Genome Evolution

Neutral Theory of Molecular Evolution

Mutation vs. Substitution Rate

• Genetic drift is a more significant force for smaller mutations
• The size of the force of genetic drift is proportional to the inverse of the population size
  • Force of Genetic Drift = 1/N
• Finite population: genetic drift will eventually either cause an allele to become fixed ( freq 100%) or lost (freq 0%)
• Fixation/loss of alleles occurs faster in smaller populations because of the stronger impact of genetic drift on small populations
• When a fixation occurs, a substitution is said to have occurred in the genome
• Substitution rate: inverse of the time between fixation events
• If drift is the only force acting, the rate of fixation of new neutral mutations depends only on the neutral mutation rate and not on the population size
  • Rate of fixation of neutral mutations is independent of the population size and depends only on the average mutation rate

Neutral Theory:

• Motoo Kimura: Japanese biologist introduced the neutral theory of molecular evolution in 1968
• Neutral Theory of Molecular Evolution: suggests that most of the variation within species are due to random genetic drift of selectively neutral mutant alleles
• Genetic drift (not selection) must explain their accumulation in gene pools
• Assumes most mutations that are not deleterious are neutral rather than beneficial
• That neutral, mutant allele can arise within a population and reach fixation by chance rather than by selective advantage
• Most alleles in natural populations are neutral

Types of Substitutions:

• Nucleotide substitution (point mutation): change in a single nucleotide in the DNA sequence
  • Synonymous: change still codes for the same amino acid, so no change
  • More likely to persist in the genome over time
  • Higher substitution rate
  • Nonsynonymous: does change amino acid sequence and has an impact
  • Most likely to be deleterious
  • Lower substitution rate
  • Nonsynonymous substitutions are most likely to be influenced by natural selection
    • They are most likely to be deleterious, so they will be removed from the population/selected against

Predicting Positive, Neutral, and Purifying Selection

• Nonsynonymous: dN
• Synonymous: dS
• Ratio of dN/dS to determine positive, neutral, or purifying selection
• Positive: dN/dS > 1
  • Amino acid residue changes
  • Directional selection, favors spread of beneficial alleles
• Neutral: dN/dS = 1
  • Genetic drift is causing random changes in the gene pool that does not convey an evolutionary advantage
  • Selection is putting no constraint on evolution
• Purifying (negative): dN/dS < 1
  • Selection against nonsynonymous substitution is weeding out harmful alleles, resisting changes in corresponding amino acid residues
  • Population becomes more pure/true breeding over time
  • if dN = 0, selective constraint is maximized, selection is allowing no change

The Molecular Clock:

• Molecular Clock Approach: allows us to make inferences about relative timing of speciation events
• DNA sequence data to determine relative time that has passed since a species diverged
• To find absolute amount of time passed, need to calibrate molecular clock with fossil evidence
• Molecular clock technique used to track down when humans were first exposed to specific strain of HIV virus

Genome Evolution:

• Vast majority of eukaryotic DNA does not code for a functional gene product

Transposable Elements:

• Transposable Elements: segments of DNA that can move within the genome of a cell by means of a DNA or RNA intermediate
  • mobile genes, jumping genes
• 2 ways transposable elements can integrate themselves within the genome:
  • Cut and paste through conservative transposition
  • Cuts itself out of the genome and puts itself somewhere else in the same genome
  • DNA transposons: cut and paste
  • Copy and paste through replicative transposition
  • Copies itself and places it somewhere else inside the same genome
    • Retrotransposons: copy and paste
• Transposons are not like viruses, can never exist outside of the host’s genome
• Transposition by transposable elements is a form of non-homologous recombination
  • Lateral gene transfer and meiosis are homologous recombination

DNA Transposons:

• DNA Transposons: cut and paste transposable elements

  • Transposase: catalyzes the excision and insertion of the transposable elements genetic sequence
  • Recognition sequence: tells the enzyme where the boundary of transposable element is

• Insertion sequence: simplest transposable element in prokaryotes, contains a gene that encodes transposase surrounded by a recognition sequence

  1. Transposase enzyme recognizes that the inverted repeats are the boundaries of the transposable element
  2. Transposase cleaves the chromosome at a target site
  3. Molecules of transposase bind to the inverted repeats and the target site, cutting and resealing the chromosome at the appropriate locations
  4. DNA polymerase and DNA ligase fill in the gaps in the DNA

• Transposition by a DNA transposon can result in the proliferation of multiple copies of the same transposable element in the genome

• The increasing number of proliferation in the genome is called transcription element proliferation

Retrotransposons:

• Retrotransposons: transposable elements that can only copy and paste

  • Reverse transcriptase: make a DNA copy of RN
  • Integrase protein: integrates DNA into another portion of the genome

• Basic Process:

  1. The gene encoding reverse transcriptase and integrase are translated, and reverse transcriptase and integrase are produced
  2. Reverse transcriptase makes a DNA copy of the mRNA for the transposon
  3. A complementary DNA strand is formed, producing double-stranded DNA
  4. Integrase integrates the double-stranded retrotransposon sequence into the genome

• Proliferation of transposable elements has consequences:

  • Increase in genome size
  • Nonautonomous transposable elements (dead) can come back to life by the enzymatic machinery of live transposable elements
  • Increase in genomic mutation rate
  • Increases the probability of ectopic (nonhomologous) recombination and translocation
  • Ectopic recombination: type of nonhomologous/illegitimate recombination, can result in translocation: rearrangement of entire parts of the chromosome

Comparative Genomes:

• Human genome: 3x10^9 base pairs
• E. coli 1x10^7 base pairs
• Lungfish 30x size of human genome
  • Proliferation of transposable elements in lungfish mostly explains this
• Negative relationship between genome size and % of genome that consists of functional genes that code for proteins

Genes and Multigene Families:

• Multigene families: refer to collections of identical or very similar genes
  • Result from gene duplication events
• Pseudogenes: nonfunctional nucleotide sequences quite similar to functional genes

Consequences of Gene Duplication:

• Gene duplication: occurs when an entirely new copy of a gene appears in a genome over evolutionary time
• When a gene is duplicated, following are possibilities:
  • Both copies retain original function, result: increase in production of protein they encode
  • Genes may come to be expressed at different times in development or in different tissues
  • One copy may retain its original function, other gene accumulates deleterious mutations that turn it into a pseudogene
  • most likely consequence
  • One copy retains its original function, other gene accumulates advantageous mutations that give it a new function
  • least likely consequence

The Evolution of Development:

• Most organisms share a common genetic toolkit, which contains regulatory genes that control developmental processes

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