chapter 16: the molecular basis of inheritance

Chapter 16:

THE MOLECULAR BASIS OF

INHERITANCE (DNA Structure and Function)

Evelyn I. Milian

Instructor

BIOLOGY I

BIOLOGY I – Chapter 16: The Molecular Basis of Inheritance (DNA)

DNA Is the Genetic Material

• What is DNA and why is it so important for life?

DNA (deoxyribonucleic acid) is a type of organic

macromolecule; it is a nucleic acid composed of subunits

called nucleotides (we will study its structure in detail).

DNA is the genetic material of nearly all organisms. It is found in eukaryotic and prokaryotic cells. The “molecular instructions” in DNA direct the life of each cell in an organism. DNA stores genetic information regarding the development, structure, and metabolic activities of a cell.

DNA also enables organisms, or cells within an organism, to transmit information accurately from one generation to the next.

2 Evelyn I. Mil ian - Instructor


The Levels of Structure and Function of the Genome

Evelyn I. Mil ian - Instructor 3

The genome is the sum total of genetic material of a cell. Although most of the genome exists in the form of chromosomes, genetic material can appear in

nonchromosomal sites as well. For example, bacteria and some fungi contain tiny extra pieces of DNA called plasmids, and certain organelles of eukaryotes (mitochondria and chloroplasts) are equipped with their own genetic material.


History: The Search for the Genetic Material

How Did Scientists Discover that Genes are Made of DNA?

• Early in the twentieth century, scientists knew that the genes are on the chromosomes, but they did not know the composition of genes. The identification of the molecules of inheritance was a major challenge to biologists.

• DNA and proteins were the candidates for the genetic material, but proteins seemed stronger because of their complexity and variety. Moreover, little was known about nucleic acids.

• Scientists knew that this genetic material must be:

1. able to store information that pertains to the development, structure,

and metabolic activities of the cell or organism;

2. stable so that it can be replicated with high fidelity during cell division

and be transmitted from generation to generation;

3. able to undergo rare genetic changes called mutations that provide the

genetic variability required for evolution to occur.



History: The Search for the Genetic Material

• Previous knowledge about nucleic acids:

1869, Johann Friedrich Miescher: He removed nuclei from

pus cells and found a chemical he called nuclein. It was rich

in phosphorus and had no sulfur, properties that distinguished

it from protein. In this way, he helped paving the way for the

identification of DNA as the carrier of inheritance.

Later, other chemists did further research with nuclein and said

that it contained an acidic substance they called nucleic acid.

However, for many years nobody thought about nucleic acids

as the genetic material because their physical and chemical

properties seemed far too uniform to account for the variety of

inherited traits exhibited by every organism.



The Search for the Genetic Material:

How Did Scientists Discover that Genes are Made of DNA?

• After several diligent experiments, by the mid-1950s

researchers realized that DNA, not protein, is the

genetic material.

• Experiments with bacteria and viruses that infect

bacteria (phages, or bacteriophages) provided the

first strong evidence that the genetic material is DNA.

• The discovery of how DNA carries life’s blueprints

was one of the greatest achievements of 20th

century biology.



Evidence That DNA Can Transform Bacteria (Transformation)

• 1928: Frederick Griffith was trying to make a vaccine to prevent bacterial pneumonia. He was working with two strains (variants) of the Streptococcus pneumoniae bacterium (pneumococcus), a pathogenic (disease-causing) strain (S) and a nonpathogenic (harmless) strain (R). The pathogenic S (smooth) strain had a resistant capsule not found in the nonpathogenic R (rough) strain.

He found that when he killed the pathogenic bacteria with heat

and then mixed the cell remains with living bacteria of the

nonpathogenic strain, some of the living cells became

pathogenic. Furthermore, this new trait of pathogenicity was

inherited by all the descendants of the transformed bacteria.

He concluded that some chemical component of the dead

pathogenic cells caused this heritable change.



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Evidence That DNA Can Transform Bacteria:

Bacterial Transformation

• Griffith’s experiments showed that some substance

in the heat-killed S strain changed the living but

harmless R strain into the deadly S strain.

• He called this phenomenon transformation, now

defined as a genetic change due to the assimilation

of external DNA by a cell.

• Griffith’s work set the stage for the search for the identity

of the transforming substance by other scientists during

the following years.



Animation: Griffith’s Experiment – Transformation

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Evidence That DNA Can Transform Bacteria

• 1944: Oswald Avery, Colin MacLeod, and Maclyn McCarty purified the transforming molecule

and published a paper demonstrating that it is DNA. Their evidence included the following observations:

1. DNA from S strain bacteria causes R strain bacteria

to be transformed.

2. Enzymes that degrade proteins (proteinases)

cannot prevent transformation, nor does RNase, an

enzyme that digests RNA (ribonucleic acid).

3. The molecular weight of the transforming substance

is so great that it must contain about 1,600

nucleotides! Certainly, this is enough for some

genetic variability.



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Confirmation of DNA Function:

Evidence That Viral DNA Can Program Cells

• Additional evidence for DNA as the genetic material came from studies of a virus that infects bacteria, called a bacteriophage or phage.

• Virus: A noncellular parasitic agent consisting of an inner core of nucleic acid (DNA or RNA) and an outer coat of protein (capsid).

• To reproduce, a virus must infect a cell and take over the cell’s metabolic machinery.

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Evidence That Viral DNA Can Program Cells

• 1952: Alfred D. Hershey and Martha Chase performed experiments with phage T2 to determine which of the phage components—protein or DNA—entered bacterial cells and directed reproduction of the virus. T2 infects Escherichia coli, a bacterium that normally lives in the intestines of mammals.

• Hershey and Chase relied on a chemical difference between DNA and protein to solve the mystery: DNA contains phosphorus but no sulfur; proteins contain sulfur but no phosphorus.

They used radioactive phosphorus to label the DNA core of the

phage and radioactive sulfur to label the protein capsid of the

phage. In this way, they were able to trace the component that

entered the bacterial cells, and they determined that it was DNA.



The Watson and Crick Model for the Structure of DNA

• 1953: James Watson and Francis Crick reported their molecular model for DNA: the double helix, for which they received a Nobel Prize in 1962.

• Their model conformed to X-ray measurements (done by Rosalind Franklin and Maurice Wilkins) and what was then known about the biochemistry of DNA.



The Structure of DNA, a Nucleic Acid

• Nucleic acids (DNA and RNA) are large organic molecules composed of subunits called nucleotides. Nucleic acids contain carbon, hydrogen, oxygen, nitrogen, and phosphorus.

• Nucleic acids store and transmit hereditary information, and are involved in the synthesis of proteins, molecules with many functions.

• Nucleotides are compounds that contain these molecules:

a phosphate group;

a pentose (five-carbon) sugar: deoxyribose in DNA; ribose in RNA;

a nitrogenous base: one of four possible bases which are: adenine, cytosine, guanine, and thymine in DNA or uracil in RNA.

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Covalent bonds:

sharing of two or

more electrons

(negatively

charged atomic

particles).

Nucleotides are linked

together by covalent

bonds between the

phosphate of one

nucleotide and the sugar

of the next nucleotide.

The numbers 1 to 5 are

the carbons.

Evelyn I. Mil ian - Instructor


The Nucleotides in Nucleic Acids


• Nucleotides contain: 1. A phosphate group.

2. A pentose (five-carbon) sugar: deoxyribose in DNA; ribose in RNA.

3. A nitrogenous base: adenine, guanine, cytosine, and thymine in DNA or uracil in RNA.

• A and G are purines, with a double ring.

• T and C are pyrimidines, with a single ring.


The Structure of DNA (Deoxyribonucleic Acid)

• 1940s: Erwin Chargaff analyzed the amounts of the four nucleotides in DNA from diverse organisms. He provided additional evidence that DNA is the genetic material.

• The result was Chargaff’s rules:

1. The amount of A, T, G, and C in DNA varies from species to species.

2. In each species, the amount of A equals the amount of T and the

amount of G equals the amount of C.



The Structure of DNA: The Watson and Crick Model

• The structure of a DNA molecule consists of two long strands of nucleotides wrapped around each other to form a double helix, (like a twisted ladder, or spiral) and oriented in antiparallel (opposite) directions (the sugar-phosphate groups are oriented in different directions).

• Within each strand, the sugar (deoxyribose) of one nucleotide is linked to the phosphate of the next nucleotide, forming a sugar-phosphate “backbone” on each side of the double helix.

• The two DNA strands are held together by hydrogen bonds between complementary nitrogenous base pairs (purine with pyrimidine) (like the rungs or steps of the ladder).

A—T: Adenine (a purine,with a double ring) forms hydrogen bonds only with thymine (a pyrimidine, with one ring).

G—C: Guanine (a purine) forms hydrogen bonds only with cytosine (a pyrimidine).



The Structure of a DNA Strand

• Each nucleotide monomer consists of

a nitrogenous base (T, A, C, or G),

the sugar deoxyribose (blue), and a

phosphate group (yellow). The

phosphate group of one nucleotide is

attached to the sugar of the next,

resulting in a “backbone” of

alternating phosphates and sugars

from which the bases project.

• The polynucleotide strand has

directionality, from the 5’ end (with

the phosphate group) to the 3’ end

(with the –OH group). 5’ and 3’ refer

to the numbers assigned to the

carbons in the sugar ring.



Watson and Crick’s

Model of DNA

a. A space-filling model of DNA.

b. The two strands of the

molecule are antiparallel—

that is, the sugar-phosphates

are oriented in different

directions: The 5’ end of one

strand is opposite the 3’ end

of the other strand.

c. Diagram of DNA double

helix shows that the

molecule resembles a

twisted ladder or a spiral.

The bases are joined by

hydrogen bonds.



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DNA, a Nucleic Acid

• Nucleotides (top) are composed of a deoxyribose (in DNA) sugar molecule linked to a phosphate group and to a nitrogenous base. The two nucleotides shown here are linked by hydrogen bonds between their complementary bases.

• The ladderlike form of DNA’s double helix (bottom) is made up of many nucleotides, with the repeating sugar-phosphate combination forming the backbone and the complementary bases the rungs.




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• The Watson and Crick model for DNA fit the mathematical measurements provided by X-ray data for the spacing between the base pairs (0.34 nm) and for a complete turn of the double helix (3.4 nm).

• The model also agreed with Chargaff’s rules, which said that the amount of A equals the amount of T and the amount of G equals the amount of C. A is hydrogen-bonded to T and G is hydrogen-bonded to C. This so-called complementary base pairing means that a purine is always bonded to a pyrimidine. Only in this way will the molecule have the width (2 nm) dictated by its X-ray diffraction pattern, since two pyrimidines together are too narrow, and two purines together are too wide.



The Structure of DNA:

The Watson and Crick Model

• In a DNA double-helix, the two

sugar-phosphate chains run in

opposite directions. This

orientation permits the

complementary bases to pair.

• Strong covalent bonds link the

units of each strand, while

weaker hydrogen bonds hold

one strand to the other by the

pairs of nitrogenous bases.

• Adenine (A) pairs with thymine

(T), and guanine (G) pairs with

cytosine (C).

• The A-T pair has two hydrogen

bonds, the G-C pair has three.




• The two upright strands, composed of the sugar deoxyribose (D) and phosphate groups (P), are held together by hydrogen bonds between complementary bases. Adenine (A) always pairs with thymine (T), and guanine (G) always pairs with cytosine (C). Each strand can thus provide the information needed for the formation of a new DNA molecule.

• The DNA molecule is twisted into a double helix. The two sugar-phosphate strands run in opposite directions (antiparallel). Each new strand grows from the 5’ (“five prime”) end toward the 3’ end.


The A-T pair has two hydrogen bonds,

the G-C pair has three hydrogen bonds.


The DNA Double Helix

• Note: The “ribbons” in this diagram represent the sugar-phosphate backbones of the two DNA

strands. The helix is “right-handed”, curving up to the right.

• Denaturation of DNA, the separation of the two strands of the double helix, occurs under

extreme (noncellular) conditions of pH (acidity level), salt concentration, and temperature.

• For example, when a double-stranded DNA molecule is heated, it denatures into two single-

stranded molecules. The heat breaks the hydrogen bonds holding the bases together in the

center of the molecule but does not affect the covalent bonds of the backbone.


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Animation: DNA Structure: Subunits


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DNA REPLICATION

• DNA replication is the process of copying a DNA molecule. Following replication, there is usually an exact copy of the DNA double helix.

• DNA replication must occur

before a cell can divide

(Remember: During the S

phase of the cell cycle).

• As soon as Watson and Crick developed their double-helix model, they commented, “It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.”



REPLICATION OF DNA

• In a second paper, Watson and Crick stated their

hypothesis for how DNA replicates:

“Now our model for deoxyribonucleic acid is, in effect, a

pair of templates, each of which is complementary to the

other. We imagine that prior to duplication the hydrogen

bonds are broken, and the two chains unwind and

separate. Each chain then acts as a template for the

formation onto itself of a new companion chain, so that

eventually we shall have two pairs of chains, where we

only had one before. Moreover, the sequence of pairs

of bases will have been duplicated exactly.” *

• * F. H. C. Crick and J. D. Watson, “The Complementary Structure of

Deoxyribonucleic Acid.” Proc. Roy. Soc. (A) 223 (1954): 80.



Proposed Models of DNA

Replication

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• Conservative model: The parent molecule somehow re-forms after the replication (it is conserved); in other words, the two parental strands are rejoined.

• Semiconservative model: Each of the two daughter molecules of DNA will have one old strand derived from the parent molecule, and one newly synthesized strand.

• Dispersive model: Each strand of DNA following replication has a mixture of old and new DNA.



Meselson & Stahl Experiment:

Semiconservative DNA Replication

• Semiconservative replication was experimentally confirmed by Matthew Meselson and Franklin Stahl in 1958. They showed that each daughter double helix contains an old strand and a new strand.

• Meselson and Stahl grew bacteria in heavy nitrogen (15N) medium to label the bases of DNA, making them more dense; and then transferred some of the cells to light nitrogen (14N, the ordinary one) so that the newly synthesized strands would be light. They isolated DNA from bacterial cells after one and two generations and centrifuged it to separate DNA into bands based on density.

• After one division in light nitrogen, DNA molecules are hybrid with intermediate density. After two divisions, DNA molecules separate into two bands—one for light DNA and one for hybrid DNA, consistent with the semiconservative model of replication.



Semiconservative

Replication of DNA

• Semiconservative

nature of DNA

replication: During DNA

replication, each parent

strand remains intact.

One new strand (gold) is

assembled on each of

the parent strands

(blue). In other words,

each of the two daughter

molecules of DNA will

have one old strand

derived from the parent

molecule, and one newly

synthesized strand.



* SUMMARY OF STEPS IN THE REPLICATION OF DNA *


• During DNA replication, each old DNA strand of the parental molecule (original double helix) serves as a template (mold) for a new strand in a daughter molecule.

• Replication requires the following steps or stages:

1. Uncoiling (unwinding). The old strands that make up the parental DNA molecule are unwound (or separated) and “unzipped” (i.e., the weak hydrogen bonds between the paired bases are broken).

• A special enzyme called helicase unwinds the molecule.

2. Synthesis: complementary base pairing and elongation. New complementary nucleotides are positioned through the process of complementary base pairing.

3. Joining and termination. The complementary nucleotides join the template strands to form new strands. Each daughter DNA molecule contains an old strand and a new strand (semiconservative replication).

• *** Steps 2 and 3 are carried out by an enzyme complex called DNA polymerase.


A Simplified View of DNA Replication: The Basic Concept

• In this simplification, a short segment of DNA has been untwisted into a

structure that resembles a ladder. The rails of the ladder are the sugar-

phosphate backbones of the two DNA strands; the rungs are the pairs of

nitrogenous bases. Simple shapes symbolize the four kinds of bases.

Dark blue represents DNA strands present in the parent molecule; light

blue represents free nucleotides and newly synthesized DNA.



DNA replication requires

protein “machinery”

• The replication of DNA by

base pairing appears simple

and straightforward, but it

requires special proteins

and enzymes (catalytic

proteins that accelerate

specific chemical reactions).



DNA Replication: Basic Steps

• After the DNA double helix unwinds (by helicase), each old strand serves as a template for the formation of the new strand.

• Complementary nucleotides available in the cell pair with those of the old strand and then are joined together to form a new strand.

• After replication is complete, there are two daughter DNA double helices. Each one is composed of an old strand and a new strand.

• Each daughter double helix has the same sequence of base pairs as the parental double helix had before unwinding occurred.



DNA Replication: A Closer Look (* Study the Figures *)


• DNA replication begins at a site called an origin of replication and proceeds in both directions from that point (it’s bidirectional). The point where the two DNA strands separate is called the replication fork.

The enzyme helicase untwists the double helix at replication forks.

Single-strand binding proteins stabilize the unpaired DNA strands.

• An RNA primer, a short polynucleotide complementary to the template strand, is synthesized (by primase) and enters the origin of replication.

The RNA primer is required as a start point for the addition of nucleotides by DNA polymerase III; it can only add nucleotides to the 3’ end of an existing polynucleotide strand or RNA primer.

• DNA polymerase then catalyzes the synthesis of the new DNA strand by adding new nucleotides in the 5’ 3’ direction.

• Because of the 5’ 3’ direction of DNA polymerase, DNA replication is continuous in one strand and discontinuous in the other: The leading strand is synthesized continuously, and the lagging strand is synthesized in short segments, called Okazaki fragments.

The fragments are joined together by DNA ligase.


A Closer Look at DNA Replication



Synthesis of leading and lagging

strands during DNA replication

1. DNA polymerase III elongates

new DNA strands in the 5’ 3’

direction (it adds nucleotides to

the 3’ end of an existing strand).

2. One new strand, the leading

strand, can elongate continuously

in the 5’ 3’ direction as the

replication fork progresses.

3. The other new strand, the lagging

strand, must grow in an overall 3’

5’ direction by addition of short

segments, Okazaki fragments,

that grow 5’ 3’ (numbered here

in the order they were made).

4. DNA ligase joins Okazaki

fragments by forming a bond

between their free ends. This

results in a continuous strand.



Origins of DNA Replication in

Bacteria and Eukaryotes

• In the circular chromosome of E. coli and many other bacteria (prokaryotes), only one origin of replication is present. The parental strands separate at the origin, forming a replication bubble with two forks. Replication proceeds in both directions until the forks meet on the other side, resulting in two daughter DNA molecules.

• In each linear chromosome of eukaryotes, DNA replication begins when replication bubbles form at many origins along the giant DNA molecule. The bubbles expand as replication proceeds in both directions. Eventually the bubbles fuse and synthesis of the daughter strand is complete.



Some of the Proteins Involved in the Initiation of DNA Replication

• Helicase unwinds and separates the parental DNA strands.

• Topoisomerase breaks, swivels, and rejoins the parental DNA ahead of

the replication fork, relieving the strain caused by unwinding.

• Single-strand binding proteins stabilize the unwound parental strands.

• Primase synthesizes RNA primers, using the parental DNA as a template.



DNA REPLICATION: Incorporation of a Nucleotide into a DNA Strand

• DNA polymerase catalyzes the addition of a nucleoside triphosphate to the 3’ end of a growing DNA strand (a nucleoside triphosphate has a nitrogenous base, a pentose sugar, and three phosphate groups).

• When a nucleoside triphosphate bonds to the sugar in a growing DNA strand, it loses two phosphates. Hydrolysis of the phosphate bonds provides the energy for the reaction.



• Review the details for this figure in your book (Campbell & Reece, Biology).



Enzymes and Other Proteins in Bacterial DNA Replication



Proofreading and Repairing DNA

• Mistakes in DNA can result in the altered or diminished function of encoded proteins and thus disrupt normal cell operations.

• During DNA replication, DNA polymerases proofread newly made DNA, replacing any incorrect nucleotides.

• Mismatched nucleotides sometimes evade proofreading by a DNA polymerase or arise after DNA synthesis is completed.

Mismatch repair. Special repair enzymes recognize incorrectly paired nucleotides and remove them. DNA polymerases then fill in the missing nucleotides.

Nucleotide excision repair. This repair mechanism is commonly used to repair DNA lesions caused by the sun’s ultraviolet radiation or by harmful chemicals. It involves three enzymes: nucleases cut out (excise) and replace damaged stretches of DNA. DNA polymerase adds the correct nucleotides, and DNA ligase closes the breaks.



Nucleotide Excision Repair

of DNA Damage

• A team of enzymes detects and

repairs damaged DNA. This figure

shows DNA containing a thymine

dimer, a type of damage often

caused by ultraviolet radiation. A

nuclease enzyme cuts out the

damaged region of DNA and a

DNA polymerase (in bacteria,

DNA pol I) replaces it with a

normal DNA segment. Ligase

completes the process by closing

the remaining break in the sugar-

phosphate backbone.



Chromatin Packing in a Eukaryotic Chromosome


• Diagrams and micrographs (done with a transmission electron microscope)

depicting the progressive levels of DNA coiling and folding. Eukaryotic chromatin

making up a chromosome is composed mostly of DNA, histones, and other proteins. The

histones bind to each other and to the DNA to form nucleosomes, the most basic units of

DNA packing. Histone tails extend outward from each bead-like nucleosome core.

Additional folding leads ultimately to the highly condensed chromatin of the metaphase

chromosome. In interphase cells, most chromatin is less compacted (euchromatin), but

some remains highly condensed (heterochromatin). Histone modifications may influence

the state of chromatin condensation.


Animation: DNA REPLICATION


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DNA STRUCTURE AND REPLICATION:

Some Websites for Review

• DNA structure interactive tutorial:

http://www.umass.edu/molvis/tutorials/dna/

• DNA replicating song (creative and funny!):

http://www.youtube.com/watch?v=dIZpb93NYlw

• DNA structure: http://www.youtube.com/watch?v=qy8dk5iS1f0

• Molecular visualization of DNA:

http://www.youtube.com/watch?v=4PKjF7OumYo

• DNA replication brief videos:

http://www.youtube.com/watch?v=teV62zrm2P0&feature=related

http://www.youtube.com/watch?v=AGUuX4PGlCc&feature=related

http://www.youtube.com/watch?v=z685FFqmrpo&feature=related


http://www.umass.edu/molvis/tutorials/dna/

http://www.youtube.com/watch?v=dIZpb93NYlw

http://www.youtube.com/watch?v=qy8dk5iS1f0

http://www.youtube.com/watch?v=4PKjF7OumYo




http://www.youtube.com/watch?v=z685FFqmrpo&feature=related


References

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Pearson Education, Inc.-Prentice Hall. NJ, USA.

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McGraw-Hill Companies, Inc. NY, USA.

• Campbell, Neil A.; Reece, Jane B., et al. (2011). Campbell Biology. Ninth Edition. Pearson Education,

Inc.-Pearson Benjamin Cummings. CA, USA.

• Cowan, Marjorie Kelly; Talaro, Kathleen Park. (2009). Microbiology A Systems Approach. Second

Edition. The McGraw-Hill Companies, Inc. NY, USA. www.mhhe.com/cowan2e

• Ireland, K.A. (2011). Visualizing Human Biology. Second Edition. John Wiley & Sons, Inc. NJ, USA.

• Mader, Sylvia S. (2010). Biology. Tenth Edition. The McGraw-Hill Companies, Inc. NY, USA.

• Martini, Frederic H.; Nath, Judi L. (2009). Fundamentals of Anatomy & Physiology. Eighth Edition.

Pearson Education, Inc. – Pearson Benjamin Cummings. CA, USA.

• Solomon, Eldra; Berg, Linda; Martin, Diana W. (2008). Biology. Eighth Edition. Cengage Learning. OH,

USA.

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http://www.wiley.com/college/apcentral

chapter 16: the molecular basis of inheritance

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