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Pathways between Genes and Behaviour Functional Genomics • Understanding the pathways between genes and behaviours (i.e., mechanisms of genes affecting behaviour) • Levels of analysis DNA RNA Protein Genome Transcriptome Proteome Brain Neurome Mind Behaviour Phenome 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 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… 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 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 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 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 Gene Expression & Environment • Individual differences in gene expression • Not necessarily highly heritable • Gene expression responds to intra- and extracellular environmental variation • Environmental influence at transcript level quite significant • Consider gene expression as a phenotype • Epigenesis: gene-gene effects and environmentgene effects 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 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) 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 The Neurome • Another step up in complexity • Trillions of synapses vs. only billions of DNA base pairs • 100s of neurotransmitters • Brain phenotypes called endophenotypes Circadian Rhythm • Approximately daily periodicity • Endogenously generated, although modifiable by external cues • From prokaryotic cyanobacteria to humans 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 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 Mice • Per2 and Bmal1 work in opposition • Per2 peaking for sleep • Bmal1 peaking for wakefulness Humans • Per2 and Bmal1 work together • Both peak around the same time 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 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 Learning and Memory • Short-term memory • Long-term memory • Long-term potentiation – Long-term synaptic changes 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> 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> 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?