Chapter 55: genetics

楊欣洲: genetics

55.1 term

• chromosome
• locus (sl.) loci (pl.)
• marker
• allele
• haplotype
• genotype
• phenotype / trait
  • endophenotype

55.2 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
  • NGS = next-generation sequencing

55.3 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
  • HapMap 3: more ancestries
• 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/

55.4 linkage analysis

• Mendel \(1^{st}\) & \(2^{nd}\) 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
  • \[P = G + E + G \cdot E\]
    • \(G \cdot E\) is the interaction between the genotypic component and environmental component
• linkage = co-segregation = cosegregation
  • \(\theta\) = 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
    • \(H_0\): no linkage \(\theta = 0.5\)
    • \(H_1\): linkage \(\theta < 0.5\)
  • statistical hypothesis testing for quantitative trait in linkage mapping: VCLA = variance component linkage analysis
    • \(H_0\): no linkage \(\sigma^2_{q} = 0\)
    • \(H_1\): linkage \(\sigma^2_{q} > 0\)
• 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
      • …
• single major locus model
  • a two-allele \(A\) and \(a\) locus influences a dichotomous trait
  • allele frequency
    • \(p = \mathrm{P}\left(A\right)\)
    • \(q = \mathrm{P}\left(a\right) = 1-p\)
  • penetrance
    • \(f_{AA} = \mathrm{P}\left(\text{affected}\mid AA\right)\)
    • \(f_{Aa} = \mathrm{P}\left(\text{affected}\mid Aa\right) = f_{aA}\)
    • \(f_{aa} = \mathrm{P}\left(\text{affected}\mid aa\right)\)
  • disease mode of inheritance
    • dominant model
      • \(\begin{cases}f_{AA} = 1 \\ f_{Aa} = 1 \\ f_{aa} = 0\end{cases}\)
    • recessive model
      • \(\begin{cases}f_{AA} = 0 \\ f_{Aa} = 0 \\ f_{aa} = 1\end{cases}\)
    • additive model
      • \(\begin{cases}f_{AA} = 1 \\ f_{Aa} = \frac{1}{2} \\ f_{aa} = 0\end{cases}\)
    • phenocopy model
      • \(f_{aa} > 0\) perhaps due to environmental cause
    • liability model
      • e.g. \(f_{AA},f_{Aa},f_{aa}\) are age-dependent

55.4.1 PLA = parametric linkage analysis

• LOD score

55.4.2 VCLA = variance component linkage analysis

• allele-sharing: IBS and IBD
  • IBS = identity-by-state
  • IBD = identity-by-descent

55.5 association analysis

• LD = linkage disequilibrium
• genotype & allele frequency
  • diallelic marker
    • \(p_{AA}\)
    • \(p_{Aa}\)
    • \(p_{aA}\)
    • \(p_{aa}\)
    • \(p_{A}\)
    • \(p_{a}\)
• HWC = Hardy-Weinberg condition
  • HWE = Hardy-Weinberg equilibrium
  • HWD = Hardy-Weinberg disequilibrium
• gametic or haplotype frequency
  • LE = linkage equilibrium
  • LD = linkage disequilibrium