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Chapter 4

Human Genetics

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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

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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.

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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

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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

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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

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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

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Alternative Splicing of mRNA

• One gene can code for more than one protein

• Exons can be spliced together into a variety of different mRNAs.

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Translation of mRNA

• mRNA begins with leader sequence– binding site for ribosome

• Start codon AUG

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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

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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

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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

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DNA and Peptide Formation

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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

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DNA Replication 1

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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

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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

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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

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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

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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

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Mitosis

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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.

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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

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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)

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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

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Mitosis: Telophase

• New nuclear envelopes formed by rough ER

• Chromatids uncoil into chromatin

• Mitotic spindle breaks down

• Nucleus forms nucleoli

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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

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Timing of Cell DivisionCells divide when:• Have enough cytoplasm for 2 daughter

cells• DNA replicated• Adequate supply of nutrients• Growth factor stimulation• Open space due to neighboring cell deathCells stop dividing when:• Loss of growth factors or nutrients• Contact inhibition

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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

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Karyotype of Normal Male

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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

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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

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Genetics of Earlobes

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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

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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

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Polygenic Inheritance

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

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Pleiotropy

• One gene produces multiple phenotypic effects– Alkaptonuria = mutation that blocks the

breakdown of tyrosine

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Sex-Linked Inheritance

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

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Penetrance and Environmental Effects

• Penetrance– % of population

expressing predicted phenotype

• Role of environment– brown eye color

requires phenylalanine from diet to produce melanin pigment

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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

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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

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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

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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

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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

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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