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BIOLOGY 207 - Dr.LockeLecture#31 – Evolution and cis-regulatory sequences

Required readings and problems:Reading: Open Genetics, Chapter 12.4Problems: Chapter 12.8Optional Griffiths (2008) 9th Ed. Readings: pp 679-714 especially 693-699 Campbell (2008) 8th Ed. Readings: Concept 25.5: pp. 527-528Assigned Problems: NoneAdditional READING:Carroll et al. Regulating Evolution. Sci.Am. May, 2008. pp. 60-67.

Concepts:How can gene regulation evolve? 1. DNA mutations in intergenic, coding sequences, and regulatory regions have

different consequences for evolution 2. Mutations in regulatory sequences can cause loss or gain of enhancers 3. Mutations changing regulatory sequences circumvent the problem of pleiotropic

effects of mutations altering coding sequences.

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Genetic Variation (random mutation to DNA sequences) Variation + Selection -> Evolution !Mutation in:1) Intergenic regions

a. no affect on gene expression/phenotype -> no selection for/againstb. random drift causes fixation of DNA sequencec. useful for markers in genetic mapping /DNA finger printing

Result: Evolution occurs via random mutation and fixation by random drift – no selection

2) Gene’s coding sequences a. changes gene product (RNA or protein) - > alters function-> affects phenotypeb. doesn’t change gene’s transcriptionc. natural selection for/against function of product

Result: Evolution occurs via random mutation and selection for/against the function of the gene’s product

3) Gene’s regulatory region/sequencesa. same product from the gene, just its pattern of transcription changed. b. altered time, tissue, level of expression. c. can affect many traits/characteristics at once -> pleiotropic. d. can create new/novel patterns of expression; gain in function – neomorph.

Result: Evolution occurs via random mutation and selection for/against the novel expression pattern

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Examples of evolution of gene regulation.

Changes DNA sequence -> changes in physical traitsResearch has focused on genes for last ~40 years –> amino acid coding sequences

Human – Drosophila comparison Drosophila ~14K genes -> human ~35K genes ~2x change in total number, but humans are much more complex Human – Chimp comparison

-> 99% same genes. -> 29% of the proteins are exactly the same.

Mouse - Whale comparisonThey use essential the same set of proteins to build a body –> just instructions are different (Hox genes - page 421-426 in text)

Vertebrate on average ~20K genes The same set of genes has been relatively stable for ~100M years The real change is in the regulation of those genes -> altered expression

Analogy: same bricks and cement to build a doghouse and a cathedral It’s the instructions that make the difference – this is what is evolving.

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Regulatory sequences are a key to understanding evolutionRegulatory sequences - need to be identified experimentally- act combinatorial – multiple independent sites

-> full extent of each genes expression.

Example yellow gene in Drosophila Loss of tissue specific enhancer - selective – tissue specific – retain function in other tissues

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Gain of enhancer – new/novel function – neomorphic

Gain or loss has selective advantages (facilitate survival)- gain may –> add spot on wing to help camouflage, or strengthen wing- loss may –> help - eg. loss of hind limb in vertebrate snakes, whales.

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Three-spine stickleback – pelvic fins. (evolutionary fore runner of hind limbs)

Pelvic fins occur in two forms:Deep, open water – full spiny pelvis – protect from being swallowed by large predatorsShallow water - reduced pelvis and shrunken spines – large spines grasped by dragon fly larvae (predator)

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Evolution Observation: 1- Same phenotypic differences have evolved repeatedly in different fish populations

over last 10K years (since last Ice Age) 2- Different fish populations are genetically close and can be inter-bred in the lab. 3- Use them to genetically map the gene(s) involved in stickleback pelvis size.4- Found Pitx1 gene -> it has multiple functions in fish development5- Found expression is selectively lost in tissues that give rise to the pelvic fin and

spine. 6- Found change in an enhancer -> no change in Pitx1 gene amino acid sequence

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Concept of Pleiotropy

Pleiotropy - one gene has influence over multiple traits- the phenomenon of a single gene being responsible for a number of distinct and

seemingly unrelated phenotypic effects. - Consequence : mutations in the gene’s protein coding sequence will have a

simultaneous affect on multiple traits -> drastic, severe (dead) -> selected against

Concept: - Mutations in regulatory sequences circumvent the severe, pleiotropic effects of

coding sequence mutations.- If gene product is required at one time and place already

-> can’t mutate structural gene sequence, but can modify expression via regulation mutation.

- Common to have selective modifications of individual body parts via mutations in regulatory sequences.

See also:Prud’homme et al. 2007. Emerging principles of regulatory evolution. PNAS 104; 8605-8612.Carroll, S.B. 2005. Evolution at two levels: genes and form. PloS Biology 3: 1159-1166.Wray, G.A. 2007. The evolutionary significance of cis-regulatory mutations. Nature Reviews

Genetics 8: 206-216.

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