1865Mendel: Laws of heredity 1882Fleming: chromosomes (1900Mendelism: rediscovered/verified) 1902Sutton: Mendels factors on chromosomes 1902Garrod: chemical individuality 1927Muller: mutagenesis of a physical entity 1944Avery, MacLeod and McCarty: DNA, the transforming principle 1952Hershey and Chase: DNA is the molecule of heredity 1952Franklin, Wilkins, Watson, Crick: /53double helix 1964Nirenberg: DNA nucleotide code 1972Recombinant DNA 1980Gene/genome mapping concept 1983Polymerase Chain Reaction technology 1990The International (Human) Genome Project(s) The Human Genome Project describes the Human Genome and thus, human genotypes will be known HYPOTHESIS: Genotype predicts phenotype. The reality - not always. GENES AND ALL THAT Genes are digital information Genes are copied Genes function in cells (and bodies) Bodies (and cells) are vehicles for passing on genes Everybody (looking at this slide) has ancestors who passed on (your) genes Genetic disease is not destiny. Destinations can be altered. Genetic disease is never simple. It is complex and subversive. Genetic disease is not rare. It is everywhere among us. Genetic variation is normal; it is dis-ease only when we experience it as illness. Genetic disease is . Who do we serve? Heredity I am the family face; Flesh perishes, I live on The eternal thing in man, That heeds no call to die. Thomas Hardy Thomas Hardy DNA as / The Eternal Molecule Dennis C., Campbell P., Nature 421, 396 (Jan 23/2003) P = G + E V P = V G + V E V G h 2 = V G + V E P = phenotype, G = genotype, E = experience h 2 = broad sense heritability of P MOLECULAR BASES OF DOMINANT PHENOTYPES One-catalyst pathways Haplo insufficiency Dominant-negative effect Gain-of-function BEYOND MENDEL: AN EVOLVING VIEW OF HUMAN GENETIC DISEASE TRANSMISSION Jose L. Badano* and Nicholas Katsanis* Methodological and conceptual advances in human genetics have led to the identification of an impressive number of human disease genes. This wealth of information has also revealed that the traditional distinction between Mendelian and complex disorders might sometimes be blurred. Genetic and mutational data on an increasing number of disorders have illustrated how phenotypic effects can result from the combined action of alleles in many genes. In this review, we discuss how an improved understanding of the genetic basis of multilocus inheritance is catalysing the transition from a segmented view of human genetic disease to a conceptual continuum between Mendelian and complex traits. NATURE REVIEWS | GENETICS VOLUME 3 | OCTOBER 2002 | A THEORY OF AGEING: THE DISPOSABLE SOMA. An Era of - OMES An Era of - OMES PHENOME ENVIRONOME GENOME GENOME TRANSCRIPTOME TRANSCRIPTOME PROTEOME COMPLEXOME METABOLOME METABOLOME EPIGENOME PhenomicLayers GENETIC SCREENING / TESTING Screening is for populations Testing is for individuals/families Three rationales for either activity: i) For diagnosis and intervention prevention) ii) For reproductive counselling (avoidance) iii) For knowledge (research / epidemiology) Help the individual or family comprehend their medical facts, including the diagnosis, the probable course of the disorder, and the available management. Help to appreciate the way heredity contributes to the disorder, and the risk of recurrence in specified relatives. Help to understand the options for dealing with the risk of recurrence. Help to choose the course of action which seems appropriate to them in view of their risk and their family goals and act in accordance with that decision. Help to make the best possible adjustment to the disorder in an affected family member and/or to the risk of recurrence of that disorder. It is much more important to know what kind of patient has a disease than to know what kind of disease a patient has. Caleb Parry, Physician of Bath Although the Word is common to all, most men live as if each had a private wisdom of his own. Herakleitos What can I know? With that knowledge, what ought I do. [Immanuel Kant] [Immanuel Kant] Who do I serve? How do I serve? Who do I serve? How do I serve? [Anon] [Anon]