C14 Videos

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University of Toronto Scarborough
Biological Sciences
Patrick Mc Gowan

Video 1 • Epigenetics = original paradigm from twin studies (monozigotic, di), share 50% of segregating polymorphisms, 99.5% DNA identical. One twin may get cancer, other may be fine, so make us believe there is something in environment that affects them differently o 1) differences in MZ twins due to environment o 2) DZ show greater difference than MZ, due to heritability (DNA seq variability) • Many problems with environmental and genetic studies o Environmental studies:  Easy to identify association between 2 things (like stress and depression), hard to see if it is causal (depression  stress or stress  depression)  Environmental has its own heritable component  Only the “non-shared environment” is important o Genetic problems  Unexplained heritability • GWAS may identify thousands of genomes, convert information into heritability estimates (heritability of autism is 90, bipolar disorder is 80%, schiz is 70%, GWAS can only explain 70% of that heritability. Huge gap between what GWAS explains and what we expect to explain) • Human diseases  DNA centered paradigm is very successful in 2% of human pathologies, 98% are complex non-Mendelian o Complex diseases do not follow those rules of inheritance o Parental origin effects (father effects with diabetes = greater chance for child to get it than id mother had it) o Sexual dimorphism = males more likely to get autism o Major phenotypic variability o Predominantly sporadic cases o Discordance of MZ twins o Late age at onset  Despite all those differences, we still focus on DNA seq variation because DNA seq variation analyses has been so effective • Their goal is to trace genetic differences to the DNA level o Molecular strategies at the moment is DNA centered • When we think of chromosomes (cells share, given to offspring), composed of difference things, such as DNA strands, among others o DNA seq wrapped around histone complexes, which together make nucleosome. Histones and DNa seq can be chemically modified (methylated, phosphorylated, etc). o He focuses on DNA modification  methylation of cytosines. There are 4 types of modification hydroxyl methyl cytosines, carboxy cytosines, formyl cytosines • 2 identical genes on slide  one has modified cytosines, other has methylated cytosines. One case has genes activated, other has genes inactivated (if methylated)  different epigenetics • We think epigenetics is linked to complex diseases because o 1) epigenetic factors can contribute to phenotype  Plants identical, fly eye identical, tissues identical. Huge phenotypic variation between them though due to differential epigenetic regulation of one gene that make some mice yellow and others dark. Yellow mice also predisposed to obesity and diabetes, etc. But genetically all identical. Environment was pretty much the same. Epigenetic variation causes those differences. • Even looking at us, our genetics are same, but epigenetics make us different o 2) Epigenetics: relevance to complex diseases. Like DNA, some epigenetic factors can be transmitted from one generation to another o 4) Unlike DNA, epigenetic factors can be modified by developmental programs, hormones, environmental stochastic events, etc.  Stochastic = 100 cells in same petri dish, still see epigenetic differences due to stochastic events • If we emphasis from DNA seq variation to putative DNA misregulation, we can explain many things (non mendellian) o Twin discordance, sex effects (hormones), parental origin effects (genomic imprinting)  Small number of key elements can explain many clinical findings (good theory) • Vs big number of key elements explain small number of clinical findings (Bad) • DNA modification profiling o DNA has components that are methylated or not, modified cytosines or not  Then see differences between people with shiz, those without (by making DNA modification profiles) • These profiles are 40kb long, some has many modified cytosines  Use statistical analyses to see which is important. They used volcano plot (looks like a U) • If MZ twins were perfectly identical, just get an accumulation at the apex of the U, but we see a huge spread to there is a huge difference in MZ twins. The differences possibly come from the environment. • When they investigate inbred animals, they see the same distributed picture, so they can eliminate genetic and environmental differences, but still see epigenetic differences, because of stochastic events that keep occurring and amplifying. • So seeing a MZ twin with a disease would mean it’s not because of just environment or genetics, but rather could be epigenetics as well • We know smoking is a risk factor for cancer • Twin studies also show: o MZ has larger difference than DZ (interclass correlation coefficients. More similar they are to each other at each locus, more different in comparison to group, higher ICC) o MZ twins not identical, but DZ shifted to left, so less similar, more different from epigenetic point of view  Each keyboard picture represents epigenetic environments of a person’s cells. In DZ, the keyboards are more different. In lab, they think the difference in DZ comes from the zygotes. • In MZ twins, epigenetic start are the same, they start from same zygote • In DZ twins, zygotes are different, genetically and epigenetically o Then we are talking about zygotic epigenetic heritability, not same as transgenerational epigenetical heritability. In this case both are same DNA-wise, not epigenetically • They scan genome of people with Schiz or anxiety, make profiles, process them, statistically significant differences are seen, zoom in on those loci and use different techniques to map each site and possible of other sites other than brain o Can we replicate microarray findings? Can we detect similar epigenetic differences in other tissues? Can we understand the mechanisms of action? • Computational approaches allow us to see differences between loci. Each circle represents group of epigenetic loci that correlate. Thousands of loci can be grouped based on their degree of correlation. Lose correlation within modules tighter correlation between modules for Schiz patients, not sure how to understand this VIDEO 2 • Estimated human genome would have 100000 genes, but found it was the same number as fish and mice. We have less genes than plants but are more complex, why? • Same key genes that make a fruitfly, worm or mouse also make a human. Chimps share 98.9% of our genome, so what accounts for the vast differences between us? Are genes not the whole story? • Before genome was mapped, geneticists found baffling genetic conditions o Angelman’s syndrome  happy, jerky movement, no speech, no learning  Key seq of DNA deleted from Chromosome 15.  Same deletion also results in Prader Willi syndrome • Floppy at birth, insatiable appetite o 2 difference diseases by same genetic abnormality o Also noticed that what really mattered was origin of chromosome that had deletion. If from father you get PWS, but if from mother, get AS o It was as if the genes knew where they came from. How does chromosome 15 know where it came from? Must surely be a tag or imprint placed on it in previous generation. Although DNA sequence is same, difference sets of genes were silenced based on parental origin • Agouti mice  twins, genetically identical, but difference colour and size. Brown has agouti gene, but yellow has it switched on all the time, inappropriately blocks a receptor in the satiation center of brain that makes them eat into obesity, diabetes and cancer o What switched agouti gene off in thin mouse? A chemical tag called a methyl molecule, fixes near agouti gene shutting it down. Some tags attach to DNA directly, others bind to histones to tighten or loosen them to turn genes on or off. Tight = hidden from view from cell, cannot be utilized. These tags control gene expression, by epigenome • Epigenetics = “above the genome”. If genome is like a computer (hardware), epigenome is software that tells the computer when to work and how much o Skin, hair, teeth, eyes, organs, all have same DNA, cannot genetically differentiate between them, but are visually different. o What distinguishes cells are not genes, but being switched on or off by epigenetics. • Cells divide, memory of if it is a brain cell or liver cell is brought about by these controls, which are stable. Can be switched on or off o To switch off the overactive agouti gene in pregnant agouti, they were given foods ri
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