Pathways between Genes and Behaviour

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Pathways between Genes and Behaviour
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Functional Genomics

• Understanding the pathways between genes and
  behaviours (i.e., mechanisms of genes affecting
  behaviour)
• Levels of analysis

RNA Transcriptome
Protein Proteome
Brain Neurome
Mind Behaviour Phenome
DNA Genome
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Levels of Analysis

• Functional genomics
• Bottom up
• Start at level of cells, molecular biology
• Work up to more complex systems
• Behavioural genomics
• Top down
• Identify relevant/interesting behaviour
• Reductionism towards genes
• Between level relationships correlational until
  proven causal
• E.g., behaviour can change brain structure, just
  as structural changes can alter behaviour

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Transcriptome

• Gene expression throughout the genome
• Gene expression beginning point for gene to
  behaviour pathway
• Housekeeping genes
• Expressed at steady rate most cells, most times
• Special purpose genes
• Only expressed when needed, at particular
  developmental points, when activated by other
  genes or environmental stimulus

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Factors on Expression

• Altering rate of transcription initiation
• Alteration of RNA transcript
• Passage of mRNA out of nucleus
• Protection/degradation of RNA transcript in
  cytoplasm
• Rate of translation
• Posttranslational modification of protein

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Gene Expression Profiling

• DNA permanent
• RNA ephemeral and specific
• RNA microarrays
• 1000s of genes simultaneously monitored
• Study effects of treatments, diseases,
  developmental stages on gene expression
• Snapshots of gene expression throughout genome

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Brain Mapping

• Can create an atlas of localized patterns of gene
  expression
• Need brain tissue, so limited in humans and
  issues of pathology
• Mouse brain atlas
• Such maps are functional, because genes only
  detected if expressed

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Genetical Genomics

• Emphasizes links between genome and transcriptome
• Treats gene expression as phenotypic trait
• Aim is to find expression QTLs (eQTLs) associated
  with gene expression
• Primarily with rodent models

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Gene Expression Environment

• Individual differences in gene expression
• Not necessarily highly heritable
• Gene expression responds to intra- and
  extra-cellular environmental variation
• Environmental influence at transcript level quite
  significant
• Consider gene expression as a phenotype
• Epigenesis gene-gene effects and
  environment-gene effects

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The Proteome

• Refers to entire compliment of proteins
• Complexity increase from transcriptome
• Many more proteins than genes
• Post-translation from mRNA, amino acid sequences
  can be modified, changing their function
• Protein function is affected by other proteins
  they work in complexes

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Analysis

• Like transcriptome, consider proteome as a
  phenotype
• Hence, gene and environmental interaction
• Useful, given high individual differences in
  protein function in different tissues
• Protein trait differences in quantity of protein
  in different tissues
• Protein microarrays
• Antibodies detect specific proteins
• Limited capacity (100s of proteins on array)

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Early Protein Microarray Findings

• Most proteins show linkage to several regions
• Chromosomal positions often differed from those
  of the genes that code for the proteins
• Suggests multiple genes affect individual protein
  traits

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The Neurome

• Another step up in complexity
• Trillions of synapses vs. only billions of DNA
  base pairs
• 100s of neurotransmitters
• Brain phenotypes called endophenotypes

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Circadian Rhythm

• Approximately daily periodicity
• Endogenously generated, although modifiable by
  external cues
• From prokaryotic cyanobacteria to humans

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Period

• Konopka Benzer (1971)
• Fruit fly
• Three mutant lines of flies showed shorter,
  longer, and no circadian rhythm
• All mutations mapped to same gene, named period
• Conservative gene
• Responsible for Familial Advanced Sleep Phase
  Syndrome in humans
• Not the only gene involved interactions between
  many genes

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PER Genes

• Per1, Per2, Per3
• Members of period family of genes
• Expressed in suprachiasmatic nucleus
• Bilateral brain region, located in anterior
  hypothalamus controls circadian rhythms
• E.g., rats with SCN damage have no circadian
  rhythm they sleep the same amount, but
  polyphasically for random lengths

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Mice

• Per2 and Bmal1 work in opposition
• Per2 peaking for sleep
• Bmal1 peaking for wakefulness

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Humans

• Per2 and Bmal1 work together
• Both peak around the same time

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Lark vs. Owl

• Genes influencing morning or night person
• Per2 produces high RNA levels around 4AM
  associated with sleeping
• Food influences gene expression Per2 has small
  peak after food intake (post-lunch slump)
• REV-ERB works in opposition to Per2, peaking its
  expression around 4PM associated with
  wakefulness
• Recent research looking to see if environmental
  factors (e.g., shift work) can permanently alter
  gene expression

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Pleiotropy

• Clock genes have many functions
• Period found to have role in long term memory
• Per genes may be involved in influencing effect
  and abuse of drugs like cocaine
• Disruption of genes linked to bipolar disorder,
  cardiovascular disease, effects of drug toxicity

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Learning and Memory

• Short-term memory
• Long-term memory
• Long-term potentiation
• Long-term synaptic changes

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Drosophila

• Dunce and rutabaga first learning and memory
  mutants
• Disrupts STM, but LTM works fine
• Encode components of an intracellular signaling
  pathway involving cAMP, protein kinase A, and a
  transcription factor (CREB)

lten.wikipedia.org/wiki/ImageDrosophila_ melanogas
ter_-_side_28aka29.jpggt
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Mouse

• Targeted mutations
• Hippocampus
• Knocked out ?-CaMKII
• Increased difficulty learning spatial tasks
• Well over 20 genes known to affect learning and
  memory in mice
• Change strength of synaptic connections

lten.wikipedia.org/wiki/ImageMorrisWaterMaze.jpggt
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Long-Term Potentiation

• Genes drive long-term potentiation
• But not an easy mechanism to understand
• 1000s of protein components involved
• Numerous systems
• Glutamate receptor, NMDA receptor, CREB, etc.,
  etc., etc.
• None of the fly or mouse genes and signaling
  molecules involved are exclusive to learning
  processes
• Many necessary for basic cell functions
• Is memory being regulated by modulating
  background function of cells involved in memory
  encoding?