lecture 11 - Lecture 10. Quantitative trait loci, QTL....

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Lecture 10. Quantitative trait loci, QTL. Quantitative traits revisited molecular markers and mapping Case study: mimulus flower colour Quantitative traits and disease in humans Human HaploMap Genome-wide Association studies (GWAS)
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Last week we saw that molecular markers are inherited in the same Mendelian patterns as genes and that we can calculate recombination frequencies between these markers. Millions of markers (SNPs) have been mapped in the human genome to create what is called a HapMap (Haplotype map) that maps genetic variation across the genome.
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haplotype: a segment of a chromosome that is defined by a sequence of molecular markers (SNPs); a group of alleles for these markers are linked and inherited together by an organism from a single parent HapMap: Genome-wide map of genetic variation through the identification of haplotypes. Haplotype association then attempts to map a disease or trait to this variation i.e. find SNPs that are associated with a tendency to show that trait
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Mapping loci associated with polygenic traits (quantitative traits) e.g. •diseases: heart disease, hypertension, cancer •traits that show a great deal of variation: Human height
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Environmental factors contribute to human height variation e.g. malnutrition
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Human height: “model” trait for quantitative genetics Population of European descent, average height is 165cm for females and 178cm for males. Heritability of about 0.8 Difference in height due to genetic differences between top 5% and bottom 5 % in this population is about 26cm. Linkage studies confirm inheritance, but no genes were identified.
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Can we identify the multiple genetic loci that contribute to variation in height? Chial, H. (2008) Polygenic inheritance and gene mapping. Nature Education 1(1).
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Recently identifed gene that inFuences height (Broad Institute) “First reproducible connection made between genes and height in humans.” •data set: 35,000 people •HMGA2 gene — a ‘C’ written in the DNA code instead of a ‘T’. •Inheriting the ‘C’-containing copy of the gene often makes people taller: one copy can add about a half centimeter in height while two copies can add almost a full centimeter. Height in humans Weedon MN et al. 2007. Nature Genetics; DOI:10.1038/ng2121 (online publication).
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Genome-wide association studies (GWAS): unbiased approach that is based upon the HapMap project association of a quantitative trait with hundreds of thousands of SNPs by carrying out a statistical test for each SNP in turn. about 63,000 person sample size 2007: two genes identified that affect height, HMGA2 and GDF5-UQCC 2008: 54 SNPs associated with variation in height identified
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What was discovered: The average effect per “increasing” allele was 0.4cm (i.e. 0.8cm between homozygous classes) variation explained by many variants with small effects Kinds of genes: muscle development, skeletal development, mitosis, cancer, signalling, chromatin remodelling, Are these loci predictive of height?
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This note was uploaded on 06/09/2011 for the course BIOLOGY 2c03 taught by Professor Dej during the Spring '11 term at McMaster University.

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lecture 11 - Lecture 10. Quantitative trait loci, QTL....

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