Download 投影片 1

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 (538GA,
G180R)
• rs6500380 in LONPL
intron 12 (AG)
• 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
G180R
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