Genetics 3200 Feb 18, 1999 When we think of evolution, most of us think of Darwin’s revolutionary mechanism of evolutionary change: NATURAL SELECTION. Though Darwin’s theory made a huge splash when introduced in 1859, it did not gain full acceptance until nearly 70 years later! Why not? There were lots of pieces missing, such as… What was the genetic material? How was the material inherited? How was variation generated such that natural selection could operate? When these pieces came together, the fields of genetics and evolution were revitalized after decades of nasty, unfruitful debate among academics. This "Modern Synthesis" married the fields of population genetics, evolution, and paleontology (blossoming in the 1930's). Natural Selection How Natural Selection works: -Say you have a gene and mutation has generated 2 allelic states of that gene: A= the wild-type allele (dominant) a= the mutant allele (recessive). -Allele "a" bears a mutation which negatively impacts the function of that particular gene and therefore the fitness of organisms carrying that allele. -The "cost" of a given deleterious mutation to an organism’s fitness is called the "selection coefficient" or "s"; this value is the decrement in fitness (from a maximum value of 1) which is caused by a mutation. The mutation in allele "a" bears an "s" value of 0.04 in the homozygous state. -Therefore, the fitness associated with the 3 genotypes for this locus are: wAA= 1.0, wAa= 1.0 and waa= 0.96. How does natural selection deal? If aa genotypes have lower fitness, then that individual’s which carry that genotype will contribute fewer progeny and fewer copies of "a" alleles to subsequent generations. Over many generations, a mutation conferring lower fitness for a given allele may be lost (purged) due to natural selection. Allelic frequencies are expected to change such that the frequency of allele "A" approaches or reaches 1.0 (fixation) and the frequency of allele "a" approaches 0.0 (loss). COMPUTER DEMO: Scenario a) Generations=1000; waa=0.96 b) Generations=1000; waa=0.90 SO, the greater the cost to fitness (larger s value)( the faster natural selection weeds out alleles bearing deleterious mutations. What about beneficial mutations? They may also arise in a population and increase the fitness of individuals carrying those mutant alleles through a positive selection coefficient. Over time, the mutant allele (a) may sweep to fixation (frequency 1.0) through natural selection. COMPUTER DEMO: Scenario a) Generations=1000, waa=1.02 b) Generations=1000; waa=1.04 Are all mutations either deleterious or beneficial? -NO, there’s a huge class of neutral mutations which arise along DNA sequences without affecting the phenotype, and therefore the fitness of an organism (s = 0). -Where are neutral mutations most likely to happen? "junk" DNA, introns, 3rd positions of codons in protein coding genes. -Alleles bearing these mutations are not subject to the forces of natural selection, but may evolve (undergo changes in frequency) in populations via Genetic Drift. Genetic Drift -Genetic drift is change in a population’s allelic frequencies resulting from chance variation in the survival and/or reproductive success of individuals. Genetic drift is a random process which, by definition, does not discriminate among alleles as would natural selection. The result is that any given allele is equally likely to be lost or fixed by genetic drift as another; genetic drift is considered "nonadaptive" evolution. Drift occurs via "sampling error" of the parental gene pool, where alleles which comprise the next generation’s gene pool are not at contributed at the same frequencies as in the parental generation. The greater the number of "samplings" from a parental gene pool (i.e. the greater the number of progeny produced in a given generation), the closer the allelic frequencies will be to their original frequencies. Thus, population size has a great effect on the magnitude of genetic drift. In fact, the rate of genetic drift= 1/2Ne, where Ne refers to the Genetic Effective Population Size. What is Ne and how does it relate to Genetic Drift? -In this course, we have only talked about population size in terms of a census population size, BUT in population genetics, you deal more frequently with the Genetic Effective Population Size= Ne. It is defined as size of theorized population (wherein no selection, migration, mutation occurs) which would lose genetic variation to drift at the same rate of the actual population. -Why do we think in terms of Ne? Often, in large populations, there is lots of variance in individual reproductive success, and not every individual is contributing equally to the next gene pool. So genetically, the population size is much "smaller" as the numbers of reproducing individuals are often far less than the census population size. In populations with large values of Ne, the effect of genetic drift is very small (barely effects allelic frequencies over time), but in populations with small Ne, drift is swift and allele frequencies may change very rapidly (rapid evolution). One of the largest consequences of swift rates of genetic drift is genetic variation is rapidly lost from a population through the fixation of a single allele for given locus. COMPUTER DEMO: NO difference in fitness between genotypes Scenario a) Generations= 100, Ne= 500 b) Generations= 100, Ne= 50 c) Generations= 100, Ne= 5 C. Neutral Theory With the advent of really good DNA sequencing technologies, lots of DNA sequence data has been rapidly generated in recent decades. It has been observed that there are many allelic variations (mutations) along closely-related DNA sequences. Under Darwinian evolution, these slight genetic changes would be operated upon by natural selection, which would ultimately determine their fate. OVERHEAD But what a guy named Kimura noticed (1968) is that most of these genetic changes occurred at positions that have no functional significance, such as 3rd position changes in protein coding genes (sites "free from selection"). He developed the Neutral Theory of Evolution which states that most evolution which is observed at the level of DNA sequences are neutral mutations which are evolving due to genetic drift. His theory claims only negative natural selection plays a role in evolution, culling mutations which are deleterious (negative s value). Neutral Theory holds that Positive Darwinian Selection is not a prominent force in the evolution of most genes because beneficial mutations at the level of DNA are VERY rarely observed. Nearly-neutral theory spurred decades-long debate about whether most evolution occurs via genetic drift (neutralists) or through natural selection (selectionists). Has anyone tested Neutral Theory? 1. Hughes and Nei challenged Neutral Theory by examining the mutational accumulation patterns at a locus influencing immune function (the antigen recognition site of Mhc proteins). They discovered results contrary to neutral theory in that the number of nonsynonymous changes was significantly greater than the number of synonymous changes. What evolutionary force would produce this kind of pattern?= Positive Darwinian Selection acting to sweep new mutational variants to fixation MUCH faster than could be accomplished by drift. *There are other cool examples and tests which we may go into later when discussing whether or not a genetic marker is truly "neutral" and the importance of neutrality for inferring phylogenetic relationships among taxa. D. Nearly-neutral theory: Shortly after Neutral Theory was proposed, another body of theory was developed by Ohta (1972). Her theory of nearly-neutral evolution addressed the countering forces of genetic drift and natural selection for a special class of mutations. We specified earlier that mutations may be deleterious, beneficial, or neutral with respect to the fitness of an organism, but nearly-neutral theory identifies that a large class of deleterious mutations (those of very slight effect, with a small "s" value) may act as neutral mutations in the gene pools of small populations. The reason follows (Keep in mind): Rate of genetic drift= 1/2Ne Selection Coefficient for a given slightly deleterious mutation= "s" 1. If "s" for a given mutation is relatively large, such that s > 1/2Ne, natural selection dominates the evolution of that allele and it is culled from a population (selected against). -Another way to express this relationship: If 2Nes > 1, then natural selection "operates" 2. If "s" for a given mutation is very small, such that s < 1/2Ne, then genetic drift overwhelms natural selection and the mutation is "free" from the influence of selection. If 2Nes < 1, then genetic drift dominates natural selection *The smaller the population size, the greater the magnitude of genetic drift and a greater number of increasingly deleterious mutations are permitting to "slip by" natural selection. Once these mutations arise in gene pool of a small population, they may sort as if neutral, THOUGH THEY CARRY A COST TO FITNESS. If these mutations become fixed, then the population’s fitness is permanently reduced by the value "s" of that particular allelic mutation. COMPUTER DEMO: Scenario a) Generations= 1000, waa= 0.96, Ne= 500 b) Generations= 1000, waa= 0.96, Ne= 50 c) Generations= 1000, waa= 0.96, Ne= 5 What does this mean for populations confined to small Ne over evolutionary time? Nearly Neutral theory predicts that small populations will accumulate greater numbers of slightly deleterious mutations in their gene pools than will large populations. Over time, the fitness of small populations may erode due to the enhanced rates of deleterious mutational accumulation, until extinction results (a "mutational meltdown"). Models of this genetic deterioration indicate extinction may occur in as few as several hundred generations (depending on the population size). Given that many endangered species are now managed as populations of very small Ne, this theory suggests that they may be increasingly vulnerable to extinction via mutational meltdown. There are very few tests of Nearly-Neutral theory and NO tests of Mutational Meltdown yet published.