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WEEK 4: GENE INTERACTION (Non-Mendelian inheritance (Incomplete dominance,…

- - - - Homozygous
        
        Both alleles are the same
        
        True-breeding individuals
      - Heterozygous
        
        One of each kind of allele
        
        Hybrids
        
        Complete dominance (one dominant, one recessive)
    - - Dominant
        
        One copy of gene mutated required to cause disease
        
        Gain of function mutations: proteins acquires new function
        
        Heterozygous mutations inherited from affected parent or de novo
      - Recessive
        
        Homozygous or compound heterozygous mutations from unaffected parents
        
        Both copies of genes mutated required to cause disease
        
        Loss of function mutations: protein absent, or reduced function
      - Observed correlations, if not interfered with by modifier genes/environment, are explained by considering specific effect that genotype has on consequent or residual protein function
  - - - Lethal yellow gene meant that observed proportions (phenotypic ratios) did not fit expected ratios
    - - 3+ alleles can exist at single locus
      - Genes at different loci interact
      - Cancer was inherited
      - Genes encoded enzymes
  - - - More prevalent form of gene expression where both alleles of a gene are transcribed
    - - Only one of the two copies of a gene is active, while the other is silent; frequently initiated early in development, then stably maintained
- - - - Amount of red pigment in flower
      - Hair texture in humans: curly, wavy, straight
  - - - Heterozygotes simultaneously express phenotypes of both homozygotes (i.e. it is not merely an intermediate between homozygotes)
    - - Three major alleles determine presence of sugar molecules that act as antigens
        
        IA
        
        _
        
        4 phenotypes (blood groups), 6 genotypes
        
        IA/IB = codominant = AB
        
        i/i = O
        
        IA/IA or IB/IB = A or B
        
        IB
        
        i (no sugar)
  - - - E.g. Six different alleles may control a trait; examine combination of alleles from each gene for AaBbCc x AaBbCc
        
        Phenotype depends on number of dominant alleles - very dark (6 dominant) or very light (6 recessive); in between, combinations give intermediate hues
    - - Polygenic traits
        
        Body type
        
        Height
        
        Skin colour
        
        Hair colour
        
        Eye colour #
        
        Intelligence
      - Genetic & environmental links
        
        Cancers
        
        Hypertension
        
        Allergies
        
        Cardiovascular diseases
        
        Diabetes
        
        Behavioural traits (alcoholism, phobias)
    - - Multiple genes work together to produce continuous (Bell) distribution curve of degrees
      - Multifactorial
        
        Trait expression is controlled by several genes and environmental factors, which can heavily influence polygenic trait expression
  - - - Can be seen in human diseases e.g. cystic fibrosis or sickle-cell anaemia, in which multiple symptoms trace back to one defective allele
        
        Sickle-cell anaemia alleles
        
        A
        
        Round cell shape
        
        Produce haemoglobin A
        
        Susceptible to malaria
        
        S
        
        Sickle cell shape (low O2)
        
        Produce haemoglobin S
        
        Resistant to malaria (A/S)
  - - - F1 generation
        
        Reciprocal cross (colour blind female + normal male) = normal female offspring + colour-blind male offspring
        
        Normal female + colour-blind male = normal offspring
- - - - Mechanism
        
        Chromosomes & Gonads
        
        Y: 231 protein-encoding genes, some unique to Y
        
        X: >1500 genes, most don't have corresponding alleles on Y
        
        Gametes (sperm/egg); gonads (testis/ovary)
        
        Genetic (1) sex determined at fertilisation; gonadal (2) sex begins in gestational Week 7 and is multifactorial*
        
        Internal duct systems in gonadal differentiation
        
        Wolffian (male)
        
        Mullerian (female)
        
        Gonads & Phenotype
        
        Male
        
        SRY gene
        
        Y-Chr. determining region causes indifferent gonad to develop as a testis, triggering hormonal (3) differentiation
        
        Testosterone (an androgen)
        
        1 more item...
        
        Mullerian Inhibiting Hormone
        
        Female
        
        X inactivation
        
        Random silencing of one X chromosome
      - Disease
        
        Klinefelter syndrome
        
        XXY, XXXY, XXXXY, or XXYY
        
        1/1000 male births
        
        True hermaphroditism
        
        46, XX
        
        Appear female but have ovotestis with both spermatogonia and ovarian follicles (very rare, usually raised as female)
        
        Turner syndrome
        
        1/3000 female births
        
        XO
        
        Androgen insensitivity syndrome
        
        Male: chromosomes, gonads (testes), prenatal hormones
        
        Female: internal/external genitalia; due to defective androgen receptor
        
        Poly-X females
        
        1/1000 female births
        
        Congenital adrenal hyperplasia
        
        Female: chromosomes, gonads (overaies)
        
        Male: prenatal hormones (due to delivery of androgen hormone), internal genitalia, external genitalia
        
        Pseudo-hermaphrodidism
        
        Males usually 46, XY with insufficient hormone production, phallic hypoplasia
        
        Females usually 46, XX but produce high levels of androgenic hormones and exhibit external genitalia masculinisation
  - - - Postulate: live-borns with Turner are cryptic mosaics as most 45, XO do not survive gestation
        
        Karyotype
        
        45, XO
        
        Phenotype: delayed puberty, infertility, morbidity through cardiac/renal abnormalities
        
        Mosaic
        
        45, XO / 46, XX
        
        Phenotype correlates with relative proportion of 45,XO cells
    - - Somatic
        
        Segmented or patchy manifestation depending on stage and somatic cell lineage of mutation
        
        Somatic mosaicism for deletion in OTC gene led to dysfunction of hepatic urea cycle due to ornithine transcarbamylase deficiency in boy
      - Germline
        
        Mutation occurs in germline cell (affect all or part) and persists in all clonal descendants of that cell; somatic cells not affected
        
        Mitotic-stage mutations
        
        30 mitotic divisions before meiosis in females
        
        100s of mitotic divisions before meiosis in males
        
        Proportion of gametes carry mutation
        
        Documented in 6% of severe lethal forms of osteogenesis imperfecta
        
        Mutation in type I collagen genes leading to abnormal collagen, brittle bones, and frequent fractures
      - Both
        
        Mutation occurs before separation of germline from somatic cells
        
        Mutation present in both and transmitted to offspring in complete form, expressed somatically in mosaic form
    - - Post-zygotic mutations resulting in 2 or more genetically distinct cell lines (mutations occurring earlier in development will have descendants in many tissues, i.e. less localised)
        
        Chromosomal or single-gene disorders
        
        Mix of cells producing normal and abnormal proteins (proportion and distribution of which determine phenotype)
  - - - 16.5 kb chromosome
      - Most cells contain 1000+ mtDNA molecules distributed among 100s of individual mitochondria
        
        Mature oocyte has >100 000 copies of mtDNA
        
        mtDNA
        contains 37 genes
        
        13 encode polypeptides
        
        2 rRNA
        
        22 tRNA
    - - Different rearrangements and point mutations in mtDNA cause human disease
        
        Mitochondrial disease and inheritance patterns reflect three unusual features of mitochondria
        
        Homoplasmy and heteroplasmy
        
        Maternal inheritance
        
        Replicative segregation
    - - Sperm mt eliminated from the embryo
        
        Affected males do not pass on disease
      - mtDNA inherited from mother
        
        Affected females pass on disease to all children
- - - - Fully penetrant disease
        
        Huntington's Disease
      - Incomplete penetrance
        
        Polydactyly
        
        Dominant allele
      - Affected by additional genetic and environmental factors
  - - - Metrics
        
        Severity of clinical features
        
        Number of clinical features
      - Polydactyly: some have extra fully functional digits, others do not
  - - - Recessive or dominant genes
        
        Hypostatic (masked)
        
        Epistatic (masks)
      - Often, gene affects early step in pathway and is epistatic to genes affecting subsequent steps
        
        Recessive epistasis of H gene to I in ABO blood groups
        
        H locus encodes a transferase that adds fucose to precursor to produce substrate H
        
        ABO locus encodes three alleles that produce transferases to add terminal sugar of antigen (A or B) and determine blood group
        
        ABO alleles are hypostatic to the recessive h allele, and I is not fully expressed in absence of H
        
        H_ii
        
        1 more item...
        
        hh_
        
        1 more item...
        
        II
        
        Ii
        
        Functional transferase adds A or B sugar (IA or IB)
        
        ii
        
        Non-functional transferase does not add sugar
        
        HH
        
        Hh
        
        Functional fucosyl transferase
        
        hh
        
        Bombay phenotype has defective fucosyl transferase
  - - - Classification depends on level at which phenotype is examined
        
        Physiological
        
        Anatomical
        
        Molecular
        
        Sickle-cell anaemia
        
        Genotype observations
        
        AS - no anaemia, RBC sickle under low [O2]
        
        SS - severe anaemia, abnormal Hb, sickle RBC
        
        AA - wild type, no anaemia, RBC never sickle
        
        Dominance conclusions
        
        Anaemia: A allele dominant
        
        Sickle shape: incomplete dominance (heterozygote has some sickly cells)
        
        Hb protein: codominant
        
        Pathophysiology
        
        Haemoglobin tetramer of 2 alpha-polypeptide chains (141AA each) and 2 beta chains (146AA each); Glu - Val in beta chain
      - Result from allelic interaction, i.e. those between genes at same locus
  - - - Four capsicum colours
        (red, peach, orange, cream)
        
        Loci encode enzymes in biochemical pathway; molecular effects give amount of pigment that determines colour