Chapter 58: genetics
58.1 term
- chromosome
- locus (sl.) loci (pl.)
- marker
- allele
- haplotype
- genotype
- phenotype / trait
- endophenotype
58.2 marker
- large marker: STRP = short tandem repeat polymorphism, STRs = short tandem repeats
- linkage analysis
- paternity testing
- taxonomy
- small marker: SNP = single-nucleotide polymorphism
- association analysis
- disease diagnosis
- pharmacodynamics? drug design / pharmacogenomics = custom drug
- RFLP = restriction fragment length polymorphism
- platform
- customized: MALDI-TOF MS(= mass spectrometry)
- whole-genome gene chip
- Affymetrix
- Taiwan BioBank: TWB2.0
- Illumina
- Affymetrix
- NGS = next-generation sequencing
58.3 genome project
- HGP = Human Genome Project
- 20~25K genes
- 3 billion bps(base pairs)
- ELSI = ethical, legal, and social issues
- 99.9% bps are exactly the same in all people
- germline mutation
- male : female = 2 : 1
- HapMap = International HapMap Project
- SNP, haplotype, tag SNP
- haplotypes are combination of SNPs
- tag SNPs can identify unique haplotypes
- HapMap 1 & 2
- between-ancestry SNP: 1 common SNP per 5 Kb to 1 common SNP per 1 Kb
- African
- European
- East Asian
- Han Chinese
- Japanese
- between-ancestry SNP: 1 common SNP per 5 Kb to 1 common SNP per 1 Kb
- HapMap 3: more ancestries
- SNP, haplotype, tag SNP
- 1000 Genomes Project
- NGS
- identify 95% genetic variants with frequencies at least 1%
- final phase 77M SNPs
- browser
- Ensembl GRCh37
- Ensembl GRCh38 http://asia.ensembl.org/Homo_sapiens/Info/Index
- TWB = Taiwan BioBank
- browser: TaiwanView https://taiwanview.twbiobank.org.tw/index
- pricing: https://www.biobank.org.tw/about_price.php
- TPMI = Taiwan Precision Medicine Initiative https://tpmi.ibms.sinica.edu.tw/www/precision-medicine/
58.4 linkage analysis
- Mendel 1st & 2nd laws
- law of segregation ~ 3 : 1
- law of assortment ~ 9 : 3 : 3 : 1
- phenotypic model by R.A. Fisher
- P=G+E
- G is the genotypic component
- E is the environmental component
- P=G+E+G⋅E
- G⋅E is the interaction between the genotypic component and environmental component
- P=G+E
- linkage = co-segregation = cosegregation
- θ = recombination fraction: 1% recombination = 1 crossover per 100 meioses = 1 cM(centiMorgan) on genetic map
- statistical hypothesis testing for in linkage mapping
- statistical hypothesis testing for categorical trait in linkage mapping: PLA = parametric linkage analysis
- H0: no linkage θ=0.5
- H1: linkage θ<0.5
- statistical hypothesis testing for quantitative trait in linkage mapping: VCLA = variance component linkage analysis
- H0: no linkage σ2q=0
- H1: linkage σ2q>0
- statistical hypothesis testing for categorical trait in linkage mapping: PLA = parametric linkage analysis
- study design
- case control
- trio
- affected / discordant sib-pair
- extended pedigree
- data format: linkage format
- family-based
- PID = pedigree Id
- IID = individual Id
- FID = father Id
- MID = mother Id
- gender
- affection
- marker
- M1 = marker 1
- M2 = marker 2
- …
- family-based
- single major locus model
- a two-allele A and a locus influences a dichotomous trait
- allele frequency
- p=P(A)
- q=P(a)=1−p
- penetrance
- fAA=P(affected∣AA)
- fAa=P(affected∣Aa)=faA
- faa=P(affected∣aa)
- disease mode of inheritance
- dominant model
- {fAA=1fAa=1faa=0
- recessive model
- {fAA=0fAa=0faa=1
- additive model
- {fAA=1fAa=12faa=0
- phenocopy model
- faa>0 perhaps due to environmental cause
- liability model
- e.g. fAA,fAa,faa are age-dependent
- dominant model
58.5 association analysis
- LD = linkage disequilibrium
- genotype & allele frequency
- diallelic marker
- pAA
- pAa
- paA
- paa
- pA
- pa
- diallelic marker
- HWC = Hardy-Weinberg condition
- HWE = Hardy-Weinberg equilibrium
- HWD = Hardy-Weinberg disequilibrium
- gametic or haplotype frequency
- LE = linkage equilibrium
- LD = linkage disequilibrium