Chapter 4 Human Genetics

1. Chapter 4 Human Genetics

2. DNA Function • Code for protein synthesis • Gene - sequence of DNA nucleotides that codes for one protein • Genome - all the genes of one person • humans have estimated 30-35,000 genes • other 98% of DNA noncoding – “junk” or regulatory

3. Discovery of the Double Helix • By 1900:components of DNA were known • sugar, phosphate and bases • By 1953: x ray diffraction determined geometry of DNA molecule • Nobel Prize awarded in 1962 to 3 men: Watson, Crick and Wilkins but not to Rosalind Franklin who died of cancer at 37 getting the x ray data that provided the answers.

4. RNA: Structure and Function • RNA smaller than DNA (fewer bases) • transfer RNA (tRNA) 70 - 90 bases • messenger RNA (mRNA) over 10,000 bases • DNA has over a billion base pairs • Only one nucleotide chain (not a helix) • ribose replaces deoxyribose as the sugar • uracil replaces thymine as a nitrogenous base • Essential function • interpret DNA code • direct protein synthesis in the cytoplasm

5. Preview of Protein Synthesis • Transcription • messenger RNA (mRNA) is formed next to an activated gene • mRNA migrates to cytoplasm • Translation • mRNA code is “read” by ribosomal RNA as amino acids are assembled into a protein molecule • transfer RNA delivers the amino acids to the ribosome

6. Genetic Code • System that enables the 4 nucleotides (A,T,G,C) to code for the 20 amino acids • Base triplet: • found on DNA molecule (ex. TAC) • nucleotides that stand for 1 amino acid • Codon: • “mirror-image” sequence of nucleotides found in mRNA (ex AUG) • 64 possible codons (43) • often 2-3 codons represent the same amino acid • start codon = AUG • 3 stop codons = UAG, UGA, UAA

7. Transcription • Copying instructions from DNA to RNA • RNA polymerase binds to DNA • at site selected by chemical messengers from cytoplasm • opens DNA helix and transcribes bases from 1 strand of DNA into pre-mRNA • if C on DNA, G is added to mRNA • if A on DNA, U is added to mRNA, etc. • rewinds DNA helix • Pre-mRNA is unfinished • “nonsense” (introns) removed by enzymes • “sense” (exons) reconnected and exit nucleus

8. Alternative Splicing of mRNA • One gene can code for more than one protein • Exons can be spliced together into a variety of different mRNAs.

9. Translation of mRNA • mRNA begins with leader sequence • binding site for ribosome • Start codon AUG

10. Steps in Translation of mRNA • Converts alphabet of nucleotides into a sequence of amino acids to create a specific protein • Ribosome in cytosol or on rough ER • small subunit attaches to mRNA leader sequence • large subunit joins and pulls mRNA along as it “reads” it • start codon (AUG) where protein synthesis begins • small subunit binds activated tRNA with corresponding anticodon • large subunit enzyme forms peptide bond

11. Steps in Translation of mRNA • Growth of polypeptide chain • next codon read, next tRNA attached, amino acids joined, first tRNA released, process repeats and repeats • Stop codon reached and process halted • polypeptide released and ribosome dissociates into 2 subunits

12. Transfer RNA (tRNA) • Activation by ATP binds specific amino acid and provides necessary energy to join amino acid to growing protein molecule • Anticodon binds to complementary codon of mRNA

13. DNA and Peptide Formation

14. Chaperones and Protein Structure • Newly forming protein molecules must coil or fold into proper 2nd and tertiary molecular structure • Chaperone proteins • prevent premature folding, assist in proper folding and escort protein to final destination • Stress or heat-shock proteins • produced in response to heat or stress • help damaged protein fold back into correct functional shapes

15. DNA Replication 1

16. DNA Replication 2 • Law of complimentary base pairing allows building of one DNA strand based on the bases in 2nd strand • Steps of replication process • DNA helicase opens short segment of helix • replication fork is point of separation of 2 strands • DNA polymerase assembles new strand of DNA next to one of the old strands • 2 DNA polymerase enzymes at work simultaneously

17. DNA Replication 3 • Semiconservative replication • each new DNA molecule contains one new helix and one conserved from parent DNA • Additional histones made in cytoplasm • Each DNA helix winds around histones to form nucleosomes • 46 chromosomes replicated in 6-8 hours by 1000’s of polymerase molecules

18. Errors and Mutations • Error rates of DNA polymerase • in bacteria, 3 errors per 100,000 bases copied • Proofreading and error correction • a small polymerase proofreads each new DNA strand and makes corrections • results in only 1 error per 1,000,000,000 bases copied • Mutations - changes in DNA structure due to replication errors or environmental factors • some cause no effect, some kill cell, turn it cancerous or cause genetic defects in future generations

19. Cell Cycle • G1 phase, the first gap phase • accumulates materials needed to replicate DNA • S phase, synthesis phase • DNA replication • G2 phase, second gap phase • replicates centrioles • synthesizes enzymes for division • M phase, mitotic phase • nuclear and cytoplasmic division • G0 phase, cells that have left the cycle • Cell cycle duration varies between cell types

20. Mitosis • one cell divides into 2 daughter cells with identical copies of DNA • Functions of mitosis • embryonic development • tissue growth • replacement of dead cells • repair of injured tissues • Phases of mitosis (nuclear division) • prophase, metaphase, anaphase, telophase

21. Mitosis

22. Mitosis: Prophase 1 • Chromatin coils into genetically identical, paired, sister chromatids • each chromatid contains a DNA molecule • remember: genetic material (DNA) was doubled during S phase of interphase • Thus, there are 46 chromosomes with 2 chromatids/chromosome and 1 molecule DNA per chromatid.

23. Mitosis: Prophase 2 • Nuclear envelope disintegrates • Centrioles sprout microtubules that push them apart and towards each pole of the cell • spindle fibers grow towards chromosomes • attach to kinetochore on side of centromere • spindle fibers pull chromosomes towards cell equator

24. Mitosis: Metaphase • Chromosomes line up on one equator • Mitosis spindles finished • spindle fibers (microtubules) attach centrioles to long centromere • shorter microtubules anchor centrioles to plasma membrane (aster)

25. Mitosis: Anaphase • Enzyme splits 2 chromatids apart at centromere • Daughter chromosomes move towards opposite poles of cells with centromere leading the way • motor proteins in kinetochore move centromeres along spindle fibers as fibers are disassembled

26. Mitosis: Telophase • New nuclear envelopes formed by rough ER • Chromatids uncoil into chromatin • Mitotic spindle breaks down • Nucleus forms nucleoli

27. Cytokinesis • Division of cytoplasm into 2 cells • overlaps telophase • Myosin pulls on microfilaments of actin in the membrane skeleton • creates crease around cell equator called cleavage furrow • Cell pinches in two • interphase has begun

28. Timing of Cell Division Cells divide when: • Have enough cytoplasm for 2 daughter cells • DNA replicated • Adequate supply of nutrients • Growth factor stimulation • Open space due to neighboring cell death Cells stop dividing when: • Loss of growth factors or nutrients • Contact inhibition

29. Chromosomes and Heredity • Heredity = transmission of genetic characteristics from parent to offspring • karyotype = chart of chromosomes at metaphase • 23 pairs homologous chromosomes in somatic cells (diploid number of chromosomes) • 1 chromosome inherited from each parent • 22 pairs called autosomes • one pair of sex chromosomes (X and Y) • normal female has 2 X chromosomes • normal male has one X and one Y chromosome • Sperm and egg contain only 23 chromosomes • fertilized egg has diploid number of chromosomes

30. Karyotype of Normal Male

31. The Genome • Human Genome project (1990-2003) • mapped entire base sequence (A,T,C,G) of 99% of our DNA • Genomics – study of how your DNA affects structure and function • Homo sapiens have 35,000 genes • these genes generate millions of different proteins with alternative splicing • All humans 99.99% genetically identical • Genomic medicine • Prediction, diagnosis and treatment of disease using knowledge of genome • Gene-substitution therapy

32. Genes and Alleles • Locus = location of particular gene • Alleles • different forms of gene at same locus on 2 homologous chromosomes • Dominant allele (D) • produces protein responsible for visible trait • Recessive allele (d) • expressed only when both alleles are recessive

33. Genetics of Earlobes

34. Genetics of Earlobes • Genotype • alleles for a particular trait (DD) • Phenotype • trait that results (appearance) • Homozygous – 2 identical alleles at a particular gene • Heterozygous – different alleles for a particular gene • Carriers of hereditary disease (cystic fibrosis) • heterozygous individual Punnett square

35. Multiple Alleles and Dominance • Gene pool • collective genetic makeup of population • Multiple alleles • more than 2 alleles for a trait • such as IA, IB, i alleles for blood type • Codominant • both alleles expressed, IAIB = type AB blood • Incomplete dominance • phenotype intermediate between traits for each allele

36. Polygenic Inheritance • 2 or more loci contribute to a single phenotypic trait (skin and eye color, alcoholism and heart disease)

37. Pleiotropy • One gene produces multiple phenotypic effects • Alkaptonuria = mutation that blocks the breakdown of tyrosine

38. Sex-Linked Inheritance • Recessive hemophilic allele on X, no gene locus for trait on Y, so hemophilia more common in men (mother is carrier)

39. Penetrance and Environmental Effects • Penetrance • % of population expressing predicted phenotype • Role of environment • brown eye color requires phenylalanine from diet to produce melanin pigment

40. Alleles at the Population Level • Dominance and recessiveness of allele do not determine frequency in a population • Some recessive alleles, blood type O, are the most common • Some dominant alleles, polydactyly and blood type AB, are rare

41. Cancer • Tumors (neoplasms) • abnormal growth, cells multiply faster than they die • oncology = study of tumors • Benign • connective tissue capsule, slow growth, stays local • potentially lethal by compression of vital tissues • Malignant tumor = cancer • unencapsulated, fast growing, metastatic (spreading), stimulate angiogenesis

42. Causes of Cancer • Carcinogens - estimates of 60 - 70% of cancers from environmental agents • chemical = cigarette tar, food preservatives, industrial chemicals • radiation • Viruses = type 2 herpes simplex - uterus, hepatitis C - liver

43. Carcinogens (Mutagens) • Trigger gene mutations • cell may die, be destroyed by immune system or produce a tumor • Defenses against mutagens and tumors • scavenger cells - remove mutagens • peroxisomes - neutralize mutagens • nuclear enzymes - repair damaged DNA • macrophages and monocytes secrete tumor necrosis factor (TNF) - destroys tumors • natural killer cells destroy malignant cells during immune surveillance

44. Malignant Tumor Genes • Oncogenes • mutated form of normal growth factor genes called proto-oncogenes • sis oncogene causes excessive production of growth factors • ras oncogene codes for abnormal growth factor receptors • Tumor suppressor genes • inhibit development of cancer • damage to one or both removes control of cell division

45. Effects of Malignancies • Displaces normal tissue and organ function deteriorates • cell growth of immature nonfunctional cells • Block vital passageways • block air flow or rupture blood vessels • Diverts nutrients from healthy tissues • tumors have high metabolic rates • causes weakness, fatigue, emaciation, susceptibility to infection • cachexia is extreme wasting away of muscle and adipose tissue