Essentials of Genetics
Why does a commercial dairy cow produce four times as much milk as most other mammals? Why do we look like our
cousins? Why do roses come in so many different colors? The answers to these and other questions about the diversity of
living things involve processes that occur at the level of genes.
Essentials of Genetics is a brief guide through the core concepts of how genes are structured and how they drive biological
diversity. This course can be used as a guide for introductory biology students, as a reference for advanced students, or as a
self-guided exploration for general science enthusiasts. Topics covered include the nature of DNA and its relationship to the
physical characteristics of organisms; the passage of DNA from organism to organism; and the variation of DNA within and
across populations of organisms. Essentials of Genetics also connects these core concepts to the scientific process by
discussing the key tools used to study DNA in the laboratory. Alongside each concept are links to biographies of scientists
who made major contributions to the field, as well as to a broad set of detailed readings on advanced topics in modern
genetics. Finally, Essentials of Genetics combines its descriptions of various core concepts with high-quality video
animations of molecular processes to stimulate an intuitive physical understanding of genetics.
Writers: Heidi Chial, Ph.D., Carrie Drovdlic, Maggie Koopman, Ph.D., Sarah Catherine Nelson, Ph. D., Angela Spivey,
Robin Smith, Ph. D., WilliamsTown Communications.
Citation
Miko, I. & LeJeune, L., eds. Essentials of Genetics. Cambridge, MA: NPG Education, 2009.
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Essentials of Genetics
Contents
Unit 1 What Is DNA? What Does DNA Do?
Unit 2
How Does DNA Move from Cell to Cell? Unit 3
How Is Genetic Information Passed between Organisms? Unit 4
How Do Scientists Study and Manipulate the DNA inside Cells? Unit 5
How Does Inheritance Operate at the Level of Whole Populations?
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Deoxyribonucleic acid, more commonly known as DNA, is a complex molecule that contains all of the information
necessary to build and maintain an organism. All living things have DNA within their cells. In fact, nearly every cell in a
multicellular organism possesses the full set of DNA required for that organism.
However, DNA does more than specify the structure and function of living things it also serves as the primary unit of
heredity in organisms of all types. In other words, whenever organisms reproduce, a portion of their DNA is passed along to
their offspring. This transmission of all or part of an organism's DNA helps ensure a certain level of continuity from one
generation to the next, while still allowing for slight changes that contribute to the diversity of life.
But what, exactly, is DNA? What smaller elements make up this complex molecule, how are these elements arranged, and
how is information extracted from them? This unit answers each of these questions, and it also provides a basic overview of
the process of DNA discovery.
Unit 1
Key Questions Introduction: What Is DNA?
Where can I learn more about
DNA? DNA Is a Structure That
Encodes Biological Information
Key Concepts
DNA Discovery of the Function of
DNA Resulted from the Work
chromosomes of Multiple Scientists
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What do a human, a rose, and a bacterium have in common? Each of these things along with every other organism on
Earth contains the molecular instructions for life, called deoxyribonucleic acid or DNA. Encoded within this DNA are
the directions for traits as diverse as the color of a person's eyes, the scent of a rose, and the way in which bacteria infect a
lung cell.
DNA is found in nearly all living cells. However, its exact location within a cell depends on whether that cell possesses a
special membrane-bound organelle called a nucleus. Organisms composed of cells that contain nuclei are classified as
eukaryotes, whereas organisms composed of cells that lack nuclei are classified as prokaryotes. In eukaryotes, DNA is
housed within the nucleus, but in prokaryotes, DNA is located directly within the cellular cytoplasm, as there is no nucleus
available.
But what, exactly, is DNA? In short, DNA is a complex molecule that consists of many components, a portion of which are
passed from parent organisms to their offspring during the process of reproduction. Although each organism's DNA is
unique, all DNA is composed of the same nitrogen-based molecules. So how does DNA differ from organism to organism? It
is simply the order in which these smaller molecules are arranged that differs among individuals. In turn, this pattern of
arrangement ultimately determines each organism's unique characteristics, thanks to another set of molecules that "read" the
pattern and stimulate the chemical and physical processes it calls for.
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During DNA packaging, long pieces of double-stranded DNA are tightly looped, coiled, and folded so that they fit easily
within the cell. Eukaryotes accomplish this feat by wrapping their DNA around special proteins called histones, thereby
compacting it enough to fit inside the nucleus (Figure 8). Together, eukaryotic DNA and the histone proteins that hold it
together in a coiled form is called chromatin.
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Watch this video for a closer look at the relationship between chromosomes and the
DNA double helix
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Unit 1
Key Questions Introduction: What Is DNA?
How can so much DNA be
packed inside a chromosome? DNA Is a Structure That
Encodes Biological Information
What are karyotypes used for? What components make up
Who is James Watson? DNA?
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1.3 Discovery of the Function of DNA Resulted from the Work of Multiple Scientists
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The chemical nature and structure of DNA were not elucidated until the middle of the twentieth century. Prior to that point,
scientists had spent years speculating about which of the many types of molecules within cells contained the hereditary
information. Was it protein? Was it something else perhaps even a molecule they had yet to discover? Eventually,
researchers zeroed in on DNA as the substance responsible for the transfer of traits from one generation to the next. From
there, the race was on to learn more about this remarkable molecule.
Although James Watson and Francis Crick determined the double-helical structure of DNA, DNA itself was identified nearly
90 years earlier by Swiss chemist Friedrich Miescher. While studying white blood cells, Miescher isolated a previously
unknown type of molecule that was slightly acidic and contained a high percentage of phosphorus. Miescher named this
molecule "nuclein," which was later changed to "nucleic acid" and eventually to "deoxyribonucleic acid," or DNA.
Interestingly, Miescher did not believe that nuclein was the carrier of hereditary information, because he thought it lacked the
variability necessary to account for the incredible diversity among organisms. Rather, like most scientists of his time,
Miescher believed that proteins were responsible for heredity, because they existed in such a wide variety of forms.
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Replication is the process by which a double-stranded DNA molecule is copied to produce two identical DNA molecules.
DNA replication is one of the most basic processes that occurs within a cell. Each time a cell divides, the two resulting
daughter cells must contain exactly the same genetic information, or DNA, as the parent cell. To accomplish this, each strand
of existing DNA acts as a template for replication.
Figure 2: While helicase and the initiator protein (not shown) separate
the two polynucleotide chains, primase (red) assembles a primer. This
primer permits the next step in the replication process.
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Meanwhile, as the helicase separates the strands, another enzyme called primase briefly attaches to each strand and
assembles a foundation at which replication can begin. This foundation is a short stretch of nucleotides called a primer
(Figure 2).
In the prokaryotic bacterium E. coli, replication can occur at a rate of 1,000 nucleotides per second. In comparison,
eukaryotic human DNA replicates at a rate of 50 nucleotides per second. In both cases, replication occurs so quickly because
multiple polymerases can synthesize two new strands at the same time by using each unwound strand from the original DNA
double helix as a template. One of these original strands is called the leading strand, whereas the other is called the lagging
strand. The leading strand is synthesized continuously, as shown in Figure 5. In contrast, the lagging strand is synthesized in
small, separate fragments that are eventually joined together to form a complete, newly copied strand.
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Unit 1
Key Questions Introduction: What Is DNA?
What if an error happens during
replication? DNA Is a Structure That
Encodes Biological Information
How is DNA stored in the cell
before and after replication? Discovery of the Function of
DNA Resulted from the Work
What do the leading and of Multiple Scientists
lagging strands look like when
they are being replicated? Cells Can Replicate Their DNA
Precisely
Key Concepts How is DNA replicated?
DNA polymerase
What triggers replication?
primer
How are DNA strands
transcription replicated?
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DNA is essentially a storage molecule. It contains all of the instructions a cell needs to sustain itself. These instructions are
found within genes, which are sections of DNA made up of specific sequences of nucleotides. In order to be implemented,
the instructions contained within genes must be expressed, or copied into a form that can be used by cells to produce the
proteins needed to support life.
The instructions stored within DNA are read and processed by a cell in two steps: transcription and translation. Each of these
steps is a separate biochemical process involving multiple molecules. During transcription, a portion of the cell's DNA
serves as a template for creation of an RNA molecule. (RNA, or ribonucleic acid, is chemically similar to DNA, except for
three main differences described later on in this concept page.) In some cases, the newly created RNA molecule is itself a
finished product, and it serves an important function within the cell. In other cases, the RNA molecule carries messages from
the DNA to other parts of the cell for processing. Most often, this information is used to manufacture proteins. The specific
type of RNA that carries the information stored in DNA to other areas of the cell is called messenger RNA, or mRNA.
Initiation
Strand elongation
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Figure 5: During elongation, the new RNA strand becomes longer and
longer as the DNA template is transcribed. In this view, the 5' end of the
RNA strand is in the foreground. Note the inclusion of uracil (yellow) in
RNA.
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Once an mRNA molecule is complete, that molecule can go on to play a key role in the process known as translation. During
translation, the information that is contained within the mRNA is used to direct the creation of a protein molecule. In order
for this to occur, however, the mRNA itself must be read by a special, protein-synthesizing structure within the cell known as
a ribosome.
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Unit 1
Key Questions Introduction: What Is DNA?
What does RNA do in the cell?
DNA Is a Structure That
What are introns and exons? Encodes Biological Information
Key Concepts Discovery of the Function of
RNA DNA Resulted from the Work
replication of Multiple Scientists
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1.6 The Information in DNA Determines Cellular Function via Translation Prev Page
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At its heart, the genetic code is the set of "rules" that a cell uses to interpret the nucleotide sequence within a molecule of
mRNA. This sequence is broken into a series of three-nucleotide units known as codons (Figure 1). The three-letter nature of
codons means that the four nucleotides found in mRNA A, U, G, and C can produce a total of 64 different
combinations. Of these 64 codons, 61 represent amino acids, and the remaining three represent stop signals, which trigger the
end of protein synthesis. Because there are only 20 different amino acids but 64 possible codons, most amino acids are
indicated by more than one codon. (Note, however, that each codon represents only one amino acid or stop codon.) This
phenomenon is known as redundancy or degeneracy, and it is important to the genetic code because it minimizes the
harmful effects that incorrectly placed nucleotides can have on protein synthesis. Yet another factor that helps mitigate these
potentially damaging effects is the fact that there is no overlap in the genetic code. This means that the three nucleotides
within a particular codon are a part of that codon only thus, they are not included in either of the adjacent codons.
Figure 1: In mRNA, three-nucleotide units called codons dictate a particular amino acid. For
example, AUG codes for the amino acid methionine (beige).
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The idea of codons was first proposed by Francis Crick and his colleagues in 1961. During that same year, Marshall
Nirenberg and Heinrich Matthaei began deciphering the genetic code, and they determined that the codon UUU specifically
represented the amino acid phenylalanine. Following this discovery, Nirenberg, Philip Leder, and Har Gobind Khorana
eventually identified the rest of the genetic code and fully described which codons corresponded to which amino acids.
Figure 2: The amino acids specified by each mRNA codon. Multiple codons can code for the same
amino acid.
Initiation
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Figure 4: During initiation, the ribosome (grey globe) docks onto the
mRNA at a position near the start codon (red).
At the start of the initiation phase of translation, the ribosome attaches to the mRNA strand and finds the beginning of the
genetic message, called the start codon (Figure 4). This codon is almost always AUG, which corresponds to the amino acid
methionine. Next, the specific tRNA molecule that carries methionine recognizes this codon and binds to it (Figure 5). At this
point, the initiation phase of translation is complete.
Elongation
Figure 7: Each successive tRNA leaves behind an amino acid that links
in sequence. The resulting chain of amino acids emerges from the top of
the ribosome.
The next step in translation, called elongation, begins when the ribosome shifts to the next codon on the mRNA. At this
point, the corresponding tRNA binds to this codon and, for a short time, there are two tRNA molecules on the mRNA strand.
The amino acids carried by these tRNA molecules are then bound together. After this binding has occurred, the ribosome
shifts again, and the first tRNA, which is no longer connected to its corresponding amino acid, is released (Figure 6). Now,
the third codon in the mRNA strand is ready to bind with the appropriate tRNA (Figure 7). Once again, the tRNA binds to the
mRNA strand, the third amino acid is added to the series, the ribosome shifts, and the second tRNA (which no longer carries
an amino acid) is released. This process is repeated along the entire length of the mRNA, thereby elongating the polypeptide
chain that is emerging from the top of the ribosome (Figure 8).
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Termination
Eventually, after elongation has proceeded for some time, the ribosome comes to a stop codon, which signals the end of the
genetic message. As a result, the ribosome detaches from the mRNA and releases the amino acid chain. This marks the final
phase of translation, which is called termination (Figure 9).
Unit 1
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2.1 Introduction: How Does DNA Move from Cell to Cell? Prev Page Prev Page
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Cell division is the mechanism by which DNA is passed from one generation of cells to the next and ultimately, from parent
organisms to their offspring. Although eukaryotes and prokaryotes both engage in cell division, they do so in different ways.
In particular, eukaryotic cells divide using the processes of mitosis and meiosis. Mitosis is common to all eukaryotes; during
this process, a parent cell splits into two genetically identical daughter cells, each of which contains the same number of
chromosomes as the parent cell. Meiosis, on the other hand, only occurs in eukaryotic organisms that reproduce sexually.
During meiosis, the cells needed for sexual reproduction divide to produce new cells called gametes. Gametes contain half as
many chromosomes as the other cells in the organism, and each gamete is genetically unique because the DNA of the parent
cell is shuffled before the cell divides. This helps ensure that the new organisms formed as a result of sexual reproduction are
also unique.
Unlike eukaryotes, prokaryotes (which include bacteria) undergo a type of cell division known as binary fission. In some
respects, this process is similar to mitosis; it requires replication of the cell's chromosomes, segregation of the copied DNA,
and splitting of the parent cell's cytoplasm. However, binary fission is less complex than mitosis due to the fact that
prokaryotic cells have a simpler structure than eukaryotic cells.
This unit concentrates primarily on the two types of cell division used by eukaryotes. It begins by explaining the major steps
involved in mitosis, and it next examines the major similarities and differences between this process and meiosis. The unit
then explores recombination and mutation two of the primary reasons why daughter cells don't always contain the same
DNA as their parent cells.
Unit 2
Key Questions Introduction: How Does DNA
Where can I learn more about Move from Cell to Cell?
what happens to DNA during
cell division? Replication and Distribution of
DNA during Mitosis
Key Concepts
DNA Replication and Distribution of
DNA during Meiosis
mitosis
DNA Is Constantly Changing
meiosis through the Process of
Recombination
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Most cells grow, perform the activities needed to survive, and divide to create new cells. These basic processes, known
collectively as the cell cycle, are repeated throughout the life of a cell. Of the various parts of the cell cycle, the division
portion is particularly important, because this is the point at which a cell passes its genetic information to its offspring cells.
In many situations, division also ensures that new cells are available to replace the older cells within an organism whenever
those cells die.
Prokaryotic cells, which include bacteria, undergo a type of cell division known as binary fission. This process involves
replication of the cell's chromosomes, segregation of the copied DNA, and splitting of the parent cell's cytoplasm. The
outcome of binary fission is two new cells that are identical to the original cell.
In contrast to prokaryotic cells, eukaryotic cells may divide via either mitosis or meiosis. Of these two processes, mitosis is
more common. In fact, whereas only sexually reproducing eukaryotes can engage in meiosis, all eukaryotes regardless of
size or number of cells can engage in mitosis. But how does this process proceed, and what sorts of cells does it produce?
Prophase
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Prometaphase
After prophase is complete, the cell enters prometaphase. During prometaphase, the nuclear membrane disintegrates and the
mitotic spindle gains access to the chromosomes. During this phase, a protein structure called the kinetochore is associated
with the centromere on each sister chromatid. Stringlike structures called microtubules grow out from the spindle and
connect to the sister chromatids at their kinetochores; one microtubule from one side of the spindle attaches to one sister
chromatid in each chromosome, and one microtubule from the other side of the spindle attaches to the other sister chromatid
(Figure 3a).
Metaphase
Following prometaphase, metaphase begins. At the start of metaphase, the microtubules arrange the chromosomes in a line
along the equator of the cell, known as the metaphase plate (Figure 3b). The centrosomes, on opposite poles of the cell, then
prepare to separate the sister chromatids.
Anaphase
After metaphase is complete, the cell enters anaphase. During anaphase, the microtubules attached to the kinetochores
contract, which pulls the sister chromatids apart and toward opposite poles of the cell (Figure 3c). At this point, each
chromatid is considered a separate chromosome.
Telophase
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Therefore, mitosis ensures that each successive cellular generation has the same genetic composition as the previous
generation, as well as an identical chromosome set.
Unit 2
Key Questions Introduction: How Does DNA
How do centromeres work? Move from Cell to Cell?
Whats the difference between Replication and Distribution of
mitosis and meiosis? DNA during Mitosis
Key Concepts What happens during mitosis?
chromosomes Why is mitosis important?
replication Watch this historic video from
meiosis 1960 to see mitosis in action
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Like mitosis, meiosis is a form of eukaryotic cell division. However, these two processes distribute genetic material among
the resulting daughter cells in very different ways. Mitosis creates two identical daughter cells that each contain the same
number of chromosomes as their parent cell. In contrast, meiosis gives rise to four unique daughter cells, each of which has
half the number of chromosomes as the parent cell. Because meiosis creates cells that are destined to become gametes (or
reproductive cells), this reduction in chromosome number is critical without it, the union of two gametes during
fertilization would result in offspring with twice the normal number of chromosomes!
Apart from this reduction in chromosome number, meiosis differs from mitosis in yet another way. Specifically, meiosis
creates new combinations of genetic material in each of the four daughter cells. These new combinations result from the
exchange of DNA between paired chromosomes. Such exchange means that the gametes produced through meiosis exhibit an
amazing range of genetic variation.
Finally, unlike mitosis, meiosis involves two rounds of nuclear division, not just one. Despite this fact, many of the other
events of meiosis are similar to those that occur in mitosis. For example, prior to undergoing meiosis, a cell goes through an
interphase period in which it grows, replicates its chromosomes, and checks all of its systems to ensure that it is ready to
divide. Like mitosis, meiosis also has distinct stages called prophase, metaphase, anaphase, and telophase. A key difference,
however, is that during meiosis, each of these phases occurs twice once during the first round of division, called meiosis I,
and again during the second round of division, called meiosis II.
Prophase I
Figure 1: Recombination is
the exchange of genetic
material between
homologous chromosomes.
During prophase I, the chromosomes condense and become visible inside the nucleus. Because each chromosome was
duplicated during the S phase that occurred just before prophase I, each now consists of two sister chromatids joined at the
centromere. This arrangement means that each chromosome has the shape of an X.
Once this chromosomal condensation has occurred, the members of each chromosome pair (called homologous
chromosomes, because they are similar in size and contain similar genes), align next to each other. At this point, the two
chromosomes in each pair become tightly associated with each other along their lengths in a process called synapsis. Then,
while the homologous chromosomes are tightly paired, the members of each pair trade adjacent bits of DNA in a process
called crossing over, also known as recombination (Figure 1). This trading of genetic material creates unique chromosomes
that contain new combinations of alleles.
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At the end of prophase I, the nuclear membrane finally begins to break down. Outside the nucleus, the spindle grows out
from centrosomes on each side of the cell. As in mitosis, the microtubules of the spindle are responsible for moving and
arranging the chromosomes during division.
Metaphase I
Anaphase I
Telophase I
Interkinesis
At this point, the first division of meiosis is complete. The cell now rests for a bit before beginning the second meiotic
division. During this period, called interkinesis, the nuclear membrane in each of the two cells reforms around the
chromosomes. In some cells, the spindle also disintegrates and the chromosomes relax (although most often, the spindle
remains intact). It is important to note, however, that no chromosomal duplication occurs during this stage.
Prophase II
As prophase II begins, the chromosomes once again condense into tight structures, and the nuclear membrane disintegrates.
In addition, if the spindle was disassembled during interkinesis, it reforms at this point in time.
Metaphase II
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Anaphase II
Figure 6: Anaphase II
involves separation of the
sister chromatids.
During anaphase II, microtubules from each spindle attach to each sister chromatid at the kinetochore. The sister chromatids
then separate, and the microtubules pull them to opposite poles of the cell. As in mitosis, each chromatid is now considered a
separate chromosome (Figure 6). This means that the cells that result from meiosis II will have the same number of
chromosomes as the "parent" cells that entered meiosis II.
Telophase II
Meiosis is important because it ensures that all organisms produced via sexual reproduction contain the correct number of
chromosomes. Meiosis also produces genetic variation by way of the process of recombination. Later, this variation is
increased even further when two gametes unite during fertilization, thereby creating offspring with unique combinations of
DNA. This constant mixing of parental DNA in sexual reproduction helps fuel the incredible diversity of life on Earth.
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Unit 2
Key Questions Introduction: How Does DNA
How did sexual reproduction Move from Cell to Cell?
evolve?
Replication and Distribution of
What happens when meiosis DNA during Mitosis
goes wrong?
Replication and Distribution of
Key Concepts DNA during Meiosis
chromosome What happens during meiosis I?
meiosis What happens during meiosis
haploid II?
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2.4 DNA Is Constantly Changing through the Process of Recombination Prev Page
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Recombination occurs when two molecules of DNA exchange pieces of their genetic material with each other. One of the
most notable examples of recombination takes place during meiosis (specifically, during prophase I), when homologous
chromosomes line up in pairs and swap segments of DNA. This process, also known as crossing over, creates gametes that
contain new combinations of genes, which helps maximize the genetic diversity of any offspring that result from the eventual
union of two gametes during sexual reproduction.
Genetic diversity occurs because certain physical characteristics, like eye color, are variable; this variability is the result of
alternate DNA sequences that code for the same physical characteristic. These sequences are commonly referred to as alleles.
The various alleles associated with a specific trait are only slightly different from one another, and they are always found at
the same location (or locus) within an organism's DNA. For example, no matter whether a person has blue eyes, brown eyes,
or green eyes, the alleles for eye color are found in the same area of the same chromosome in all humans. The unique
combination of alleles that all sexually reproducing organisms receive from their parents is the direct result of recombination
during meiosis.
Recombination isn't limited to eukaryotes, however. A special type of recombination called conjugation occurs in many
prokaryotes, and it has been particularly well studied and characterized in E. coli bacteria. During conjugation, genetic
material from one bacterium is transferred to another bacterium, and it is then recombined in the recipient cell.
Recombination also plays important roles in DNA repair in prokaryotic organisms, just as it does in eukaryotic organisms.
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Unit 2
Key Questions Introduction: How Does DNA
How are recombination and Move from Cell to Cell?
sexual reproduction related?
Replication and Distribution of
Can errors in DNA be repaired? DNA during Mitosis
How did Barbara McClintock Replication and Distribution of
discover recombination? DNA during Meiosis
Key Concepts DNA Is Constantly Changing
DNA through the Process of
meiosis Recombination
What happens during
mitosis recombination?
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2.5 DNA Is Constantly Changing through the Process of Mutation Prev Page
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DNA is a dynamic and adaptable molecule. As such, the nucleotide sequences found within it are subject to change as the
result of a phenomenon called mutation. Depending on how a particular mutation modifies an organism's genetic makeup, it
can prove harmless, helpful, or even hurtful. Sometimes, a mutation may even cause dramatic changes in the physiology of
an affected organism. Of course, in order to better understand the varying effects of mutations, it is first necessary to
understand what mutations are and how they occur.
Base substitution
Base substitutions are the simplest type of gene-level mutation, and they involve the swapping of one nucleotide for another
during DNA replication. For example, during replication, a thymine nucleotide might be inserted in place of a guanine
nucleotide. With base substitution mutations, only a single nucleotide within a gene sequence is changed, so only one codon
is affected (Figure 1).
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Insertions and deletions are two other types of mutations that can affect cells at the gene level. An insertion mutation
occurs when an extra nucleotide is added to the DNA strand during replication. This can happen when the replicating strand
"slips," or wrinkles, which allows the extra nucleotide to be incorporated (Figure 2). Strand slippage can also lead to deletion
mutations. A deletion mutation occurs when a wrinkle forms on the DNA template strand and subsequently causes a
nucleotide to be omitted from the replicated strand (Figure 3).
Frameshift mutations
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Methionine-Lysine-Leucine-Arginine-Arginine-Methionine-Methionine-Methionine
Figure 5: This sequence of mRNA codes for the amino acids methionine-lysine-leucine-arginine-
arginine-methionine-methionine-methionine.
Now, suppose that a mutation occurs during replication, and it results in deletion of the fourth nucleotide in the sequence.
When separated into triplet codons, the nucleotide sequence would now read as follows (Figure 6):
This series of codons would encode the following sequence of amino acids:
Methionine-Asparagine-Phenylalanine-Alanine-Glycine-STOP-STOP
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Figure 6: If the fourth nucleotide in the sequence is deleted, the reading frame shifts and the
amino acid sequence changes to methionine-asparagine-phenylalanine-alanine-glycine-STOP-
STOP
Each of the stop codons tells the ribosome to terminate protein synthesis at that point. Consequently, the mutant protein is
entirely different due to the deletion of the fourth nucleotide, and it is also shorter due to the appearance of a premature stop
codon. This mutant protein will be unable to perform its necessary function in the cell.
Mutations are a source of genetic diversity in populations, and, as mentioned previously, they can have widely varying
individual effects. In some cases, mutations prove beneficial to an organism by making it better able to adapt to
environmental factors. In other situations, mutations are harmful to an organism for instance, they might lead to increased
susceptibility to illness or disease. In still other circumstances, mutations are neutral, proving neither beneficial nor
detrimental outcomes to an organism. Thus, it is safe to say that the ultimate effects of mutations are as widely varied as the
types of mutations themselves.
Watch these videos for a summary of the different types of gene-level mutation
Unit 2
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2.6 Some Sections of DNA Do Not Determine Traits, but Affect the Process of Transcription: Gene
Regulation
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The genetic code is universal and contains the instructions for all life on Earth. But the diversity of life relies on more than
just the genetic code itself it also relies on the variety of ways in which this code is used in different organisms. In much
the same way that an orchestra depends upon a conductor to direct the individual musicians, all cells depend upon regulatory
mechanisms to determine which of their genes are "turned on" and which are "turned off" at any given time. In other words,
these regulatory mechanisms control gene expression.
But why is this control necessary? To better understand the answer to this question, consider the example of a skin cell and a
brain cell located within the same organism. Both of these cells contain the same set of genetic information, but each has a
unique function within the organism. Both cells, for instance, carry the gene associated with skin pigmentation, but only the
skin cell actually expresses this particular gene and produces the pigment. In order for this gene to be expressed by the skin
cell, it must be transcribed into mRNA and then translated into protein and regulatory mechanisms are what trigger the
transcription of this particular gene to occur (or not occur, in the case of the brain cell). In fact, regulatory mechanisms are the
reason why some genes are expressed in every cell in an organism regardless of type, but other genes are expressed by only
certain types of cells under specific sets of circumstances.
Turning genes on
One especially well-known operon is the lac operon found in E. coli bacteria. This operon contains the three genes E. coli
cells need to break down lactose. (Lactose is a sugar molecule that these cells often use as a source of energy.) When lactose
is not present in a bacterium's environment, the protein products of these three genes aren't needed. As a result, a repressor
protein binds to the operator of the lac operon and blocks transcription of the three genes. In contrast, when lactose is
present, a molecule of this sugar binds to the repressor protein and changes its shape. The shape change prevents the
repressor from binding to the operator, thereby permitting transcription of the three genes in the lac operon to occur. In this
case, lactose itself "turns on" the genes of the lac operon, which means that it acts as an inducer.
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one major difference specifically, the repressor protein in this system only binds with the operator sequence when
tryptophan is present. Here, tryptophan binds with the repressor, thereby changing the repressor's shape such that it fits with
the operator. This means that tryptophan acts as a co-repressor, because it helps turn the genes of the trp operon off.
Figure 1: Eukaryotic cells must tightly fold their DNA so that it fits
within the cellular nucleus.
Eukaryotic cells contain a large amount of DNA, and they must tightly fold this DNA to fit it inside the cellular nucleus
(Figure 1). One consequence of this folding, however, is that under normal circumstances, RNA polymerase cannot bind to
promoter sequences and trigger transcription of the related genes. Thus, by selectively unfolding certain segments of their
DNA at certain times, eukaryotic cells can control gene expression simply by making promoter sequences accessible to
binding by RNA polymerase. In addition, some cells produce and transcribe multiple RNA copies of important genes, which
results in the production of large amounts of protein product.
In some cases, transcription occurs, but the resulting mRNA is not translated exactly as it was created. This is the result of
another control mechanism known as alternative splicing. Splicing is a normal process by which noncoding regions of a
gene, known as introns, are cut out of a segment of mRNA. In alternative splicing, some of the coding regions are cut out as
well, which results in the eventual creation of a different protein than originally coded for in the DNA. Specific conditions
within a cell dictate which coding sequences to remove, and alternative splicing can result in the creation of many different
proteins from only a single gene.
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After a gene has been transcribed, control mechanisms can still regulate its expression during the translation process. Within
eukaryotes, special repressor proteins can bind to mRNA molecules and physically block their translation. In addition, after
translation, unneeded proteins may be marked for degradation by certain molecules before they have the opportunity to do
their job.
Unit 2
Key Questions Introduction: How Does DNA
What else is there to know Move from Cell to Cell?
about operons?
Replication and Distribution of
How do environmental DNA during Mitosis
influences affect gene
expression? Replication and Distribution of
DNA during Meiosis
What role does noncoding RNA
play in gene expression? DNA Is Constantly Changing
through the Process of
How do genes express and Recombination
regulate themselves?
DNA Is Constantly Changing
Key Concepts through the Process of Mutation
intron
Some Sections of DNA Do Not
exon Determine Traits, but Affect the
splicing Process of Transcription: Gene
Regulation
transcription factor Promoters and proteins
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3.1 Introduction: How Is Genetic Information Passed between Organisms? Prev Page
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Inheritance is the passing of traits from parents to offspring. Our modern understanding of inheritance comes from a set of
principles proposed by Austrian monk and researcher Gregor Mendel in 1865. Interestingly, Mendel didn't arrive at these
principles by studying human beings, but rather by studying the common pea plant, Pisum sativum. Although scientists
now know that there are many exceptions to the patterns Mendel described, these principles describe the simplest
mechanisms of inheritance. Moreover, because these so-called principles of Mendelian genetics hold true for organisms of
many different types (including humans), they serve as the foundation for scientists' current understanding of heredity.
This unit takes a closer look at the concept of inheritance. It begins with a description of Mendel's basic principles, each of
which is illustrated with the fruit fly Drosophila melanogaster, an insect that is widely used in the field of modern
genetics. The unit then examines how variability in inheritance patterns can help researchers understand and test relationships
between genes. Finally, the unit concludes with a discussion of how inheritance can involve different mechanisms in different
organisms, including bacteria.
Unit 3
Key Questions Introduction: How Is Genetic
Where can I learn more about Information Passed between
how DNA is inherited? Organisms?
Key Concepts Each Organism's Traits Are
inheritance Inherited from a Parent through
Mendelian trait Transmission of DNA
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3.2 Each Organism's Traits Are Inherited from a Parent through Transmission of DNA
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Drosophila chromosome
Scientists first discovered chromosomes in the nineteenth century, when they were gazing at cells through light microscopes.
But how did they figure out what chromosomes do? And how did they link chromosomes and the specific genes within
them to the concept of inheritance? After a long period of observational studies through microscopes, several experiments
with fruit flies provided the first evidence.
What is a gene?
Physically, a gene is a segment (or segments) of a chromosome. Functionally, a gene can play many different roles within a
cell. Today, most scientists agree that genes correspond to one or more DNA sequences that carry the coding information
required to produce a specific protein, and that protein in turn carries out a particular function within the cell. Scientists also
know that the DNA that makes up genes is packed into structures called chromosomes, and that somatic cells contain twice as
many chromosomes as gametes (i.e., sperm and egg cells).
But what were the key scientific discoveries that helped establish these principles? As it turns out, the connections between
genes, chromosomes, DNA, and heredity were not recognized until long after researchers caught their initial glimpse of
chromosomes. The following sections present an abbreviated summary of the major discoveries that revealed these
connections.
Gregor Mendel
Charles Darwin
Researchers began hypothesizing about the existence of genes as early as the mid-1800s although they used different
terminology than today's scientists when doing so. For example, during the 1860s, Austrian monk and scientist Gregor
Mendel examined how certain physical characteristics of pea plants (e.g., seed color, seed shape, flower color, etc.), which he
called traits, were passed down to successive generations. Mendel speculated that the cells that made up the pea plants
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contained material that carried the information about these traits from one generation to the next. Mendel called this material
"elementen," and he proposed that during sexual reproduction, each parent contributed a form of elementen to the resulting
offspring. This combination of parental elementen then determined which form of a trait was visible in the offspring.
Around the same time, British biologist Charles Darwin independently proposed that traits could be passed on to successive
generations in packets he referred to as "gemmules." Darwin also speculated that gemmules traveled from every body part to
the sexual organs, where they were stored. The most remarkable feature of both Mendel's and Darwin's proposals is that
neither of the two scientists knew about nucleotides or about any of the biochemical substances that are now widely
recognized as DNA.
After Mendel and Darwin put their ideas forward, several other scientists reported their own discoveries about the ways in
which the appearance of the cellular nucleus changed during cell division. Although these scientists' observations connected
genes to chromosomes, they still didn't use the word "gene" to represent what Mendel called "elementen" or what Darwin
called "gemmules." The concept of the "chromosome," however, was rapidly becoming much clearer.
Describing chromosomes
In 1882, German biologist Walther Flemming was the first person to describe what scientists now know as chromosomes.
Flemming's elegant drawings showed how chromosomes aligned and were eventually pulled apart during mitosis (Figure 1).
Then, in 1914, another German researcher named Theodor Boveri provided the first descriptions of meiosis, also supported
by detailed drawings, except these drawings showed how the number of chromosomes in a parent cell was reduced by half in
the resulting gametes.
Walter Sutton
Scientists now knew how chromosomes behaved during both mitosis and meiosis, but they still hadn't linked Mendel's ideas
of heredity with these observations.
Some thirty-five years after Mendel's work, however, American researcher Walter Sutton proposed a connection between
trait inheritance and the path that chromosomes travel during meiotic cell division and gamete formation. In particular, when
observing meiotic cells in the testes of the lubber grasshopper (Brachystola magna), Sutton noted that it was possible to
distinguish and track the individual chromosomes in these cells. He also noticed that these chromosomes existed in pairs that
could be distinguished from other pairs by their size, and that upon the union of two gametes during fertilization, the
chromosomes in the newly fertilized cell maintained their original forms. Sutton therefore proposed that all chromosomes
have a stable structure, or "individuality," that is maintained between generations. Bringing the idea full circle, Sutton also
concluded that the association of paternal and maternal chromosomes in pairs after gamete fusion, and their subsequent
separation during the reducing division of meiosis, "may constitute the physical basis of the Mendelian law of heredity."
With these words, Sutton first articulated what is now known as the chromosome theory of inheritance.
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heredity through multiple series of breeding experiments with fruit flies, and in doing so, they hoped to discover exactly how
heredity was or was not related to chromosomes. Eventually, the answer to this question became clear-all because of the
appearance of a lone fly with unusually colored eyes.
Summary
Walther Flemming
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When considered in view of all this information, the chromosome theory of inheritance was not the work of a single scientist.
Rather, the theory was built on collaboration between multiple researchers working over a period of many decades. The seeds
of this theory were first planted in the 1860s, when Gregor Mendel and Charles Darwin each proposed possible physical
elements of heredity. It wasn't until several decades later, following Walther Flemming's discovery of chromosomes and
description of their behavior during mitosis, that a probable mechanism for the transmission of traits was uncovered.
Subsequently, Theodor Boveri and Walter Sutton's research strengthened the idea of a connection between chromosomes and
hereditary elements. But direct evidence that explicitly demonstrated that traits exist on specific chromosomes wasn't
delivered until the Morgan lab's experiments with fruit flies at the beginning of the twentieth century. Thus, after nearly fifty
years of speculation, scientists were finally able to confirm what they had long suspected: chromosomes are indeed the
physical carriers of hereditary information, and this information exists in the form of genes.
Unit 3
Key Questions Introduction: How Is Genetic
What else can go wrong with Information Passed between
chromosomes in meiosis? Organisms?
How do meiosis and mitosis Each Organism's Traits Are
differ in the transmission of Inherited from a Parent through
genes? Transmission of DNA
Key Concepts What is a gene?
meiosis The first words for genes:
gametes Elementen and gemmules
Summary
Inheritance of Traits by
Offspring Follows Predictable
Rules
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3.4 Some Genes Are Transmitted to Offspring in Groups via the Phenomenon of Gene Linkage
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Figure 1: A classic Mendelian example of independent assortment: the 9:3:3:1 phenotypic ratio associated with a dihybrid cross
(BbEe BbEe).
In another example of Mendel's independent assortment principle, a test cross between a heterozygous BbEe fly and a
homozygous bbee fly will yield offspring with only four possible genotypes (BbEe, Bbee, bbEe, and bbee) and four possible
phenotypes (brown body with red eyes, brown body with brown eyes, black body with red eyes, and black body with brown
eyes), as shown in Figure 2. Thus, in this case, the ratio of phenotypes observed among the offspring will be 1 (brown body,
red eyes): 1 (brown body, brown eyes): 1 (black body, red eyes): 1 (black body, brown eyes).
Figure 2: This 1:1:1:1 phenotypic ratio is the classic Mendelian ratio for a test cross in which the alleles of the two genes assort
independently into gametes (BbEe bbee).
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gene alleles are much less likely to segregate independently into gametes. In addition, if two genes are linked in this way,
then gametes are more likely to contain specific allele combinations. In this example, those combinations of alleles are BV
and bv. As such, the heterozygous parent produces more BV and bv gametes than Bv and bV gametes. (Recall that the
homozygous parent can only produce bv gametes.) This is why, when the BbVv fly is crossed with the bbvv fly, the
resulting offspring are more likely to have BbVv and bbvv genotypes than Bbvv and bbVv genotypes, and the observed
phenotypic ratio is 5:1:1:5. In fact, because the alleles do not assort independently into gametes during meiosis, Punnett
squares like the ones shown in Figures 2 and 3 cannot be used to accurately predict inheritance patterns for crosses involving
linked genes.
To return to the fruit fly example, linkage means that the BbVv parent is more likely to produce gametes that match those
contributed by its own parents: BV and bv. Therefore, offspring with parental genotypes (BbVv and bbvv) are more common
than offspring with non-parental, or recombinant, genotypes (Bbvv and bbVv) after the test cross. This means the parental
genotypes and their corresponding phenotypes are observed five times more often than the recombinant genotypes and their
corresponding phenotypes.
Summary
What is the lesson to be learned from the body color-wing length example? In short, whenever two genes are linked because
of their location on a chromosome, their alleles will not segregate independently during gamete formation. As a result, test
crosses involving alleles of linked genes will yield phenotypic ratios that stray from the classic Mendelian ratios. Also in the
case of linked genes, the phenotypic ratio will show higher numbers of offspring with the parental genotypes than offspring
with the recombinant genotypes.
Breeding flies is an exciting way to learn genetics. There are many possible allele combinations within a fruit fly, and you
can explore them via the interactive image below. Just click on a genotype button from each category below to make your
own customized fly (Drosophila melanogaster).
Unit 3
Key Questions Introduction: How Is Genetic
Who discovered gene linkage? Information Passed between
What is sex linkage in flies? Organisms?
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Exceptions to independent
assortment
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In humans and many other animal species, sex is determined by specific chromosomes. How did researchers discover these
so-called sex chromosomes? The path from the initial discovery of sex chromosomes in 1891 to an understanding of their
true function was paved by the diligent efforts of multiple scientists over the course of many years. As often happens during a
lengthy course of discovery, scientists observed and described sex chromosomes long before they knew their function.
Figure 1: Cell division observed through the microscope (left) is redrawn to show the action of
chromosomes (right). Arrows indicate the axis along which the cell divides.
The first indication that sex chromosomes were distinct from other chromosomes came from experiments conducted by
German biologist Hermann Henking in 1891. While using a light microscope to study sperm formation in wasps, Henking
noticed that some wasp sperm cells had 12 chromosomes, while others had only 11 chromosomes. Also, during his
observation of the stages of meiosis leading up to the formation of these sperm cells, Henking noticed that the mysterious
twelfth chromosome looked and behaved differently than the other 11 chromosomes. Accordingly, he named the twelfth
chromosome the "X element" to represent its unknown nature. Interestingly, when Henking used a light microscope to study
egg formation in female grasshoppers, he was unable to spot the X element.
Based on his observations, Henking hypothesized that this extra chromosome, the X element, must play some role in
determining the sex of insects. However, he was unable to gather any direct evidence to support his hypothesis.
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XX-XO system found in crickets, grasshoppers, and some other insects, sperm cells that lack an X chromosome (referred to
as O) determine maleness. Here, females carry two X chromosomes (XX) and only produce gametes with X chromosomes.
Males, on the other hand, carry only one X chromosome (XO) and produce some gametes with X chromosomes and some
gametes with no sex chromosomes at all (Figure 5).
Figure 7: A side-by-side comparison of sex determination systems in humans, insects, and birds.
The variety of inheritance patterns described in this article illustrate that sex determination is a complex and varied feature
among organisms. The XX-XY, XX-XO, and ZZ-ZW systems are only a sample of the wide variety of sex determination
systems that scientists have documented in the wide world of living beings, however.
Unit 3
Key Questions Introduction: How Is Genetic
How can environmental Information Passed between
conditions determine sex in Organisms?
some animals?
Each Organism's Traits Are
What have honeybees taught Inherited from a Parent through
scientists about sex Transmission of DNA
determination?
Inheritance of Traits by
What do transgenic mice reveal Offspring Follows Predictable
about sex reversal? Rules
Key Concepts Some Genes Are Transmitted to
sex chromosomes Offspring in Groups via the
X chromosome Phenomenon of Gene Linkage
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3.6 Some Organisms Transmit Genetic Material to Offspring without Cell Division
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Prokaryotes, which include bacteria and single-celled microorganisms called Archaea, usually pass their chromosomal DNA
on to their offspring asexually. In other words, a bacterial cell reproduces by simply replicating its chromosome and dividing
into two daughter cells. The daughter cells that result from this division are genetically identical to each other and to the
original parent cell. Thus, over time, asexual reproduction in bacteria can lead to a population of hundreds of thousands of
cells, all of which are genetically identical to a lone original parent cell.
Given their asexual method of reproduction, it is tempting to think that bacteria are sorely lacking in genetic variation, but
this is not the case. Prokaryotic cells have developed a number of methods for recombining their genetic material, which, in
turn, contributes to their genetic diversity. The three most common ways that bacteria diversify their DNA are
transformation, conjugation, and transduction. However, not all types of bacterial cells are capable of engaging in all three
processes.
Transformation
Transformation is a process by which a susceptible or "competent" bacterial cell acquires new genetic material from its
environment. There are two types of transformation: natural and artificial. But where does the environmental DNA required
for transformation come from? And how does this DNA become part of a bacterium's genome?
Natural transformation, as its name implies, is a natural mechanism used by some bacterial cells to take up DNA from the
environment. This environmental DNA was, at one point, located in other bacteria. For instance, when bacteria die and
disintegrate, their chromosomal DNA is released. Fragments of this DNA remain in the environment and are freely available
to other living cells, including other bacteria. These naturally occurring DNA fragments can enter a living bacterium through
its cell membrane, after contact with that membrane. If the DNA is double stranded, one of the strands will pass across the
cell membrane into the cell, and the other strand will be dissolved, or hydrolyzed. Parts of the newly introduced single-
stranded DNA molecule may then recombine with similar regions on the bacterial chromosome and become incorporated into
the bacterium's genome.
In contrast, during artificial transformation, DNA uptake by bacterial host cells occurs under certain laboratory conditions.
In the lab, scientists often introduce foreign DNA into bacterial cells via transformation in order to study specific genes and
their functions. Typically, these researchers use E. coli cells that have been chemically treated so that their outer cell
membranes are permeable to foreign DNA. In addition, transformation can be induced by electroporation, a process in
which the bacterial host cells are subjected to an electric field that allows molecules to pass more easily across the membrane.
Heat shock is another way that transformation can occur, wherein host cells are exposed to extreme temperatures that also
cause the cell membrane to temporarily allow molecules of foreign DNA into the cell.
Within the lab environment, bacteria are also commonly transformed with sequences of DNA called plasmid vectors. These
naturally occurring DNA molecules are circular, and they can replicate inside a bacterium independent of the bacterial
chromosome (which can also be circular). Plasmid vectors can be used to clone, transfer, and manipulate genes. Often, these
plasmids carry a gene for antibiotic resistance, which means that researchers can select for cells that are resistant to a given
antibiotic in order to determine whether a bacterium has been successfully transformed.
The following animation depicts the process of transformation:
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Conjugation
Conjugation is a process by which one bacterium transfers genetic material to another bacterium through direct contact.
During conjugation, one of the bacterial cells serves as the donor of the genetic material, and the other serves as the recipient.
The donor bacterium carries a circular, double-stranded DNA sequence called the fertility factor, or F-factor. The F-factor
allows the donor to produce a thin, tubelike protuberance called a pilus. The donor uses the pilus to contact the recipient. The
pilus then shortens and draws the two bacteria together, at which time the donor bacterium transfers genetic material to the
recipient bacterium. This genetic material is in the form of a plasmid, or a small, circular piece of non-chromosomal DNA.
The newly transferred genetic material often provides the recipient bacterium with some sort of genetic advantage. In many
cases, conjugation results in the transfer of a plasmid containing an antibiotic resistance gene.
The following animation depicts two bacteria exchanging DNA via conjugation:
Transduction
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Finally, transduction is a process by which a virus transfers genetic material from one bacterium to another bacterium. This
process depends on a specific type of virus called a bacteriophage, which is capable of infecting bacterial cells and using
them as hosts to produce more viruses.
At the beginning of a transduction cycle, a bacteriophage injects its DNA into a host bacterium. The phage DNA then takes
over the host cell's machinery and directs it to synthesize and assemble more phages. During this process, the host cell's DNA
breaks into fragments; after that, the host cell replicates the phage DNA and assembles new phages. Occasionally, some of
the bacterial host cell's DNA is included with the phage DNA during assembly. Once phage assembly is complete, the
bacterial cell breaks open, and the newly assembled phages are released into the environment. This is called a lytic cycle
because the original bacterial host cell is destroyed, or lysed. Later, when one of the newly released bacteriophages infects a
new bacterium, any bacterial DNA that the phage contains may become incorporated into the genome of the new host.
The original bacterial host cell is not always destroyed during transduction, however. In some cases, the phage DNA does not
direct the host cell to produce more phages; instead, it incorporates itself into the chromosomal DNA of the bacterial host
cell. This is called a lysogenic cycle. The phage DNA is then maintained within the bacterial chromosome through many
generations of cell division. Eventually, at a point in the future when conditions are right, the phage DNA removes itself from
the bacterial chromosome and initiates a lytic cycle.
The following animation shows the process of transduction. The first part of the animation depicts a lytic cycle, and the
second part shows a lysogenic cycle:
Unit 3
Key Questions Introduction: How Is Genetic
How is DNA organized in Information Passed between
prokaryotes? Organisms?
Key Concepts Each Organism's Traits Are
prokaryote Inherited from a Parent through
plasmid Transmission of DNA
Inheritance of Traits by
Offspring Follows Predictable
Rules
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Conjugation
Transduction
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4.1 Introduction: How Do We Study the DNA Inside Cells? Prev Page Prev Page
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Scientists began their studies of genes on a small scale. Typically they would conduct research on single genes, then use their
results to hone in on the functions of these genes. Later, newer scientific techniques made it possible for researchers to
analyze multiple genes in concert, and eventually to analyze all of an organism's genes at once.
This unit explores some of the ways in which researchers can use modern laboratory techniques to monitor gene
transcription, expression, and regulation on small and large scales alike. The unit begins with an explanation of two common
processes for determining gene expression Northern blot analysis and serial analysis of gene expression (SAGE) both
of which allow researchers to measure levels of messenger RNA in a sample, and thereby determine which genes are
expressed in the sample and to what degree. Next, the unit examines some of the processes by which researchers have
determined the actual sequence of nucleotides within genes. Here, the unit's primary focus is on the technique known as
Sanger sequencing, wherein DNA replication is used to detect the presence and arrangement of individual nucleotides.
When studying the function of a particular gene, scientists often need large amounts of the DNA sequence of interest in order
to conduct their experiments. Thus, the next portion of this unit describes the sophisticated lab technique called the
polymerase chain reaction (PCR), which enables researchers to rapidly generate multiple copies of genetic sequences.
Thereafter, the unit describes the creation of a gene deletion model called a knockout mouse. By disabling or "knocking out"
specific genes within these mice, researchers are able to uncover a wealth of information about the function of the missing
genes. Lastly, the unit concludes with a look at microarray analysis, a technique that makes it possible to screen for vast
amounts of genes at once, which permits more efficient examination of an organism's entire genome.
Unit 4
Key Questions Introduction: How Do We
Where can I learn more about Study the DNA Inside Cells?
gene expression and regulation?
The Order of Nucleotides in a
Key Concepts Gene Is Revealed by DNA
DNA Sequencing
DNA sequencing Scientists Can Make Copies of
PCR a Gene through PCR
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4.2 The Order of Nucleotides in a Gene Is Revealed by DNA Sequencing Prev Page
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All of the information needed to build and maintain an organism whether it's a human, a dog, or a bacterial cell is
contained in its DNA. DNA molecules are composed of four nucleotides, and these nucleotides are linked together much like
the words in a sentence. Together, all of the DNA "sentences" within a cell contain the instructions for building the proteins
and other molecules that the cell needs to carry out its daily work.
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Adding ddNTPs
Figure 3: By adding together information about all of the truncated strands, researchers can determine the nucleotide sequence of the
DNA target.
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evolutionary history and degree of relatedness. DNA sequencing has also aided complex disease research by allowing
scientists to catalogue certain genetic variations between individuals that may influence their susceptibility to different
conditions.
At the individual level, biomedical research into the cause and course of common human diseases is primed to greatly
improve health care. The application of DNA sequencing to the identification of disease-causing genetic variants will lead to
improvements and expansion in genetic testing, as well as development of more targeted, personalized drug therapies in the
years to come. Already today, the benefits of DNA sequencing can be seen in agriculture thanks to the production of disease-
resistant plants and animals. In addition, microbial genome sequencing projects may someday lead to the development of new
biofuels and pollutant-monitoring systems. DNA sequencing techniques are also used in forensic science, providing crucial
evidence in criminal cases. In the United States, for instance, the Federal Bureau of Investigation (FBI) funds and operates a
national database containing the genetic profiles of known offenders that can be searched whenever DNA evidence is
obtained at a crime scene. According to the FBI, as of 2008, this database had profiles of over 6.5 million offenders and had
assisted in almost 81,000 investigations.
Unit 4
Key Questions Introduction: How Do We
What are some other methods Study the DNA Inside Cells?
for DNA sequencing?
The Order of Nucleotides in a
How much does gene Gene Is Revealed by DNA
sequencing cost? Sequencing
How was the human genome How do researchers "read" gene
sequenced? sequences?
How has the polymerase chain How can all people benefit from
reaction (PCR) revolutionized DNA sequencing?
biotechnology?
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What has genomics done for the Watch this video for a summary
biofuel industry? of the Sanger sequencing
process
What ethical problems does
DNA sequencing raise?
Scientists Can Make Copies of
How is sequencing done on a a Gene through PCR
large scale?
Scientists Can Analyze Gene
Key Concepts Function by Deleting Gene
Human Genome Project Sequences
bioinformatics Gene Expression Is Analyzed
genome by Tracking RNA
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What is PCR?
The key element of PCR is heat. Throughout the PCR process, DNA is subjected to repeated heating and cooling cycles
during which important chemical reactions occur. During these thermal cycles, DNA primers bind to the target DNA
sequence, enabling DNA polymerases to assemble copies of the target sequence in large quantities.
PCR makes it possible to produce millions of copies of a DNA sequence in a test tube in just a few hours, even with a very
small initial amount of DNA. Since its introduction, PCR has revolutionized molecular biology, and it has become an
essential tool for biologists, physicians, and anyone else who works with DNA.
A small amount of DNA that serves as the initial template or target sequence
A pair of primers designed to bind to each end of the target sequence
A DNA polymerase
Four dNTPs (i.e., dATP, dCTP, dGTP, dTTP)
A few essential ions and salts
The PCR process then uses these ingredients to mimic the natural DNA replication process that occurs in cells. To automate
this process, a machine called a thermocycler jump-starts each stage of the reaction by raising and lowering the temperature
of the chemical components at specific times and for a preset number of cycles.
Each cycle of PCR has three main steps, as described in the following sections.
Step 1: Denaturation
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During the first step in PCR, the starting solution is heated to the necessary temperature, usually between 90 and 100C. As
the heat builds, it breaks the bonds joining the two strands of the DNA double helix, thereby enabling the DNA to separate
into two single strands. This "melting" of the DNA into single strands is called denaturation (Figure 2).
Step 2: Annealing
Step 3: Extension
During the final, or extension, stage of PCR, the sample is heated again, usually to between 60and 75C, and it is held at that
temperature for less than one minute. At this point, the DNA polymerase begins making a new DNA strand by attaching to
the primers and then adding dNTPs to the template strand, thereby creating a complementary copy of the target sequence
(Figure 4).
The number of new copies of the DNA sequence of interest doubles with each three-step cycle. Thus, if the PCR process is
repeated 40 or 50 times, even small samples of template DNA can yield millions of identical copies (Figure 5).
Copying and quantifying DNA at the same time using real-time PCR
One modification of conventional PCR allows researchers to copy a particular DNA sequence and quantify it simultaneously.
Dubbed quantitative real-time PCR (qPCR), this technique makes it possible to measure the amount of DNA
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produced during each PCR cycle. This refinement involves the use of fluorescent dyes or probes that label double-stranded
DNA molecules. These fluorescent markers bind to the new DNA copies as they accumulate, making "real-time" monitoring
of DNA production possible.
As the number of gene copies increases with each PCR cycle, the fluorescent signal becomes more intense. Plotting
fluorescence against cycle number and comparing the results to a standard curve (produced by real-time PCR of known
amounts of DNA) enables scientists to determine the amount of DNA present during each step of the PCR reaction.
Real-time PCR can also be used to calculate the amount of specific kinds of genetic material other than DNA, such as RNA.
This extension of real-time PCR technology, called reverse transcription PCR (RT-PCR), combines real-time PCR with
reverse transcription, the process that makes DNA from mRNA. RT-PCR can be used to determine how gene expression
changes over time or under different conditions. For this reason, this technique is sometimes used to verify microarray data.
Unit 4
Key Questions Introduction: How Do We
What is DNA cloning? Study the DNA Inside Cells?
Key Concepts The Order of Nucleotides in a
primer Gene Is Revealed by DNA
DNA polymerase Sequencing
Variations on conventional
PCR
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4.4 Scientists Can Analyze Gene Function by Deleting Gene Sequences Prev Page
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One way to understand the function of a gene is to observe a biological system that lacks that gene. But what is the best
system to use? When studying human genes, researchers typically employ biological systems that approximate these genes
and their functions as closely as possible. In particular, researchers often turn to mice because of all the various model
organisms most commonly used in the lab (e.g. fruit flies and yeast), mice have the genome that most closely resembles that
of humans. Consequently, manipulation of genes within the mouse genome has proven an effective method for learning about
human gene functioning. Indeed, experimentally removing or altering certain genes within a mouse allows for the
examination of a biological system with specific gene alterations.
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Figure 1: The targeting vector is designed to contain both neomycin-resistant and a ganciclovir-sensitive (TK)
sequences.
Currently, the neomycin-resistance gene, called NeoR, is a popular marker gene of choice for generating knockout mice. The
antibiotic neomycin is toxic to mouse cells because they do not normally contain the NeoR gene. However, when the NeoR
gene is added to mouse cells, these cells can survive in the presence of neomycin. Within the targeting vector, the NeoR gene
is located between two other pieces of DNA: the "right arm" and the "left arm" of the targeting vector. The right arm of the
targeting vector contains DNA with a nucleic acid sequence that matches the stretch of DNA immediately before the gene
segment that will be deleted. The left arm of the targeting vector contains DNA with a nucleic acid sequence that matches the
stretch of DNA immediately after the gene segment that will be deleted. The right and left arms of the targeting vector
facilitate homologous recombination between the targeting vector and the target gene, thereby enabling the NeoR gene to
replace the target gene segment.
The targeting vector also contains one additional piece of DNA, called a negative selection marker gene. This gene is
located at the right end of the targeting vector, after the right arm. The thymidine kinase (TK) gene from the herpes simplex
virus is the most commonly used negative selection marker gene. Normally, mouse cells can grow in the presence of the
antiviral drug ganciclovir. The TK gene is considered a "cell suicide gene," however, as cells containing the TK gene convert
ganciclovir into a lethal toxin.
Why is it necessary to include a cell suicide gene as part of the targeting vector? The reason is purely a matter of
identification - specifically, the TK gene helps researchers locate cells that have correctly replaced the targeted gene segment
with the NeoR gene. Often, mouse cells randomly insert the targeting vector in the wrong chromosomal location. If random
insertion occurs, both the NeoR gene and the TK gene are inserted into the genome. As a result, the cells are resistant to
neomycin, but they die in the presence of ganciclovir. In comparison, when the targeted gene segment is correctly replaced,
the TK gene is not inserted into the chromosome along with the NeoR gene, so the resultant cells are resistant to both
neomycin and ganciclovir. Therefore, the presence of the TK gene in the targeting vector allows researchers to efficiently
screen for mouse cells that have correctly replaced the targeted gene segment by growing these cells in the presence of both
neomycin and ganciclovir.
Step 2: Inserting the target sequence and selecting cells with the insertion
After the targeting vector is made, it is used to knock out one copy of the target gene in mouse embryonic stem (ES) cells
(Figure 2). But why must mouse ES cells be used? Why can't the targeting vector be introduced into any type of mouse cell?
Figure 2: The targeting vector is inserted into the ES cell genome, and disables the target gene.
It is certainly possible to use the targeting vector to knock out one of the two copies of the target gene in a standard somatic
cell. However, unless that cell is an ES cell, the knockout mutation cannot be incorporated into a growing embryo. Therefore,
it would not be possible to study the effects of the knockout mutation in a developing mouse.
What makes ES cells so special? Primarily, it is their ability to become any one of the different adult cell types. When
injected into a mouse embryo, the ES cells themselves are capable of maturing into some of the tissues of the developing
mouse.
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But how, exactly, are targeting vectors delivered into ES cells? Most often, a technique called electroporation is used. When
ES cells are electroporated, a brief pulse of an electrical field is applied to the outside of the cells, creating a momentary
increase in plasma membrane permeability and allowing the uptake of foreign DNA into the ES cells.
After the ES cells have been electroporated, they are grown in the presence of neomycin to select for those particular cells
that have taken up the targeting vector. Next, the neomycin-resistant cells are grown in the presence of ganciclovir to select
for those that have inserted the targeting vector at the correct location within the mouse genome.
Step 4: Injecting heterozygous knockout ES cells into a developing embryo and transferring the embryo into
a mouse
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In September 2006, the U.S. National Institutes of Health (NIH) initiated a five-year, $52 million project called the Knockout
Mouse Project (KOMP). Together with the Texas A&M Institute of Genomic Medicine (TIGM), the North American
Conditional Mouse Mutagenesis Project (NorCOMM) in Canada, and the European Conditional Mouse Mutagenesis
Program (EUCOMM), KOMP set the goal of knocking out every one of the 20,000 mouse protein-encoding genes within
five years.
Similar to the mouse knockout consortia mentioned above, a number of labs have also collaborated to establish standardized
methods for the phenotypic characterization of knockout mice. The European Union Mouse Research for Public Health and
Industrial Applications (EUMORPHIA) group developed the first set of standard phenotyping protocols, which was validated
among several different labs. The European Mouse Phenotypic Resource for Standardized Screens (EMPReSS) then
established the primary phenotypic screen used by the European knockout mouse labs, one that comprises a subset of the
standard protocols of EUMORPHIA.
Future directions
Future studies of knockout mice will continue to yield new and unexpected discoveries regarding the function of mouse
genes and their human counterparts. An increased understanding of human gene function will also lead to the design of more
effective treatments for human disease.
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Unit 4
Key Questions Introduction: How Do We
What is EUMORPHIA? Study the DNA Inside Cells?
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Capturing mRNA
To begin a SAGE analysis, researchers must first separate the mRNA in a sample from the other cellular contents. To do this,
they attach long strips of thymine nucleotides to tiny magnetic beads. When researchers flush the contents of a cell over the
beads, these thymine strips form complementary base pairs with the poly-A tails of the mRNA molecules. Thus, when the
flushing process is complete, the mRNA transcripts from the sample are captured because they are attached to the magnetic
beads, while the other contents of the cells flush past the beads and are discarded.
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In addition to Northern blot tests and SAGE analyses, there are several other techniques for analyzing gene expression. Most
of these techniques, including microarray analysis and reverse transcription polymerase chain reaction (RT-PCR), work by
measuring mRNA levels. However, researchers can also analyze gene expression by directly measuring protein levels with a
technique known as a Western blot.
Unit 4
Key Questions Introduction: How Do We
What do we call the entire set of Study the DNA Inside Cells?
mRNA in a cell or organism?
The Order of Nucleotides in a
What does the transcriptome Gene Is Revealed by DNA
reveal about the genome and Sequencing
gene function?
Key Concepts
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4.6 Scientists Can Study an Organism's Entire Genome with Microarray Analysis
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To compare all the genes of one organism to those of another organism, we must first know how to define the entire gene
sequence of each organism. However, looking at all of an organism's genes can be quite daunting. Sometimes, a better option
is to consider only those genes expressed by an organism, because these genes may represent just a portion of all the genetic
material that the organism contains. That is, an organism may only use a small fraction of its entire genetic sequence,
otherwise known as its genome.
Figure 1: The two temperature conditions for E. coli: normal (left) and
heat-exposed (right).
Gene expression in colonies of E. coli bacteria can change when these colonies are exposed to short periods of intense heat.
But exactly how do the patterns of gene expression differ? What genes are expressed under one condition, and not the other?
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The best way to go about answering this question is to do a microarray analysis of the genomes in each experimental
condition: normal temperature and heat-exposed. The first step is to create the two conditions by exposing one colony of E.
coli to normal temperatures and the other colony to a short burst of high temperature (Figure 1).
Converting RNA
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Figure 6: A photograph of real microarray chip data, arranged in a grid. Multiple chips, such as
the ones shown here, reveal expression data for an entire genome.
Unit 4
Key Questions Introduction: How Do We
What does whole-genome Study the DNA Inside Cells?
microarray look like?
The Order of Nucleotides in a
How have microarrays aided in Gene Is Revealed by DNA
the treatment of cancer? Sequencing
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5.1 Introduction: How Does Inheritance Operate at the Level of Whole Populations? Prev Page
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Population genetics involves the study of populations at the genetic level. A population is made up of members of the
same species that interbreed and live in the same area at the same time. The collective set of all the alleles that exist within a
population is referred to as its gene pool. Changes in the gene pool pave the way for species adaptation, the emergence of
new species, and, ultimately, evolution.
Population genetics involves the study of populations at the genetic level. A population is made up of members of the same
species that interbreed and live in the same area at the same time. The collective set of all the alleles that exist within a
population is referred to as its gene pool. Changes in the gene pool pave the way for species adaptation, the emergence of
new species, and, ultimately, evolution.
This unit provides an introduction to the vast and complex field of population genetics. It begins with the concept of the gene
pool, descriptions concerning the emergence of variations in the gene pool, and the task of measuring these variations. The
unit concludes with an explanation of genetic variation in human populations, as well as a look at the technological advances
that have allowed scientists to explore the human genome.
Unit 5
Key Questions Introduction: How Does
Where can I learn more about Inheritance Operate at the Level
genes at a population level? of Whole Populations?
Key Concepts The Collective Set of Alleles in
Hardy-Weinberg equation a Population Is Its Gene Pool
Hardy-Weinberg equilibrium The Variety of Genes in the
Natural selection Gene Pool Can Be Quantified
within a Population
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5.2 The Collective Set of Alleles in a Population Is Its Gene Pool Prev Page
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The fact that genes exist in alternate forms, called alleles, forms the basis for the study of population genetics. Populations
are made up of members of the same species that interbreed. Population geneticists study the variation that naturally occurs
among the genes within a population. The collection of all the genes and the various alternate or allelic forms of those genes
within a population is called its gene pool.
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each show different wing color and pattern phenotypes (bottom row). This
is a reflection of the variation that exists in the gene pool.
Tropical butterflies provide an excellent example of genetic variation within species. In these butterflies, temperature and
light can influence gene expression. Consequently, wing color and pattern can vary depending on the season during which a
butterfly is born. The top row of Figure 2 shows examples of three different butterfly species. The bottom row shows
butterflies from the same three species, but these individuals were born under different temperature and light conditions than
those in the top row. How can this happen? The differences in wing colors and patterns of butterflies of the same species
reflect the underlying genetic variability within a population. Even though each butterfly within a species has the potential to
develop the wide variety of colors and patterns shown above, its environment influences the phenotypic expression of its
genetic characteristics. The gene pool of each species, therefore, contains a collection of many different alleles whose
phenotype may or may not be observable.
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5.3 The Variety of Genes in the Gene Pool Can Be Quantified within a Population
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Most populations have some degree of variation in their gene pools. By measuring the amount of genetic variation in a
population, scientists can begin to make predictions about how genetic variation changes over time. These predictions can
then help them gain important insights into the processes that allow organisms to adapt to their environment or to develop
into new species over generations, also known as the process of evolution.
Genetic variation is usually expressed as a relative frequency, which means a proportion of the total population under study.
In other words, a relative frequency value represents the percentage of a given phenotype, genotype, or allele within a
population.
Relative phenotype frequency is the number of individuals in a population that have a specific observable trait or
phenotype. To compare different phenotype frequencies, the relative phenotype frequency for each phenotype can be
calculated by counting the number of times a particular phenotype appears in a population and dividing it by the total number
of individuals in the population.
Relative genotype frequency and relative allele frequency are the most important measures of genetic variation. Relative
genotype frequency is the percentage of individuals in a population that have a specific genotype. The relative genotype
frequencies show the distribution of genetic variation in a population. Relative allele frequency is the percentage of all copies
of a certain gene in a population that carry a specific allele. This is an accurate measurement of the amount of genetic
variation in a population.
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[p p] + [2 p q] + [q q]
or
p2 + 2pq + q2
This equation is known as the Hardy-Weinberg equation, and it defines a population in which relative allele frequencies
do not change over successive generations. Such a population is said to be in equilibrium. This state of equilibrium
represented by the Hardy-Weinberg equation is an ideal model against which to compare observed changes in relative allele
and genotype frequencies in natural populations.
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Genetic variation describes naturally occurring genetic differences among individuals of the same species. This variation
permits flexibility and survival of a population in the face of changing environmental circumstances. Consequently, genetic
variation is often considered an advantage, as it is a form of preparation for the unexpected. But how does genetic variation
increase or decrease? And what effect do fluctuations in genetic variation have on populations over time?
Distribution
How does the physical distribution of individuals affect a population? A species with a broad distribution rarely has the same
genetic makeup over its entire range. For example, individuals in a population living at one end of the range may live at a
higher altitude and encounter different climatic conditions than others living at the opposite end at a lower altitude. What
effect does this have? At this more extreme boundary, the relative allele frequency may differ dramatically from those at the
opposite boundary. Distribution is one way that genetic variation can be preserved in large populations over wide physical
ranges, as different forces will shift relative allele frequencies in different ways at either end.
If the individuals at either end of the range reconnect and continue mating, the resulting genetic intermixing can contribute to
more genetic variation overall. However, if the range becomes wide enough that interbreeding between opposite ends
becomes less and less likely, and the different forces acting at either end become more and more pronounced, and the
individuals at each end of the population range may eventually become genetically distinct from one another.
Migration
Migration is the movement of organisms from one location to another. Although it can occur in cyclical patterns (as it does in
birds), migration when used in a population genetics context often refers to the movement of individuals into or out of a
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defined population. What effect does migration have on relative allele frequencies? If the migrating individuals stay and mate
with the destination individuals, they can provide a sudden influx of alleles. After mating is established between the
migrating and destination individuals, the migrating individuals will contribute gametes carrying alleles that can alter the
existing proportion of alleles in the destination population.
Here is an example of migration affecting relative allele frequency:
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Summary
Genetic variation in a population is derived from a wide assortment of genes and alleles. The persistence of populations over
time through changing environments depends on their capacity to adapt to shifting external conditions. Sometimes the
addition of a new allele to a population makes it more able to survive; sometimes the addition of a new allele to a population
makes it less able. Still other times, the addition of a new allele to a population has no effect at all, yet the new allele will
persist over generations because its contribution to survival is neutral.
Unit 5
Key Questions Introduction: How Does
How can genetic variation Inheritance Operate at the Level
influence evolution? of Whole Populations?
What is an example of genetic The Collective Set of Alleles in
drift? a Population Is Its Gene Pool
Key Concepts The Variety of Genes in the
genetic drift Gene Pool Can Be Quantified
population bottleneck within a Population
Distribution
Migration
Summary
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Thinking about population genetics often brings to mind visions of animals in the wild being swept along by the tide of
natural catastrophes, soil depletion, or predation. However, over the past ten years the field of population genetics has
undergone major renovations because of recent advances in gene sequencing and screening technologies. These technological
innovations have allowed scientists to tackle bigger and broader questions related to population trends, and to study genetic
variation on a much broader scale than ever before possible with older methods, such as test crosses, random sampling, and
field work. Today, discoveries can be facilitated by the ever-expanding field of genomics, which is the use of large databases
for the purpose of studying genetic variation on a large scale across many different organisms.
What is genomics?
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After the completion of the HGP in 2003, researchers began to pinpoint locations within the genome that varied among
individuals. These scientists discovered that the most common type of DNA sequence variation found in the human genome
is the single nucleotide polymorphism (SNP, pronounced "snip"). There are approximately 10 million SNPs in the human
genome.
A worldwide effort known as the HapMap Project is mapping SNPs and other genetic variants in human populations around
the world. By mapping the distribution of SNPs among different human populations, researchers can begin to learn which
types of variation are most common in certain regions of the world. This information will help explain human origins and
disease risks as well as how they relate to environmental conditions, both past and present. To date, the HapMap project has
identified over 3.1 million SNPs across the human genome that are common among individuals of African, Asian, and
European ancestry.
The HapMap database has also helped foster a new type of research in personalized medicine called the genome-wide
association study (GWAS). With these studies, the distribution of SNPs is determined in hundreds, or even thousands, of
people with and without a particular disease. Comparisons between diseased and non-diseased groups of individuals help
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determine which SNPs co-occur with disease symptoms. With this information in hand, scientists can carry out statistical
analyses to help predict whether a certain SNP is associated with a specific disease, with the hope of identifying individuals
who may be at risk.
For example, in a recent study conducted in the United Kingdom, researchers genotyped 2,000 individuals who had one of
seven common disorders. Next, those individuals were compared to 3,000 genotyped control individuals who did not have
the common disorders. With these comparisons, the researchers identified new genetic markers associated with increased risk
for disorders such as heart disease and diabetes. In the future this study will be expanded to include 36,000 more individuals,
and it will focus on 14 more health-related disorders as well as individual responses to certain drugs. Using these types of
studies, scientists can sample large numbers of people and make meaningful predictions regarding disease risk for individuals
based on the presence or absence of genetic markers within their genome.
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