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Human Genetics II, III, IV (Lectures 61, 62, 63), Hardy-Weinberg Law -…

- - - - Cystic Fibrosis
        
        Mutated CFTR
        
        Most common in European, then African, then Asia Amercian
      - Sickle Cell Anemia
        
        HBB Gene
        
        Single mutant alleles protective against malaria
        
        Symptoms
        
        Anemia, repeat infections, acute vaso-occlusive pain, hyposplenism
  - - - Marfan Syndrome
        
        Mutated Fibrillin-1 (25% Novel) Loss of function or protein reduction
        
        30-40% die from aortic dissections
        
        Defective Connective Tissue
        
        wrist, thumb sign
        
        Severe pectus excavatum
        
        scoliosis
      - Achondroplasia
        
        FGFR3 (80% novel) gain of function (signal transduction protein is always on)
        
        Homozygous LETHAL
        
        Defective cartilage growth
- - - - due to X-chromosome inactivation (random)
      - occurs very early in development of progenitor cells and carriers on down through every daughter cell
  - - - X-linked recessive hemophilia A
        
        Nonsense/frameshift mutations are SEVERE
        
        Missense mutations are mild to moderate
        
        Primarily in males, but females can have mosaic expression
        
        Deficiency in factor VIII of clotting cascade
      - Color blindness
      - Duchenne
      - Glucose 6 dehydrogenase deficiency
      - Hydoidrotic ectodermal dysplasia
        
        Mutations in EDA gene
        
        impairs development of hair, sweat glands, teeth
        
        Females very mosaic
  - - - Hypophosphatemic rickets
      - Incontinentia pigmenti type I
      - Rett syndrome
- - - - chorea, cognitive impairment, dementia, mood change
    - - progressive muscle weakness, myotonia, cataracts, cardiac conduction defects
- - - - Neural Tube defects
        
        spina bifida and anencephaly
        
        Genetic and environmental factors (folic acid intake)
        
        predisposed gene and good environment can mean no disease or vise versa
        
        Recurrence risk for NTD
        
        None in family = 0.5%
        
        1 child in family = 5%
        
        2 children with NTD = 10%
        
        3 children in family = 21%
        
        Rest of population is 0.1%
        
        This is called EMPIRICAL RISK
        
        Because you cannot calculate exact recurrence risk
        
        Risk based on observable data (SPECIFIC to population)
        
        Based on collection of family studies
      - Congenital Malformations
        
        Cleft lip/palate
        
        Pyloric Stenosis
        
        Male bias
        
        Male with malformation son = 5.5%, daughter is 2.4% risk
        
        Female with malformation son = 19.4%, daughter is 7.3%
        
        Risk is higher passed from mother with malformation because she has to have had WORSE GENES to get the disease, thus has more bad genes to pass on
      - Hypertension
        
        Genetic component is 30-50%
        
        Small % of hypertension due to single-gene mutation (Liddle Syndrome
      - Diabetes type II
        
        Risk factors are family history and obestiy
        
        70 loci contribute to susceptibility
        
        Variants of TCF7L2 identified in populations
      - CANCER
        
        All cancer has a genetic component
        
        Genetic predisposition (such as BRCA) and environmental factors (directly alter DNA and gene function)
        
        Oncogenes
        
        Proto-oncogene: normal gene involved in cell-cycle/proliferation (subject to gain-of-function)
        
        Oncogene: mutated proto-oncogene
        
        Responsible for sporadic cancers
        
        Ras proto-oncogene
        
        small gtp-ase involved in signal transduction, 1 mutation means it is always on
        
        Found in 30% of all cancers
        
        Philadelphia chromosome
        
        Translocation in BRA-ABL1 fusion
        
        ABL1 tyrosine kinase becomes overactive with fusion
        
        Found in CML and 25% of ALL
        
        Tumor Suppressor P53
        
        50% of sporadic cancers include P53 mutaitons
        
        SUPPOSED to induce apoptosis in damaged DNA
        
        Benzopyrene in cigarette smoke directly linked to altering P53
        
        Tumor Suppressor Genes
        
        Normal gene involved in suppressing cell cycle
        
        Subject to loss-of-function mutation
        
        Need mutations in both alleles
        
        Examples
        
        Retinoblastoma
        
        Two-hit hypothesis
        
        Oncogenes work in a dominant fashion
        
        Tumor suppressors need a different mechanism
        
        Loss of hetrozygosity
        
        BASICALLY!
        
        2 more items...
        
        Mutated RB1 gene
        
        Retinoblasts SHOULD stop dividing after embryogenesis
        
        90% penetrance