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What is Development?

NeuroDevNet. What is Development?. Thomas R. Insel, M.D. Director, NIMH September, 2012 [Disclosures - None]. What is development?. The coordinated and reciprocal unfolding of biological and psychological processes over time. . Time. Individual Generational Evolutionary.

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What is Development?

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  1. NeuroDevNet What is Development? Thomas R. Insel, M.D. Director, NIMH September, 2012 [Disclosures - None]

  2. What is development? The coordinated and reciprocal unfolding of biological and psychological processes over time. Time Individual Generational Evolutionary

  3. Sequencing Costs Drop Faster than Moore’s Law Cost per Megabase of DNA Sequence 28,500X Moore’sLaw CostperMb

  4. Development: Embracing Complexity DNA RNA Protein Central Dogma of Biology Mom Dad Genome–Transcriptome-Proteome Every cell has the same DNA, but each cell type has different RNA “expressed” and different proteins produced. Development = Process of differentiation.

  5. Embracing Complexity: Transcriptomics 11/11 90% of genes vary across development Fetal brain: 60% expressed differently; 83% processed differently Same cell but different transcriptome during development Figure 1c. Global spatiotemporal dynamics of gene expression.

  6. Embracing Complexity: Transcriptomics AJHG Feb 12, 2012 108 subs from fetal to elderly 14,500 genes; 27,000 CpG loci PFC – marked change from fetal to postnatal

  7. Brain Cloud

  8. Somatic Mutations 12/11 18,000 insertions unique to human brain Genome is dynamic and unstable following fertilization 8

  9. De Novo Variation (et al.)

  10. Unexpected High Variation in Human Genome Complete Sequencing in the 1000 Genomes Project 185 genomes from “healthy” subjects Approx 100 LoF variants per genome Approx 20 homozygous LoF variants (KOs) per genome Identified >1,000 KOs of human genes, most with no functional annotation

  11. DNA is not Destiny • DNA sequence is not fixed. Variation can be tissue specific. • Development is resilient. Each of us is a “knockout” for several genes. • Genetic ≠ Inherited. It’s not (all) your parent’s (or grandparent’s) fault.

  12. Development: Revising the Central Dogma Developmental Biology DNA RNA Protein Mom Dad RNA and protein depend on age Infant’s germline DNA not a perfect replication of parents Brain’s DNA not a perfect replication of germline DNA

  13. Embracing Complexity – Parental Imprinting Science 2010 DNA – parental origin matters, according to brain area, age, and sex of offspring Mom Dad

  14. What is development? Development = Process of differentiation Experience

  15. Epigenomics Changes in gene expression in the absence of changes in DNA sequence. Some experience-dependent Some age-dependent Some sex-dependent Mechanisms and Duration - TBD

  16. Multigenerational Transmission of Traits Biological Psychiatry 2010 Biological Psychiatry 2011

  17. Epigenetic Transgenerational Effects Nature Rev Genetics March 2012 Epigenetic marks survive “erasure” during fertilization metastable epialleles environmentally sensitive Diffusible elements: RNA species transferred during fertilization

  18. Developmental Microbiomics We are not alone: 90% of “our” DNA is not human DNA Asthma Allergies Type 1 Diabetes CNS?

  19. Developmental Microbiomics We are not alone: 90% of “our” DNA is not human DNA

  20. Summary What is development? The coordinated and reciprocal unfolding of biological and psychological processes.

  21. Summary What is development? DNA contains many types of variation, some of which is not “inherited”, some potentially specific to brain, and some modified by epigenetic marks during critical periods RNA highly variable across time, especially in brain where expression may depend on parent of origin as well as experience Human development occurs in a microbial ecosystem.

  22. Summary I have no doubt that in reality the future will be vastly more surprising than anything I can imagine. Now my own suspicion is that the Universe is not only queerer than we suppose, but queerer than we can suppose. JBS Haldane Possible Worlds and other papers, p 227 1927

  23. Paving the Way for Prevention, Recovery, and Cure www.nimh.nih.gov

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