1. Biology – Premed Windsor University School of Medicine and Health Sciences
DR. UCHE AMAEFUNA

2. THERE ARE MORE TO LECTURES THAN SLIDES………

3. There is more to lectures than the power point slides!
Pre Med – Biology Genetic Review Autosomal Dominant, Autosomal Recessive & Sex-linked Disorders and Pedigrees
There is more to lectures than the power point slides!
Engage your mind

4. What is the difference between an Autosome and a Sex-chromosome?
Autosomes are the first 22 homologous pairs of human chromosomes that do not influence the sex of an individual.
Sex Chromosomes are the 23rd pair of chromosomes that determine the sex of an individual.

5. Autosomal Traits
Genes located on Autosomes control Autosomal traits and disorders.
2 Types of Traits:
Autosomal Dominant
Autosomal Recessive

6. Autosomal Dominant Traits
If dominant allele is present on the autosome, then the individual will express the trait.
A = dominant a = recessive
What would be the genotype of an individual with an autosomal dominant trait?
AA and Aa (Heterozygotes are affected)
What would be the genotype of an individual without the autosomal dominant trait? aa

7. Autosomal Recessive Traits
If dominant allele is present on the autosome, then the individual will not express the trait. In order to express the trait, two recessive alleles must be present.
A = dominant a = recessive
What would be the genotype of an individual with an autosomal recessive trait? aa
What would be the genotype of an individual without the autosomal recessive trait?
AA or Aa
Aa – called a Carrier because they carry the recessive allele and can pass it on to offspring, but they do not express the trait.

8. Sex-Linked Traits
Sex-linked traits are produced by genes only on the X chromosome.
They can be Dominant or Recessive.
A = dominant a = recessive
What would be the genotypes of a male and female that have a Sex-linked Dominant trait and do not express the trait?
Expresses Trait: Male - XA Y Female - XA XA or XA Xa
No Expression: Male - Xa Y Female - Xa Xa
What would be the genotypes of a male and female that have a Sex-linked Recessive trait and do not express the trait?
Expresses Trait: Male - Xa Y Female - Xa Xa
No Expression: Male - XA Y Female - XA XA or XA Xa
(Carrier)
Most Sex-linked traits are Recessive!

9. Genetic Counselor Activity
Imagine that you are a Genetic Counselor assigned to family to discuss with them the possibility of their child inheriting a genetic disorder.
You are given the family history and whether or not the disorder is Autosomal Dominant or Autosomal Recessive.
Draw Punnett Squares to determine odds of children inheriting the disease and answer the questions on the worksheet.

10. Punnett Square If male & female are heterozygous for eye color maleX
brown: 3/4 offspring
blue: 1/4 offspring

11. How to Construct a Pedigree?
A Pedigree is a visual showing the pattern of inheritance for a trait. (Family tree)
Symbols and Rules:
Male = Female =
Affected = Unaffected = Carrier =
Link parents together with a line and then make a vertical line to connect to offspring.

12. Autosomal Dominant Pedigree
Draw a Pedigree showing a cross between Heterozygous parents that have 2 boys and 2 girls. (Show all possibilities)
Genotypes of Affected and Unaffected:
AA and Aa = Affected aa = Unaffected Aa AA aa

13. Autosomal Recessive Pedigree
Draw a Pedigree showing a cross between Heterozygous parents that have 2 boys and 2 girls. (Show all possibilities)
Genotypes of Affected and Unaffected:
AA=Unaffected Aa=Carrier, Unaffected aa=Affected Aa AA aa

14. Sex-Linked Recessive Pedigree
Draw a Pedigree showing a cross between a Red eyed Male fruit fly and a Carrier Female fruit fly which have 2 males and 2 females. (Show all possibilities) Red is dominant to white.
Genotypes of Parents:
Male = XR Y Female = XR Xr
XRY
XRXr
XrY
XRXR

15. Characteristics of Autosomal Dominant, Autosomal Recessive, and Sex-linked Recessive Traits
In groups, analyze your notes on each type of disorder and examine the pedigrees.
Come up with rules/characteristics for each type of Trait.

16. Autosomal Dominant Traits
Heterozygotes are affected
Affected children usually have affected parents.
Two affected parents can produce an unaffected child. (Aa x Aa)
Two unaffected parents will not produce affected children. (aa x aa)
Both males and females are affected with equal frequency.
Pedigrees show no Carriers.

17. Autosomal Recessive Traits
Heterozygotes are Carriers with a normal phenotype.
Most affected children have normal parents. (Aa x Aa)
Two affected parents will always produce an affected child. (aa x aa)
Two unaffected parents will not produce affected children unless both are Carriers. (AA x AA, AA x Aa)
Affected individuals with homozygous unaffected mates will have unaffected children. (aa x AA)
Close relatives who reproduce are more likely to have affected children.
Both males and females are affected with equal frequency.
Pedigrees show both male and female carriers.

18. Sex-Linked Recessive Traits
More males than females are affected.
An affected son can have parents who have the normal phenotype. (XAY x XAXa)
For a daughter to have the trait, her father must also have it. Her mother must have it or be a carrier (XaY, XaXa, XAXa)
The trait often skips a generation from the grandfather to the grandson.
If a woman has the trait (XaXa), all of her sons will be affected.
Pedigrees show only female carriers but no male carriers.

19. Examples of Autosomal Dominant Disorders
Dwarfism
Polydactyly and Syndactyly
Hypertension
Hereditary Edema
Chronic Simple Glaucoma – Drainage system for fluid in the eye does not work and pressure builds up, leading to damage of the optic nerve which can result in blindness.
Huntington’s Disease – Nervous system degeneration resulting in certain and early death. Onset in middle age.
Neurofibromatosis – Benign tumors in skin or deeper
Familial Hypercholesterolemia – High blood cholesterol and propensity for heart disease
Progeria – Drastic premature aging, rare, die by age 13. Symptoms include limited growth, alopecia, small face and jaw, wrinkled skin, atherosclerosis, and cardiovascular problems but mental development not affected.

20. Examples of Autosomal Recessive Disorders
Congenital Deafness
Diabetes Mellitus
Sickle Cell anemia
Albinism
Phenylketoneuria (PKU) – Inability to break down the amino acid phenylalanine. Requires elimination of this amino acid from the diet or results in serious mental retardation.
Galactosemia – enlarged liver, kidney failure, brain and eye damage because can’t digest milk sugar
Cystic Fibrosis – affects mucus and sweat glands, thick mucus in lungs and digestive tract that interferes with gas exchange, lethal.
Tay Sachs Disease – Nervous system destruction due to lack of enzyme needed to break down lipids necessary for normal brain function. Early onset and common in Ashkenazi Jews; results in blindness, seizures, paralysis, and early death.

21. Examples of Sex-Linked Recessive Disorders
Red/Green Colorblindness – Difficulty perceiving differences between colors (red or green, blue or yellow).
Hemophilia – Absence of one or more proteins necessary for normal blood clotting.
Deafness
Cataracts – opacity in the lens that can lead to blindness
Night blindness – (Nyctalopia) rods do not work so that can not see in the dark
Glaucoma – pressure in the eye that can lead to optic nerve damage and blindness
Duchenne Muscular Dystrophy – progressive weakness and degeneration of skeletal muscles that control movement due to absence of dystrophin (protein that maintains muscle integrity). Mainly in boys, onset 3-5 yrs, by 12 years can’t walk, and later needs respirator.

22. Genetic Mutations: Chromosomal

23. What are Chromosomal Mutations?
Damage to chromosomes due to physical or chemical disturbances or errors during meiosis.
Two Types of Chromosome Mutations:
Chromosome Structure
Chromosome Number

24. Problems with Chromosome Structure:
Deletion – during cell division, especially meiosis, a piece of the chromosome breaks off, may be an end piece or a middle piece (when two breaks in a chromosome occur).
Inversion – a segment of the chromosome is turned 180°, same gene but opposite position
Translocation – movement of a chromosome segment from one chromosome to a non-homologous chromosome
Duplication – a doubling of a chromosome segment because of attaching a broken piec form a homologous chromosome, or by unequal crossing over.

25. Problems with Chromosome Number
Monosomy – only one of a particular type of chromosome (2n -1)
Trisomy – having three of a particular type of chromosome (2n + 1)
Polyploidy – having more than two sets of chromosomes; triploids (3n = 3 of each type of chromosome), tetraploids (4n = 4 of each type of chromosome).

26. How do you think Chromosomal Mutations with differing number of chromosomes develops?
Monosomy and Trisomy due to Nondisjunction – members of homologous chromosomes do not move apart in Meiosis I or sister chromatids do not separate during Meiosis II leaves one cell with too few chromosomes and one cell with too many.
Triploids develop from the fertilization of an abnormal diploid egg, produced from the nondisjunction of all chromosomes. Tetraploids develop from the failure of a 2n zygote to divide after replicating its chromosomes, subsequent mitosis would produce 4n embryo.
Polyploidy is common in the plant kingdom, spontaneous origin of polyploid individuals plays important role in evolution of plants. In the animal kingdom, natural occurrence of polyploids is extremely rare. In general, polyploids are more nearly normal in appearance than having monosomy or trisomy, which is more disruptive to have one extra chromosome in a pair.

27. Genotypes Phenotypes
At each locus (except for sex chromosomes) there are 2 genes. These constitute the individual’s genotype at the locus.
The expression of a genotype is termed a phenotype. For example, hair color, weight, or the presence or absence of a disease.

28. Genotypes Phenotypes (example)
Eb- dominant allele.
Ew- recessive allele.

29. Dominant vs. Recessive
A dominant allele is expressed even if it is paired with a recessive allele.
A recessive allele is only visible when paired with another recessive allele.

30. Mendel’s 1st Law Mendel’s 2nd Law
Two members of a gene pair segregate from each other into
the gametes, so half the gametes carry one member of the
pair and the other half carry the other member of the pair.
Mendel’s 2nd Law
Different gene pairs assort independently
in gamete formation.
This “law” is true only in some cases.
Gene pairs on SEPARATE CHROMOSOMES
assort independently at meiosis.

31. X-linked Inheritance
Different results obtained from reciprocal crosses between red-eyed and white-eyed Drosophila.
Explanation: The gene
responsible for eye-color
is X-linked. Females have
2 X-chromosomes, while
males have 1 X-chromosome
and 1 Y-chromosome.

32. Medical Genetics
When studying rare disorders, 6 general patterns of inheritance are observed:
Autosomal recessive
Autosomal dominant
X-linked recessive
X-linked dominant
Codominant
Mitochondrial

33. Medical Genetics (cont.)
Autosomal recessive
The disease appears in male and female children of unaffected parents.
e.g., cystic fibrosis

34. Medical Genetics (cont.)
Autosomal dominant
Affected males and females appear in each generation of the pedigree.
Affected mothers and fathers transmit the phenotype to both sons and daughters.
e.g., Huntington disease.

35. Medical Genetics (cont.)
X-linked recessive
Many more males than females show the disorder.
All the daughters of an affected male are “carriers”.
None of the sons of an affected male show the disorder or are carriers.
e.g., hemophilia

36. Medical Genetics (cont.)
X-linked dominant
Affected males pass the disorder to all daughters but to none of their sons.
Affected heterozygous females married to unaffected males pass the condition to half their sons and daughters
e.g. fragile X syndrome

37. Medical Genetics (cont.)
Co-dominant inheritance
Two different versions (alleles) of a gene can be expressed, and each version makes a slightly different protein
Both alleles influence the genetic trait or determine the characteristics of the genetic condition.
E.g. ABO locus

38. Medical Genetics (cont.)
Mitochondrial inheritance
This type of inheritance applies to genes in mitochondrial DNA
Mitochondrial disorders can appear in every generation of a family and can affect both males and females, but fathers do not pass mitochondrial traits to their children.
E.g. Leber's hereditary optic neuropathy (LHON)

39. Question #1 Write the genotypes in every possible place.2
Write the genotypes in every possible place.
If individuals 1 and 2 marry, what is the probability that
their first child will be sick?

40. Question #2
PKU is a human hereditary disease resulting from inability of the body to process the Amino Acid phenylalanine (contained in protein that we eat).
It is caused by a recessive allele with simple Mendelian inheritance.
Some couple wants to have children. The man has a sister with PKU and the woman has a brother with PKU. There are no other known cases in their families.
What is the probability that their first child will have PKU ?

41. Question #2-Solution Highlights
P/p
p/p
P/-
P – the normal allele
p – the mutant allele

42. Question #3 1 2 3 4 5 6 7 8 9 10 The disease is rare.
What is the most likely mode of inheritance ?
What would be the outcomes of the cousin marriages
1 x 9, 1 x 4, 2 x 3, and 2 x 8 ?

43. Question #3-Solution Highlights
Observations:
After the disease is introduced into the family in generation #2, it appears in every generation  dominant!
Fathers do not transmit the phenotype to their sons 
X-linked!
The outcomes:
1 x 9: 1 must be A/a
9 must be A/Y
1 x 4: 1 must be A/a
4 must be a/Y
2 x 3: 2 must be a/Y
3 must be A/a
2 x 8: 2 must be a/Y
8 must be a/a
Same
All normal

44. Notes
Cystic fibrosis – disease affecting the mucus lining of the lungs, leading to breathing problems and other difficulties
Huntington disease - or Huntington's chorea is an inherited disorder characterized by abnormal body movements called chorea, and loss of memory. There also is evidence that doctors as far back as the Middle Ages knew of this devastating disease. The incidence is 5 to 8 per 100,000. It takes its name from the New York physician George Huntington who first described it precisely in 1872.

45. Notes
Hemophilia-illness that impair the body's ability to control bleeding.
Fragile X syndrome - is a genetic condition that causes a range of developmental problems including learning disabilities and mental retardation. Usually males are more severely affected by this disorder than females. In addition to learning difficulties, affected males tend to be restless, fidgety, and inattentive. Affected males also have characteristic physical features that become more apparent with age.

46. Notes -cont
DNA - a pair of molecules joined by hydrogen bonds: it is organized as two complementary strands, head-to-toe, with the hydrogen bonds between them. Each strand of DNA is a chain of chemical "building blocks", called nucleotides, of which there are four types:adenide (abbreviated A), cytozyne (C), guanine (G) and thymine (T).
Mitochondria, which are structures in each cell that convert molecules into energy, each contain a small amount of DNA.
A chromatid forms one part of a chromosome after it has coalesced for the process of mitosis or meiosis. During either process, the word "chromosome" indicates a pair of two exactly identical ("sister") chromatids joined at the central point of each chromatid, called the centromere.

47. Notes -cont
Mitosis is the process by which a cell separates its duplicated genome into two identical halves
Meiosis is the process that transforms one diploid into four haploid cells.
Reciprocal cross a cross, with the phenotype of each sex reversed as compared with the original cross, to test the role of parental sex on inheritance pattern. A pair of crosses of the type genotype A(female) X genotype B(male) and genotype B(female) X genotype A(male).

48. Genetic Disorders

49. What Are Mutations? Changes in the nucleotide sequence of DNA
May occur in somatic cells (aren’t passed to offspring)
May occur in gametes (eggs & sperm) and be passed to offspring

50. Are Mutations Helpful or Harmful?
Mutations happen regularly
Almost all mutations are neutral
Chemicals & UV radiation cause mutations
Many mutations are repaired by enzymes

51. Are Mutations Helpful or Harmful?
Some type of skin cancers and leukemia result from somatic mutations
Some mutations may improve an organism’s survival (beneficial)

52. Types of Mutations

53. Chromosome Mutations May Involve:
Changing the structure of a chromosome
The loss or gain of part of a chromosome

54. Chromosome Mutations Five types exist: Deletion Inversion
Translocation
Nondisjunction
Duplication

55. Deletion
Due to breakage
A piece of a chromosome is lost

56. Inversion Chromosome segment breaks off Segment flips around backwards
Segment reattaches

57. Duplication
Occurs when a gene sequence is repeated

58. Translocation Involves two chromosomes that aren’t homologous
Part of one chromosome is transferred to another chromosomes

59. Translocation

60. Nondisjunction Failure of chromosomes to separate during meiosis
Causes gamete to have too many or too few chromosomes
Disorders:
Down Syndrome – three 21st chromosomes
Turner Syndrome – single X chromosome
Klinefelter’s Syndrome – XXY chromosomes

62. Chromosome Mutation Animation

64. Gene Mutations Change in the nucleotide sequence of a gene
May only involve a single nucleotide
May be due to copying errors, chemicals, viruses, etc.

65. Types of Gene Mutations
Include:
Point Mutations
Substitutions
Insertions
Deletions
Frameshift

66. Point Mutation Change of a single nucleotide
Includes the deletion, insertion, or substitution of ONE nucleotide in a gene

67. Point Mutation
Sickle Cell disease is the result of one nucleotide substitution
Occurs in the hemoglobin gene

68. Frameshift Mutation Inserting or deleting one or more nucleotides
Changes the “reading frame” like changing a sentence
Proteins built incorrectly

69. Frameshift Mutation Original: The fat cat ate the wee rat.
Frame Shift (“a” added):
The fat caa tet hew eer at.

70. Amino Acid Sequence Changed

71. Mutations
Gene mutations can be either inherited from a parent or acquired. A hereditary mutation is a mistake that is present in the DNA of virtually all body cells. Hereditary mutations are also called germ line mutations because the gene change exists in the reproductive cells and can be passed from generation to generation, from parent to newborn. Moreover, the mutation is copied every time body cells divide

72. Mutations occur all the time in every cell in the body
Mutations occur all the time in every cell in the body. Each cell, however, has the remarkable ability to recognize mistakes and fix them before it passes them along to its descendants. But a cell's DNA repair mechanisms can fail, or be overwhelmed, or become less efficient with age. Over time, mistakes can accumulate.

73. nondisjunction at anaphase I
chromosome alignments at metaphase I
n - 1
nondisjunction at anaphase I
alignments at metaphase II
anaphase II

74. Down’s Syndrome Caused by non-disjunction of the 21st chromosome.
This means that the individual has a trisomy (3 – 2lst chromosomes).

75. Down’s Syndrome or Trisomy 21

77. Symptoms of Down Syndrome
Upward slant to eyes.
Small ears that fold over at the top.
Small, flattened nose.
Small mouth, making tongue appear large.
Short neck.
Small hands with short fingers.

78. Symptoms of Down Syndrome
Low muscle tone.
Single deep crease across center of palm.
Looseness of joints.
Small skin folds at the inner corners of the eyes.
Excessive space between first and second toe.
In addition, down syndrome always involves some degree of mental retardation, from mild to severe. In most cases, the mental retardation is mild to moderate.

79. Kleinfelter’s syndrome (or Klinefleter’s)
Disorder occurring due to nondisjunction of the X chromosome.
The Sperm containing both X and Y combines with an egg containing the X, results in a male child.
The egg may contribute the extra X chromosome.

80. XXY
Males with some development of breast tissue normally seen in females.
Little body hair is present, and such person are typically tall, have small testes.
Infertility results from absent sperm.
Evidence of mental retardation may or may not be present.

82. Klinefleter’s

83. Turner’s
Turner syndrome is associated with underdeveloped ovaries, short stature, webbed, and is only in women.
Bull neck, and broad chest. Individuals are sterile, and lack expected secondary sexual characteristics.
Mental retardation typically not evident.
Chromosomal or monogenic?

84. Turner’s Syndrome

85. Sickle Cell Anemia
An inherited, chronic disease in which the red blood cells, normally disc-shaped, become crescent shaped. As a result, they function abnormally and cause small blood clots. These clots give rise to recurrent painful episodes called "sickle cell pain crises".

86. Sickle Cell
Sickle cell disease is most commonly found in African American populations. 
This disease was discovered over 80 years ago, but has not been given the attention it deserves.

87. Cystic Fibrosis (CF) Monogenic
Cause: deletion of only 3 bases on chromosome 7
Fluid in lungs, potential respiratory failure
Common among Caucasians…1 in 20 are carriers
Therefore is it dominant or recessive?

88. Tay-Sachs disease Monogenic, autosomal recessive
Central nervous system degrades, ultimately causing death.
Most common among people of Jewish, eastern Europe descent.

89. Muscular Dystrophy
What Is Muscular Dystrophy? Muscular dystrophy is a disease in which the muscles of the body get weaker and weaker and slowly stop working because of a lack of a certain protein (see the relationship to genetics?)
Can be passed on by one or both parents, depending on the form of MD (therefore is autosomal dominant and recessive)

90. Hemophilia, the royal disease
Hemophilia is the oldest known hereditary bleeding disorder.
Caused by a recessive gene on the X chromosome.
There are about 20,000 hemophilia patients in the United States.
One can bleed to death with small cuts.
The severity of hemophilia is related to the amount of the clotting factor in the blood. About 70% of hemophilia patients have less than one percent of the normal amount and, thus, have severe hemophilia.

91. X-linked Inheritance pedigree chart

92. Huntington’s Disease
Huntington's disease (HD) is an inherited, degenerative brain disorder which results in an eventual loss of both mental and physical control. The disease is also known as Huntington's chorea. Chorea means "dance-like movements" and refers to the uncontrolled motions often associated with the disease.

95. Huntington’s
Looking back at the pedigree chart is Huntington’s dominant or recessive?
Scientists have discovered that the abnormal protein produced by the Huntington's disease gene, which contains an elongated stretch of amino acids called glutamines, binds more tightly to HAP-1 than the normal protein does.

96. Phenylketonuria or PKU
People with PKU cannot consume any product that contains aspartame.
PKU is a metabolic disorder that results when the PKU gene is inherited from both parents (recessive or dominant?)
Caused by a deficiency of an enzyme which is necessary for proper metabolism of an amino acid called phenylalanine.

97. PKU
Phenylalanine is an essential amino acid and is found in nearly all foods which contain protein, dairy products, nuts, beans, tofu… etc.
A low protein diet must be followed.
Brain damage can result if the diet is not followed causing mental retardation…and mousy body odor (phenylacetic acid is in sweat).

98. PKU

99. Phenylalanine. Free diet

100. ALS (Amyotrophic Lateral Sclerosis, or Lou Gehrig’s disease)
the disease strikes people between the ages of 40 and 70, and as many as 30,000 Americans have the disease at any given time
This monogenic mutation is believed to make a defective protein that is toxic to motor nerve cells.
A common first symptom is a painless weakness in a hand, foot, arm or leg, other early symptoms include speech swallowing or walking difficulty

101. Adenoleukodystrophy (ALD)
ALD is a rare, inherited metabolic disorder that afflicts the young boy Lorenzo Odone, whose story is told in the 1993 film 'Lorenzo's oil'. In this disease the fatty covering (myelin sheath) on nerve fibers in the brain is lost, and the adrenal gland degenerates, leading to progressive neurological disability and death.

102. Diabetes Disease in which the body does
not produce or properly use insulin.
Insulin is a hormone that is needed to convert sugar, starches, and other food into energy needed for daily life.
Genetic mutation can lead to Type 1 diabetes, but no one sure if relative to a specific gene

103. Diabetes Warning signs
Type 1 reveals itself in childhood, Type 2 can be made worse from excessive lifestyle
Warning signs
Extreme thirst
Blurry vision from time to time
Frequent urination
Unusual fatigue or drowsiness
Unexplained weight loss
Diabetes is the leading cause of kidney failure, blindness, and amputation in adults, and can also lead to heart disease.

104. Color Blindness Cause: x-linked recessive
1/10 males have, 1/100 females have. Why the difference?
Individuals are unable to distinguish shades of red-green.
Are you color blind?
                                          

106. Albinism
Patients are unable to produce skin or eye pigments, and thus are light-sensitive
Autosomal recessive

107. Genetic Screening
Large-scale screening programs detect affected persons
Newborns in United States routinely tested for PKU
Early detection allows dietary intervention and prevents brain impairment

108. Prenatal Diagnosis Amniocentesis Chorionic villus sampling Fetoscopy
All methods have some risks

109. Prenatal Diagnosis
Amniocentesis
Chorionic villus sampling

110. The Genetic Code

111. The Genetic Code: How many code words (codons)
The Genetic Code: How many code words (codons)? [43 = 64 codons of 3 bases each (all are used)]
Arg = CG(N)
(Start) AUG

112. Genetic Code Consists of a triplet code
That is, a sequence of three bases codes for a particular amino acid.
There are 43, or 64 possible combinations
A group of 3 bases coding for an amino acid in mRNA is called a codon

113. Genetic Code
Degenerate: an amino acid can be coded for by more than one codon
Unambiguous: each condon indicates a single, specific amino acid
Non-overlapping: when translated, the "reading frame" is advanced 3 bases at a time
61 codons are for amino acids, and the remaining three are "stop codons" that terminate the polypeptide

114. GATCTACCATGAAAGACTTGTGAATCCAGGAAGAGAGACTGACTGGGCAACATGTTATTCAGGTACAAAAAGATTTGGACTGTAACTTAAAAATGATCAAATTATGTTTCCCATGCATCAGGTGCAATGGGAAGCTCTTCTGGAGAGTGAGAGAAGCTTCCAGTTAAGGTGACATTGAAGCCAAGTCCTGAAAGATGAGGAAGAGTTGTATGAGAGTGGGGAGGGAAGGGGGAGGTGGAGGGATGGGGAATGGGCCGGGATGGGATAGCGCAAACTGCCCGGGAAGGGAAACCAGCACTGTACAGACCTGAACAACGAAGATGGCATATTTTGTTCAGGGAATGGTGAATTAAGTGTGGCAGGAATGCTTTGTAGACACAGTAATTTGCTTGTATGGAATTTTGCCTGAGAGACCTCATTGCAGTTTCTGATTTTTTGATGTCTTCATCCATCACTGTCCTTGTCAAATAGTTTGGAACAGGTATAATGATCACAATAACCCCAAGCATAATATTTCGTTAATTCTCACAGAATCACATATAGGTGCCACAGTTATCCCCATTTTATGAATGGAGTTheGeneticBasisofHumanVariationGATGAAAACCTTAGGAATAATGAATGATTTGCGCAGGCTCACCTGGATATTAAGACTGAGTCAAATGTTGGGTCTGGTCTGACTTTAATGTTTGCTTTGTTCATGAGCACCACATATTGCCTCTCCTATGCAGTTAAGCAGGTAGGTGACAGAAAAGCCCATGTTTGTCTCTACTCACACACTTCCGACTGAATGTATGTATGGAGTTTCTACACCAGATTCTTCAGTGCTCTGGATATTAACTGGGTATCCCATGACTTTATTCTGACACTACCTGGACCTTGTCAAATAGTTTGGACCTTGTCAAATAGTTTGGAGTCCTTGTCAAATAGTTTGGGGTTAGCACAGACCCCACAAGTTAGGGGCTCAGTCCCACGAGGCCATCCTCACTTCAGATGACAATGGCAAGTCCTAAGTTGTCACCATACTTTTGACCAACCTGTTACCAATCGGGGGTTCCCGTAACTGTCTTCTTGGGTTTAATAATTTGCTAGAACAGTTTACGGAACTCAGAAAAACAGTTTATTTTCTTTTTTTCTGAGAGAGAGGGTCTTATTTTGTTGCCCAGGCTGGTGTGCAATGGTGCAGTCATAGCTCATTGCAGCCTTGATTGTCTGGGTTCCAGTGGTTCTCCCACCTCAGCCTCCCTAGTAGCTGAGACTACATGCCTGCACCACCACATCTGGCTAGTTTCTTTTATTTTTTGTATAGATGGGGTCTTGTTGTGTTGGCCAGGCTGGCCACAAATTCCTGGTCTCAAGTGATCCTCCCACCTCAGCCTCTGAAAGTGCTGGGATTACAGATGTGAGCCACCACATCTGGCCAGTTCATTTCCTATTACTGGTTCATTGTGAAGGATACATCTCAGAAACAGTCAATGAAAGAGACGTGCATGCTGGATGCAGTGGCTCATGCCTGTAATCTCAGCACTTTGGGAGGCCAAGGTGGGAGGATCGCTTAAACTCAGGAGTTTGAGACCAGCCTGGGCAACATGGTGAAAACCTGTCTCTATAAAAAATTAAAAAATAATAATAATAACTGGTGTGGTGTTGTGCACCTAGAGTTCCAACTACTAGGGAAGCTGAGATGAGAGGATACCTTGAGCTGGGGACTGGGGAGGCTTAGGTTACAGTAAGCTGAGATTGTGCCACTGCACTCCAGCTTGGACAAAAGAGCCTGATCCTGTCTCAAAAAAAAGAAAGATACCCAGGGTCCACAGGCACAGCTCCATCGTTACAATGGCCTCTTTAGACCCAGCTCCTGCCTCCCAGCCTTCT

115. Whose genome was sequenced?
International Human Genome Sequencing Consortium
The human genome reference sequence does not represent an exact match for any one person's genome.
The draft genome is composed of the DNA of an estimated 10 to 20
anonymous individuals across different racial and ethnic groups.

116. The Genetic Basis for Human Variation
Frequency
Example
Rules for assigning allele to class
Class of variation
5,692,700
(~93%)
A/T
Single base substitution involving A,T,C, or G
Single Nucleotide Polymorphism (SNP)
431,319
(~7%)
T/-CCTA/G
Designated using the full sequence of the insertion as one allele, and either a fully defined string for the variant allele or a “-” character to specify the
deleted allele.
Deletion/Insertion Polymorphisms (DIPs)
2,440 (0.04%)
(CAC)8/9/10/11
Alleles are designated by providing the repeat motif and the copy number for each allele.
Microsatellite or short tandem repeat (STR)
1,859
(0.03%)
(alu) / -
Applies to insertion/deletion polymorphisms of longer sequence features, such as retroposon dimorphism for Alu or line elements.
Named variant

117. Any 2 human genomes are roughly 99.9% identical
On average ~ 0.1%
Chr - chromosome
n - Number of samples examined
bp - Number of basepairs sequences
S - Number of polymorphic sites
p - Nucleotide divergence
Przeworski, M., et al. (2000) Trends Genet 16,

118. Molecular Biology of Inheritance
DNA Is the Genetic Material
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119. DNA is a transforming substance
During the late 1920s, the bacteriologist Frederick Griffith was attempting to develop a vaccine against Streptococcus pneumoniae (pneumococcus)
Griffith’s transformation experiment

120. DNA, not protein, is the genetic material
Hershey and Chase Experiment
In their experiment, Hershey and Chase relied on a chemical difference between DNA and protein to solve whether DNA or protein was the genetic material
Structure of the virus (T2 bacteriophage) used by Hershey and Chase

121. Hershey and Chase experiment I

122. Hershey and Chase experiment II

123. DNA and RNA are polymers of nucleotides
Nucleic acids contain only nucleotides, molecules that are composed of a nitrogen-containing base, a phosphate, and a pentose
(5-carbon sugar)
DNA (deoxyribonucleic acid) contains the
5-carbon sugar deoxyribose
DNA contains four nucleotides with different bases
Adenine, Guanine, Thymine, and Cytosine

124. DNA is a polynucleotide—contains many nucleotides

125. The four bases in DNA nucleotides

126. RNA RNA (ribonucleic acid) another polymer of nucleotides
RNA differs from DNA
Has ribose as a sugar, not deoxyribose
Has uracil in place of thymine
The uracil nucleotide in RNA replaces thymine in DNA

127. DNA meets the criteria for the genetic material
The genetic material must be:
Variable between species and able to store information that causes species to vary from one another
Constant within a species and able to be replicated with high fidelity during cell division
Able to undergo rare changes, called mutations, that provide the genetic variability that allows evolution to occur

128. Complementary base pairing

129. DNA is a Double Helix
The double helix suggests that the stability and variability of the molecule is in the sequence of bases
X-ray diffraction of DNA

130. The Watson and Crick model of DNA

131. DNA replication is semi-conservative
DNA replication - the process of copying a DNA molecule
Replication requires the following steps:
Unwinding: Old strands are unwound and “unzipped”
Complementary base pairing: New complementary nucleotides are positioned by the process of base pairing
Joining: Complementary nucleotides join to form new strands
Each daughter DNA molecule contains a template strand, or old strand, and a new strand
Steps 2 and 3 are carried out by DNA polymerase

132. Semi-conservative replication (simplified)

133. Many different proteins help DNA replicate
DNA replication (in depth)

134. Genes are linked to proteins
Chemical basis of sickle-cell disease in humans

135. The making of a protein requires transcription and translation
Gene - segment of DNA that specifies the amino acid sequence of a protein
During transcription DNA serves as a template for RNA formation
DNA is transcribed, monomer by monomer, into RNA
During translation an RNA transcript directs the sequence of amino acids in a polypeptide

136. Genetic code
1966
The Genetic code was discovered; scientists are now able to predict characteristics by studying DNA. This leads to genetic engineering, genetic counseling.

137. Overview of gene expression

138. The genetic code for amino acids is a triplet code
Genetic code - sequence of nucleotides in DNA specifies the order of amino acids in a polypeptide
Codon - three base sequence corresponding to a specific amino acid
Important properties of the genetic code:
The genetic code is degenerate
The genetic code is unambiguous
The code has start and stop signals

139. RNA Codons

140. During transcription, a gene passes its coded information to an mRNA
messenger RNA (mRNA) - takes instructions from DNA in the nucleus to the ribosomes in the cytoplasm
RNA polymerase joins the nucleotides together
Promoter defines the start of a gene, the direction of transcription, and the strand to be transcribed
Stop sequence causes RNA polymerase to stop transcribing the DNA and to release the mRNA molecule, called an mRNA transcript

141. Transcription: synthesis of RNA

142. In eukaryotes, an mRNA is processed before leaving the nucleus
Primary mRNA is composed of exons and introns
The exons of mRNA will be expressed, but the introns will not
Function of Introns
Might allow exons to be put together in different sequences so that various mRNAs and proteins can result from a single gene
Some introns might regulate gene expression by feeding back to determine which coding genes are to be expressed and how they should be spliced

143. During translation, each transfer RNA carries a particular amino acid
transfer RNA (tRNA) molecules transfer amino acids to the ribosomes
Anticodon - a group of three bases that is complementary to a specific codon of mRNA at a ribosome
Wobble hypothesis - the first two positions in a tRNA anticodon pair obey the A–U/G–C configuration, but the third position can be variable
Helps ensure that, despite changes in DNA base sequences, the correct sequence of amino acids will result in a protein

144. Cloverleaf model of tRNA

145. Space-filling model of tRNA molecule

146. Translation occurs at ribosomes in cytoplasm
ribosomal RNA (rRNA) is produced from a DNA template in the nucleolus of a nucleus
Polyribosome - several ribosomes are often attached to and translating the same mRNA

147. Ribosome structure and function

148. 10.15 Initiation begins the process of polypeptide production
Initiation - the step that brings all the translation components together
Figure Initiation

149. Elongation builds a polypeptide one amino acid at a time
Elongation - a polypeptide increases in length one amino acid at a time
Elongation cycle

150. Let’s review gene expression

152. Mutations affect genetic information and expression
Genetic mutation - a permanent change in the sequence of bases in DNA
Point mutations - a change in a single DNA nucleotide and, therefore, a change in a specific codon
Frameshift mutations occur when one or more nucleotides are either inserted or deleted from DNA

153. Types of point mutations

154. Many agents can cause mutations
Some mutations are spontaneous while others are due to environmental mutagens
Environmental Mutagens
Mutagen - an environmental agent that increases the chances of a mutation
Carcinogens - cancer-causing agents
Tobacco smoke contains a number of organic chemicals that are known carcinogens

155. Transposons are “jumping genes”
Transposons have the following effects:
Are involved in transcriptional control because they block transcription
Can carry a copy of host genes when they jump and can be a source of chromosomal mutations such as translocations, deletions, and inversions
Can leave copies of themselves and certain host genes before jumping and be a source of duplication
Can contain one or more genes that make a bacterium resistant to antibiotics

156. Connecting the Concepts
Using all previously collected data concerning DNA structure, Watson and Crick were able to arrive at the legendary design of DNA—a double helix
Complementary base pairing explains the replication of DNA, how RNA molecules are made
Geneticists have confirmed that proteins are the link between the genotype and the phenotype
DNA base sequence → amino acid sequence → enzyme → organism structure