Lec 7 Flashcards
The Neutral Theory of molecular evolution
In the 1960s enzyme electrophoresis provided evidence of cryptic molecular variation: differences in amino acid sequences that do not manifest in phenotypic differences
- Allowed us to visualize differences in amino acids
- Synonymous mutations make changes at nondegenerate/redundant bases = no phenotypic change
At the time it was thought that natural selection was responsible for the maintenance of genetic variation, but these variations appeared to be neutral
The prevalence of apparently neutral variation led to debate about whether natural selection is really an important driver of evolutionary change
Why are there so many neutral variants in the genome?
a) Most of the genome is non-coding DNA, so mutations accumulate that don’t have fitness consequences
b) Mutations with large phenotypic effects are typically deleterious and are weeded out by natural selection
c) Mutations in coding regions can be synonymous and not have phenotypic effects
d) All of the above
d) All of the above
The Neutral Theory
Motoo Kinura compared amino acid sequence differences in well-studied vertebrate proteins
By extrapolating backward to the common ancestor of the two, using fossil evidence Kimura estimated that a new mutation must have been formed and achieved fixation every 2 years on average
Motoo Kimura (1968):
- The vast majority of molecular variation within species and DNA differences between species is selectively neutral
- Genetic drift is the major driving force of evolution on the molecular level
Tomoko Ohta (1973): -"Nearly neutral" theory: The vast majority of molecular variation within species and DNA differences between species is the regime
Synonymous substitutions
2 sea urchin species have several substitutions int he Histone 3 gene but all are silent
NO amino acid change
Selection and effectively neutral alleles
In infinite populations, selection cannot operate effectively on mutations that have extremely small fitness consequences
The random change in allele frequencies due to drift overwhelms any effects due to selection
Even alleles with positive or deleterious fitness effects can be effectively neutral
The neutralist-selectionist debate
Fraction of mutations that have that selection coefficient on y-axis
The vast majority have LOW selection coefficients
Neutralists will point out that many have strong selection coefficients and that most are NEUTRAL
Positive selection = favors new mutations
Negative selection = acts against new mutations
The neutral theory
The neutral theory has been very helpful for understanding how stochastic (random) process can contribute to evolutionary dynamics
With the advent of population genomic data it has become increasingly clear that natural selection does often play an important role in molecular evolution
Neutral theory is a useful null model for molecular evolution
Allows us to make predictions about how much variation and allele frequency change we expect if selection is NOT operating
Deviations from these predictions are then further support for selection
In particular, we use ratios of synonymous to non-synonymous mutations to detect selection
More non-synonymous changes than expected is often evidence of positive selection
Drift is a more important driver of allele frequency change than selection when:
The population is small and selection is weak
Population genetics at multiple loci
Thus far we have been working with a single locus with two alleles that determines phenotypes with major fitness effects
Is that realistic? NO
Quantitative vs. Qualitative
Qualitative (discrete) traits:
Traits with discrete distributions
Quantitative (continuous) traits:
Traits with continuously distributed phenotypes - they are determined by the genotype at many loci and environmental factors. These are much more common
Evolution of polygenic traits
Darwin believed that natural selection acted on continuous variation, but Mendel showed that variation was discrete
The first step in reconciling those two ideas was to recognize that some traits are polygenic - they are coded by multiple genes
Polygenic traits show almost continuous variation, but each individual allele is inherited in a particulate way
Reconciling Darin and Mendel
Experiments with kernel colors showed continuous variation
Color have additive genetic effects - the phenotype of one individual is the result of the sum of the effects of each allele it carries
Although more complicated, phenotypes were still predictable under Mendelian inheritance
Small, graded effects are critically important to genetic variation and natural selection, and consistent with Mendel’s laws of inheritance
Look at this figure. Which is not true about polygenic traits?
The phenotypes of offspring are completely unpredictable based on the genotypes of the parents
Latent Variation
Experimental data showed that polygenic traits produced the necessary variation for natural selection to operate
But in some cases new phenotypes not seen in the parental population could appear in the offspring
How can we explain the emergence of novel phenotypes?
Ten loci with 2 alleles each could produce 60,000 different phenotypes
Some populations may be too small (or we have observed too few individuals) for all of these phenotypes to be detected
When a new phenotype is observed is not necessarily the result of mutation - it could be a new assortment of previously occurring Mendelian variation
Populations thus contain latent variation - undetected phenotypes that can appear from existing genetic variation
Epistasis (gene interactions)
In some cases the interaction of multiple loci do not produce additive effects but result in epistatic effects
The phenotypic effects of one allele at a locus are determined by the allele present at the other locus
Phenotypic effects are context dependent
Mendel’s Laws of Derived from experiments
The Law of Independent Assortment: Which allele is passed down to the next generation at one locus is INDEPENDENT of which allele is passed down at another locus
- Mendel also experimented with other traits like seed shape
- The allele passed down at one locus (e.g. flower color) is INDEPENDENT (not influenced by) the allele at another locus (e.g. seed shape)
- Today we know that story is more complex
Allele and Haplotype frequencies
We have been discussing how we measure allele frequency change - how common a particular allele at a particular locus is in a population
Now we extend these ideas to multiple loci - the multilocus genotype of a chromosome or gamete
This is called the HAPLOTYPE: A set of alleles, one at each locus we are interested in
Here we have two chromosomes, one with the haplotype AB and one with the haplotype ab
This diploid organism would have the genotype AaBb
When we talk about haplotypes, we often mean a set of alleles that are inherited together because they are on the same chromosome
To understand the population genetics of multiple loci, we need to keep track of halplotypes - which alleles occur together - to help us predict genotypes
We need to remember that loci that are __________________ on chromosomes are more likely to be associated with each other - loci across the genome are NOT independent
Closer together
For example, if I tell you that in this classroom: 50% of the students have blonde hair 50% of the students have brown hair and 50% of the students have blue eyes 50% of the students have brown eyes
How many students have brown hair and blue eyes?
Not enough information to determine
We could have:
Perfect equilibrium: Alleles are inherited independently as Mendel predicted (and like his pea plants)
- 25% blonde and blue eyes (A1B1)
- 25% blonde and brown eyes (A1B2)
- 25% brown hair and blue eyes (A2B1)
- 25% brown hair and brown eyes (A2B2)
Perfect disequilibrium: Alleles are always inherited together
- 50% blonde and blue eyes (A1B1)
- 50% brown hair and brown eyes (A2B2)
Physical linkage
When the A and B loci are on separate chromosomes, the alleles segregrate independently. A double heterozygote produces four different gamete types, each with equal frequency
When the A and B loci are CLOSE together on the SAME chromosome, the alleles segregate together, In the absence of recombination, a double heterozygote produces only two gamete types
Recombination breaks up associations between alleles
Therefore generating new haplotypes
Alleles that always appear close together are often close together on chromosomes
A haplotype is
The combination of alleles present across multiple loci on a single chromosome or gamete
Alleles that always appear together in HAPLOTYPES are often close together on chromosomes
Because these loci are close together, we are UNLIKELY to get a mix/recombination
Linkage disequilibrium
Two loci are in linkage EQUILIBRIUM when the genotype of a chromosome at one locus is INDEPENDENT of its genotype at the other locus
Two loci are in linkage DISEQUILIBRIUM when there is a non-random association between the genotypes at both loci
The non-random association of alleles at different loci
Loca are said to be in linkage disequilibrium when the frequency of association of thier different alleles is HIGHER or LOWER than what would be EXPECTED if the loci were independent and associated randomly
How do we quantify linkage disequilibrium and clarify our expectations about independent vs non-independent assortment?
Build a model
Linkage disequilibrium is how we describe ______ that are associated with each other
Alleles
How many possible combinations of alleles (haplotypes) are there?
4
AB, Ab, aB, ab
Each combination of alleles = 1 haptlotype
