretend that this is not the same old, same old creationist argument, and that you really did think of this question all by yourself and actually want to hear the answer. Humans and chimpanzees diverged about 5 million years ago from a common ancestor. Since then, humans have undergone 5 million years of evolution, and chimpanzees have undergone 5 million years of evolution. Modern chimpanzees in no way resemble that common ancestor, any more than we do.

    For example (and very much in line with the original topic of this post) here's a New York Times article:

    https://www.nytimes.com/2005/09/01/science/01chimp.html

    reporting on some Y-chromosome genes that chimpanzees lost over the years, but humans still have.

    Thanks for the information, Bill. Yes, I did think of this all by myself and it is not the same old creationist argument. It was just something I've been thinking about for some time. I am not a scientist and cannot pretend to understand all of what is said about genomes and the like. It just seemed to me that humans have evolved at such an accelerated rate when compared to other species, especially our cousin, the chimpanzee. With that said this looked like a great place to ask the question without digging through all the research that has been done already. Even after reading the Times article, my mind circles back to the relative short time humans have had to make such progress. It is almost as if our species was given a gene boost along the way.

    I thank you for the response.

    Brian-