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The Genetic of Earwax • Wet earwax is a dominant allele! – Petrakis et. al (1967) Science 158, p1992 World wild distribution of earwax types Open: dry type Dark: wet type Yoshiura (2006) Nat. Genetics Earwax type linked to a disease? • Japanese Case Report: – A Paroxysmal kinesigenic choreoathetosis, (PKC, 陣發性運動障礙性疾病) patient who told that six people in her family also had choreoathetosis, and that those with the disease had wet earwax. – Wet earwax is rare in Japan and PKC is rare, too! – The cause of PKC is still unknown but seem linked to chromosome 16 near centremere • Swoboda, et al. Neurology 2000;50:224-30. Genetic marker typing LOD > 3 : evidence of linkage Recombination rate Genotype A B (n1) a b (n2) A b (n3) A B (n4) Total Experiment 1 17 14 8 11 50 Experiment 2 34 28 16 22 100 總樣品數 互換率 θ 範圍 [0, 0.5] 當 θ = 0 代表完全連鎖 當 θ = 0.5 代表不連鎖 LOD score • logarithm (base 10) of odds • Developed by Newton E. Morton • NR: non recombination; R: recombination • LOD score > 3.0: evidence for linkage. (A score of 3.0 means the likelihood of observing the given pedigree if the two loci are not linked is less than 1 in 1000). • LOD score < -2.0: evidence to exclude linkage 108 people: 64 wet earwax; 54 dry earwax More detail study • More microsatellite markers • Use SNP study • 37 SNPs used • rs17822931 in ABCC1 exon 4 (538GA, G180R) • rs6500380 in LONPL intron 12 (AG) • ss49784070 in LONPL intron 14 (A G) SNP • Single nucleotide polymorphism (SNP, pronounced snip) • Within a population, SNPs can be assigned a minor allele frequency (>1%) • may fall within coding sequences of genes, non-coding regions of genes, or in the intergenic regions between genes • synonymous or nonsynonymous • Missense or nonsense How to find out new SNP? • Sequencing • SSCP (single strand conformation polymorphism) How to determine SNP types? • SNP array • Next Generation Screening® microarray with 25,000 features Genotyping of three SNPs • • • • • • • Dry earwax (63/64): AA-AA-AA Dry earwax (1/64): GA-GA-GA Wet earwax (6/54): GG-GG-GG Wet earwax (33/54): GA-GA-GA Wet earwax (15/54): AA-AA-AA Only two haplotypes in Japan; Phenotype - genotype inconsistency Do more case study • • • • • New series of 126 cases Dry type (87/88): AA homozygotes Wet type (38/38) GA or GG Only rs17822931 is nonsynonymous Dry type is recessive What happened to 1/88? • • • • A allele to dry type, G allele to wet type One exception is dry type with GA allele Sequence the gene of ABCC11 G allele had a 27-bp deletion (3939-3965) in exon 29 What is the function ABCC11? • Multidrug resistance-associated protein 8 (MRP8) Rs17822931 G180R Effect of SNP rs17822931 • Dry type: A allele G180R: Low activity in cGMP transport Low lipophiles secretion Genetics Leads the Bioscience Researches 10 9 論文發表篇數 8 7 6 5 4 3 2 1 0 2001 2002 2003 2004 2005 年份 2006 2007 2008 2009