EEB 122. Principles of Evolution, Ecology and Behavior?

Lecture?04.?Neutral Evolution: Genetic?Drift

https://oyc.yale.edu/ecology-and-evolutionary-biology/eeb-122/lecture-4

When people think about evolution they often think that it's only natural selection. But it's not. It is both micro and macro. So macro gives us history and constraint, and micro consists basically of natural selection and drift; and developmental biology is involved in both.?And?neutral evolution occurs when?genes or traits are not making any difference to reproductive success.

1. How meiosis is like a fair coin. The probability that a gene will get into a specific gamete in meiosis is 50%.

2. How the fixation of a neutral allele in a population is like radioactive decay. In neither the case of the fixation of neutral alleles, nor in the case of looking at a gram of uranium-238, do you know which mutation will be fixed or which atom will decay. But, because there's so many of them, in both cases you know very precisely how many events will happen in a certain period of time.?It is a kind of law of large numbers for random events. If a lot of random events go on, the average is a very predictable thing. But if you just examine one nucleotide in a genome, or one atom in a gram of uranium, you can't predict when it will mutate, when it might be fixed, when it will decay.

3. This regular fixation of neutral alleles, this steady process whereby if you look at an entire genome, over a given period of time,?a certain very predictable, average number of mutations will be fixed if they're neutral. So if you can locate the neutral ones in the genome, you can use them to estimate relationships and the times to the last common ancestors. The regular fixation of neutral alleles generates a molecular clock that allows us to connect micro to macroevolution.

Genetic neutrality means that?genetic variation might not produce any variation in fitness, therefore?there's variation at one level but it doesn't make any difference to reproductive success. Many of these?genotypes will produce the same phenotype, and that's because many of the genes and many of the nucleotides in the genome, many of the DNA sequences in the genome, are not making any difference to the proteins that are being produced.?

1. First, some of the mutations in DNA sequences are synonymous. That means they don't produce any change in the amino acids that are coded in the proteins.

2. Secondly, there are pseudogenes and other kinds of non-transcribed DNA in the genome. A pseudogene is a gene that resulted from a gene duplication event sometime in the past and never got used to make anything. Their?usual fate is to be eroded by mutation?because there isn't any particular reason for repair mechanisms to pay any more attention to them than they do to anything else. So gradually the useful information that was once in them gets destroyed by mutation, and if they sit around long enough they are no longer detectible. For example, there is junk DNA, and some of it's there because either fossil viruses or?transposons, jumping genes, got into positions where they could no longer be transcribed, and they then become a graveyard.

3. Thirdly, there's neutral amino acid variation, for a variety of reasons. Some amino acids have very similar molecular size and charge properties, so that if you substitute them in a protein they don't really make much difference to?the?geometry?and electrochemistry of a functional site within a protein.

   If we look at the?alpha-globin?sequences,?across?a pretty broad range of vertebrates, and we take samples in such a way?that?we can?look?fairly far back in?time, we can date these branch points approximately from the fossil?records.?So take the sequences for all the alpha?hemoglobins?that you pull out of these things--it's a convenient molecule, you just need a blood sample--and plot them on a graph. Then?estimate the time from the fossils and the average differences. It?is some of the earliest evidence--this was before DNA sequencing became easy, this was when protein sequencing was easier than DNA sequencing--that there's something like?a?molecular clock.?
   

4. the fourth reason why genetic variation might be neutral is canalization. Now canalization in general means that there are developmental buffering?mechanisms that are limiting the range of phenotypic variation, so these?canalizing?mechanisms?resist the tendency of variation in either genetic or environmental factors to?perturb the phenotype; they keep it in a stable state, such as the fact that you have four limbs and?five fingers is?ancient and stable and there are developmental buffering mechanisms that keep them that way.

   And those?genes that are forming these?phenotypes?are then freer to accumulate neutral variation, because basically the fitness consequences of a mutation in those genes have been removed, they've been buffered out.?Canalization exists and allows hidden genetic variation to accumulate.

What causes random or genetic drift?

1. Mutation:?a molecular event

2. Mendelian lottery:?a?cellular?event,?the idea that meiosis is like a fair coin

3. Founder effects and genetic bottlenecks:?population effects

4. Demographic effect:?variation in reproductive success in a population of any size.

• 1.?Mutation:?a?molecular?event

Mutations?occur at some sites more?frequently?than others. In a?pathogenic bacterium?that is encountering a challenging environment, it will?up its entire mutation rate by down-regulating its DNA repair.?It's a?fairly?simple thing?to increase the mutation rate on a whole genome by?neglecting to repair it and?it will?mutate faster.?The?transitions between the nucleotide classes--so?purine to?purine,?pyrimidine?to pyrimidine--are?more frequent than transversions. So purines will?mutate to purines more frequently than purines will mutate to pyrmidines.?

Mutations?do not produce random?changes in?phenotype space. Instead,?a?mutation?can only?cause a change?in the inherited?set of?possibilities.?So mutations do not cover all of conceivable phenotypic space.?Mutations are only causing?perturbations?in the inherited set of possibilities that a given evolutionary?lineage?has produced.?

There is?no?systematic?relationship between the?phenotypic effect?of a mutation and the need of the organism?in which it occurs. They're?random with respect to fitness.?So when those bacteria are going into the vertebrate immune systems and it would be extremely convenient for them?to have?a?mutation that was just exactly the right thing that they needed to avoid that particular defensive maneuver on the part of their host, they don't get it.?All nature will give them?is random mutations with respect to that particular function, and then if they have a lot of?progeny, one of them may have the right one by luck.?

Mutation is not going to happen, because you need that function. Your genome is going to be covered by random mutations, and it may very well be that one of your children is able to have that function. But that will be because it happened at random, not because somehow development or evolution could anticipate that that function was going to be useful.?

So the process of mutation produces a lot of variation, and then natural selection edits it, it sorts it, it screens it. And at the point at which that variation is produced, the potential function of the variation is not a question, it's not an issue; it's just making variations.?

• 2.?Mendelian lottery:?a?cellular?event,?the idea that?meiosis is like a fair coin

The probability that a child will be a boy or a girl is 50%, and that's because at the sex chromosomes,?the probability that the chromosome will go one way or the other is 50%.?If you construct a system in which every one of the potentially competing elements has been forced to have the same chance, those elements must then cooperate, because the only way they can increase their own chances is by increasing everybody else's as well.?

This?effect is called the parliament of the genes,?selected to repress conflict. For example, there are things called meiotic drivers. So there are genes which actually change Mendel's Laws; they change the probability that they will get into the next generation.?They use a long-range poison and a short-range antidote. So a meiotic driver usually operates by wiping out the competition and promoting their own interests?by giving an antidote to its own cell. They are common in drosophila.?Throughout the genome various mechanisms arose to repress meiotic drive; and the result was a very complicated mechanism and we call it meiosis.?

• 3.?Founder effects and genetic bottlenecks:?population?effects

Mechanisms that cause random change also occur at the population level. One of them is the founder effect. At the founding of that population there was a random event, which was?just sampling a couple of individuals out of a big population. As a result, there are certain human genetic diseases?that are rare in the human population in general, but are common in populations that were founded by just a few people.

Another population level phenomenon that yields randomness is a bottleneck. So that will happen when a population crashes to a very, very small size, and then only a few alleles make it through. So you might have a lot of versions of a gene in a big population, but if you're only founding a new population with two or three individuals, they're--and they're diploid, well two individuals only carry four copies of the gene.?

• 4.?Demographic effect:?variation in reproductive success?in a population of any size.

Genetic drift is then a consequence of neutrality. It's the random wandering of the frequencies of neutral genes.A gene which has gone through the Mendelian lottery of meiosis lands in a zygote.?This particular gene is neutral. It's not making any difference to reproductive success. But that particular individual that it landed in could have a small family or a big family, for reasons that have nothing to do with the function of the gene. It's just a flip of the coin that determines whether it will be in a family that produces two children, zero children, or a lot of children.?

There are the four reason explaining?what causes a gene to end up at random in an individual making one,?two?or three, or zero recruits per lifetime; what makes the difference between an adaptive and?a neutral gene.?So that's what I mean by combining the lottery of meiosis with variation in reproductive success. It is not?something that happens in small populations, although one?might argue that?small populations don't have all the smoothing effects of the Law of Large Numbers.?It willhappen in a population of any size. And basically what I mean by that is this interesting consequence of variation in reproductive success. If it's correlated with a trait or with a gene, strongly, it produces natural selection. If it's not correlated it produces drift.?

What is it that happens to neutral alleles??

• If we draw time on the X-axis, and we draw frequency on the Y-axis, and a mutation occurs.?

• A?mutation will increase a little bit and disappear. Then we wait for awhile, another mutation occurs.?The probability that it will ever get fixed is pretty low because the probability is proportional?to 1/N, frequency equal to 1/N. When it's rare, its frequency is very low and so its probability of being fixed is low.

• Once in a?while a mutation comes along that manages to go through all of this drift, and making it through organisms that had, on average, more than two progeny per lifetime, and it gets fixed.?The time that it takes them to fix is proportional to the population size.

• Things will get fixed faster in small populations than they will in big ones. There will be more of them, more mutations will occur in a big population, but it will take them longer to get fixed.

• Because the bigger populations have more mutations, it turns out that their size exactly compensates for the longer fixation times. So if you're just counting how many get fixed--it doesn't matter whether you're in a small population or a big one--the same number of mutations are getting fixed in both cases.?

We don't know which one will be fixed. We do know how many will be fixed. So this is why the molecular clock is like an atomic clock; it's driven by radioactive decay. The reason for this is that there's regularity in large numbers. It emerges because there are a large number of independent events. Our haploid genome has about three billion base pairs. One mole of uranium has about 6 times 1023?atoms--actually if it's a mole it has exactly that many atoms--and these large numbers give the regularity to the process.?

This is what connects microevolution to macroevolution. It creates uniform substitution rates in neutral portions of the genome. And this is the assumption that molecular evolution makes when it reconstructs the Tree of Life. It allows us to estimate branch lengths and branch points to last common ancestors. It allows us to make comparative inferences on phylogenetic trees. And therefore neutral evolution is a actually a central tool in the construction of the evolutionary framework.?

As an example, here are nucleotide substitutions occurring in flu.?All the mechanisms of genetic drift are in play here, except meiosis, because flu is a virus, doesn't go through meiosis. The effect of variation in population size was exactly compensated by the much slower rate of fixation of neutral mutations in larger populations. So even in an epidemic disease, like flu, the molecular clock is nice and steady.?

Here's the basic idea of maladaptation. If natural selection is strong in one place and organisms get really well adapted to it, but they move to another place, where they don't do well, for whatever reason, we call the place that is producing an excess of organisms the source, and the place which is not good for the organisms a sink. The genes in the sink represent organisms usually that were adapted to the source. So if organisms get well adapted in one place and moved to another that's quite different, and they never get an opportunity to come into evolutionary equilibrium with that new place, which we call the sink, then they are maladapted to the sink.?