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A. Novelletto, F. De Rango Dept. Cell Biology, University of Calabria GENOTYPING CONCORDANT / DISCORDANT COUSIN PAIRS

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SUMMARY OF STUDY DESIGN CONCORDANT DISCORDANT IBD25% IBD> 25% < 25% Parametric Non parametric I-1

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QUESTIONS RAISED IBD IBS ; to what extent this difference affects the feasibility Power of the experiment How can info on the age of I-2, II-1 and II-2 be exploited Under which circumstances the typing of I-1 becomes informative Can the linkage analysis be extended to physical variables (e.g. MMSE, handgrip)

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Response to selection design Marker gene diversity n. of pairs n. of typings for centenarians Param. vs. non param. analysis RELEVANT VARIABLES

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EXPLORING THE PERFORMANCE OF THE DESIGN DATA SIMULATION EVALUATION WITH AVAILABLE SOFTWARE Parametric LOD score NPL scoreQTL mapping concordant disc.

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ftp://ftp-genome.wi.mit.edu/distribution/software/genehunter Very rapid extraction of complete multipoint inheritance information from pedigrees of moderate size. This information is then used in exact computation of multipoint LOD scores, non-parametric linkage statistics, and now in a wide range of sibpair analyses and a new variance components analysis. The multipoint inheritance information allows the reconstruction of maximum-likelihood haplotypes for all individuals in the pedigree and information content mapping which measures the fraction of the total inheritance information extracted from the marker data. GENEHUNTER

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PART 1 - effect of:n. of pairs marker allele freq. CONCORDANT – all pairs alike 1/2 2/3 1/23/4 2 sharing 1 sharing 0 sharing I-1

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sharing 1 sharing 2 sharing n. of pairs Log 10 (p) NPL score CONCORDANT, rare marker allele (q =.05)

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CONCORDANT, medium marker allele (q =.12) Log 10 (p) NPL score 0 sharing 1 sharing 2 sharing n. of pairs

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Log 10 (p) NPL score 0 sharing 2 sharing n. of pairs CONCORDANT, common marker allele (q =.20) 1 sharing

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CONCORDANT, common marker allele (q =.20), dominant model LOD score 0 sharing 1 sharing 2 sharing n. of pairs -1.00E E E E E E

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CONCORDANT, common marker allele (q =.20), dominant model, I-1 typed LOD score 0 sharing 1 & 2 sharing n. of pairs -1.00E E E E E E

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CONCORDANT, common marker allele (q =.20), recessive model LOD score 0 sharing 1& 2 sharing n. of pairs -1.00E E E E E E

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CONCLUSION SET 1 - CONCORDANT NPL more appropriate Dramatic effect of allele frequencies at marker loci Minor advantage in typing I-1 in CONCORDANT pairs

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PART 2 - effect of response to selection design CONCORDANT – different proportions of 0, 1, 2 sharing 1/2 2/3 1/23/4 2 sharing 1 sharing 0 sharing I-1

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:12:11.4:11:1 96 pairs 48 pairs (p) NPL score rare allelecommon CONCORDANT, 0:1 sharing ratios

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CONCLUSION SET 2 - CONCORDANT Dramatic effect of allele frequencies at marker loci confirmed Haplotyping (and perhaps search for private SNPs) needed to increase marker diversity Ratio of non sharing/sharing cousin pairs approaching 1:1 preferred Entire study needed to reach significance with concordant pairs only

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PART 3 - effect of: n. of pairs marker allele freq. DISCORDANT – all pairs alike 1/2 2/3 1/23/4 2 sharing 1 sharing 0 sharing Very different liabilities for genotypes at the longevity locus I-1

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LOD score 0 sharing 1 sharing 2 sharing DISCORDANT, recessive model rare marker allele (q =.05) n. of pairs

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LOD score 0 sharing 1 sharing 2 sharing DISCORDANT, dominant model rare marker allele (q =.05) n. of pairs

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LOD score I-1 untyped DISCORDANT, recessive model n. of pairs 0,0 1,0 2,0 3,0 4,0 5,0 6,0 7,0 8,0 9, I-1 typed

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LOD score I-1 untyped DISCORDANT, dominant model n. of pairs I-1 typed 0,0 1,0 2,0 3,0 4,0 5,0 6,0 7,0 8,0 9,

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CONCLUSION SET 3 - DISCORDANT Parametric LOD SCORE analysis obligate Minor effect of allele frequencies at marker loci Strong advantage in typing I-1 in DISCORDANT pairs

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PART 4 - effect of response to selection design DISCORDANT – different proportions of 0, 1, 2 sharing 1/2 2/3 1/23/4 2 sharing 1 sharing 0 sharing I-1

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LOD score DISCORDANT, recessive model, 0:1 sharing ratios common allelerare 0 0,5 1 1,5 2 2,5 3 3,5 4 1:12:13:15:1 96 pairs 48 pairs

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LOD score DISCORDANT, dominant model, 0:1 sharing ratios common allelerare 1:12:13:15:1 0 0,5 1 1,5 2 2,5 3 3,5 4 4, pairs 48 pairs

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CONCLUSION SET 4 - DISCORDANT Allele frequencies at marker loci not as crucial as in CONCORDANT pairs Lack of informativeness can be compensated by typing I-1

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SHORT-TERM DEVELOPMENTS Approaching the CV/CD hypothesis by modulating parameters of the longevity locus (allele frequencies and GRR) Exploring the same data sets with different algorithms (e.g. MCMC, Simwalk) Exploring multipoint data -2, ,5 -0,5 0 0,5 1 1, map position

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APPROACHING THE REAL DATA Typing of cousing pairs Haplotyping from family data Collecting population data Determining allele frequencies Haplotyping from population data ( PHASE, Arlequin) Real time monitoring of results

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