GENETIC DISORDERS SAQs EXAMINATION — Notes OmpathStudy

GENETIC DISORDERS - 30 KEY SHORT ANSWER QUESTIONS Comprehensive coverage: Mutations, Mendelian Disorders, and Inheritance Patterns --- SECTION A: INTRODUCTION & APPLICATIONS OF GENETICS (4 Questions) 1. What is the lifetime frequency of genetic disease and why is it higher than commonly appreciated? Answer: Lifetime frequency: 670 per 1000 individuals Higher than appreciated because includes:"Classic" genetic disorders (single gene, chromosomal) Cardiovascular diseases with genetic components Disorders of immunity Cancers (genetic mutations in somatic cells) Variable expressivity (mild/hidden presentations) ~50% of early pregnancy miscarriages have chromosomal abnormalities ~5% of individuals <25 years develop serious disease with significant genetic component Many mild genetic disorders remain undiagnosed 2. Explain the human genome composition and genetic diversity. Answer: Genome composition: Approximately 30,000 genes in human genome <2% code for proteins (protein-coding genes) 50% are repetitive sequences of unknown function Includes regulatory sequences, introns, non-coding RNAs Genetic diversity: Humans share 99.9% of DNA sequence 0.1% difference = ~3 million base pairs This 0.1% accounts for:Individual variations Disease susceptibility Physical characteristics Drug responses Ethnic diversity 3. Compare functional cloning and positional cloning approaches. Answer: Functional (Classic) Cloning: Start with: Known affected protein/clinical phenotype Steps:Identify abnormal protein through clinical/biochemical studies Isolate and clone normal gene Determine molecular changes in disease Example: Sickle cell anemia (abnormal hemoglobin identified first) Positional (Candidate Gene) Cloning: Start with: Chromosome location of disease Steps:Map disease phenotype to chromosome location (linkage analysis) Clone multiple DNA pieces from that region Identify aberrant proteins from mutated genes Work backwards from location to function Example: Huntington disease (location found before gene function known) 4. Describe four major applications of genetics in medicine. Answer: 1. Molecular basis of human disease: Understanding disease mechanisms at genetic level Both approaches: functional and positional cloning 2. Production of biologically active agents: Insert genes into bacteria/tissue culture cells Examples: TNF receptor, tissue plasminogen activator, growth hormone, erythropoietin, insulin 3. Gene therapy: Transfer of somatic cells with normal genes Treat genetic diseases at source Ethical considerations: benefits vs risks 4. Disease diagnosis: Molecular probes for genetic diseases Prenatal diagnosis Carrier detection Diagnosis of infectious diseases (pathogen DNA detection) Personalized medicine approaches --- SECTION B: TYPES AND CATEGORIES OF MUTATIONS (7 Questions) 5. Define mutation and distinguish between germline and somatic mutations. Answer: Mutation: Permanent change in DNA sequence Can affect single base pairs to large chromosomal segments Germline mutations: Occur in germ cells (sperm/egg) Transmitted to progeny Present in all cells of offspring Cause inherited/hereditary diseases Examples: Hemophilia, cystic fibrosis, sickle cell disease Somatic mutations: Occur in body (somatic) cells NOT transmitted to progeny Present only in affected tissue/cell lineage Cause: cancers, some congenital malformations Examples: Most cancers, some birthmarks 6. Describe the three major categories of mutations. Answer: 1. Genome mutations: Affect whole chromosome number Monosomies: Loss of one chromosome (e.g., Turner syndrome 45,X) Trisomies: Gain of one chromosome (e.g., Down syndrome, trisomy 21) Result from nondisjunction during meiosis 2. Chromosome mutations: Rearrangement of genetic material Visible structural changes under microscope Types: deletions, duplications, inversions, translocations Example: Philadelphia chromosome t(9;22) in CML 3. Gene mutations: Changes within individual genes May involve:Single base pair (point mutations) Small deletions/insertions Partial or complete gene deletion NOT visible cytogenetically 7. Explain point mutations and their three types. Answer: Point mutations: Substitution of single nucleotide base 1. Missense mutations: Change one amino acid to another Conservative: Similar amino acid (minimal effect) Non-conservative: Different amino acid properties (significant effect) Example: Sickle cell anemia (glutamic acid → valine) 2. Nonsense mutations: Change amino acid codon to stop codon (UAA, UAG, UGA) Premature termination of translation Truncated, non-functional protein Usually severe effect 3. Silent mutations: Change nucleotide but same amino acid (genetic code redundancy) No change in protein sequence Generally no clinical effect 8. What are frameshift mutations and their consequences? Answer: Definition: Insertion or deletion of nucleotides NOT divisible by 3 Alters reading frame of DNA Mechanism: Genetic code read in triplets (codons) Insertion/deletion of 1 or 2 base p