4c - Mutation and Neutral Theory

Motoo Kimura
- A key theoretician in molecular evolution.
- Focused on the origins and maintenance of micro-genetic variation.

Proposes that most molecular variation is neutral, meaning it does not influence an organism's fitness negatively or positively.
New mutations fall into two categories:
- Disadvantageous mutations: Quickly removed by natural selection.
- Favorable mutations: Very rare and contribute to evolutionary change.

Kimura proposed models to describe how mutation and genetic drift interact:
- Mutation: The ultimate source of new genetic variation.
- Genetic Drift: Tends to reduce genetic variation, primarily in small populations.

Time to Fixation: The average time for a neutral mutation to become fixed in a population is given by:
$4N<em>e$ generations, where $Ne$ is the effective population size.
Mutation Rate and Fixation: The rate of neutral mutations to become fixed is equivalent to the mutation rate itself.
Average Homozygosity at Equilibrium: $H = rac{1}{4N_e imes ext{mutation rate}} + 1$
- Higher effective population size ($N_e$) results in higher homozygosity.
- As $N_e$ decreases, homozygosity decreases.

Large populations with high mutation rates tend to have high levels of homozygosity, as observed with STR markers.
In contrast, smaller populations with lower mutation rates have reduced homozygosity due to a lack of genetic variation.
Model operates under the assumption of no selection, migration, or inbreeding.

Allele frequency over time is influenced by
- Mutation introduction (allele spikes represent new mutations).
- Fixation time depending on mutation rate.
- Comparison between populations with different sizes or mutation rates.

Neutral theory posits that most mutations are neutral and do not influence fitness.
Selection acts to remove deleterious mutations.
Evidence supports that proteins with high rates of deleterious mutations have lower effective evolutionary rates due to selection pressures.
Rates of molecular evolution can differ from morphological evolution across taxa (e.g., frogs vs. mammals).

LD refers to a non-random association of alleles at different loci.
Correlation exists between genotypes at different markers, meaning that the allele received from one marker is influenced by alleles at another marker.

Typically caused by loci in close physical proximity on a chromosome, leading to them being inherited together.
Generation of LD can arise from:
- Natural selection.
- Recombination processes during meiosis.
- Population structure and mating factors.
- Statistically by chance in smaller populations due to limited recombination opportunities.

LD is a powerful tool for studying genetic structures and effects of evolution.
Can be observed between unlinked loci if specific allele frequencies are in equilibrium.
Crucially influences forensic DNA analysis as independent markers are necessary for valid statistical calculations of likelihood ratios.
When using YSTRs, alleles tend to be inherited together, complicating separate frequency calculations.

Haplotype represents a combination of alleles at multiple loci inherited as a single unit.
Haplotype frequencies inform about genetic diversity and population structure.

Size of LD blocks varies:
- Generally around a few thousand bases.
- Larger blocks observed on larger chromosomes or specific genomic regions due to low recombination rates.

After significant recombination events, chromosomes become mosaic, leading to varied haplotypes in populations over generations.
Understanding LD can inform about ancient mutations and shared genetic heritage.

LD can be quantified and represented in various forms:
- D, D prime, R squared, Delta squared.
Observed size of LD blocks differs across the genome based on chromosome size and recombination rates.