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Bimodality: Hallmark of a major gene effect on a quantitative trait.

Bimodality: Hallmark of a major gene effect on a quantitative trait. Bimodality: Hallmark of a major gene effect on a quantitative trait. 1 Gene  3 Genotypes  3 Phenotypes. 2 Genes  9 Genotypes  5 Phenotypes. 3 Genes  27 Genotypes  7 Phenotypes. 4 Genes

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Bimodality: Hallmark of a major gene effect on a quantitative trait.

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  1. Bimodality: Hallmark of a major gene effect on a quantitative trait.

  2. Bimodality: Hallmark of a major gene effect on a quantitative trait.

  3. 1 Gene  3 Genotypes  3 Phenotypes 2 Genes  9 Genotypes  5 Phenotypes 3 Genes  27 Genotypes  7 Phenotypes 4 Genes  81 Genotypes  9 Phenotypes Polygenic Traits

  4. Complex Trait Model Linkage Marker Gene1 Linkage disequilibrium Mode of inheritance Linkage Association Gene2 Disease Phenotype Individual environment Gene3 Common environment Polygenic background

  5. CHGA genetic variation: Risk factor for hypertensive ESRD in blacks J Am Soc Nephrol. 2008 Mar;19(3):600-14. Chromogranin A polymorphisms are associated with hypertensive renal disease. Salem RM, Cadman PE, Chen Y, Rao F, Wen G, Hamilton BA, Rana BK, Smith DW, Stridsberg M, Ward HJ, Mahata M, Mahata SK, Bowden DW, Hicks PJ, Freedman BI, Schork NJ, O'Connor DT.

  6. Gene (fixed at conception) Mechanism Time (decades . . . ) “Intermediate” in time and causality Twins Cardiorenal disease trait (later life)

  7. Twins: window into heritability (h2) of any phenotype Monozygotic (MZ, identical) twins: Billy and Benny . . . VP = VG + VE h2 = VG/VP = 2(RMZ - RDZ) Source: Guinness Book of World Records.

  8. Total mole count for MZ and DZ twins MZ twins - 153 pairs, r = 0.94 DZ twins - 199 pairs, r = 0.60 400 400 300 300 Twin 1 Twin 1 200 200 100 100 0 0 0 100 200 300 400 0 100 200 300 400 Twin 2 Twin 2

  9. Family studies (twin pairs, pedigrees). Fam hx as a risk factor. In 1st degree relatives: Parents, siblings. Heritability (h2): Fraction of trait variance accounted for by genetic variance. VP = VG + VE h2 = VG/VP Estimate h2 from twin pair (or pedigree) studies: Type of twin pair Allele sharing across the genome. MZ = monozygotic = identical. 100% DZ = dizygotic = fraternal ~50% (on average), like any sib pair Quick-and-dirty algorithm: h2 = VG/VP = 2(RMZ – RDZ)

  10. Family history as a risk factor for complex traits. Family history West J Med. 1984 Dec;141(6):799-806. Understanding genetic and environmental risk factors in susceptible persons. Williams RR.

  11. Linkage = Meiotic co-segregation A3A4 A1A2 A1A3 A2A4 A2A3 Marker allele A1 cosegregates with dominant disease A1A2 A1A4 A3A4 A3A2

  12. Linkage Markers…

  13. Thomas Hunt Morgan – discoverer of linkage

  14. Idiosyncratic features of genetic linkage (= meiotic co-segregation). Units. Metric = meiotic recombination (~50 meioses/generation). Units of genetic distance = recombination during meiosis (cM). cM = (recombinant meioses/total meioses)*100 E.g.: [8/(8+86)]*100 =(8/94)*100 = 8.5 cM 1 cM ~ 1 Mb Range ~0.5-2.0 Varies by species, sex, chromosomal region (meiotic “hot spots”) Significance. “LOD” scores. LOD = Log10 of the odds ratio for linkage Odds ratio: Co-segregation (marker and trait) Not Significant: LOD >3.0 (i.e., odds ratio > 1000/1) Why 3.0? ~50 “linkage groups” (meiotic breaks/generation), target =0.05. 1/50*1/20=1/1000.

  15. Genetic linkage: Meiotic recombination distance in cM cM = (recombinant meioses/total meioses)*100 [8/(8+86)]*100 =(8/94)*100 = 8.5 cM 1 cM ~ 1 Mb Range ~0.5-2.0 Varies by species, sex, chromosomal region (meiotic “hot spots”) Mahata SK, Kozak CA, Szpirer J, Szpirer C, Modi WS, Gerdes HH, Huttner WB, O'Connor DT. Dispersion of chromogranin/secretogranin secretory protein family loci in mammalian genomes. Genomics. 1996 Apr 1;33(1):135-9.

  16. Mouse SBP crosses: “Genome scan”  linkage. Wright FA, O'Connor DT, Roberts E, Kutey G, Berry CC, Yoneda LU, Timberlake D, Schlager G. Genome scan for blood pressure loci in mice. Hypertension. 1999 Oct;34(4 Pt 1):625-30.

  17. Genetic linkage: What the data (marker, trait) look like. J Clin Invest. 1996 May 1;97(9):2111-8. Quantitative trait locus mapping of human blood pressure to a genetic region at or near the lipoprotein lipase gene locus on chromosome 8p22. Wu DA, Bu X, Warden CH, Shen DD, Jeng CY, Sheu WH, Fuh MM, Katsuya T, Dzau VJ, Reaven GM, Lusis AJ, Rotter JI, Chen YD.

  18. Genetic linkage: What the data (marker, trait) look like. J Clin Invest. 1996 May 1;97(9):2111-8. Quantitative trait locus mapping of human blood pressure to a genetic region at or near the lipoprotein lipase gene locus on chromosome 8p22. Wu DA, Bu X, Warden CH, Shen DD, Jeng CY, Sheu WH, Fuh MM, Katsuya T, Dzau VJ, Reaven GM, Lusis AJ, Rotter JI, Chen YD.

  19. The catecholamine biosynthetic pathway. T Flatmark. Regulation of catecholamine biosynthesis. Acta Physiol Scand 168:1-17, 2000.

  20. Figure 8: TH haplotypes in vivo

  21. Hypertension: “Intermediate” phenotypes and candidate genes. Gene  Biochemical trait  Physiological trait Disease trait Tyrosine hydroxylase C-824T   Catecholamines   Baroreceptor function  Stress blood pressure   Hypertension Mechanism Time Figure 7: Intermediate phenotypes

  22. Haplotype: Ordered array of alleles along a single chromosome. Biallelic SNPs (single nucleotide polymorphisms). Typically “transitions”: Purine  Purine (G  A) Pyrimidine  Pyrimidine (C  T) Chromosome Paternal Maternal T C A G C T G A pter  qter 5’  3’

  23. “Linkage disequilibrium” (LD): Local, marker-on-marker locus Equilibrium = randomness (no correlation, r2=0) Disequilibrium = non-random (correlated, r2>0) Marker-on-trait locus: Mapping tool 0.0 r2 0.5 0.5 0.9 0.9 0.90.00.90.9 0.9 T A C G T A C G Paternal Maternal Biallelic SNPs C G T C C G T A 5’  3’ Ancestral (shared) Meiotic recombination

  24. Linkage disequilibrium (LD). Marker  trait Marker  marker In population genetics, linkage disequilibrium is the non-random association of alleles at two or more loci. Linkage disequilibrium describes a situation in which some combinations of alleles or genetic markers occur more or less frequently in a population than would be expected from a random formation of haplotypes from alleles based on their frequencies. Non-random associations between polymorphisms at different loci are measured by the degree of linkage disequilibrium (LD). The level of linkage disequilibrium is influenced by a number of factors including the rate of meiotic recombination (crossovers) and the rate of mutation.

  25. HapMap: View variation patterns Triangle plot shows LD values using r2 or D’/LOD scores in one or more HapMap population

  26. The International HapMap Project(Identification of SNPs that ‘tag’ haplotypes within blocks) Daly, M.J., Rioux, J.D., Schaffner, S.F., Hudson, T.J. and Lander, E.S. (2001). High-resolution haplotype structure in the human genome. Nature Genet.29: 229-232.

  27. Linkage disequilibrium (LD) “blocks” on human chromosome 14q32 100 kbp displayed, from <www.HapMap.org> 3 short-range (~30 kbp) LD blocks No long-range (~100 kbp) LD

  28. Gene-by-Environment (GxE) interaction probed by MZ twin intra-pair trait differences: HDL-cholesterol effect of T-cadherin (CDH13, novel adiponectin receptor) genetic variation revealed by dense, genome-wide profiling in 1662 MZ pairs p=8.5x10-8  100 kbp Region of the genome around around SNP rs9941339 in CDH13 (T-cadherin = novel adiponectin receptor) on 16q24 associated with intra MZ pair differences in HDL cholesterol (GWAS in n=1662 MZ pairs). Black points represent SNPs genotyped in the study and gray points represent SNPs whose genotypes were imputed. In middle panel, red line shows the fine-scale recombination rate (centimorgans per Mb) estimated from Phase II HapMap and the black line shows the cumulative genetic distance (in cM). Association p=8.5x10^-8.

  29. Accumulation of deleterious rare amino acid substitution variants at extremes of human body mass index (BMI) Ahituv N, Kavaslar N, Schackwitz W, Ustaszewska A, Martin J, Hebert S, Doelle H, Ersoy B, Kryukov G, Schmidt S, Yosef N, Ruppin E, Sharan R, Vaisse C, Sunyaev S, Dent R, Cohen J, McPherson R, Pennacchio LA. Medical sequencing at the extremes of human body mass. Am J Hum Genet. 2007 Apr;80(4):779-91.

  30. Drilling down to the “QTN” (“Quantitative Trait Nucleotide”) • Haplotype “block” is the lower limit of resolution of marker-on-trait mapping. • Switch to studies of associated variants: • In cella. E.g., transfected/expressed variants. • In vitro. E.g., kinetic properties of variants. • In vivo: transgenic mice (BAC haplotype variant expression on knockout background).

  31. Positional candidate genetic loci.

  32. “Positional candidate” locus Wong C, Mahapatra NR, Chitbangonsyn S, Mahboubi P, Mahata M, Mahata SK, O'Connor DT. The angiotensin II receptor (Agtr1a): functional regulatory polymorphisms in a locus genetically linked to blood pressure variation in the mouse. Physiol Genomics. 2003 Jun 24;14(1):83-93.

  33. “Positional candidate” locus Wong C, Mahapatra NR, Chitbangonsyn S, Mahboubi P, Mahata M, Mahata SK, O'Connor DT. The angiotensin II receptor (Agtr1a): functional regulatory polymorphisms in a locus genetically linked to blood pressure variation in the mouse. Physiol Genomics. 2003 Jun 24;14(1):83-93.

  34. “Positional candidate” locus Wong C, Mahapatra NR, Chitbangonsyn S, Mahboubi P, Mahata M, Mahata SK, O'Connor DT. The angiotensin II receptor (Agtr1a): functional regulatory polymorphisms in a locus genetically linked to blood pressure variation in the mouse. Physiol Genomics. 2003 Jun 24;14(1):83-93.

  35. Promoter variant characterization Variant Agtr1a promoter Wild-type Agtr1a promoter Luciferase reporter Luciferase reporter Transcription Transcription Promoter/reporter plasmid (pGL3-Basic) Promoter/reporter plasmid (pGL3-Basic) Transfection Luciferase transcription Nucleus Luciferase translation Cytosol Firefly luciferase enzymatic activity assay Cell lysis Chromaffin cell

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