Pathways between Genes and Behaviour

1. Pathways between Genes and Behaviour

2. 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

3. 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

4. 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…

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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)

12. 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

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

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

15. 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

16. 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

17. Mice • Per2 and Bmal1 work in opposition • Per2 peaking for sleep • Bmal1 peaking for wakefulness

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

19. 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

20. 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

21. Learning and Memory • Short-term memory • Long-term memory • Long-term potentiation • Long-term synaptic changes

22. 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) <en.wikipedia.org/wiki/Image:Drosophila_ melanogaster_-_side_%28aka%29.jpg>

23. 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 <en.wikipedia.org/wiki/Image:MorrisWaterMaze.jpg>

24. 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?