Epigenetics is a word that has had a variety of meanings historically, and it's sometimes unclearly employed, even by the user. But these days, when people talk about epigenetics they generally mean the chemical modification of DNA sequence in a way that does not change the sequence itself but affects the expression of genes in or near the modified DNA region--that is why it is called 'epi' genetic. Such chemical modifications affect whether or not the cell uses a particular gene (only a subset of all genes is used in any particular cell, but that subset changes depending on the cell's local environment at any given time). That is, epigenetic changes essentially are regulatory; the epigenetically modified DNA sequences are not mutations of the coding of the structure of a particular protein (or a directly functional RNA), just how or when or how intensely it is used by the cell. Likewise, epigenetic modification doesn't change the affected sequence itself, but affects whether regulatory proteins can bind there to cause a nearby gene to be expressed, that is, transcribed into RNA. The phenomenon of such DNA 'marking' itself isn't controversial, and a few of the means by which it happens in a cell are known. Indeed, unlike mutations in the sequence itself, the marking is easily erased and there are known mechanisms that do that.
However, reports that epigenetic marking can be inherited are quite legitimately controversial. There are a few reasons for this.
How can local gene usage be inherited?
Cells respond to their environment--to extra-cellular conditions--via cell-surface receptors or other similar means. If they don't have receptors for a signal floating by, they can't detect or respond to that signal. But cells that do detect a signal change whether they start or stop using a particular set of genes. That's how complex multicellular, multi-organ system organisms become differentiated, as well as to respond to environmental conditions. Most examples of epigenetic inheritance relate to experience that affects particular types of cells, though many 'housekeeping' genes, genes that carry on basic metabolism, are used by all cells, and any environmental change could in principle induce all cells to change their gene usage.
Unless there is subsequent environmentally-induced change, once modified, when they divide, cells transmit their particular expression state to their daughter cells. If an epigenetic modification causes a cell to respond to a particular environmental signal by turning on the expression of a particular gene, that 'use it!' state would be passed on when the cell divides to produce other cells in its lineage, unless or until another modification occurred to reverse the original change. Thus, if some particular cell, say a lung cell, is induced by some environmental factor like a nutrient to express some set of lung-related genes, the effect is local, specific to lung cells. How that works is complex but some of the mechanisms are known. However, they have to do with how chromosomes specifically in lung cells are packaged; that is a local fact. For example, it need not also affect nerve or vessel or skin or stomach cells. Again, that is because in a differentiated organism different tissues are separated from each other so they can be different.
This raises a serious problem: Local effects on gene expression will be passed on to daughter cells in that tissue, but this is not the same as transmitting the effect to the next generation of organisms. Intergenerational transmission requires that the modification also be made in germline--sperm or egg cells--because the offspring organism starts out life just as a single fertilized egg (which has no lung cells!). Germline cells generally need to have genes switched on (or off) to enable them to make a new organism from scratch, from that single fertilized egg cell. Some temporary change that was important to the embryo's future lung cells would not likely be appropriate for the development of those cells in the first place during embryogenesis. So it is no surprise that there are active mechanisms to strip off epigenetic changes in germ cells' DNA, to reprogram those cells' gene usage to prepare them for their embryonic duties, this is done by erasing and re-setting DNA modification in the sperm or egg cell. If the embryo's lungs, when they eventually have them, need to modify what they due based on the air their exposed to, then new epigenetic changes will occur. Thus, the process of erasing and reprogramming removes those changes. Some bits of the genome are protected from this but it is not automatically true that even environmentally induced changes in housekeeping gene usage will be transmitted.
It was first systematically shown by Weismann in the 19th century and has been a theoretical bulwark against the idea of Lamarckian inheritance, that at least in most animals, somatic (body) and germline cells are separated, independent lineages isolated from each other (the situation is different in many or most plants). That means that for epigenetic changes to become heritable--and hence affect evolution--modifications to particular body cells would have to be applied to germline cells and not be erased before fertilization.
Without some clear mechanism, there is no reason that future sperm or egg cells will even 'know' about, much less respond to, the signal that induces change in the lung or nerve or stomach cells. So for epigenetic change to be inherited, there is the serious question of how the genomes in germline cells are specifically modified by signals that affect nerve or lung, etc. If a lung cell alters its use of gene X related to how lungs work, when it detects some (say) pollutant in the air, how does that specific change also get imposed on the germ line? Explanations that have been suggested so far are mainly not very convincing. That's why most reports of inherited epigenetic modification are properly received with skepticism.
Still, many investigators are seriously interested in epigenetic changes, especially when or if they are inherited, for a few reasons. This sort of inheritance, which modifies DNA usage differently among a person's many different localized tissues, threatens the degree to which traits can be predicted from a person's DNA sequence alone (obtained, for example, from a blood sample), and among other things that threatens realization of the promise of 'precision' genome-based medicine. Secondly, accurate assessment of epigenetic effects could lead to a better understanding of important environmental exposures and/or what to do about them, so that newborns are not doomed by their parents' habits to live with pre-set epigenetic traits that they now cannot prevent. And the least legitimate reason, but one important in the real world of today is that is a lucrative and sexy new finding that can be made to seem a melodramatic 'transformative' shift in our understanding of life.
An important criterion for claims of true epigenetic inheritance is that they must pass through at least to a 3d generation without the presence of the environmentally causal trigger. That is, transgenerational transmission is evidence that the genome is in fact preserving the change rather than just each new individual learning it from environmental experience (such as in utero). While there have been various generally convincing reports of true transgenerational inheritance in some species like the simple nematode (C. elegans) or plants, this hasn't clearly been shown in mammals (or humans), even if one or even two generational inheritance, usually through the maternal line, has been found.
Most of the literature consists of curious reports or claims of epigenetic inheritance, reviews of the germline erasure process and what areas of germline DNA could perhaps escape erasure of epigenetic marking, and some examples that seem to be truly transgenerational. At present, the excitement seems generally far exceeding the reality. But since epigenetics is potentially quite important, and the methods for understanding it rather new, it is being given serious attention.
A paper by Bohacek and Mansuy (November 2015 Nature Reviews Genetics), reviews what is known about the degree to which epigenetic 'marking' is inherited. This is a very good, measured paper that in our reading of it makes it clear that claims of non-trivial multi-generational DNA modification effects still need careful documentation. But if life-experience by parents can affect their offsprings' traits in substantial ways related to the offsprings' future life experience, even if they are not exposed to the risk factors that set their parents' genome usage patterns, then if we could understand how this works perhaps such modifications would not be destiny, and means of prevention or control could be developed if the phenomenon were to be better understood.
Gene usage isn't the same thing as gene structure
Epigenetic inheritance can also affect ideas about how evolution works, if they really have long-term (many generational) effects. The suggestion is now routinely being made that the phenotypic effects of epigenetics we are seeing introduces a Lamarckian view of evolution that may, after all, have to be melded with our Darwinian theory (e.g., see Skinner, MK, Gen Biol Evol. 7: 1296-1302, 2015). But the idea that this is a genuine revival of Lamarckism is still treated with sneering. Should it be?
We have written a 2015 series of posts about Lamarckian ideas. Lamarck was interested in the evolution of adaptive traits, like flying or ocean-living mammals, not just some specific minor traits. He had some non-starter ideas, but so did Darwin and they had far less knowledge than we do! So one can't defend his theory per se for various reasons. Still, it's worth thinking about rather than just sneering at Lamarck. That's for tomorrow's post.....
Showing posts with label inheritance. Show all posts
Showing posts with label inheritance. Show all posts
Tuesday, November 24, 2015
Wednesday, August 10, 2011
Mendelian inheritance and evolution. Part III
We've discussed some problems with the idea of Mendelian inheritance as a misleading legacy from the kinds of work that Mendel had to do, that has persisted deeply into modern thinking in ways that we think are misleading at best, or even plain wrong for several reasons.
First, because genetic units, not traits are what is inherited. A fertilized egg doesn't have legs or a brain nor pollenated pea seed have color, wrinkles, or plant-height. What is inherited are genetic variants that affect these traits in the adult organism.
Mendelism was wrong because most variation, the variation that enabled the modern synthesis to unite discrete Mendelian genetic inheritance with gradual Darwinian evolution, was generally minor relative to Mendel's purposes. Clear discrete states and dominance are not the general ground state of biology. In a population individual genes have many more than 2 alleles (variant sequences) and the effects of their paired combinations in individuals (plants and animals) is associated with more than two trait states (yellow or green). Even at single loci, even when some alleles are in the traditional sense dominant relative to others, the dominance is usually not complete or invariate.
Mendelism was wrong in that the key to uniting discrete genetic inheritance with gradual variation in traits and their evolution, was that many different genotypes--combinations of alleles--yield the same trait. When many genes co-contribute, as is widely the case, the trait can be called complex or 'polygenic'. This is because the individual effects are generally small relative to the variation in the trait. Small basically 'additive' effects predominate, rather than strongly determinative ones. We had to give up on notions of Mendelian inheritance were then (and still widely are today) widespread. But that this was the key to the modern synthesis was not widely perceived in these terms.
One could object that oh, yes what we say applies to multigenic traits, but not to single-gene traits. Aren't there hundreds of these on the books, in human disease and in other species as well? We'd respond that in real life most clear dominance or single-locus traits are much less dichotomous or simple that in general perception or in the textbooks, and adaptation and complex function are demonstrably cooperative and multigenic rather than singe-factor competitive. Complex organisms couldn't really function or evolve if they were just a bag of individual dominant, Mendelianly inherited traits. And not only are most traits multi-genic, but genes, no matter how our definitions what a gene is change, are multi-allelic in natural populations.
Once we realize this, we have to accept that in general, statistical dominance, which we explained in an early post in these series, is a population rather than biologically inherent property of individuals. It is the exception, and only a partial exception that is classically Mendelian: partial, because often even in these cases we overlook variation because it may not be great relative to our pragmatic purposes (such as diagnosing the presence of a disease). But pragmatic considerations like this often turn out to be wrong and science is about understanding nature.
The problems mainly follow from falsely confounding inheritance of genes and with inheritance of traits, and from using the extreme of a distribution--the few nearly-dominant examples--to characterize the whole distribution of the effects of individual genetic variants.
At the time of the synthesis, not enough was known about genes (or, at least, seriously and widely enough accepted) to recognize the implications of polygenic inheritance. But now there is no excuse for clinging to theoretical concepts that are misleading and, at best, inaccurate ways to understand life. Doing so has led us down the paths that we imagine will promise simple answers of immediate clinical or commercial value. Each approximate 'hit' entices us to go deeper into the woods of our dreams.
First, because genetic units, not traits are what is inherited. A fertilized egg doesn't have legs or a brain nor pollenated pea seed have color, wrinkles, or plant-height. What is inherited are genetic variants that affect these traits in the adult organism.
Mendelism was wrong because most variation, the variation that enabled the modern synthesis to unite discrete Mendelian genetic inheritance with gradual Darwinian evolution, was generally minor relative to Mendel's purposes. Clear discrete states and dominance are not the general ground state of biology. In a population individual genes have many more than 2 alleles (variant sequences) and the effects of their paired combinations in individuals (plants and animals) is associated with more than two trait states (yellow or green). Even at single loci, even when some alleles are in the traditional sense dominant relative to others, the dominance is usually not complete or invariate.
Mendelism was wrong in that the key to uniting discrete genetic inheritance with gradual variation in traits and their evolution, was that many different genotypes--combinations of alleles--yield the same trait. When many genes co-contribute, as is widely the case, the trait can be called complex or 'polygenic'. This is because the individual effects are generally small relative to the variation in the trait. Small basically 'additive' effects predominate, rather than strongly determinative ones. We had to give up on notions of Mendelian inheritance were then (and still widely are today) widespread. But that this was the key to the modern synthesis was not widely perceived in these terms.
One could object that oh, yes what we say applies to multigenic traits, but not to single-gene traits. Aren't there hundreds of these on the books, in human disease and in other species as well? We'd respond that in real life most clear dominance or single-locus traits are much less dichotomous or simple that in general perception or in the textbooks, and adaptation and complex function are demonstrably cooperative and multigenic rather than singe-factor competitive. Complex organisms couldn't really function or evolve if they were just a bag of individual dominant, Mendelianly inherited traits. And not only are most traits multi-genic, but genes, no matter how our definitions what a gene is change, are multi-allelic in natural populations.
Once we realize this, we have to accept that in general, statistical dominance, which we explained in an early post in these series, is a population rather than biologically inherent property of individuals. It is the exception, and only a partial exception that is classically Mendelian: partial, because often even in these cases we overlook variation because it may not be great relative to our pragmatic purposes (such as diagnosing the presence of a disease). But pragmatic considerations like this often turn out to be wrong and science is about understanding nature.
The problems mainly follow from falsely confounding inheritance of genes and with inheritance of traits, and from using the extreme of a distribution--the few nearly-dominant examples--to characterize the whole distribution of the effects of individual genetic variants.
At the time of the synthesis, not enough was known about genes (or, at least, seriously and widely enough accepted) to recognize the implications of polygenic inheritance. But now there is no excuse for clinging to theoretical concepts that are misleading and, at best, inaccurate ways to understand life. Doing so has led us down the paths that we imagine will promise simple answers of immediate clinical or commercial value. Each approximate 'hit' entices us to go deeper into the woods of our dreams.
Tuesday, August 9, 2011
Mendelian inheritance and evolution. Part II
The modern evolutionary synthesis reconciled what Mendel had showed about the discrete nature of inheritance (or so it was thought), and what Darwin had insisted on was the major gradual, more or less continuous, nature of the variation in traits and their evolution.
A lot of things contributed to this reconciliation. Many experiments, largely stimulated by the 1900 rediscovery of Mendel's 1866 work, began to find mutations that were not grotesque, but had small effects, and were perfectly viable for the organism. Big bad mutations did still arise and had been obvious and easy to see, but now the majority of mutations seemed to be of the lesser type.
Quantitative traits like stature varied gradually rather than by discrete jumps (such as between yellow and green peas). Darwin's distant cousin Francis Galton had shown formally what had been obvious, that even for quantitative traits relatives resembled each other--indeed, they did so more than they might for traits with strong dominance (yellow peas did not resemble their green-pea ancestors in that trait). A variety of investigators, most notably the statistical geneticist RA Fisher (in 1918) recognized how the two types of inheritance could be brought under the same umbrella. If complex or quantitative traits were caused by the effects of many different genes, each making a small contribution, then the resemblance among relatives, the quantitative variation, and Mendelian inheritance were all consistent.
If that was so, then Darwinian gradual evolution was possible even with Mendelian inheritance as the basic fact of life. That's what the modern synthesis showed. It seemed wholly legitimate, indeed perhaps strikingly insightful, and it became the core theory of biology (and in many eyes, we think somewhat erroneously in ways similar to the adherence to Mendelism as the ground-state of inheritance, it still is). The formal theory of evolution or, to many, of life was the mathematical theory called population genetics. Well, Isaac Newton said something to the effect that if it can't be expressed mathematically it can't be a law of Nature, so we needed something real, not soft for biology!
It is strange for a central theory in a serious science to say nothing whatever about actual traits of the entities--organisms--that it purports to explain, but that's what population genetics does. It says only that variation is comprised of discrete Mendelian (that is, discretely transmitted) units of inheritance ('genes' has been the word for them), and that by chance and mainly by the systematic force of natural selection, changes in the frequency of genetic variants were responsible for variation among organisms and among species. Surprisingly, this theory became accepted even before there was any real theory of what a 'gene' is! That means it was such a blanket view, so mathematically rigorous, that it could be universally applied to entities that hadn't even been discovered. Reconciling this theory with actual traits has only come in recent decades under rubrics like EvoDevo (the evolution of development). Our book, Mermaid's Tale, deals with these issues extensively, and we try to show that there has been far too much stress in biology that rested on the Competition-among-clearcut-units-is-almost-everything worldview of the modern synthesis.
The dogma became that Mendelism and Darwinism are compatible.
But in a real sense, we think, this is fundamentally wrong. The modern synthesis essentially was possible only because Mendelian inheritance was itself wrong!
A lot of things contributed to this reconciliation. Many experiments, largely stimulated by the 1900 rediscovery of Mendel's 1866 work, began to find mutations that were not grotesque, but had small effects, and were perfectly viable for the organism. Big bad mutations did still arise and had been obvious and easy to see, but now the majority of mutations seemed to be of the lesser type.
Quantitative traits like stature varied gradually rather than by discrete jumps (such as between yellow and green peas). Darwin's distant cousin Francis Galton had shown formally what had been obvious, that even for quantitative traits relatives resembled each other--indeed, they did so more than they might for traits with strong dominance (yellow peas did not resemble their green-pea ancestors in that trait). A variety of investigators, most notably the statistical geneticist RA Fisher (in 1918) recognized how the two types of inheritance could be brought under the same umbrella. If complex or quantitative traits were caused by the effects of many different genes, each making a small contribution, then the resemblance among relatives, the quantitative variation, and Mendelian inheritance were all consistent.
If that was so, then Darwinian gradual evolution was possible even with Mendelian inheritance as the basic fact of life. That's what the modern synthesis showed. It seemed wholly legitimate, indeed perhaps strikingly insightful, and it became the core theory of biology (and in many eyes, we think somewhat erroneously in ways similar to the adherence to Mendelism as the ground-state of inheritance, it still is). The formal theory of evolution or, to many, of life was the mathematical theory called population genetics. Well, Isaac Newton said something to the effect that if it can't be expressed mathematically it can't be a law of Nature, so we needed something real, not soft for biology!
It is strange for a central theory in a serious science to say nothing whatever about actual traits of the entities--organisms--that it purports to explain, but that's what population genetics does. It says only that variation is comprised of discrete Mendelian (that is, discretely transmitted) units of inheritance ('genes' has been the word for them), and that by chance and mainly by the systematic force of natural selection, changes in the frequency of genetic variants were responsible for variation among organisms and among species. Surprisingly, this theory became accepted even before there was any real theory of what a 'gene' is! That means it was such a blanket view, so mathematically rigorous, that it could be universally applied to entities that hadn't even been discovered. Reconciling this theory with actual traits has only come in recent decades under rubrics like EvoDevo (the evolution of development). Our book, Mermaid's Tale, deals with these issues extensively, and we try to show that there has been far too much stress in biology that rested on the Competition-among-clearcut-units-is-almost-everything worldview of the modern synthesis.
The dogma became that Mendelism and Darwinism are compatible.
But in a real sense, we think, this is fundamentally wrong. The modern synthesis essentially was possible only because Mendelian inheritance was itself wrong!
Monday, August 8, 2011
Wicked smart apes
I tried to hate it. I really did.
But despite all the Hollywood violence; despite its (inadvertent but dangerous) glorification of the life of a pet chimp and of having one; despite the digital movements that weren’t always quite right… I still enjoyed Rise of the Planet of the Apes.
[If you’re worried about spoilers, (A) Don’t read the title of the movie, and (B) Don’t read any further until you’ve seen it. But to be honest, I'm not sure I reveal anything that wasn't already revealed in the trailers.]
I can't control how apologetic I feel for liking this flick so much. As a human I care deeply what other humans think of me and my movie tastes. And in a weird way I care what chimps, bonobos, gorillas and orangutans would think of me liking it. I guess I shouldn't apologize for being human and I can't easily stop being such a dork.
Perhaps it was the near-future sci-fi possibility of it. Perhaps it was all the sneaky little throwbacks to the original flick. Perhaps it was the attempt to tackle issues of personal bias, emotions, and capitalistic greed in the world of science. Perhaps it was the way James Franco wore that little white lab coat. Perhaps it was my adoration of apes overpowering the fact that these were mere digitized computer actor-humans. Perhaps it was the triumph of the apes! Perhaps it was impossible to go anywhere but up from my subterranean expectations. Perhaps I’m just a human and we humans love our big loud, manipulative blockbuster movies, especially ones that ask, “What does it mean to be human?”
The shows were all sold out on Sunday in West Warwick, so I’m betting most of my students will see this movie—if not this summer, then soon. And I’m sure to be fielding the questions they’re bound to have after watching it. You may have to field the same ones.
I may even use the movie as a teaching tool to help with topics like gene therapy, virus biology and therapeutic use, non-human disease models and test subjects, transgenic lab animals, and inheritance.
Although I’ve worked with custom-engineered virus vectors to modify and to shut down specified protein synthesis in epithelial cells, my experience stops there. And to help me try to make sense of this movie, I asked Ken and Anne to answer some questions that movie goers are bound to wonder.
Ken and Anne: Fire away.
Holly: In the movie Rise of the Planet of the Apes, a scientist invents a possible treatment for Alzheimer’s that regenerates neurons and they test it on chimpanzees in a fantastic lab (and the scientist also administers it to his father at home). The delivery system for the treatment is a virus vector injected into the bloodstream (for humans) or administered through a gas mask (for the lab chimps) that changes known genes associated with Alzheimer’s in humans (not chimps!). When a chimpanzee (who does not have Alzheimer's) is infected with the virus she becomes significantly more intelligent.
1. How does one test a cure for a human disease in non-affected non-humans?
Ken: We've not seen the movie but here are some guesses at your questions. In principle (far from practice at the moment), one could get such a vector into a person that could target the particular gene in cells, and replace it with a gene the vector carries. (If this were incorporated in the germ line of the mother or father, it would be passed on to their kids as part of their genome.) Testing simply would be taking a DNA sample (any cells--blood, cheek swab, etc) and looking for the sequence of the inserted gene. This is what is done to make transgenic mice (but the gene is inserted into an egg, not breathed in by an adult).
Anne: There are 2 things that normally would need to be tested in developing gene therapy; the system for delivering the genetic modification, and the efficacy of that modification. In principle they could/should be tested separately, so the delivery system would be tested on normal subjects before the efficacy of the cure is tested, so that, if it doesn't work, the researcher knows it's not because of the delivery system. Testing of many pharmaceutical products is done in similar stages -- first determine whether it's safe on normal people, then whether it actually cures. The first stage is often done on 'professional guinea pigs', people who make their living volunteering to test drug safety. But you're right, it's not the cure that's being tested on people without the disease, it's the efficacy or safety of the procedure.
2. The Alzheimer's (AD) cure not only heals neural degeneration (as evident in the human test case), but it improves cognition too and when both humans and normal chimps are infected their intelligence increases literally over night. Could that be possible? How?
Ken: It could (in principle) fix damaged neurons in the patient (this is at the moment largely fantasy but by now there may be some precedents--we're not up to date on what claims may be being made.) If the person's inherited genes that led to AD also led to poor cognition, and if changing the gene once their brain is developed could goose up the neurons' activities, then this, too, could occur in principle. Suppose for example that the problem were a neurotransmitter receptor that was somehow not very efficient, and this were replaced so that signals traveled between synapses more rapidly. Again this is all 'suppose' at present!
Anne: If intelligence is due to synapse speed, say, one could imagine that could be upgraded quickly. It's harder to imagine that the biochemistry underlying chimp intelligence is the same as that that causes dementia, and that therefore they'd have the same fix!
3. Also—and this is the real question I’m interested in discussing especially considering the recent Mendel-Wasn’t-Right theme here on the MT!—A female chimp who has been infected actually passes the positive genetic affects onto her offspring. They even remark how her son is intelligent because it's "in his genes." How could this be possible?
Ken & Anne: In the same way as related to #1 above, the offspring would inherit the faster-firing receptor gene and would be smarter.
All of this assumes that one gene change would work across genomic background variation, with no side effects, and all that. But the dream of real gene therapy has been to do what you're describing (again, we didn't see the movie). A good example would be replacing sickle cell hemoglobin (the beta globin gene) with a normal version, or replacing the mutant Tay Sachs or Cystic Fibrosis gene with normal sequences. But to be inherited it has to involve the germ line cells.
There are some known mechanisms that illustrate how such a dream scenario could be plausible. Cells have receptors that bring what binds to them into the cell (usually, this is for some normal cell response to the environment). A virus could be engineered to be taken into some specific cell, like a neuron, in this way. The virus could be designed so that genes it carries are made into RNA corresponding to the 'good' gene version, along with code for a protein like reverse transcriptase that turns RNA into DNA and inserts it into chromosomes could be used. The latter is how viruses currently incorporate into DNA and cause trouble; our genomes are littered with such inserted elements. The difference is that they insert only occasionally and even then into random places in the genome, or places of their choosing.
To get this into places of our choosing, we would have to engineer the system to recognize some sequence of the target gene area and insert the virus's passenger gene at that place, excising the current (bad) gene there.
In any cell in which this occurred, the transgene would have replaced the normal gene, and the job would be done for that cell. If in a sperm or egg precursor, then that would be transmitted to (half of) the person's offspring.
There are versions of each of these transgenic techniques already in practice, but in every case there are limits relative to the desired outcome, and they mainly work in mice that have already been prepared for the experiment by manipulating mouse egg cells. We use such transgenic mice in our own work here on craniofacially relevant genes.
There used to be a lot of hope for such gene therapy, but failures have led many if not most companies to give up the effort. Mostly what is still being tried (I think) is and has always been to administer something to a patient and change his or her genes, or insert a compensatory gene, in affected cells. Injections of such things into muscle to alleviate muscular dystrophy, or by inhaler to alleviate CF, or to fix immune system problems have been tried and probably some at least are still under test.
That still leaves movie goers wondering how someone, like Caesar-the-chimp’s mother in the movie, could contract a virus orally or through the bloodstream which somehow finds its way to the eggs or sperm and then inserts its DNA into those cells and modifies them. That’s the only way the modified DNA sequence could be inherited by future generations, like Caesar, but it's not outside the realm of plausibility. Just think of the evolutionary possibilities!
Thursday, August 4, 2011
Mendelian Inheritance and evolution. Part I
We recently discussed problems with the idea of Mendelian inheritance, and the way that assuming that was a mode of trait inheritance has been so misleading and, we think for that reason incorrect. (Here's the first of the five posts in that series.) We'd now like to consider some of the implications of our point of view, when it comes to evolution. We think this in fact reinforces that point of view, as we'll try to show.
Some traits do seem clearly to 'segregate' (be distributed) among family members in a present or absent mode, associated with a single allele (variant) at a gene, and if one allele is more likely to prevail that is called 'dominant'.
We pointed out that Mendel chose traits that 'worked'--that provided clear-cut material that allowed him to understand the nature of 'inheritance.' That word is actually somewhat off, because Mendel was interested in the nature of hybridization (inheritance in a mixed cross between strains), and there was the confusion that still widely reigns, between inheritance of traits and inheritance of genes. By pragmatically equating the two, because that wasn't too far off in his chosen model situation, Mendel got his result. Even he knew that most traits didn't work that way (and even some traits that should, in some species he later studied, didn't).
For many decades after Mendel, it was thought that such traits had two important properties: they were stable, and they made clear-cut qualitative trait differences. If either wasn't true, then Mendel's rules wouldn't work, hybridization wouldn't work as expected, and how inheritance worked would remain obscure.
And, when Darwin's and Wallace's ideas came along, it was clear that evolution wouldn't work, either! The most one might expect would be that one of the alleles would replace the other over time, by natural selection. But this was not satisfactory, because evolution clearly involved smaller, gradual changes more than big dramatic ones. And evolution, even by Darwin's mistaken genetic ideas, would continually generate new variation for selection to screen. That was a big problem, because the observed new alleles, traits in offspring that were not present in their ancestors, seemed mainly to be grotesquely harmful, not material that selection could work with to adapt to changing circumstances.
Darwin was aware of much of this, too, in fact. He could not see how immutable traits, like the dominant/recessive ones, could evolve and also he felt that evolution simply had to be gradual and more or less continuous. Among his reasons were his erroneous largely Lamarckian notion of the physical basis of inheritance, and the fear that without gradualism traits or species might arise suddenly....requiring explanations for their origin.
As a result, for decades leading biologists, realizing that Darwin's gradual inheritance theory (that he called 'pangenesis') was fundamentally wrong, were not convinced that natural selection could account for adaptive evolution or, in particular, that this had anything to do with the known mechanisms of inheritance.
The solution that was widely accepted and prevails (not always accurately) to today, was worked out in the 1930s and later, based on some theory and data from earlier in the 1900s. This solution was known by names like the 'modern evolutionary synthesis.' It reconciled Mendelian inheritance with gradual evolution in ways that were consistent with variation within and between species, and with the fossil record.
There are many things to dispute about the modern synthesis, and we'll point them out (and have mentioned them before here on MT). But one thing that is important, but so far as we know hardly if at all recognized, was that the modern synthesis was possible only if Mendel was wrong, in ways we tried to outline in our recent previous series.
We'll elaborate on these thoughts in the next installment.....so stay tuned!
Some traits do seem clearly to 'segregate' (be distributed) among family members in a present or absent mode, associated with a single allele (variant) at a gene, and if one allele is more likely to prevail that is called 'dominant'.
We pointed out that Mendel chose traits that 'worked'--that provided clear-cut material that allowed him to understand the nature of 'inheritance.' That word is actually somewhat off, because Mendel was interested in the nature of hybridization (inheritance in a mixed cross between strains), and there was the confusion that still widely reigns, between inheritance of traits and inheritance of genes. By pragmatically equating the two, because that wasn't too far off in his chosen model situation, Mendel got his result. Even he knew that most traits didn't work that way (and even some traits that should, in some species he later studied, didn't).
For many decades after Mendel, it was thought that such traits had two important properties: they were stable, and they made clear-cut qualitative trait differences. If either wasn't true, then Mendel's rules wouldn't work, hybridization wouldn't work as expected, and how inheritance worked would remain obscure.
And, when Darwin's and Wallace's ideas came along, it was clear that evolution wouldn't work, either! The most one might expect would be that one of the alleles would replace the other over time, by natural selection. But this was not satisfactory, because evolution clearly involved smaller, gradual changes more than big dramatic ones. And evolution, even by Darwin's mistaken genetic ideas, would continually generate new variation for selection to screen. That was a big problem, because the observed new alleles, traits in offspring that were not present in their ancestors, seemed mainly to be grotesquely harmful, not material that selection could work with to adapt to changing circumstances.
Darwin was aware of much of this, too, in fact. He could not see how immutable traits, like the dominant/recessive ones, could evolve and also he felt that evolution simply had to be gradual and more or less continuous. Among his reasons were his erroneous largely Lamarckian notion of the physical basis of inheritance, and the fear that without gradualism traits or species might arise suddenly....requiring explanations for their origin.
As a result, for decades leading biologists, realizing that Darwin's gradual inheritance theory (that he called 'pangenesis') was fundamentally wrong, were not convinced that natural selection could account for adaptive evolution or, in particular, that this had anything to do with the known mechanisms of inheritance.
The solution that was widely accepted and prevails (not always accurately) to today, was worked out in the 1930s and later, based on some theory and data from earlier in the 1900s. This solution was known by names like the 'modern evolutionary synthesis.' It reconciled Mendelian inheritance with gradual evolution in ways that were consistent with variation within and between species, and with the fossil record.
There are many things to dispute about the modern synthesis, and we'll point them out (and have mentioned them before here on MT). But one thing that is important, but so far as we know hardly if at all recognized, was that the modern synthesis was possible only if Mendel was wrong, in ways we tried to outline in our recent previous series.
We'll elaborate on these thoughts in the next installment.....so stay tuned!
Tuesday, July 26, 2011
Mendelian Inheritance: Basic Genetics or Basic Mistake? Part II.
The idea of Mendelian inheritance, revered for more than a century, was initially about the inherently causal nature of dominance and recessiveness. The A allele always and, presumably, inherently, made its effects manifest, as in the accompanying figure. Even as late as 1995, an influential paper termed this 'physiological' dominance.
But why so long after Mendel's rules were deeply established, was there a need for such a term?
In the genetics of quantitative traits, one can look at the average trait value (say, stature or body fat content of pigs or oil content of corn) in AA's and aa's. If the 'A' were physiologically dominant, then the Aa's should have the same mean value as the AA's. These are clearly statistical statements because unlike green vs yellow peas, there is variation and there are sampling issues (in fact, even Mendel's classical traits had some variation, but little overlap between dominant and recessive plants).
What transpires as a rule, however, is that the Aa's are not exactly like the AA's. But a common alternative to Mendelian ideas was that rather than being dominant and recessive, the contributions of the alleles at a gene were additive, like doses of medicine: Each copy of, say, an A allele you have, is a jump in your trait value. In such situations, Aa's would be exactly intermediate between AA's and aa's. If instead they shift towards one of the two homozygote (AA or aa) individuals, this is called statistical dominance.
Unlike physiological dominance, statistical dominance has to be evaluated by sampling from a population, and that means in turn that the idea of estimating the net or 'actual' effects of the A and a alleles, depends on the frequencies of these in the population, and more importantly, that also means that environmental and other genomic effects will affect the mean values of the carriers of the 3 genotypes. Statistical geneticists now treat these two kinds of dominance differently, often ignoring the physiological because it is hard to identify in real-world situations of quantitatively variable traits, as opposed to experimental settings with only two clear states, that have been part of genetics ever since Mendel himself.
We can relate this to GWAS findings a simple way. If a given allele is common enough in cases for its effects to be found and reach statistical significance, relative to its frequency in controls, then it has a chance to be detected in a GWAS study. But this depends on its penetrance, that is, on the strength of its effects, on their own, on a trait measure like stature or blood pressure, or on the presence of a disease. Highly penetrant alleles will be found more frequently in cases than controls because they have a higher chance of 'causing' the trait. The greater the effect, the more likely if you have the allele you have the disease.
This is a kind of 'dominance', because the allele is being detected against the other allele at that gene in individuals, plus whatever other relevant variants they have in their genome. That typically only a few genes are identified in this way shows how relatively rare real dominance is--how far it is from being the baseline, basic nature of inheritance! In fact, most variants that contribute contribute so little--have so little 'dominance' in this context--that we simply cannot detect their individual effects (or those effects are not enough to generate a statistically 'significant' association with the trait). So, dominance is far from the general rule. We will see in the next installment why this should not be any kind of surprise.
In the genetics of quantitative traits, one can look at the average trait value (say, stature or body fat content of pigs or oil content of corn) in AA's and aa's. If the 'A' were physiologically dominant, then the Aa's should have the same mean value as the AA's. These are clearly statistical statements because unlike green vs yellow peas, there is variation and there are sampling issues (in fact, even Mendel's classical traits had some variation, but little overlap between dominant and recessive plants).
What transpires as a rule, however, is that the Aa's are not exactly like the AA's. But a common alternative to Mendelian ideas was that rather than being dominant and recessive, the contributions of the alleles at a gene were additive, like doses of medicine: Each copy of, say, an A allele you have, is a jump in your trait value. In such situations, Aa's would be exactly intermediate between AA's and aa's. If instead they shift towards one of the two homozygote (AA or aa) individuals, this is called statistical dominance.
Unlike physiological dominance, statistical dominance has to be evaluated by sampling from a population, and that means in turn that the idea of estimating the net or 'actual' effects of the A and a alleles, depends on the frequencies of these in the population, and more importantly, that also means that environmental and other genomic effects will affect the mean values of the carriers of the 3 genotypes. Statistical geneticists now treat these two kinds of dominance differently, often ignoring the physiological because it is hard to identify in real-world situations of quantitatively variable traits, as opposed to experimental settings with only two clear states, that have been part of genetics ever since Mendel himself.
We can relate this to GWAS findings a simple way. If a given allele is common enough in cases for its effects to be found and reach statistical significance, relative to its frequency in controls, then it has a chance to be detected in a GWAS study. But this depends on its penetrance, that is, on the strength of its effects, on their own, on a trait measure like stature or blood pressure, or on the presence of a disease. Highly penetrant alleles will be found more frequently in cases than controls because they have a higher chance of 'causing' the trait. The greater the effect, the more likely if you have the allele you have the disease.
This is a kind of 'dominance', because the allele is being detected against the other allele at that gene in individuals, plus whatever other relevant variants they have in their genome. That typically only a few genes are identified in this way shows how relatively rare real dominance is--how far it is from being the baseline, basic nature of inheritance! In fact, most variants that contribute contribute so little--have so little 'dominance' in this context--that we simply cannot detect their individual effects (or those effects are not enough to generate a statistically 'significant' association with the trait). So, dominance is far from the general rule. We will see in the next installment why this should not be any kind of surprise.
Monday, July 25, 2011
Mendelian Inheritance: Basic Genetics or Basic Mistake? Part I.
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| Gregor Mendel |
Mendel carefully chose strains of basically inbred pea plants that had simple patterns of inheritance: the dichotomous traits 'bred true' from parent to offspring. He knew there were many traits that did not just have two states, or that did not breed true in this simple way. But to understand the effects of hybridization--or we now wrongly say, inheritance--he picked appropriate traits. His seven carefully chosen traits all had an additional attribute that was important in this sense. One of the states was 'dominant' to the other state, which was therefore 'recessive'. These are essentially the terms Mendel himself used.
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| The 7 traits of interest to Mendel |
Note right off the bat that there was a very big mistaken conclusion that followed: Mendel was showing the nature of trait inheritance, but it was interpreted to mean the laws of genetic inheritance. It worked only because of the 100% correspondence due strictly to the careful choice of 2-state, highly determinative traits in his experiments. Although even that isn't strictly true (see my 2002 paper in Evolutionary Anthropology), it was close enough that even now we confuse inheritance that strictly applies only to genes, with the appearance of traits in offspring compared to their parents.
Classically, many 'Mendelian' diseases were identified, because they approximately followed Mendel's laws. Modern biomedical genetics began, around 1900, with Archibald Garrod's studies of 'recessive' traits that arose in inbred marriages, that raised the chance that a child would inherit the recessive allele from both parents (because the genetically related parents shared the allele from their common ancestor). Step by step, we built in the illusion that genes were just waiting their transubstantiation into traits.
Until the nature of DNA was understood and we could examine DNA directly we had to work through traits rather than genes, even though we called the field 'genetics'. For decades it was observable traits in experimental species, such as fly eye color, or 'Mendelian' disease, or similar traits in plants. Genetics split into two parts, one dealing with this kind of 'clear cut' particulate inheritance, which eventually led to understanding of how protein-coding areas were arranged along chromosomes, the nature of chromosomes, the nature of genes coding for proteins, and the transmission of DNA from parent to offspring.
The other segment of geneticists dealt with the majority of traits that clearly did not 'segregate' from parent to offspring, the quantitative traits like stature, milk-yield, grain nutrient properties and the like, from which the field of quantitative genetics developed. It was more pragmatic and said that a quantitative or complex trait was due to the inheritance of many genes: we might not be able to identify them, but jointly they were responsible for traits in organisms. The similarities between parents and offspring for complex traits was consistent with this view as well.
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| Cajanus Cajan; Wikimedia Commons |
Of course all of this is manifestly a Grand Illusion! Even a fertilized pea ovule does not have peas, wrinkled, green, or otherwise! Once the connection between a gene and a trait becomes less than 100%, or once many genes contribute information about a trait, we see how obviously Mendelian ideas were a badly misleading mistake. They were great for providing ways to set up experiments that isolated genetic effects and led to an understanding of genetic inheritance. But they were, from the beginning, very misleading about trait inheritance.
In the next installments of this series, we'll examine the idea of dominance and genetic effects further, and will eventually ask whether, surprisingly, there really is such thing as dominance in the first place!
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