Lecture 2 - mechanisms 2017.pdf

Nucleotide polymorphisms snps measured in 124000

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nucleotide polymorphisms (SNPs) measured in 124,000 individuals. They identified 32 genes that predicted BMI. Together these genes explained only 1.45% of the variance in BMI. 98.55% of variance is explained by something else
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Newer obesity GWAS meta-analysis Locke et al (2015), Nature GWAS meta-analysis of ~200,000 single nucleotide polymorphisms (SNPs) measured in 339,224 individuals. They identified 97 genes that predicted BMI. Together these genes explained only 2.7% of the variance in BMI. Taking a less stringent approach, they identify 2346 SNPs that explained 6.6% (the average SNP explains 0.002% of BMI variance!)
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Why do you think it is difficult to identify genetic risk factors for common diseases like obesity?
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Systems involved in obesity? Examples: Energy metabolism Tissue growth and development Stress physiology Reproductive hormones Appetite regulation Physical activity Heat production (e.g. after meal)
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Why single genes rarely determine traits in a simple fashion 1) Most traits are polygenic , i.e. influenced by many genes with small effect. 2) Gene x gene interaction (epistasis ): effect of one gene on trait often depends on which other genes are present. 3) Gene x environment interaction : effect of gene on trait often depends on environment.
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One important mechanism of gene X environment interaction: epigenetics A newer subfield of genetic research Studies patterns of gene expression Basic idea: it’s not only which genes you inherit, but how your cells express them, that matters Genes can be “silenced” in specific tissues. Epigenetics = “volume control” for a gene A powerful mechanism of developmental plasticity.
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Part II: The epigenetic code
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The epigenetic code Genetic code: DNA (nucleotide sequences) Epigenetic code: chemical modifications in the structure and shape of the chromosomes, or in RNA, that influence which genes are expressed .
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Mechanisms of epigenetic memory Source: NIH Epigenomics roadmap 2) methylation 1) histone modification 3) non-coding RNA
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Some epigenetic changes are sensitive to the environments that an individual experiences.
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Example #1 of how environments influence gene expression via methylation: maternal protein restriction Æ offspring liver metabolism
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Control PR 0 20 40 60 80 100 120 140 160 180 200 220 * Maternal dietary group Relative to control (%) Control PR 0 20 40 60 80 100 120 * Maternal dietary group Relative to control (%) Control PR 0 20 40 60 80 100 120 * Maternal dietary group Relative to control (%) Target gene: PEPCK Gene Expression Methylation Lillycrop et al J Nutr. 2005 Jun;135(6):1382-6. (Slide: Mark Hanson) protein restriction (pregnant mother) glucose (adult offspring) Prenatal protein restriction (rats): effects on liver glucocorticoid receptor in adult offspring
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Example #2 of how environments influence gene expression via methylation: maternal rearing style Æ offspring stress regulation
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Weaver et al (2004) Nature Neuroscience, 7(8)847-54 Heavy licking and grooming rats Increased GR expression (reduced anxiety) Epigenetic model of stress hormone (HPA) physiology
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Maternal transgenerational epigenetic inheritance Drake & Liu (2009), Trends Endocrinology Metab 21(4) Also applies to fathers!
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