Figure 3.1 ~ 3.4 Figure 3.5 ~ 3.8 Figure 3.9 ~ 3.11

3.1 Mendelian pedigree patterns

• - a particular genotype at one locus is both necessary and sufficient for the character to be expressed, given the normal genetic and environmental backgroud of the organism, such character is called mendelian - over 10,000 mendelian charaters are known OMIM === 3.1.1 Dominance and recessiveness are properties of characters, not genes === - dominant - recessive - most human dominant syndromes are known only in heterozygotes

  • (often the homozygotes are much more severel afftected)
  - semidominant(Huntington disease) - hemizygotes

Box 3.1

• 1. Autosomal dominant inheritance

  2. Autosomal recessive inheritance

  3. X-linked recessive inheritance

  4. X-linked dominant inheritance

  5. Y-linked inheritance

  === 3.1.2 There are five basic mendelian pedigree patterns ===
  • ==== X-inactivation blurs the distinction between dominant and recessive X-linked conditions ====
  female(X'X)에서 recessive 인데 severe phenotype이 나타날 경우 - X inactivation 때문
  • ==== There are probably no Y-linked diseases ====
  no Y-linked diseases are known - trace family through the male line not been noted - Y chromosome cannot carry any genes ( important for health), females are perfectly normal without any Y-linked genes === 3.1.3 The mode of inheritance can rarely be defined unambiguously in a single pedigree === - numbers are too small - can bias the ratio of affected to unaffected children === 3.1.4 One gene - one enzyme does not imply one gene - one syndrome === - how genes determine phenotypes
  • ==== Locus heterogeneity is common in syndromes that result from failure of a complex pathway ==== - Complementation
    • aaBB ㅡㅡㅡ AAbb
      • ㅣ

      • AaBb (wild type)

    - locus heterogeneity (autosomal recessive의 경우) ==== Allelic series are a cause of clinical heterogeneity ==== - CAG(glutamine) repeat에 따른 phenotype의 변화
  === 3.1.5 Mitochondrial inheritance gives a recognizable matrilinear pedigree pattern === - matrilineal inheritance - heteroplasmy : transmit from heteroplasmic mother to heteroplasmic child - homoplasmy

3.2 Complications to the basic pedigree patterns

• === 3.2.1 Common recessive conditions can give a pseudo-dominant pedigree pattern ===

  - blood group O (-> recessive character)

  • heterozygote O 와 repeated marriages -> the pattern resembles dominant inheritance

  - Fig 3.5A === 3.2.2 Failure of a dominant condition to manifest is called nonpenetrance ===
  • - penetrance - nonpenetrance - Fig. 3.5B ==== Late-onset diseases show age-related penetrance ==== - genotype is fixed at conception, but the phenotype may not manifest until adult life ( penetrance is age-related) - Huntington disease - cuased by slow accumulation of noxious substance, by slow tissue death... - Fig. 3.6
  === 3.2.3 Many conditions show variable expression ===
  • - Fig. 3.5C - same as with nonpenetrace : other genes, environmental factors - balancing - more conspicuous in human than plants and animals ==== Anticipation is a special type of variable expression ==== - tendency of some variable dominant conditions to become more severe in successive generations - Fragile-X syndrome, Myotonic dystrophy, Huntington disease - Fig. 3.6
  === 3.2.4 For imprinted genes, expression depends on parental origin ===
  • - inherit the gene from who - Fig. 3.5D

    - Imprinting

    • ex) glomus tumors - from father
      • Beckwith wiedemann syndrome - from mother
  === 3.2.5 Male lethality may complicate X-linked pedigrees ===
  • - some X-linked dominant - lethal - Fig. 3.5F - male not born, only female affect - ex) incontinentia pigmenti(색소실조증)
  === 3.2.6 New mutations often complicate pedigree interpretation, and can lead to mosaicism ===
  • - new mutation의 경우
    • autosomal recessive - assume parent carriers autosomal dominant - much faster (constantly exposed)
    - Fig. 3.5H - thanatophoric dysplasia - germinal mosaicism ==== Mosaics have two (or more) genetically different cell lines ====

    • - normal person이 single mutant gamete를 가진다고 가정 -> gametogenesis 동안 발생 - mosaicism - somatic and germ line tissue에 영향 미침 - post-zygotic mutation - mosaics을 형성 (normal cell + mutant cell)

      • - not frequent , but 필연적 현상

        • because 10^{-7 / gene / cell generation ( body contain 10}13 cells)

      - germ line에서 mutation 발생 -> de novo mutation in child - Fig. 3.7 - Fig. 3.8 -> molecular studies

    ==== Chimeras contain cells from two separate zygotes in a single organism ====
    • - Chimera는 single embryo안으로 two zygote가 fusion 되어 형성

      • -> several loci에서 two many parental allele가 존재

3.3 Factors affecting gene frequencies

• === 3.3.1 There can be a simple relation between gene frequencies and genotype frequencies ===
  • ==== A thought experiment: picking genes from the gene pool ====

    • - Gene pool consist of all alleles at the A locus in the populaion - gene frequency (p & q ) - ex) allele A1, A2 가정

    ==== The Hardy-Weinberg distribution ====

    • - A1A1 = p^2,  A1A2 = 2pq,  A2A2 = q^2 - simple relationship between gene frequencies and genotype frequencies - only allele A1, A2 p+q=1

      • other allele p+q<1

      - Box 3.3
    ==== Limitations of the Hardy-Weinberg distribution ====
    • - two gene이 not independently picking이면 H-W break cown

      - Assortative mating - Inbreeding

      • -> resemble gene이 too many ( homozygous increase, heterozygous decrease )

    ==== Use of the Hardy-Weinberg distribution in genetic counseling ====
    • - essential input such as linkage analysis, segregation analysis
  === 3.3.2 Genotype frequencies can be used (with caution) to calculate mutation rate ===
  • - population에서 loss 와 replacement rate가 평형을 이루고 있다면, mutation rate(u, /gene/generation) can calculate

    • -> coefficient of selection (S) ; fittest type (S=0), genetic lethal (S=1)

    - autosomal reccesive - q^{2 ; frequencies(sq}2)

    • sq^{2 = u(1-q}2) (q is small) u=sq^2

    - rare autosomal dominant

    • homozygote is very rare, heterozygote = 2pq -> gene의 half가 disease allele ; nearly sp sp=uq^2 (q가 거의 1이면) u=sp

    - X-linked recessive

    • male = sq, mutation rate 3u와 balance

      3u = sq ; u=sq/3

    - Box 3.5 - generally mutation rate 10^{-5~ 10}-7

  • ==== Heterozygote advantage can be much more important than recurrent mutation for determining the frequency of a recessive disease ====
    • - ex) Cystic Fibrosis (CF) - heterozygote advantage

3.4 Nonmendelian characters

• === 3.4.1 Research into simple and complex traits has long defined two separate traditions within human genetics ===
  • - Francis Galton

    - Biometrics

  • ==== A historical controbersy ====
    • - mendelian analysis requires dichotomous characters - RA Fisher : independent mendelian factor에 의해 좌우되는 continuous character가
      • quantitative variation(by biometrician)과 family correlation을 정확하게 보여줌을 보임
    ==== Two traditions in human genetics ====
    • - mendelian : 1970~1990 발전

      - quantitative character (nonmendelian) -> family resemblance의 통계적 연구에 그침

  === 3.4.2 Multifactorial nonmendelian characters can be oligogenic or polygenic ===
  • - DNA sequence variants - always mendelian, as genetic marker - protein variants - usually mendelian, can depend on more than one locus

    - Multifactorial - nonmendelian character requires more two loci -oligogenic -polygenic - dichotomous characters - as susceptibility genes

    • quantitative characters - as [QTL](Quantitative Trait loci)
    - Fig 3.11
  === 3.4.3 The new synthesis uses mendelian markers to analyze nonmendelian phenotypes ===
  • - mendelian genes, polygenes
  === 3.4.4 Counseling in nonmendelian conditions uses empiric risks ===
  • - In genetic counseling for nonmendelian conditions, risks are not derived from polygenic theory;

    • they are empiric risks obtained through population surveys (% birth of sons, daughters, sisters, brothers..)