EEB 122:?Principles of Evolution, Ecology and Behavior

Lecture 10.?Genomic Conflict

https://oyc.yale.edu/ecology-and-evolutionary-biology/eeb-122/lecture-10

There are cases where the conflict of interest is arising because there's selection going on at two different levels; on the whole organism, and then within the cell, on the cytoplasmic organelles.?

• Plantago flower is?a rosette plant. It is gynodioecious, which means that it has two kinds of flowers. It's got flowers that have both male and female parts, and it's got flowers that just have the female parts and greatly reduced?or almost absent?male sterile parts. The?50:50 sex ratio has been subverted, and all they do is reproduce as females. Now it turns out that the genes that control this morphological switch are in the cell organelles; they're not in the nuclear genome. The genes that are sitting in the organelles in the cell, be they mitochondria or chloroplasts, can only get into the next generation through female function, namely?the eggs. They are not transmitted through pollen. It is in their interests to take the organism that they're sitting in and turn it into a pure female.

• This same process goes on in insects and in crustaceans, when they are infected by a cytoplasmic bacterium called Wolbachia. It is in Wolbachia's interests only to occur in females, because they can only get into the next generation in eggs; they can't get into the next generation in sperm. And Wolbachia will feminize the organisms that it's in, and in some cases Wolbachia will kill the males, so that the male offspring don't develop.?

Bill Hamilton, the guy that came up with?kin selection,?wrote a lot on?evolutionary conflict.?If there's potential, through either hierarchical selection or asymmetry of information?transmission, to generate evolutionary conflict, then we see that we're not even in principle the consistent wholes that you might think we are.?

• The outline basically is going to be how you can generate genomic conflict out of hierarchical selection.

• I'm going to make a strong point that the opportunities for conflict are much greater in sexual than in asexual species.

• Then I'll mention that the uniparental transmission of cytoplasmic genomes is probably a method of conflict resolution.

• Then I'll go on to talk about genomic imprinting and parent-offspring conflict in mammals.?

Conflict can arise in two situations.?

• One is the Russian doll situation, the babushka situation; multilevel hierarchical selection. That is when one selection process is contained inside another selection process; and here you should think of things like meiotic drive and cancer.

• The other situation is where the transmission is asymmetrical, so that the different genetic elements in the system do not all follow the same transmission pathways. The cytoplasmic organelles are the classic example. They can only go through the female line, they can't go through the male line. The nuclear genes are going equally through both male and female inheritance. So there's a large and striking difference in the way the cytoplasmic organelles are inherited.?

So when we think about two-level selection, there are really two things that can be going on.?

1. If A has a replication advantage?at the lower level, then it can just build up more copies of itself, and then when this larger thing divides and reproduces, it will end up in more copies, because at this stage it was reproducing faster.

   Think petite mutation in yeast. A petite mutation in yeast is a mitochondrial mutation, and the petite mutation cuts out a chunk of the DNA in the mitochondrial genome, so that the mitochondrial genome can be replicated faster. If you cut out a bunch of the mitochondrial genome, the mitochondria?will not?be?a good energy factory for that cell that they're living in. So they're gaining an individual advantage from mitochondria, but they're damaging the interests of the cell that contains them. And what happens is that the ones that cut out the DNA, that can replicate faster, do build up a replication advantage at the lower level.

2. The other possibility in two-level selection is that there's a segregation advantage. There are just as many copies made of each type?at the lower level, but in the process of then forming the gametes (mitotic or meiotic), if there's a segregation advantage, one of them is going to get into more copies. So it takes the same number, and then just in the process of making the new cells it gains an advantage. And think here meiotic drive.

   So in the petite mutation in yeast, there's a deletion in the mitochondrial genome, which?allows the shorter genome to be replicated faster. It builds up a big population in the cell. However, there's a disadvantage at the higher level, and that is defective metabolism. The result is that the cell lineage goes extinct. They have a lower level replication advantage, but they have a high cost for the cells that contain them, and they disappear. It's almost exactly analogous to cancer.?

In an asexual lineage, the only kind of conflict that is in principle possible is one selection process contained inside another one, and the conflict would occur if the lower level response differs from the higher level response; so if what's good at the lower level is bad at the higher level. Petite mutation is a good example.?

There's no horizontal transmission, because there's no sexual reproduction going on. So two independent lineages are not coming into contact with each other and mixing; they're staying separate through generations. And so there isn't any way for the lower level response to escape the fate of the upper level response. So if there's a significant conflict, a significant cost, the lineages will die out. So this is something that actually can drive asexual extinction.?

In a sexual lineage, sex is creating genetic variation within the nuclear genome. It has the potential to create genetic variation in cytoplasmic genomes, and it creates opportunities for non-chromosomal genetic elements to change hosts.?So some kinds of mechanisms?during sex?formally resemble pathogen transmission.?

So one cost of sex might be the potential it creates for inter-genomic conflict. I'm not talking here directly about sexually transmitted diseases like gonorrhea or syphilis. I'm talking about the possibility that genetic elements infect the genomes of other cells.?For example, there could be a conflict between bacterial plasmids and chromosomes.?

• Bacteria usually contain plasmids, and these things are small circular genetic elements and they live in the bacterial cytoplasm.?The rest of the bacterial genome is a large single circular chromosome which is attached to the cell wall of the bacterium.

• The plasmids often are the elements in the bacterium that have genes for antibiotic resistance, and they can be advantageous when antibiotics are present. There are other plasmids that will addict their host cells, the bacterial cells, to their presence by making a poison antidote system. They're protecting their own cells and they are producing chemicals that destroy cells that don't contain the plasmids.

• If you make a long distance poison and a short distance antidote, you protect the environment that you're in and you destroy the competition. So any bacterial cell that doesn't inherit the antidote, via a plasmid, but gets the poison, will die. So that changes selection dynamics, at a higher level, and this plasmid will spread through the population.?

Very similar to that?is segregation distortion.?

• There is a gene that was first found in mice and?it's just an arbitrary accident of developmental biology that this segregation distorter happens to also result in mice with short tails.?

• There's a t and a normal allele that we call +. So these are the two versions of this gene that are sitting at the same place in the chromosome. If you have tt homozygotes, they're lethal or sterile.

• If you have a mouse that is heterozygous with t and +, they live just fine?and they produce 90 to 100% t-bearing sperm. This is again done with a long distance poison and a short distance antidote system. The sperm that have the t are also making an antidote, but it's only effective inside their own sperm. So t is just wiping out the competition?inside the testes.

• So you have hierarchical selection at the level of the gamete. You have got selection for t and against t, up at the level of the diploid individuals, because up there the tt homozygotes are lethal or sterile.

• If the tt homozygotes didn't die?but they suffered a sufficiently small, sub-lethal fitness reduction,?then t would spread?all the way through the population. Everybody's got the antidote, and you don't have any segregation distortion anymore, and everything goes back to normal. If that is the case, once t takes over the population, there's no more segregation distortion.?

This introduces the interesting possibility that most species may have had a history of segregation distortion and we just don't notice it anymore, because they've gone to fixation.

Now what about conflicts between the nucleus and the cytoplasm? Any cytoplasmic genome?that's replicating faster?gets a segregation advantage, because there is no?meiotic mechanism that assures fair segregation of organelles.?

• The chromosomes are controlled by the spindle apparatus. They line up at the plate?at the middle of the cell and?make two copies. The spindle grabs one copy and pulls it one way?and the other?pulls it another way. So that's really fair and?exactly 50:50.

• The organelles are floating around. They're not attached to a spindle when the cell divides, and so basically if they can just make more copies of themselves, they'll have a better chance of getting into the dividing cells.

• If you had biparental inheritance of cytoplasmic genomes, that would mean that in the same cytoplasm you would have genetically different, unrelated mitochondria or?chloroplasts. And the consequence of that would be conflict, and that would be expressed as an organelle cancer.

• If you only get the cytoplasmic genome from one parent, then they'll very likely all be the same genotype--any kind of process like this going on in the past would have assured that there would only be one left standing, in that parent--and therefore they're not in conflict with each other.?

So, in fact, you all only contain mitochondria from your mothers. It's extremely rare that a human will ever have a mitochondrion from a father.?Those are some of the well established cell level scenarios in which conflict plays out. This is a vision of evolution in which there is continual conflict, and in some cases it's never resolved.

In mammals there are conflicts between mother and fetus over how much the mother should invest in the fetus. The symptoms of that are pre-eclampsia and diabetes. There are conflicts between mother and father over maternal provisioning, and those are related to genetic imprinting of growth genes, and there are disturbances and a tug-of-war balance produced by evolutionary conflict in genes that are expressed in the infant brain, and those are thought to deal with mental illness.

The arenas in which these things play out are in the placenta and uterus, and in the developing brain. And this is the sequence of ideas,?so I'll give you a little intellectual history.?

1. In?1961, Bill Hamilton has the idea of kin selection, the idea that a gene can increase its fitness, either by its actions on my own body, or by influencing the actions that I take to improve the reproductive success of relatives in which that gene also probably exists. Then Bob Trivers developed Bill's idea into parent-offspring conflict.

   A mother is 50% related to all of her offspring. She is interested in making sure that each of them has an equal chance therefore to have grandchildren.

   Now switch your point of view to one of the offspring. It's 100% related to itself; it's 50% related to a full sib; and it's only 25% related to a half-sib. So from the point of view of a gene which is sitting in our focal offspring, it wants to titrate its mother's investment away from its potential future siblings and into itself, until the probability of grandchildren, through itself, exactly matches the probability of grandchildren through the others multiplied by degree of relationship.

2. Now David Haig then picked up on Bob's idea and claimed?that conflict?is also realized through imprinted genes in pregnancy. There is conflict between the mother and the father over how much the mother should give to the baby, and the baby take from the mother. If the father can put into the baby a gene that then extracts more from that mother than the mother wants to give, the father can gain, to a certain point, an advantage. And this is mediated by genomic imprinting.

3. The final step in this little bit of intellectual history is Bernie Crespi and Chris Badcock, who came up with the idea that this conflict that David Haig identified, which is going on during pregnancy and is probably mediated mostly by genes that are having interaction in the fetus and in the placenta, extends into early life during the period of suckling?before the child is weaned, and the conflict is then expressed in genes that are in the brain of the infant, and when their tug of war, which is in evolutionary equilibrium, is disrupted, Crespi and Badcock think that you get mental disease.?

The conflict between mother and fetus over maternal provisioning is basically this:

• The fetus is selected to extract more from the mother than the mother is selected provide. It's 100% related to itself. She's 50% related to each of her offspring. It wants to take more from her. She wants to hold some back, so she can give the same amount to future offspring. The way that it will do this is by using tissue in the placenta to secrete hormones into the mother to manipulate her metabolism.

• It also does it?morphologically. It is fetal tissue in the placenta that invades maternal tissue?aggressively, and establishes tighter and tighter connections with the maternal blood circulation.

• So the symptoms experienced by the mother are high maternal blood pressure and pregnancy-related diabetes, and this will happen particularly when this gets a bit out of balance. So if you're a baby,?you can pump up her blood pressure so it'll force more nutrient through the placental barrier, and you can play with her metabolism so there's more sugar in her blood. Too much of that and the mother gets pretty sick.?

So the evolutionary logic behind the mother-father conflict is:

• The father isn't going to be related to the mother's later offspring, if they have other fathers.

• Now there is an asymmetry in the male and female reproductive possibilities. The father's reproductive success depends on his successful matings. The mother's reproductive success depends on the number of offspring she personally can bear. And if you state that brutally, he can have several children and other females, while she's dealing with this one.

What does this have to do with imprinting, and what is imprinting anyway??Imprinting is a process of methylating genes, and if you imprint a gene, you turn it off; it will not be transcribed if it's methylated. Imprinting is used in a number of contexts. It's an epigenetic mechanism that's used in development to control cell fate.

• The kind of imprinting that we're talking about today is a special kind. It's differential imprinting by sex, and it's not happening during the development of the body in order to decide whether a cell becomes a liver cell or a brain cell, it's happening in the germ line of the parents, just before the gametes are produced. And the point is that the father is imprinting certain sets of genes and turning them off, and the mother is imprinting other sets of genes and turning them off.

• These genes that are imprinted in the germ line are not expressed in the fetus, and they are then reprogrammed in the germ line of the adult. The adult could be either male or female. So when it makes its gametes?in the next generation, it doesn't make them with programming the imprinting pattern it had when it was a baby, it makes them with the imprinting pattern that is appropriate to its sex.

• The father is turning off genes that down-regulate growth in the embryo. The mother is turning off genes that up-regulate growth, and so?it's kind of double negative, because the father's turning off stuff that acts in the mother's interests, and the mother's turning off stuff that acts in the father's interests. But the upshot of that is that the father is trying to program the embryo to extract more than the mother is prepared to give, and the mother is resisting.

You can only see this going on when you disturb the equilibrium. You can do it by genetically transforming mice, and the gene that you choose to disturb the equilibrium is the gene that does the imprinting.?

• You mutate that gene?or you delete it, and then you observe the outcome. And the effect is roughly plus or minus 10% in birth weight. If the mother's genes are not doing their job, so that only the father's interests are expressed, the embryo is about 10% heavier; and if it's the other way around, the embryo is about 10% lighter.

• This scenario is also supported by the fact that if you look at all of the genes in the body, there are only about 100 or 200 genes?that are imprinted. There are very few that are imprinted differently in the mother and in the father, and the ones that are imprinted differently in the mother and the father mostly have to do with the control of fetal growth.

Now, going into speculation. The primary site is the placenta, where there are small deviations that can benefit child or mother. Large deviations are costly to both. So the normal situation might be that there would be a small deviation. You only get a big deviation and disease when there's a real disruption of the imprinting patterns and they get out of balance; so that if you're thinking of a tug of war, one side falls over.?

Where are the rest of these genes? They're in the brain. These are the sex differentially imprinted genes, the ones that are imprinted differently in mother and father, and they're not controlling fetal growth or being expressed in the placenta, but they are being expressed in the brain. And this is now Crespi and Badcock's idea.?

• A deviation toward paternal gene expression should result in a relatively selfish offspring. So it should be trying to take more from the mother, and it should be doing it now through infant behavior rather than through fetal physiology.

• And a deviation towards maternal gene expression should result in an easy offspring that would be letting the mother relax and store up nutrition for the next baby.

What Crespi and Badcock have done is they've looked at neurogenomic syndromes, single gene effects, and idiopathic psychiatric conditions, to see what happens when this tug of war in the brain is disturbed.?

• There are imprinted genes on chromosome 15, that are expressed in the brain.

• Angelman syndrome is that the maternal copy is deleted. The paternal copy is only imprinted in the brain; it's not imprinted in other parts of the body, it's very specifically imprinted in this tissue. Angelman children are happy, retarded and uncoordinated.

• The same gene, but with paternal copy deleted, maternal copy imprinted, after the age of two, you get uncontrolled eating, hypogonadism, delayed puberty, and a completely different syndrome.

• Angleman types, with father's interests over-expressed, have prolonged suckling, frequent crying, hyperactive, sleepless; they're difficult children and they have high rates of autism.

• The Prader-Willi children, with maternal interest over-expressed, don't feed very well, they cry weakly, they're inactive or sleepy, and they have high rates of psychosis; some kinds of psychosis are called schizophrenia.?

So what Crespi and Badcock proposed is that if there's an imbalance during fetal development, in the brain, towards paternally expressed imprinted genes, you get higher birth weight, a larger brain, faster growth, a cost to the mother. The costs to the mother are coming from selfish, egocentric cognition and behavior, and both mother and child are bearing costs from any of the negative aspects of autistic spectrum.?

If the mother's interests are over-expressed, then during fetal development you get a smaller birth weight; you get a smaller brain, less lateralized brain; slower growth. The benefits to the mother is that the child is easier to take care of. There's a cost to the offspring, it has schizophrenic behavior.?

Everything that I've told you about a potential connection between evolutionary conflicts of interest and mental disease is speculative. There is correlative not experimental evidence, but it is possible to go out there in the literature and to pull together a lot of studies.

If you want to get rid of a conflict, make the interest of the competing elements symmetric.?

• You can do this in a host pathogen relationship by shifting the transmission from horizontal to vertical. That will reduce their virulence. Because?then the pathogen can only get into the next generation if its host survives. If it's a vertically transmitted parasite, that means it's transmitted from parent to offspring. So the parent has to survive, to have a baby, so that the pathogen can make it. So it's not in the pathogen's interests to kill the parent. A horizontally transmitted pathogen, on the other hand, can have actually quite a high level of virulence; and that is where all the major diseases are, they're all horizontally transmitted pathogens.

• Wolbachia?feminizes its hosts, so that it would always be occurring in the body of a female. Well there's some crustacea that have figured out how to solve this problem. They take the Wolbachia and they chop out its sex determining gene, and they implant the Wolbachia sex determining gene on one of their chromosomes, et voilà, there is no conflict anymore because now the whole business is vertically transmitted.

• So they just took the?offending element out of the bacterium and?stuck it into their nuclear genome, and they created a new sex chromosome for the crustacean. So they made the interest symmetric. Both genetic elements then had the same vertical transmission route.

• Another way that you can resolve conflict is this. You can suppress the meiotic drive and?punish the offenders. And the evidence is the fairness of meiosis. You can also homogenize the reproductive success of competing elements within a group, at the human level. This can be done with monogamy. Anything that will make individual success depends on group success. The way to suppress conflict is to generate a situation in which everyone is dependent upon partners for success.?