1. The Molecular Basis of Inheritance
Chapter 16
The Molecular Basis of Inheritance

2. Question 1 – Who discovered the helical structure of DNA, and when?
In 1953, James Watson and Francis Crick introduced a double-helical model for the structure of deoxyribonucleic acid, or DNA
DNA, the substance of inheritance, is the most celebrated molecule of our time
Hereditary information is encoded in DNA and reproduced in all cells of the body
This DNA program directs the development of biochemical, anatomical, physiological, and (to some extent) behavioral traits
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3. DNA Francis Crick James Watson Fig. 16-1
Figure 16.1 How was the structure of DNA determined?
James Watson

4. Question 2 – What makes nucleic acids unique among all of nature’s molecules?
They are unique in their ability to direct their own replication from monomers.

5. Question 3 – What molecule was originally thought to be the genetic material?
Early in the 20th century, the identification of the molecules of inheritance loomed as a major challenge to biologists.
The two candidates were DNA and proteins, with more evidence supporting proteins initially.
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6. Question 4 – Describe the experiment performed by Frederick Griffith
Question 4 – Describe the experiment performed by Frederick Griffith. What conclusion was drawn from it?
The discovery of the genetic role of DNA began with research by Frederick Griffith in 1928
Griffith worked with two strains of a bacterium, one pathogenic (S strain) and one harmless (R strain)
When he mixed heat-killed remains of the pathogenic strain with living cells of the harmless strain, some living cells became pathogenic
He called this phenomenon transformation, now defined as a change in genotype and phenotype due to assimilation of foreign DNA
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7. EXPERIMENT RESULTS Mixture of heat-killed S cells and living R cells
Fig. 16-2
Mixture of heat-killed S cells and living R cells
EXPERIMENT
Living S cells (control)
Living R cells (control)
Heat-killed S cells (control)
RESULTS
Figure 16.2 Can a genetic trait be transferred between different bacterial strains?
Mouse dies
Mouse healthy
Mouse healthy
Mouse dies
Living S cells

8. Animation: Phage T2 Reproductive Cycle
Question 5 – Describe the experiment performed by Alfred Hershey and Martha Chase. What conclusion was drawn from this?
More evidence for DNA as the genetic material came from studies of viruses that infect bacteria
Such viruses, called bacteriophages (or phages), are widely used in molecular genetics research
Animation: Phage T2 Reproductive Cycle
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9. Phage head Tail sheath Tail fiber DNA 100 nm Bacterial cell Fig. 16-3
Figure 16.3 Viruses infecting a bacterial cell
100 nm
Bacterial
cell

10. Animation: Hershery-Chase Experiment
In 1952, Alfred Hershey and Martha Chase performed experiments showing that DNA is the genetic material of a phage known as T2
To determine the source of genetic material in the phage, they designed an experiment showing that only one of the two components of T2 (DNA or protein) enters an E. coli cell during infection
They concluded that the injected DNA of the phage provides the genetic information
Animation: Hershery-Chase Experiment
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11. EXPERIMENT Empty protein shell Radioactivity (phage protein) in liquid
Fig
EXPERIMENT
Empty protein shell
Radioactivity (phage protein) in liquid
Radioactive protein
Phage
Bacterial cell
Batch 1: radioactive sulfur (35S)
DNA
Phage DNA
Centrifuge
Radioactive DNA
Pellet (bacterial cells and contents)
Figure 16.4 Is protein or DNA the genetic material of phage T2?
Batch 2: radioactive phosphorus (32P)
Centrifuge
Radioactivity (phage DNA) in pellet
Pellet

12. Question 6 – What did Chargaff discover about the ratios of nucleotide bases in organisms?
It was known that DNA is a polymer of nucleotides, each consisting of a nitrogenous base, a sugar, and a phosphate group
In 1950, Erwin Chargaff reported that DNA composition varies from one species to the next
This evidence of diversity made DNA a more credible candidate for the genetic material
Chargaff’s rules state that in any species there is an equal number of A and T bases, and an equal number of G and C bases
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13. Sugar–phosphate backbone 5 end Sugar (deoxyribose) 3 end
Fig. 16-5
Sugar–phosphate backbone  end
Nitrogenous bases
Thymine (T)
Adenine (A)
Figure 16.5 The structure of a DNA strand
Cytosine (C)
Phosphate
DNA nucleotide
Sugar (deoxyribose)  end
Guanine (G)

14. Franklin produced a picture of the DNA molecule using this technique
Question 7 – Who was Rosalind Franklin, and what role did she play in the discovery of the structure of DNA?
After most biologists became convinced that DNA was the genetic material, the challenge was to determine how its structure accounts for its role (structure and function)
Maurice Wilkins and Rosalind Franklin were using a technique called X-ray crystallography to study molecular structure
Franklin produced a picture of the DNA molecule using this technique
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15. (b) Franklin’s X-ray diffraction photograph of DNA
Fig. 16-6
Figure 16.6 Rosalind Franklin and her X-ray diffraction photo of DNA
(a) Rosalind Franklin
(b) Franklin’s X-ray diffraction photograph of DNA

16. Animation: DNA Double Helix
Franklin’s X-ray crystallographic images of DNA enabled Watson to deduce that DNA was helical
The X-ray images also enabled Watson to deduce the width of the helix and the spacing of the nitrogenous bases
The width suggested that the DNA molecule was made up of two strands, forming a double helix
Animation: DNA Double Helix
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18. 5 end Hydrogen bond 3 end 1 nm 3.4 nm 3 end 0.34 nm 5 end
Fig. 16-7a
5 end
Hydrogen bond
3 end
1 nm
3.4 nm
Figure 16.7 The double helix
3 end
0.34 nm
5 end
(a) Key features of DNA structure
(b) Partial chemical structure

19. Watson and Crick built models of a double helix to conform to the X-rays and chemistry of DNA
Franklin had concluded that there were two antiparallel sugar-phosphate backbones, with the nitrogenous bases paired in the molecule’s interior
At first, Watson and Crick thought the bases paired like with like (A with A, and so on), but such pairings did not result in a uniform width
Instead, pairing a purine with a pyrimidine resulted in a uniform width consistent with the X-ray
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20. Purine + purine: too wide
Fig. 16-UN1
Purine + purine: too wide
Pyrimidine + pyrimidine: too narrow
Purine + pyrimidine: width consistent with X-ray data

21. Watson and Crick reasoned that the pairing was more specific, dictated by the base structures
They determined that adenine (A) paired only with thymine (T), and guanine (G) paired only with cytosine (C)
The Watson-Crick model explains Chargaff’s rules: in any organism the amount of A = T, and the amount of G = C
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22. Adenine (A) Thymine (T) Guanine (G) Cytosine (C) Fig. 16-8
Figure 16.8 Base pairing in DNA
Guanine (G)
Cytosine (C)

23. Question 9 – DNA Replication
Since the two strands of DNA are complementary, each strand acts as a template for building a new strand in replication
In DNA replication, the parent molecule unwinds, and two new daughter strands are built based on base-pairing rules
Animation: DNA Replication Overview
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24. (b) Separation of strands
Fig A T A T A T A T C G C G C G C G T A T A T A T A A T A T A T A T G C G C G C G C
(a) Parent molecule
(b) Separation of strands
(c) “Daughter” DNA molecules, each consisting of one parental strand and one new strand
Figure 16.9 A model for DNA replication: the basic concept

25. Question 8 – DNA replication is considered semiconservative
Question 8 – DNA replication is considered semiconservative. What does that mean?
Watson and Crick’s semiconservative model of replication predicts that when a double helix replicates, each daughter molecule will have one old strand (derived or “conserved” from the parent molecule) and one newly made strand
Competing models were the conservative model (the two parent strands rejoin) and the dispersive model (each strand is a mix of old and new)
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26. (a) Conservative model
Fig
First replication
Second replication
Parent cell
(a) Conservative model
(b) Semiconserva- tive model
Figure Three alternative models of DNA replication
(c) Dispersive model

27. DNA Replication: A Closer Look
The copying of DNA is remarkable in its speed and accuracy
More than a dozen enzymes and other proteins participate in DNA replication
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28. Animation: Origins of Replication
Getting Started
Replication begins at special sites called origins of replication, where the two DNA strands are separated, opening up a replication “bubble”
A eukaryotic chromosome may have hundreds or even thousands of origins of replication
Replication proceeds in both directions from each origin, until the entire molecule is copied
Animation: Origins of Replication
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29. Parental (template) strand
Fig a
Origin of replication
Parental (template) strand
Daughter (new) strand
Replication fork
Double-stranded DNA molecule
Replication bubble
0.5 µm
Two daughter DNA molecules
Figure Origins of replication in E. coli and eukaryotes
(a) Origins of replication in E. coli

30. Double-stranded DNA molecule
Fig b
Origin of replication
Double-stranded DNA molecule
Parental (template) strand
Daughter (new) strand
0.25 µm
Bubble
Replication fork
Figure Origins of replication in E. coli and eukaryotes
Two daughter DNA molecules
(b) Origins of replication in eukaryotes

31. At the end of each replication bubble is a replication fork, a Y-shaped region where new DNA strands are elongating
Helicases are enzymes that untwist the double helix at the replication forks
Single-strand binding protein binds to and stabilizes single-stranded DNA until it can be used as a template
Topoisomerase corrects “overwinding” ahead of replication forks by breaking, swiveling, and rejoining DNA strands
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32. Single-strand binding proteins
Fig
Primase
Single-strand binding proteins 3
Topoisomerase 5 3
RNA primer 5
Figure Some of the proteins involved in the initiation of DNA replication 5 3
Helicase

33. The initial nucleotide strand is a short RNA primer
DNA polymerases cannot initiate synthesis of a polynucleotide; they can only add nucleotides to the 3 end
The initial nucleotide strand is a short RNA primer
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34. An enzyme called primase can start an RNA chain from scratch and adds RNA nucleotides one at a time using the parental DNA as a template
The primer is short (5–10 nucleotides long), and the 3 end serves as the starting point for the new DNA strand
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35. Synthesizing a New DNA Strand
Enzymes called DNA polymerases catalyze the elongation of new DNA at a replication fork
Most DNA polymerases require a primer and a DNA template strand
The rate of elongation is about 500 nucleotides per second in bacteria and 50 per second in human cells
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36. Nucleoside triphosphate
Fig
New strand 5 end
Template strand 3 end
5 end
3 end
Sugar A T A T
Base
Phosphate C G C G G C G C
DNA polymerase
3 end A T A T
Figure Incorporation of a nucleotide into a DNA strand
3 end C
Pyrophosphate C
Nucleoside triphosphate
5 end
5 end

37. Antiparallel Elongation
The antiparallel structure of the double helix (two strands oriented in opposite directions) affects replication
DNA polymerases add nucleotides only to the free 3end of a growing strand; therefore, a new DNA strand can elongate only in the 5 to 3direction
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38. Animation: Leading Strand
Along one template strand of DNA, the DNA polymerase synthesizes a leading strand continuously, moving toward the replication fork
Animation: Leading Strand
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39. Overall directions of replication
Fig
Overview
Origin of replication
Leading strand
Lagging strand
Primer
Lagging strand
Leading strand
Overall directions of replication
Origin of replication 3 5
RNA primer 5
“Sliding clamp” 3 5
DNA poll III
Parental DNA
Figure Synthesis of the leading strand during DNA replication 3 5 5 3 5

40. Animation: Lagging Strand
To elongate the other new strand, called the lagging strand, DNA polymerase must work in the direction away from the replication fork
The lagging strand is synthesized as a series of segments called Okazaki fragments, which are joined together by DNA ligase
Animation: Lagging Strand
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41. Overall directions of replication
Fig
Overview
Origin of replication
Leading strand
Lagging strand
Lagging strand 2 1
Leading strand
Overall directions of replication 3 5 5 3
Template strand 3
RNA primer 3 5 1 5
Okazaki fragment 3 5 3 1 5 5 3 3 2 1 5
Figure 16.6 Synthesis of the lagging strand 3 5 3 5 2 1 5 3 3 1 5 2
Overall direction of replication

42. Overall directions of replication
Fig a
Overview
Origin of replication
Leading strand
Lagging strand
Lagging strand 2 1
Leading strand
Figure 16.6 Synthesis of the lagging strand
Overall directions of replication

43. Figure 16.6 Synthesis of the lagging strand
Fig b6 3 5 5 3
Template strand 3 5
RNA primer 3 1 5 3
Okazaki fragment 5 3 5 1 3 5 3 2 1 5 5 3
Figure 16.6 Synthesis of the lagging strand 3 5 2 1 5 3 3 1 5 2
Overall direction of replication

44. Table 16-1

45. Single-strand binding protein Overall directions of replication
Fig
Overview
Origin of replication
Leading strand
Lagging strand
Leading strand
Lagging strand
Single-strand binding protein
Overall directions of replication
Helicase
Leading strand 5
DNA pol III 3 3
Primer
Primase 5
Parental DNA 3
Figure A summary of bacterial DNA replication
DNA pol III
Lagging strand 5
DNA pol I
DNA ligase 4 3 5 3 2 1 3 5

46. Proofreading and Repairing DNA
DNA polymerases proofread newly made DNA, replacing any incorrect nucleotides
In mismatch repair of DNA, repair enzymes correct errors in base pairing
DNA can be damaged by chemicals, radioactive emissions, X-rays, UV light, and certain molecules (in cigarette smoke for example)
In nucleotide excision repair, a nuclease cuts out and replaces damaged stretches of DNA
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47. Nuclease DNA polymerase DNA ligase Fig. 16-18
Figure Nucleotide excision repair of DNA damage
DNA ligase

48. Replicating the Ends of DNA Molecules
Limitations of DNA polymerase create problems for the linear DNA of eukaryotic chromosomes
The usual replication machinery provides no way to complete the 5 ends, so repeated rounds of replication produce shorter DNA molecules
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49. Figure 16.19 Shortening of the ends of linear DNA molecules5
Ends of parental DNA strands
Leading strand
Lagging strand 3
Last fragment
Previous fragment
RNA primer
Lagging strand 5 3
Parental strand
Removal of primers and replacement with DNA where a 3 end is available 5 3
Second round of replication
Figure Shortening of the ends of linear DNA molecules 5
New leading strand 3
New lagging strand 5 3
Further rounds of replication
Shorter and shorter daughter molecules

50. Eukaryotic chromosomal DNA molecules have at their ends nucleotide sequences called telomeres
Telomeres do not prevent the shortening of DNA molecules, but they do postpone the erosion of genes near the ends of DNA molecules
It has been proposed that the shortening of telomeres is connected to aging
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51. Fig
Figure Telomeres
1 µm

52. If chromosomes of germ cells became shorter in every cell cycle, essential genes would eventually be missing from the gametes they produce
An enzyme called telomerase catalyzes the lengthening of telomeres in germ cells
The shortening of telomeres might protect cells from cancerous growth by limiting the number of cell divisions
There is evidence of telomerase activity in cancer cells, which may allow cancer cells to persist
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53. Question 11 – Briefly describe the structure of a chromosome.
The bacterial chromosome is a double-stranded, circular DNA molecule associated with a small amount of protein
Eukaryotic chromosomes have linear DNA molecules associated with a large amount of protein
In a bacterium, the DNA is “supercoiled” and found in a region of the cell called the nucleoid
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54. Animation: DNA Packing
Chromatin is a complex of DNA and protein, and is found in the nucleus of eukaryotic cells
Histones are proteins that are responsible for the first level of DNA packing in chromatin
For the Cell Biology Video Cartoon and Stick Model of a Nucleosomal Particle, go to Animation and Video Files.
Animation: DNA Packing
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55. Nucleosomes, or “beads on a string” (10-nm fiber)
Fig a
Nucleosome
(10 nm in diameter)
DNA double helix (2 nm in diameter) H1
Histone tail
Histones
Figure 16.21a Chromatin packing in a eukaryotic chromosome
DNA, the double helix
Histones
Nucleosomes, or “beads on a string” (10-nm fiber)

56. Looped domains (300-nm fiber) Metaphase chromosome
Fig b
Chromatid
(700 nm)
30-nm fiber
Loops
Scaffold
300-nm fiber
Figure 16.21b Chromatin packing in a eukaryotic chromosome
Replicated chromosome (1,400 nm)
30-nm fiber
Looped domains (300-nm fiber)
Metaphase chromosome

57. Loosely packed chromatin is called euchromatin
Most chromatin is loosely packed in the nucleus during interphase and condenses prior to mitosis
Loosely packed chromatin is called euchromatin
During interphase a few regions of chromatin (centromeres and telomeres) are highly condensed into heterochromatin
Dense packing of the heterochromatin makes it difficult for the cell to express genetic information coded in these regions
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58. Fig. 16-UN5