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Cellular Consequences
of Evolution
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Cellular Consequences
of Evolution
A. Malcolm Campbell, PhD

Christopher J. Paradise, PhD
Cellular Consequences of Evolution

Copyright © A. Malcolm Campbell and Christopher J. Paradise. 2016.
All rights reserved. No part of this publication may be reproduced, stored

in a retrieval system, or transmitted in any form or by any means—
electronic, mechanical, photocopy, recording, or any other except for
brief quotations, not to exceed 250 words, without the prior permission
of the publisher.
First published in 2016 by

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Abstract
Once the first cell arose on Earth, how did genetic diversity arise if DNA
replication and cell division generate exact copies? The answer is that
neither process is perfect and that changes do occur at each step. Some
changes are small and subtle while others are large and dramatic. As DNA
mutates, evolution of a population takes place. But when can someone
determine if a single species has changed enough to be considered two
separate species? How is a species defined and is this definition useful in
the real world? Real biological data will be examined to confront and an-
swer these questions. Finally, the book examines an example of evolution
that takes place in humans on a regular basis—the mammalian immune
system. White blood cells evolve rapidly to confront any substance that
enters a body and is perceived as a threat. With each exposure, these cells
get better and better at neutralizing the threat.
Keywords
DNA polymerase, allele, whole genome duplication, mutation, natural
selection, single nucleotide polymorphism, dot plot, speciation, insertion,
deletion, horizontal gene transfer, GC content, provirus, copy number
variation, cancer, ploidy, paralogs, genetically modified organisms, allergy,
B cells, antibodies, secondary immune response, memory B cells, survival
signal, somatic hypermutation
Contents
Preface...................................................................................................ix
Acknowledgments....................................................................................xi
Introduction.........................................................................................xiii
Chapter 1 The Origins of New Mutations..........................................1
Chapter 2 The Origins of New Species...............................................7
Large Scale Genome Changes............................................9
Clinical Whole Genome Changes....................................14
Genome Duplication and Speciation................................17
Ethical, Legal, Social Implications: The safety
of GMOs......................................................................19
Chapter 3 Evolution of Allergic Responses........................................23
Ethical, Legal, Social Implications: Balancing the
Rights of the Individual vs. the Group..........................29
Conclusion............................................................................................33
Glossary................................................................................................35
Index....................................................................................................37
Preface
This book about evolution after the first cells were formed is part of a
thirty book series that collectively surveys all of the major themes in
biology. Rather than just present information as a collection of facts, the
reader is treated more like a scientist, which means the data behind the
major themes are presented. Reading any of the thirty books by Campbell
and Paradise provides readers with biological context and comprehensive
perspective so that readers can learn important information from a single
book with the potential to see how the major themes span all size scales:
molecular, cellular, organismal, population and ecologic systems. The major
themes of biology encapsulate the entire discipline: information, evolution,
cells, homeostasis and emergent properties.
In the twentieth century, biology was taught with a heavy emphasis
on long lists of terms and many specific details. All of these details were
presented in a way that obscured a more comprehensive understanding.
In this book, readers will learn about consequence of evolution at the
cellular level and some of the supporting evidence behind our under-
standing. The historic and more recent experiments and data will be
explored. Instead of believing or simply accepting information, readers of
this book will learn about the science behind evolution of cells the same
way professional scientists do—with experimentation and data analysis.
In short, data are put back into the teaching of biological sciences.
Readers of this book who wish to see the textbook version of
this content can go to www.bio.davidson.edu/icb where they will find
pedagogically-designed and interactive Integrating Concepts in Biology for
introductory biology college courses or a high school AP Biology course.
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Acknowledgments
Publishing this book would not have been possible without the generous
gift of Dr. David Botstein who shared some of his Breakthrough Prize
with AMC. David’s gift allowed us to hire talented artists (Tom Webster
and his staff at Lineworks, Inc.) and copyeditor Laura Loveall. Thanks go
to Kristen Mandava for project management and guidance on the pub-
lishing process. In particular, we are indebted to Katie Noble and Melissa
Hayban for their many hours of help and attention to detail.
Kristen Eshleman, Paul Brantley, Bill Hatfield and Olivia Booker
helped us with technology at Davidson College. We are grateful to ad-
ministrators Tom Ross, Clark Ross, Carol Quillen, Wendy Raymond,
Verna Case, and Barbara Lom who had confidence in us and encouraged
us to persist despite setbacks along the way.
These books were the product of the shared labor of my two vision-
ary coauthors Laurie Heyer and Chris Paradise. We shared the dream
and the hardships and developed this book from scratch. My family has
been very supportive and I thank Susan, Celeste and Paulina for their
support and patience. I also want to thank Jan Serie, my pedagogical
mentor, who taught me so much about the art and science of helping
students learn. I benefited from the support of the Howard Hughes Med-
ical Institute grant 52006292, the James G. Martin Genomics Program,
and Davidson College. This book would not have survived its first draft
without my students who endured the typos and the early versions of this
book. These undergraduates participated in a bold experiment to see if
beginners could construct their own knowledge, retain what they learned,
and transform the way they see themselves and the discipline of biology.
While many people said that beginning students were not up to the task,
my students proved them wrong.
Introduction
Over the last twenty years, biologists have produced reliable data and
provided a probable scenario for the origin of life on Earth. When think-
ing of evolution, most people picture dinosaurs and early human hunter
gatherers. However, evolution is not limited to animals or multicellu-
lar organisms. Evolution can happen when populations of cells change
their genotypes over time. The definition of evolution is the change in allele
frequency in a population over time. In this book, the population will
be composed of cells. The DNA content of any population varies due to
the inherent potential for DNA polymerases to make mistakes. As pre-
sented in this book, DNA is subject to many more changes than just
DNA polymerase errors. Furthermore, the human immune system has
evolved to introduce many more mutations in order to provide a better
immune response that evolves over the course of an infection.
Evolution at the cellular level can be rapid, but when a system is
well suited to meet a particular function, the system tends to evolve very
slowly if at all. As the old expression goes, “If it ain’t broke, don’t fix it.”
But it is important to understand the extremes of cellular evolution, rapid
and slow, in order to discuss ethical dilemmas that face humans today.
Are genetically modified organisms (GMOs) always bad or always good?
Should peanut butter be banned from schools even when no child has suf-
fered a severe allergy attack? As a biologist, your family and community
will look to biologists for answers and it is important to understand cellu-
lar evolution in order to provide them with enough information to form
a reasoned opinion. The three chapters of this book focus on evolution at
the cellular level.
CHAPTER 1
The Origins of New

Mutations
Meselson and Stahl’s classic experiment discovered that DNA uses semi-
conservative replication to make new copies. Once semiconservative
DNA replication was known, many biochemists focused their attention
on DNA polymerase to figure out how it works normally and how new
mutations occur. How can a genetic disease appear in offspring if the
parents do not have a disease allele? In other words, how do genetic mu-
tations come into being if most people don’t have the disease and DNA
replication uses one strand to produce a new copy? Of course the answer
is that DNA is not always replicated faithfully, and sometimes mutations
are introduced into DNA. A mutation can be incorporated into DNA,
and once a mutation is formed, it gets replicated as faithfully as any
other portion of the DNA. Investigators wanted to better understand
how often mutations were made in DNA but they had to learn how to
polymerize DNA in vitro first.
David Baltimore and his colleague Donna Smoler wanted to know
how DNA polymerase starts the process of replication. Could DNA
polymerase start anywhere, or did it require some prior DNA on which
to add? To determine what DNA polymerase requires to start polymer-
izing, the investigators mixed equal amounts of E. coli DNA polymerase,
deoxyribonucleotide triphosphates (dNTPs), and DNA template to
three tubes. In addition to all four bases of dNTPs, the investigators
added a small amount of deoxyguanosine triphosphate (dGTP) that
contained radioactive phosphorous (32P-dGTP), which would be incor-
porated into new DNA polymers as 32P-dGMP. Each tube contained a
different amount of DNA primer as the independent variable. During
2 CELLULAR CONSEQUENCES OF EVOLUTION
the reaction, the investigators removed aliquots and quantified the

amount of radioactive dGMP incorporated (dependent variable) into
the newly-formed DNA polymers. The amount of DNA increased over
time, with more DNA formed when more primer was added. Once
they knew it was possible to initiate DNA polymerization by mixing
primers with template DNA, the investigators wanted to characterize
the chemical requirements of primers used by E. coli DNA polymerase.
They set up three reactions as before, but this time they added equal
amounts of three different types of primers. One primer was composed
of normal DNA nucleotides deoxyadenosine monophosphate (dAMP),
the second primer was composed of normal RNA nucleotides adenosine
monophosphate (AMP), and the third primer was composed of a modi-
fied dAMP with its 39 OH group removed.
The two biochemists learned that DNA polymerases require primers
to make new polymers from DNA template. The more primer available,
the more radioactive dGMP was incorporated into new DNA strands.
Under these in vitro experimental conditions, E. coli DNA polymerase
works best if the primer is a polymer of dAMP instead of AMP. Further-
more, the primer must have a 3′ OH group, or the DNA polymerase
cannot add the next nucleotide onto the primer. However, subsequent
research showed that in living cells, the primer is typically composed of
RNA produced by an RNA polymerase as happens during transcription.
The distinction of RNA versus DNA primer is not as important as the
fact that all DNA polymerases require a 3' OH to add onto and they can-
not start polymerizing without a primer.
Thanks to research by Baltimore and other biochemists, investigators
got very good at conducting in vitro DNA polymerization experiments.
With their experimental capacity, biologists turned their attention to
what role DNA polymerase plays in the appearance of new mutations in
DNA. One of the first tasks was to determine if a cell’s DNA polymerase
had a constant rate of polymerase activity during the life of an organism.
By 1976, biologists had already discovered that non-cancerous cells have a
finite lifespan and eventually human cells die. Could the finite lifespan of
cells be caused by DNA error accumulation as a result of mutations pro-
duced by DNA polymerase? British scientists grew some human skin cells
in petri dishes and isolated DNA polymerase from an aliquot of the cells
The Origins of New Mutations 3
right away and again later from cells that had grown for many days in the
petri dish. These two isolations yielded DNA polymerase proteins from
the human skin cells of two different ages. The investigators measured
the speed of the young versus old polymerases (Table 1). They wanted
to know if the DNA polymerases from young and old cells had the same
level of polymerase activity (quantified as units of activity).
Table 1 DNA polymerase activity comparison.

cell extracts activity
young 982 units
old 58 units
Source: From Linn et al., 1976; their table 1.
It is clear that the younger DNA polymerase was more active than
the older polymerase, but this did not necessarily mean that the younger
DNA polymerase made fewer mistakes. For example, if a student takes
an exam in 5 minutes and everyone else requires 50 minutes, the fast
student’s exam grade will not necessarily be 10 times higher than everyone
else’s, right? An exam grade does not depend on how fast the test is com-
pleted, but how few mistakes are made. Similarly, DNA polymerases need
to be accurate more than they need to be fast. The biochemists compared
the error rate for the old and young two sources of DNA polymerase
(Table 2). They also compared young and old DNA polymerase in the pres-
ence of two different metal ions (Mg2+ and Mn2+) because it was known
that ions with a +2 charge were required for DNA polymerase activity.
Table 2 Comparison of old and young DNA polymerase

capacity.
DNA polymerase ion bases polymerized error rate
young Mg2+ 17,300 1 in 1821 bases
old Mg2+ 5,400 1 in 474 bases
young Mn2+ 26,800 1 in 1848 bases
old Mn2+ 18,800 1 in 556 bases
Source: From Linn et al., 1976; their table 2.
A few years later, a different group of biochemists wondered what

effect different +2 ions might have on human DNA polymerase ac-
curacy (Table 3). The investigators tested the effects of a few different
metal ions that humans are exposed to in the environment. They com-
pared the effects of nickel (Ni2+), cadmium (Cd2+), and calcium (Ca2+)
on the accuracy of DNA polymerase isolated from young cells. They
tested at least two different concentrations of each ion to see if dosage
had an effect on the DNA polymerase.
Table 3 Comparison of ions on young human DNA

polymerase accuracy.
ions (concentration in mM) error rate
Mg2+ (1.0) 1 in 41,000
Ni2+ (1.0) 1 in 5,030
Ni2+ (2.0) 1 in 1,850
2+
Cd (0.1) 1 in 7,810
Cd2+ (0.2) 1 in 5,070
Ca2+ (0.6) 1 in 7,520
Ca2+ (1.0) 1 in 5,500
Ca2+ (2.5) 1 in 3,760
Source: From Seal et al., 1979; their table 4.
From Table 1, it is clear that older DNA polymerases generate more

mutations when DNA is replicated. In addition, it can be seen that both
young and old DNA polymerases produce more mutations in the presence
of Mg2+ than Mn2+ but without an indication of variance, it is impos-
sible to know if these values are significantly different or not. Older DNA
polymerase is affected more by the difference in ions than the young DNA
polymerase, which is consistent with younger cells containing more accu-
rate DNA polymerases. When exposed to heavy metal ions Ni2+ or Cd2+
(as found in batteries), DNA polymerases make more mutations. Table 3
illustrates why it is important to recycle old batteries rather than throw
them away. Batteries in landfills increase the odds of someone developing
cancer and the odds that children will develop new genetic diseases.
This chapter focused on how DNA replication could produce new
mutations and possibly genetic diseases. Genetic diseases are caused by
mutations in DNA sequence, which are often produced by DNA poly-
merase errors. Genomic research from 2012 has shown that each child
inherits about 100 mutations that were not present in either parent.
Therefore, mutations are common enough that everyone should think of
DNA replication as producing an equivalent DNA copy rather than an
The Origins of New Mutations 5
exact copy. Regardless of whether the DNA polymerase produces a new

mutation or not, they all require primers with 3′ OH to initiate DNA
elongation. You can search the Internet with the phrase “3D Structure
of DNA During S Phase Jsmol” to see a Jsmol interactive tutorial show-
ing DNA polymerase frozen in action. When viewing the Jsmol tutorial,
try to identify which base is the template and which base is about to be
added. It is possible to see the 3′ end of the last base added to the growing
DNA chain which is where the next base will be added. It is important
to see the 3′ end of the growing strand, because replicating DNA grows
from this end in all species.
By studying how DNA polymerase works and contributes to muta-
tions, this chapter has presented how heritable information provides for
the continuity of life by replicating DNA. Furthermore, this chapter has
presented how inherited DNA can contain mutations which generate
variation in the population. Mutation is one of the four mechanisms of
evolution and it generates variation in a population that can be acted on
during natural selection. Double-stranded DNA uses semiconservative
replication because both strands become the template for the comple-
mentary strand. DNA polymerase requires a primer with a 3' OH group
to initiate elongation, and cells contain enzymes that produce primers as
needed. If DNA replication were perfect, it would be possible to imagine
a world with no genetic diseases and reduced variation. Chapter 2 will
present how genetics variation is beneficial and contributes to natural
selection in populations.
Bibliography
Baltimore D, Smoler D. Primer requirement and template specificity
of the DNA polymerase of RNA tumor viruses. Proc Natl Acad Sci
USA 68(7):1507–1511, 1971.
Kornberg T, Gefter ML. Purification and DNA synthesis in cell-free
extracts: properties of DNA polymerase II. Proc Natl Acad Sci USA
68(4):761–764, 1971.
Lehman IR, Bessman MJ, Simms ES, et al. Enzymatic synthesis of deoxy-
ribonucleic acid: preparation of substrates and partial purification of
an enzyme from Escherichia coli. J Biol Chem 233(1):163–170, 1958.
www.Ebook777.com
Linn S, Kairis M, Holliday R. Decreased fidelity of DNA polymerase

activity isolated from aging human fibroblasts. Proc Natl Acad Sci
USA 73(8):2818–2822, 1976.
Seal G, Shearman CW, Loeb LA. On the fidelity of DNA replication:
studies with human placental DNA polymerases. J Biol Chem
254(12):5229–5237, 1979.
CHAPTER 2
The Origins of New Species
Though the details and timing are unknown, recent research has demon-
strated that it is possible for living cells to evolve from abiotic molecules
functioning in the absence of life. Even if some of the details are wrong,
it is safe to say that at some point Earth was occupied by many copies of
one or more ancient, single-celled species. Perhaps they were Archaea or
Eubacteria; we don’t know for sure. Therefore, we will take as our starting
place a planet with at least one prokaryotic species. The genotype of these
pioneer species populations could change as a consequence of natural
selection, genetic drift, gene flow, or mutation. As defined in Chapter 1,
the definition of evolution is a change in allele frequency in a population
over time. This chapter will consider a very difficult question: How many
changes in allele frequency are needed before a new species is formed?
So far, changes in DNA and phenotype have been presented in the
abstract rather than real-world mutations and consequences. Let’s refer
back to Mendel’s discovery of genetics using pea plants and clearly inher-
ited traits. One of the seven traits Mendel studied in detail was the height
of the pea plants. Mendel had discovered that pea plants could be either
normal height or about one-third normal height. The difference in height
was due to the length of the stem between each leaf. The name of the gene
that determines the height of the plant was subsequently called Le, and
the short phenotype can reappear when two phenotypically normal plants
are pollinated. In 1997, two research groups independently identified the
genetic cause for the short pea plants.
Like animals, plants produce hormones that stimulate cell division,
and one of the most potent plant hormones is called gibberellin. The Le
recessive allele encodes an enzyme, gibberellin 3 beta-hydroxylase, which
catalyzes the final step in synthesis of the pea’s growth hormone. When
wild-type and mutant Le alleles are aligned, the only difference is a single
nucleotide polymorphism (SNP, pronounced snip) at base number 685

changing a guanine (G) to an adenine (A). Using the genetic code, it is
possible to determine that this SNP changes amino acid number 229
from alanine (A) to threonine (T). One way to compare two sequences is
to use an online tool called BLAST2. BLAST2 can align every nucleotide
in the two Le alleles and generate a dot plot, which is a visualization of
the similarity between two sequences. As soon as the recessive Le mu-
tation appeared, the pea population Mendel worked with had evolved
because the allele frequency had changed. Was Mendel correct to consider
the two pea plant phenotypes to be the same species, or should he have
called the two types of plants different species?
Seeds and young plants produce the enzyme gibberellin 3 beta-
hydroxylase as the stem grows either tall or short, depending on the plant’s
genotype. Changing alanine to threonine at amino acid position 229 re-
duced the activity of the hormone-producing enzyme by 95%. If the en-
zyme activity of a wild-type plant cell is 100 units, short plants would
have only 5 units of enzyme activity per cell. Heterozygous cells would
have 55 units of enzyme activity. These differences produced two differ-
ent phenotypes, but the plants were still the same species. Remember that
variation in the population of a single species is normal. This still leaves
the question of how to know whether to call a variant a new species or not.
Alleles change when they accumulate a new SNP, and this muta-
tion might change the phenotype. What was known about gibberellin
3 beta-hydroxylase in pea plants was true for every gene in every spe-
cies, even the very first species. It would be expected that over time,
genome changes would accumulate as long as they did not harm the cell.
If a DNA mutation resulted in a detrimental phenotype in the existing
environment, then it would be appropriate to expect natural selection
to purge less competitive cells from the population. Some mutations
cause no change in phenotype, some mutations cause a change in pheno
type that survives natural selection, and even detrimental mutations can
reappear later by chance. The probability of a random change can be
predicted, but the precise outcome of a given instance is unpredictable.
Despite the natural human tendency to value clear rules, no rules exist
for when two individuals with different genomes should be considered
different species instead of two members of a single population. The
The Origins of New Species 9
following case studies will consider examples of genomics changes that

illustrate how evolution proceeds, but it is unclear when to designate a
new genotype as a different species.
Large Scale Genome Changes

One reason some people have a hard time accepting evolution is that they
mistakenly think all evolution takes place gradually, one SNP at a time. If
the only way to evolve a new species was through slow steady accumula-
tion of SNPs, then it would be difficult to explain the full diversity of life
on Earth. However, there is a great deal of evidence to demonstrate that
big, dramatic changes in chromosomes can happen quickly. If big seg-
ments of chromosomes were altered in a single generation, then it would
appropriate to predict that speciation would accelerate. A familiar exam-
ple of big, dramatic changes in chromosomes is in the news frequently:
E. coli outbreaks.
E. coli is a common bacterium that all of us have in our intestines
and is used in research labs all over the world. When a Google search for
“e coli news” is conducted, the most common hits discuss food poison-
ing due to a strain of E. coli called O157:H7. The laboratory strain of
E. coli, called K-12, is the same type of E. coli living quietly in everyone’s
intestines now. It is possible to compare the pathogenic O157:H7 chro-
mosome (X-axis) against the chromosome of the harmless K-12 strain
(Y-axis) in a dot plot (Figure 1).
Each bacterial chromosome is approximately 5 million base pairs
long. The first difference to be noticed in the dot plot is that the two
genomes are not exactly the same length, with O157:H7 containing
about 900,000 more bases than the harmless K-12 strain. The most visu-
ally striking difference is one segment of DNA that has the opposite slope
of the larger trend of a diagonal line. This inverted line indicates that a
segment of DNA was cut out of the chromosome, flipped 180 degrees,
and inserted back into the chromosome. The DNA within this inverted
piece is very similar in sequence for both strains, only its orientation has
inverted from one to the other. In Figure 1, it would be possible to color
code all inverted DNA in the graph to indicate DNA flipped in O157:H7
relative to the K-12 strain. Biologically, we will never know for sure which
= DNA in the same orientation

= DNA in the reverse orientation
4639221
chromosome of E. coli, strain K-12
3711377
2783533
1855689
927845
1
1 2211378 4422756
1105689 3317067 5528445
chromosome of E. coli, strain O157:H7
Figure 1 Dot plot comparing the chromosome of E. coli strain K-12 on

the vertical axis with E. coli O157:H7 on the horizontal axis. Colored
dots can be used to indicate similar DNA sequences that are inverted.
Source: Generated using Comprehensive Microbial Resource (CMR).
strain flipped its DNA and which strain has the original orientation. Dot
plots are not good at revealing small changes in DNA, but they do illus-
trate three common DNA changes on the large scale (Figure 2).
comparison genome
comparison genome
comparison genome
B
A A
A reference genome B reference genome C reference genome
Figure 2 Diagrams of dot plot patterns. These three panels show

common large-scale genome rearrangements that indicate rapid
mutations that lead to evolution in populations. A, Inversion of
DNA segment. B, Insertion or deletion (indel) of DNA segment.
C, Duplication of DNA segment.
Source: Original art.
Panel A of Figure 2 shows an inversion as has happened in E. coli

strains (see Figure 1). Panel B of Figure 2 shows the consequences of one
genome deleting a segment of DNA or the other genome inserting addi-
tional DNA. An insertion or a deletion is often called an indel because it
is impossible to know whether the difference in DNA is due to a deletion
or an insertion. The strain with the extra DNA (y-axis) has a gap parallel
to its axis. Several small regions in Figure 1 indicate that genome K-12
might have lost several small pieces of DNA. However, rather than the
harmless strain losing some DNA, it is equally possible that the patho-
genic strain might have gained some extra DNA. Because it is known that
the harmless genome is smaller than the pathogenic one, it is evident in
Figure 1 that each line shift to the right of the diagonal represents the
absence of DNA in the K-12 genome compared to O157:H7.
If the two genomes each contained one copy of every gene, then the
dot plot would exhibit the main diagonal line and perhaps some inver-
sions. In addition to the shifts due to deletions, it is possible to also see
some parallel segments of DNA that appear well off the diagonal line in
Figure 1. Often times, two segments of DNA in a genome are similar to
each other within the same genome. Dots off the diagonal in Figure 1
represent portions of DNA that have been duplicated, which is also de-
picted in Figure 2C. For example, if gene #2348 were duplicated in both
genomes, the dot plot would show two short parallel lines on either side
of the larger diagonal line. Gene duplication is how multiple genes with
similar functions can appear within a single generation of a species. If
the duplicate gene is advantageous, individuals with the duplication will
outcompete others and produce offspring that also contain the duplicated
gene. If one of the two copies were inverted, the flipped version would
appear in a dot plot as a short line off the diagonal line but with opposite
slope. Gene duplication is more common than we used to think, and
more examples will be presented this later in this chapter.
Figure 1 compared two very closely related strains of E. coli and
detected that there are three different types of large changes in DNA—
inversions, deletions, and duplications. Deletions and duplications are
forms of mutations that contribute to evolution, but an inversion often
does not necessarily change allele frequency. Only in the break points
of the inversion are within genes would an allele frequency be changed.
The lengths of DNA that are affected can vary substantially from a few
bases to millions of bases. All of these changes could lead to very different
phenotypes in a single generation, which may or may not be advanta-
geous and survive natural selection. It is not possible to predict the out-
come of natural selection, but it is possible to find evidence in many
species that changes in DNA led to new species. Should divergent strains,
such as O157:H7 and K-12, be called different species instead of differ-
ent strains of the same species? It is well known that different dog breeds
are strains of a single species generated by directed evolution which is
the name given when natural selection is intentionally manipulated by
humans. With microbes, it is harder to know when to call two of them
different strains or species. Defining what constitutes a new species is still
an open question.
When dot plots exhibit shifts in aligned genomes as illustrated in
Figure 2B, it is clear that the reference genome lost some DNA or the
comparison genome acquired some additional DNA due to an indel. It
is hard to understand how DNA can come or go given the semiconser-
vative nature of DNA replication, but it is possible to find genes within
E. coli that appear to have come from a different species. The movement
of DNA from one species to another outside of mating is called horizon-
tal gene transfer. To understand horizontal gene transfer, first it is impor-
tant to know how to identify DNA that was acquired through horizontal
gene transfer. The next example will show how biologists identify DNA
that may have originated from a different species.
Thousands of genomes have been sequenced so far, with more
sequenced every day. From this vast collection of sequenced genomes, ge-
nomics researchers noticed that every species has an average GC content.
For example, the primary pathogen that causes malaria has a GC content
of 19.4%, but the overall all human GC content is 41%, and the single-
celled alga Chlamydomonas is 61% GC. If a malaria gene were to hori-
zontally transfer into Chlamydomonas, what would the modified genome
look like? The new genome would contain one gene with a very low GC
content inserted into a genome with a very high GC content. If several
genes in a row were transferred all at once, a comparison would show
a block of genes with abnormal GC content inserted into the chromo-
some. Do any real genomes show evidence of horizontal gene transfer?
Return to E. coli O157:H7 as our example. Bioinformatics tools allow

biologists to draw the entire genome as a circle, with each gene appearing
as one perpendicular line along the circular genome. Each line is given
a color along a spectrum with the color indicating the percent GC for
each gene. The pathogenic strain of E. coli has an overall GC content
of 50.4%, although individual genes vary. In one particular version of
this illustrated genome, the average GC content is given the color yel-
low. Genes with lower GC are colored green, and those with higher GC
content are colored red. From this display of the entire E. coli O157:H7
genome, it can be seen that some genes are colored green or red, which
may indicate that they have arrived via horizontal gene transfer. Rather
than hunting randomly, online versions of such displays allow the user
to can search for specific genes to see if a gene of interest shows signs of
horizontal gene transfer.
GC content alone is insufficient evidence to convince a skeptical
scientist that a gene arrived into a new genome via horizontal transfer.
Genuine horizontal gene transfer might exhibit additional features, such
as several genes in a row with abnormal GC content, sequential genes
in the same order and orientation as found in another species, duplicate
genes in the recipient genome with only one copy having GC content
closer to the average, and so on. In E. coli, for example, gene Z6034 is
particularly interesting because its sequence reveals this gene not only has
a very high GC content, it comes from a provirus, which means that the
virus has integrated its genome into the host genome. Viral DNA inserted
into a host genome is hypothesized to be the most common cause of
horizontal gene transfer.
Although there are many more genomes to be sequenced, genomicists
have detected several trends already. It is clear that prokaryotes share DNA
via horizontal gene transfer. In a 2008 study, investigators from Germany
and Israel surveyed 181 prokaryote genomes containing 539,723 genes
and found evidence that 437,175 genes had moved across species at least
once. Similarly, Sallie W. Chisholm from MIT discovered the existence
of viruses that can infect cyanobacteria in the open ocean. Cyanobacteria
are very abundant in the ocean and are responsible for about half of all
photosynthesis on Earth. Her team of investigators also discovered car-
ried genes involved in photosynthesis within these viral genomes, and yet
viruses cannot photosynthesize. These cyanobacteria viruses must have

acquired their photosynthesis genes from one cyanobacteria species and
now they can infect multiple different species of cyanobacteria and con-
tinue the process of horizontal gene transfer. Horizontal gene transfer also
happens in eukaryotes with evidence that plants and animals, including
humans, can acquire DNA from prokaryotes, perhaps through viruses.
So far, this book has provided evidence that cells can evolve slowly
through SNPs, or quickly through large-scale DNA changes and
horizontal gene transfer. We still are uncertain when to call a modified
genome a different species. Would it be appropriate to consider a cell to
be a different species if the genome was two or four times bigger than
its ancestors? Keep this question in mind as more case studies of rapid
genome changes are presented.
Clinical Whole Genome Changes

Though most people don’t realize it, nearly everyone is familiar with cells
that contain two to four times more DNA than normal. These rapidly
mutating cells evolve through large-scale DNA changes within a person’s
lifetime, but their appearance is not cause for celebration of a new spe-
cies. This unfortunate case study of whole genome duplication looks at
human cancers.
The human genome was sequenced in 2003, but most non-biologists
do not understand what this means. The human genome reference se-
quence deposited in a database is a composite of DNA from several peo-
ple. Therefore, the DNA sequence should be used as a stable comparison
sequence and not a standard for the perfect human. From now on, every
human genome sequence will be compared to this reference sequence so
that we can quantify the variations within the human population. There
are many efforts to sequence the genomes of more and more people, such
as the 1000 Genomes Project. As more genomes are compared, a new
form of variation is becoming apparent—copy number variation. Copy
number variations indicate that some alleles appear multiple times within
a genome. Since evolution is the change in allele frequency within a
population over time, copy number variation represents another example
of evolution through mutation. If the genomes of two unrelated people
were compared, they would find different numbers of alleles for some
genes. Different numbers of alleles means the amount of messenger RNA
(mRNA) the two people produce would differ, which helps explain some
of the phenotype diversity we see in humans all over the world. When bi-
ologist Craig Venter’s diploid genome was sequenced and compared with
the human reference sequence, they documented 95 copy number vari
ations, seven of which were known to be associated with genetic diseases.
Copy number variation is widespread in humans and usually harmless,
but another form of human cellular evolution is much more extreme—
cancer. Every human cell within a person started with the same DNA,
but over time, different mutations accumulate. If a person smokes or is
exposed to other mutagens, then some of their cells will accumulate mu-
tations even faster. Some of these mutated cells will die because they are
less fit, and they will fail natural selection within their body. However,
some of these mutated cells will develop advantageous phenotypes that
increase their fitness relative to healthy cells. These more fit cells will grow
uncontrollably, which is the definition of cancer. Cancer cells outcompete
healthy cells, continue to grow, and can spread all over the body, which is
why cancer is lethal. In short, cancer is a form of cellular evolution that
takes place within a person’s lifetime.
One way to detect large scale genome changes is to measure the DNA
content of wild-type and cancerous cells. Biologists compared the DNA
of wild-type mouse cells and two different tissue samples of mouse cancer,
AB98 and AB152. They quantified the total amount of DNA measured
and graphed them in “whole genome units”. In wild-type cells, they found
most mouse cells were diploid, but about 25% were tetraploid. Using a
different measure of the same types of cells, chromosome numbers per
cell were counted while looking through a microscope, and sometimes
the investigators could not see every chromosome in every cell. The nor-
mal number of chromosomes in a mouse is 40, which is how many 75%
of the wild-type cells exhibited. When describing the number of genomes
a cell has, biologists often describe the ploidy number. Haploid cells have
one genome copy, diploid cells have two, and so on.
When analyzing experimental data, always start with the controls
to make sure they behaved as expected. The biologists found that wild-
type cells were predominantly diploid, but some cells have twice that
amount of DNA. Tetraploid cells in normal individuals have undergone

genome replication but not mitosis and cytokinesis, so they are tempo-
rarily tetraploids. Cancer cell type AB98 was similar to wild-type cells,
except some cells appeared to carry a small number of extra chromo-
somes. AB98 contained some triploid cells existing between the diploids
and tetraploids. Furthermore, AB98 appeared to have slightly fewer
diploids than in wild-type cells. Cancer AB152 had almost no diploid
cells, and most of its DNA content was tetraploid but its genome could
be as large as octaploid! AB152 cells had undergone radical genome
alterations that presumably led to a selective advantage in growth and a
very aggressive cancer. The two different methods of quantifying DNA
led to small differences in ploidy for the two cancer cell lines. Subtle
differences should not distract from the main point that genomes can
duplicate quickly, and tetraploid cells can replicate through imperfec-
tions in mitosis and cytokinesis. Cancer is a form of cellular evolution
that will affect about half of all American men at some point in their
lives, and one-third of all American women. In this case, whole ge-
nome duplication did contribute to evolution, but the clinical outcome
is often very troubling.
For a genome alteration to be passed on to the F1 generation of multi
cellular organisms, the variations must be present in gametes. If a varia-
tion was not present in one of the parents, then the mutation occurred
during the formation of the gamete or subsequent mutation soon after
fertilization that led to the new individual. It is hard to imagine how
DNA polymerase could make two copies of one allele on a single chro-
mosome, but perhaps during prophase I of meiosis, the recombination
was not performed equally such that one chromatid gained DNA at the
expense of another chromatid. It is possible, however, for a subset of an
organism’s cells to have a unique mutation caused during mitosis, long
after fertilization. Examples of such mutations could be moles or other
skin aberrations caused by alterations in DNA for a small subset of skin
cells. Each person’s body represents an ecosystem of limited food resources
and different populations of cells exhibiting slight variations. As in every
ecosystem, variation in a population where resources are limited sets the
conditions for competition and natural selection. If one cell mutates into
cancer that grows faster, the cancer could outcompete the other cells and
overwhelm all the healthy cells. The spread of cancer and eventual death
of the human host is an evolutionary outcome for this short-term cel-
lular evolution, which ultimately could lead to the extinction of all cells
in the individual’s ecosystem. However, despite the dramatic changes in
the patients’ genomes, no one considers cancer to be cells of a different
species. How many DNA mutations are necessary before an organism is
considered a different species?
Genome Duplication and Speciation

Consider one final case of rapid genome change that had a significant
impact on animal evolution. Major chromosomal duplications are evi-
dent when whole genomes are sequenced and compared. If a genome had
experienced a duplication that led to a new species, it would be expected
that this new species would have two copies of every gene compared to the
parental species. Over time, some of these redundant gene copies could
either get deleted, or they could experience further mutations and stop
resembling the original gene. One of the best cases of genome duplication
leading to massive speciation took place over 400 million years ago.
Biologists have wondered for many years how vertebrates evolved from
invertebrates because the anatomical leap seems so great. Genomicists seq
uenced the puffer fish genome, which has one of the smallest genomes of
any vertebrate. After the genome had been sequenced, investigators
mapped all the obvious gene duplicates to their chromosomal locations.
Duplicate genes within a single species are called paralogs. A puffer fish
has 21 pairs of chromosomes. The investigators drew one copy of each
numbered chromosome as a series of numbered black arcs. Red lines con-
nect paralogs which revealed that several pairs of chromosomes shared
many paralogs. For example, chromosomes 2 and 3 shared many paralogs,
and they appeared in the same order on both chromosomes—as indicated
by the red lines connecting these chromosomes but not crossing each
other. Because every chromosome contained many paralogs, it appears
the entire genome was duplicated rather than just bits and pieces of the
chromosomes. Based on the data from their genome analysis, it appears
the origin of vertebrates was a result of a duplicated genome in an inverte
brate followed by additional mutation of the redundant genes.
If all vertebrates evolved from a common ancestor that had a genome

duplication, it would be expected that some remnants of genome dupli-
cation could be found in the human genome too. Although the human
genome is too large to show in its entirety, investigators selected four
human chromosomes and mapped all the paralogs. Human paralogs on
chromosomes 2 and 10, for example, were connected by colored lines.
Humans had fewer paralogs than puffer fish, but loss of recognizable
paralogs might have been caused by deletions of redundant genes or con-
tinued mutation until the genes no longer appear to be paralogs. Never-
theless, the investigators saw many instances of multiple paralogs in a row
on paired chromosomes as was seen in puffer fish.
If chromosomal mutations stopped once vertebrates evolved, it would
be predicted that all duplicate genes would map to their paired chromo-
somes. Furthermore, it would be expected for vertebrates to have exactly
twice as many genes and invertebrates. Genome duplication is only one
form of large-scale genome changes. If one looks at chromosome 7 in the
puffer fish, it appears that many of its paralogs are on the smaller chro-
mosome 16, but quite a few are also on chromosomes 1 and 10. These
mapped paralogs indicate that segments of DNA of any given chromo-
some can merge with other chromosomes, perhaps during prophase I of
meiosis when recombination is already a common phenomenon. Alterna-
tively, big chromosomes could split into two smaller ones, or two smaller
chromosomes could merge into a single larger chromosome. In addition,
duplicated genes could accumulate more mutations until they were un-
recognizable as paralogs and encode new functions. Therefore, it should
not be surprising that vertebrates do not have exactly twice as many genes
as invertebrates. Likewise, vertebrate species have different numbers of
genes because each species experienced further evolution of its genome
through the four mechanisms of mutation, genetic drift, gene flow, and
natural selection.
Evolution, change in allele frequency in a population over time,
can happen slowly or quickly, and evidence of cellular evolution is all
around. Because genomes are replicated by cells, it makes sense to think
of evolution within the context of cells. Simultaneously, species can go
extinct if the variation within its populations is too narrow to adapt
to the ever-changing environment. As the global climate continues to
change, humans will witness the loss of more species than has happened
in the last 10,000 years. And yet, as some species die, they will leave
niches unoccupied and perhaps new species will evolve to take their
places. The ongoing evolution of species is why all vertebrates have dif-
ferent numbers of genes, even though all vertebrates have a common an-
cestor with a genome duplication that happened inside a cell hundreds
of millions of years ago. Life continues to evolve, and if a trait continues
to be beneficial, it will persist over long periods of time. Chapter 3 will
examine how populations of a person’s immune cells evolve rapidly dur-
ing an allergic reaction.
Ethical, Legal, Social Implications:

The Safety of GMOs
Genetically modified organisms, frequently referred to by the acronym
GMOs, had their genomes manipulated intentionally by adding or de-
leting particular genes in order to produce a new phenotype. The genes
were altered in a lab using molecular biology methods as opposed to
selective breeding. These new phenotypes might increase food produc-
tion, reduce pollution, or improve healthcare. Genomic alterations can
produce glow-in-the-dark fish for aquarium enthusiasts, seedless plants
that increase profits for agribusiness, or alter farm animals to become
better organ donors for humans. The range of possibilities for GMOs
increases each year, and yet most people do not know where science ends
and fiction begins.
First, consider the most common misconception about GMOs—
genome manipulation is a new phenomenon. Humans have been ma-
nipulating plant and animal genomes for over 10,000 years. Wheat, rice,
and corn are very different than the ancestral plants from which they
were derived. Early farmers used selective breeding to alter the genotypes
of species in order to produce more desirable phenotypes. Owners of a
pet dog or cat enjoy the outcome of genetically manipulated mammals.
Another common misconception is that only GMOs contain foreign
DNA about which the consumer is uninformed. We eat DNA in every
fruit, vegetable, and meat. In addition, unknown microbes are everywhere,
and we eat their genomes by the millions. DNA is an energy-rich molecule
that does not survive a person’s digestive system, so eating GMO DNA
is not a threat to human health. One final argument is that humans are
“playing God” by altering the natural course of evolution. If altering the
course of evolution constitutes playing God, then every time a patient ac-
cepts medical treatment or is helped to recover from an illness, the person
is helped by people who are playing God too. Prehistoric humans were
unable to improve their health, and they felt the direct effects of natural
selection. With every use of glasses, antibiotics, vaccines, surgery, chemo-
therapy, dialysis, dental braces and so on, we “play God” and alter the
biological consequence of our genotypes and natural selection. The God
argument against GMOs ignores similar behavior that almost everyone
accepts as appropriate.
Now that some common misconceptions have been dispelled, con-
sider two real examples of GMOs that might seem more helpful than
harmful. Golden rice is a GMO that derived its name from its yellow-
ish color. The genome of golden rice was modified by the insertion of
two daffodil genes and one bacterial gene. The yellow color indicates
an overproduction of β-carotene, which human bodies can convert to
vitamin A. In Southeast Asia, millions of children go blind from a lack
of vitamin A, and rice is their staple food. Golden rice is given away
freely to subsistence farmers so that communities can grow their own
nutritional intervention to prevent childhood blindness. The second
GMO example is bacteria that can produce biodegradable plastics that
are not toxic to the environment and do not require petroleum. Using
biodegradable bio-plastic can reduce pollution and shrink human de-
pendence on oil. GMO bacteria can be genetically modified to produce
more versatile and less expensive forms of bio-plastic. Look at all of the
plastic around, and consider whether bio-plastic is a good use of GMOs.
Next time the topic of GMOs comes up, stop to think if the application
is a good one or a bad one.
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Spring Harbor Press.
CHAPTER 3
Evolution of Allergic
Responses
In America and other countries, the number of people who have an

allergy is increasing. Some people are allergic to peanuts, dust, grass, or
pollen. The first time someone is exposed to an allergen, they cannot have
an allergic reaction. Each subsequent exposure leads to a stronger and
faster reaction—why? Cellular evolution is responsible for the increased
strength of an allergic response, and this evolution happens in a matter of
days. In particular, evolution happens in a subset of a person’s white blood
cells called B cells that produce antibodies. Chapter 3 will examine the
original data that demonstrated evolution in a population of B cells that
is essential to a healthy immune system and stronger allergic responses.
One way an immune system protects a person from pathogens and
toxins is to produce antibodies (Figure 3) that can bind and neutralize
the pathogen or toxin. The antibodies produced after a person’s second
exposure of antigen are shaped like the letter “Y” and have two identical
binding sites at the tips of the two arms. The two arms are composed of
identical copies of the same two proteins called heavy and light chains.
Heavy chain refers to the longer subunits, whereas light chains are the
shorter subunits. Particular amino acids generate the shape of the very
tip of these chains, and this shape is complementary to the shape of the
molecule that the antibody can bind (Figure 3B). Two molecules of a
particular allergen can bind to each antibody.
To understand an allergic response, it is important to understand a
normal immune response. To learn about an antibody response, this chap-
ter will present some classic experiments that helped biologists determine
how antibody-producing cells evolve and function. Immunology experi-
ments often are conducted with rodents, because their immune systems
two light
chains
identical identical
binding binding
sites sites
two heavy chains
antigen antigen
molecule molecule
Figure 3 Antibody structure and function. A, Antibody

composed of two identical heavy chains and two identical light
chains. B, The same antibody with two identical antigen
molecules bound. The arms of the antibody have been filled in
to highlight their mass.
Source: Original art from PDB files.
are similar to ours and they are inexpensive to maintain. In 1961, three
immunologists from New York University conducted some of the first ex-
periments using guinea pigs to document how immune responses to anti-
gens get more robust with subsequent exposures. They injected guinea pigs
with small amounts of protein and measured over time the amount of an-
tibody in the animals’ blood that bound to the injected protein. Within a
few days, the animals began to produce more antibodies until the amount
leveled off later in the month. Three weeks later, the immunologists re-
injected the same animals with more of the same antigen, and then they
quantified the amount of specific antibody in the animals’ blood.
When exposed to a new antigen in the blood or outside cells within
tissues, antibodies will accumulate in about a week and bind to the an-
tigen molecules. When the antibodies bind, they can form large protein
clusters that are easily cleared from the blood by white blood cells. Once
the antigen molecules are removed from the blood, the immune system
Evolution of Allergic Responses 25
stops making new antibodies and the old ones gradually degrade. A sec-
ondary immune response to the same antigen produces at least ten times
more antibodies than the primary response. The secondary response anti-
bodies clear the blood of the antigen faster, so the level of antibodies goes
down faster because the antigens are removed quicker. However, the sec-
ondary response level of antibodies is greater than the primary response.
A strong secondary response is why people get immunized and sometimes
get booster shots—to generate a robust antibody response in case a person
is exposed to a toxin such as tetanus, or a pathogen such as measles. It is
impossible to have an allergic reaction with a primary antibody response
because of a complex change in the types of antibodies produced, which
is beyond the scope of this book. Through vaccination, a person’s B cells
are ready to make more antibodies after the second exposure than they
were on the first exposure.
From personal experience, everyone knows that pathogens don’t get
in a queue and attack one at a time. Similarly, some people are allergic to
more than one antigen at a time. Could the secondary response happen
to people when they are challenged by more than one antigen at a time?
Does the secondary response apply to all antigens simultaneously, or is it
individualized for each specific antigen? In 1965, three immunologists
from Melbourne, Australia, conducted a series of experiments using rats.
They injected a group of rats with one antigen, and then they waited
6 weeks. For the second injection, they gave the same rats a second dose
of the original antigen and simultaneously injected a new antigen for
the first time. The investigators quantified the concentration of antigen-
specific antibodies in the rats, and once again, they saw that the secondary
response was more robust with no significant delay in binding the original
antigen.
Based on the faster and larger secondary antibody response, the im-
munologists knew something was different between the primary and sec-
ondary responses. They knew each response for one antigen was unrelated
to the initial response for a different antigen. Two rival hypotheses were
competing in the mid-1960s. The first hypothesis was that the antibody-
antigen complex acted like an immune system stimulant, and thus the sec-
ond exposure gave a larger response. The competing hypothesis was that
more antigen-specific B cells were available to produce antibodies in the
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B cell
antigen B
B B
B
B
memory B
B mB
B
B
B
B B
B B
B
B
B B
B
secondary
response
primary response
Figure 4 Primary and secondary response. The primary

response produces B cells making antibodies as well as memory
B cells (mB). The memory B cells produce many more B cells
during the secondary response. The length of the arrows
indicates relative passage of time.
Source: Original Artwork.
secondary response and that the immune system had a cellular memory
of previous exposures (Figure 4). After more experimentation, it became
clear that there are two types of B cells; antibody-producing B cells and
memory B cells. The memory B cells are stem cells that persist and pro-
duce more copies of genetically equivalent antibody-producing B cells,
but memory cells do not secrete antibodies.
So far, this chapter has presented half of the reason why allergic
responses get stronger with time—memory B cells. The formation of
memory B cells allows many new B cells to be produced quickly, and
memory cells are genetically identical to the original B cells. However,
the progeny of memory B cells are the product of cellular evolution, be-
cause their allele frequency for antibody genes has changed within the
population of all of B cells. In order to survive, B cells need to receive a
“survival signal,” or they will die in a day or two. To receive a survival
signal, non-memory B cells must produce antibodies that can bind an
existing antigen. At first, it may seem that every B cell would get the same
survival signal and they would all die at the same time. However, B cells
have an unusual property—their antibody alleles mutate at a very high

rate but only in the portion of the heavy and light chain coding DNA
that form the binding sites of antibodies. During a primary response, the
first wave of B cells do not mutate the DNA encoding antibody bind-
ing sites, and so the first wave of antibodies from a particular B cell in
the primary response have identical antigen binding sites. However, dur-
ing the secondary response, memory B cells migrate to a special place in
lymph nodes where their progeny undergo somatic hypermutation.
During somatic hypermutation, the secondary response B cells mutate
at an extremely rapid rate but only in a small segment of their heavy and
light chain alleles. As the coding portions of the antigen binding sites
change, so do the B cells’ capacity to bind the antigen and receive the
survival signal. It is easy to imagine that some mutations would decrease
an antibody’s affinity for the antigen, some mutations would increase its
affinity, and some mutations would have no effect at all.
Three immunologists from Germany isolated mouse B cells during a
primary response as well as during a secondary response to the same anti-
gen. They sequenced the antibody heavy chain coding DNA for the anti-
gen binding sites from four B cells in the primary response and ten B cells
in the secondary response. They also measured the affinity of each encoded
antibody. Antibodies with reduced affinity, indicated by a larger number
such as 5 µM, need a higher concentration of antigen in order to bind and
thus facilitate B-cell survival. B cells with mutations that increase antibody
binding affinity, indicated by a smaller number such as 0.05 µM, need a
lower concentration of antigen to bind and survive. The affinity number
refers to the concentration of antigen required to occupy half of the anti-
body binding sites. A small concentration indicates a high affinity of anti-
body for antigen. The immunologists found that antibodies produced by
the primary response B cells had a lower affinity for the antigen than most,
but not all, of the antibodies produced by the secondary response B cells.
The increased antibody affinity was a result of random DNA mu-
tations that increased the affinity of the antibodies encoded by most
of the B cells during the secondary immune response (Figure 5).
During an immune response, a person has many B cells capable of pro-
ducing antibodies for the same antigen. As the antigen concentration
decreases, the B cells experience a competition for the survival signal
second
generation
secondary change relative memory B
response in affnity survival cells
B
B B
B much BB B many
higher B B
B cell modestly B B B
antigen B B several
higher
B mB
memory B
weakly B
B a few
higher B
B
B same B very
few
primary
response
B lower none
inside inside
lymph lymph
node node
Figure 5 Summary of long-term B-cell responses. Antigen stimulates

B cells to make antibody and memory B cells. Second generation
B cells undergo somatic hypermutation, which alter antibody binding
affinity. B cells with the highest affinity receive the most survival
signals and produce the most B cells and memory B cells.
Source: Original artwork.
(binding the antigen), and those with the highest affinity will survive
and produce memory B cells. Thus, the secondary response not only
produces more antibodies, the antibodies have greater affinities for the
antigen. In B cell responses, one can see the five tenets of natural selec-
tion. The evolution of B cells includes: 1) Overproduction of B cells; 2)
Variation in the population due to DNA mutations; 3) Competition for
survival signal; 4) Selective advantage for B cells with higher affinity; and
5) Reproduction in the form of memory B cells. In short, white blood
cells evolve every time a person is exposed to a virus, bacterium, or al-
lergen. B-cell evolution is rapid and imparts a selective advantage to the
person, because that person can produce a better immune response with
each subsequent exposure to a pathogen, assuming the person survived
the previous one. Unfortunately, this evolution also leads to increasing
severity of allergic response.
In this chapter, a very rapid form of cellular evolution that happens
within an organism was considered but the products of this evolution
are not propagated beyond that individual. As a consequence of cellular
evolution, secondary antibody responses are more robust as a result of

the memory B cells, antibodies with higher affinity, and the increased
number of B cells producing antibodies. If a person has allergies, that per-
son produces more antibodies with higher affinity after each additional
exposure to an allergen. Like some examples of evolution described in
Chapter 2, a person’s immune system can evolve rapidly using the mecha-
nisms of evolution followed by natural selection that accounts for the
changes in environmental exposure to pathogens and allergens. All mam-
mals and birds have the same capacity to use B-cell evolution to improve
an immune response. The vertebrate immune system is another exam-
ple of species linked by lines of descent from common ancestry. B-cell
immune responses originated long ago and have persisted for millions of
years because of the adaptive advantage they provide within the popula-
tion of organisms. Humans alter the course of B-cell evolution through
immunization to protect people from harmful pathogens.
Ethical, Legal, Social Implications:

Balancing the Rights of the Individual vs. the Group
The headlines read, “Teen with peanut allergy dies after kiss: Girl’s
boyfriend had just eaten peanut butter snack.” This tragic story from
Canada was broadcast around the world when 15-year-old Christina
Desforges died in November 2005. Desforges’s death is every teach-
er’s nightmare, and schools have responded to the shock and concern
prompted by the tragic death. Peanut butter and jelly (PB&J) sand-
wiches have been banned from some schools, even though PB&J is the
most popular lunch in America. Some parents were angered by the ban,
because their children suffered due to another child’s allergy. The PB&J
debate raises an interesting question that requires an understanding of
cellular evolution.
The new school peanut butter policies pose a difficult question. How
much effort is too much to protect a small number of individuals? If
half of the school were allergic, the decision seems easy. But what if only
one child is allergic and the other 999 are not? What if 30 students are
allergic, would it be appropriate to have a special lunch room for them?
It is impossible to quantify the value of a child’s life, and it is impossible
to quantify the inconvenience experienced by others. Without quantifi-

cation, comparing the costs and benefits of a policy becomes a personal
judgment. What should a superintendent of schools do when weighing
the options? Keep in mind that many foods use peanut products, so PB&J
is not the only potentially toxic food. On one hand, one can sympathize
with parents who want their children to eat peanut products. On the other
hand, one would hate for a child to die in any school. Given the litigious
nature of American society, a superintendent might be sued by the family
if a child were to die. However, school policy makers need to understand
B-cell evolution before reaching their decisions.
Whenever the peanut allergy debate arises, at least one parent will argue
that if peanut butter is lethal and PB&J is present now, the children must
not be severely allergic because they have not reacted yet. As was presented
in Chapter 3 of this book, allergies get worse with time. If a child is mildly
allergic to peanuts now, additional exposures might eventually produce a
lethal reaction. Cellular evolution of B cells is well documented, and all par-
ents should know about B cell evolution to understand the basis for any pol-
icy decision. Another area that needs clarification is the original story about
Desforges. The Canadian coroner determined that Desforges had died of
an asthma attack and not a food allergy. Desforges had an EpiPen, which
is a self-administered epinephrine injection device used to prevent allergy
attacks. In this case, she did not use her EpiPen, because she knew that she
was not experiencing an allergy attack. The final report of her tragic death
did not receive much publicity, which is often the case after sensational sto-
ries are found to be inaccurate. Therefore, many parents still believe that
their child could be killed by a miniscule second hand peanut exposure.
Second hand exposure raises another set of issues. What if a child
has peanut butter on toast for breakfast? Should home use of peanut
butter be banned too? Can schools make policies that reach beyond the
school grounds? And what about children who are allergic to wheat or
dust? Should schools also ban all wheat products and dust? It is easy to
see that the consequences of establishing policy can lead to untenable
situations. Should children with allergies be required to carry EpiPens?
Or perhaps PB&J could be banned on Monday, Wednesday, and Friday
but permitted on Tuesdays and Thursdays when allergic children eat in
hypoallergenic rooms?
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Unfortunately, schools are left to figure out the best response on a case-
by-case basis without the understanding of B-cell evolution. However,
there is some good news. The US Department of Agriculture (USDA)
is funding research on ways to process peanuts so that the allergen is de-
stroyed. A team of biochemists in Arkansas identified the peanut aller-
gen proteins. Now that we know the allergens are proteins, the USDA
is funding research to see if post-harvest peanut processing can eliminate
the allergens. Companies are trying to generate GMO peanuts to produce
hypoallergenic peanuts (see the debate about GMOs immediately prior to
this chapter). The debate over peanut products may be moot in the near
future if food scientists can remove allergens from peanuts. Until that time,
it is important that biology be used to formulate policies rather than inac-
curate reporting or ignorance about the immune system. Cellular evolu-
tion continues every day, and everyone needs to understand why allergies
can get worse with time.
Bibliography
Behbehani AM. The smallpox story: life and death of an old disease.
Microbiol Rev 47(4):455–509, 1983.
Eisen HN, Siskind GW. Variations in affinities of antibodies during the
immune response. Biochemistry 3(7):996–1008, 1964.
Kocks C, Rajewsky K: Stepwise intraclonal maturation of antibody
affinity through somatic hypermutation. Proc Natl Acad Sci USA
85(21):8206–8210, 1988.
Montagu MW. Letters of the Right Honourable Lady M–y W—y M—e :
written, during her travels in Europe, Asia and Africa, to persons of
distinction, men of letters, etc. in different parts of Europe : which
contain, among other curious relations, accounts of the policy and
manners of the Turks : drawn from sources that have been inaccessible
to other travelers. London, 1763, T. Becket and P.A. De Hondt.
Nossal GJ, Austin CM, Ada GL. Antigens in immunity. VII. Analysis of
immunological memory. Immunology 9(4):333–348, 1965.
Rajewsky K, Förster I, Cumano A. Evolutionary and somatic selection of
the antibody repertoire in the mouse. Science 238(4830):1088–1094,
1987.
Uhr JW, Finkelstein MS, Baumann JB. Antibody formation. III: The
primary and secondary antibody response to bacteriophage phi C 174
in guinea pigs. J Exp Med 115:655–670, 1962.
Ethical, Legal, Social Implications: Balancing the rights of the

individual vs. the group
Associated Press. Teen with peanut allergy dies after kiss: girl’s boyfriend had
just eaten peanut butter snack, officials say. MSNBC (website): http://
www.msnbc.msn.com/id/10243950/. Accessed January 23, 2009.
Maleki S, Hurlburt B, Chung SY. Research project: reducing the aller-
genic properties of peanuts. Project Number: 6435-43440-020-00,
USDA (website): http://www.ars.usda.gov/research/projects/projects
.htm?ACCN_NO=409180. Accessed January 23, 2009.
Hartocollis A. Nothing’s safe: some schools ban peanut butter as allergy
threat. The New York Times (website): http://query.nytimes.com/gst/
fullpage.html?sec=health&res=9907E3D81E30F930A1575AC0A
96E958260. Accessed January 23, 2009.
Michel M. Death of Christina Desforges: asthma and food allergies:
education and awareness—English translation. Ottawa Anaphylaxis
Support Group (website): http://www.ottawaasg.com/OASG2006/
Downloads/QCMay06.pdf. Accessed January 23, 2009.
Rabjohn P, Helm EM, Stanley JS, et al. Molecular cloning and epitope
analysis of the peanut allergen Ara h 3. J Clin Invest 103(4):535–542,
1999.
Conclusion
This book focused on evolution at the cellular level. The first chapters pro-
vided original data showing how DNA polymerase begins the replication
process, as well as how errors in replication increase as the cells age. The data
illustrated how environmental factors (such as, heavy metals) can acceler-
ate the mutation rate of DNA polymerase. DNA is replicated faithfully,
but not perfectly. Errors incorporated by DNA polymerases contribute to
the variation of a population, provide new genetic information, and enable
the ongoing evolution of a species. Chapter 2 considered an intractable
question: How many changes in DNA are required before the genome en-
codes a new species? The chapter presented SNPs, copy number variations,
horizontal gene transfer, indels, and inversions, as well as whole genome
duplications. In all of these cases, there is no agreed upon amount of change
that is required before a cell has mutated into a new species. This is equally
true for GMOs whose genomes are intentionally mutated. The final ex-
ample of evolution at the cellular level involved evolving B-cell responses
to antigens. B cells evolve every time a person is vaccinated, exposed to a
pathogen, or an allergen. Given that B cells evolve, is it possible to develop
a reasonable school policy about banning peanut products from schools?
This booked addressed several examples of cellular evolution that var-
ied in time scale. Cellular evolution can happen within a couple of weeks
in an immune system. Evolution can happen within minutes during cell
replication. Large changes happen when genomes duplicate or alter large
segments of DNA, as was seen in cancers and puffer fish. Evolution of
cells happens in and around everyone. Evolution does not have a goal
or an endpoint, but it is dynamic because the environment changes over
time. This book presented examples of some recurring themes of evolu-
tion. Life continues to evolve within a changing environment. Organisms
are linked by lines of descent from common ancestry. The four mecha-
nisms of evolution allow populations to adapt to changing conditions.
Finally, human activity can alter the course of evolution as exhibited by
global climate change, which is addressed in many other books in this
series by Campbell and Paradise.
Glossary
allele. alleles are different versions of the same gene.
allergen. any substance that stimulates an allergic reaction.
allergy. immune system response to a non-harmful substance that triggers an
antibody response.
antibodies. Y-shaped proteins that bind to foreign proteins or other molecules as
part of the immune response.
B cells. the white blood cells that produce antibodies.
cancer. uncontrolled cell growth.
copy number variation. it indicates a portion of the genome can be duplicated
n times for each individual.
deletion. loss of a segment of DNA that could range from one nucleotide, to
millions.
dependent variable. it is measured in response to the independent variable.
directed evolution. it improves a known function through multiple rounds of
variation and selecting optimal function.
DNA polymerase. it is the protein enzyme that produces a DNA polymer from
dNTP monomers.
DNA primer. short nucleotide polymer that binds to DNA template and onto
which DNA polymerase adds more nucleotides to replicate the template.
DNA template. strand of DNA to which a primer has bound and will inform the
DNA polymerase to add complementary bases to make the other strand of DNA.
dNTP. any of the four deoxyribonucleic acid (DNA) nucleotides that will be
used by DNA polymerase to elongate DNA during replication.
dot plot. graph that displays sequence similarity between two DNA or protein
sequences.
GC content. the percentage of bases in a genome that are either G or C.
genetically modified organisms. GMOs, organisms who have had their DNA
manipulated by molecular biology methods to produce a desired trait.
gibberellin. plant hormone that induces growth among other physiological
changes.
GMOs. see genetically modified organisms.
horizontal gene transfer. the movement of DNA between different species.
in vitro. in vitro literally means “in glass”, but, in general, it refers to experiments
performed outside live cells.
indel. DNA mutation that involves an insertion or deletion, used when compar-
ing two genomes.
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36 GLOSSARY
independent variable. the variable manipulated by the investigator.

insertion. addition of DNA segment from one to one million nucleotides in
length.
memory B cells. long-lived stem cells that are produced after a primary immune
response and allows for faster secondary immune responses to produce better
antibodies for binding to a specific antigen.
mutation. a change in DNA sequence.
natural selection. one mechanism by which evolution takes place and is often
summarized as survival of the fittest.
paralogs. duplicate genes found within the genome of a single species.
ploidy. it quantifies how many copies of its genome a cell contains.
polymorphism. variation in DNA sequence within a population.
provirus. a virus with its genome inserted into the host’s genome.
random. a chance event whose precise outcome is unknowable, but whose
probabilities can be calculated.
secondary immune response. faster and more robust immune response after
second exposure to allergen.
single nucleotide polymorphism. (SNP) at a particular place in the DNA, more
than one nucleotide can be found in the population (G, C, A or T).
SNP. see single nucleotide polymorphism.
somatic hypermutation. it happens in B cells when they are evolving antibodies
with different affinities.
speciation. the formation of new species through any evolutionary mechanism.
stem cells. long lived, produce daughter cells. and replenish themselves indefinitely.
survival signal. information required by a B cell in order to continue living and
dividing; signal is provided by antigen binding to antibody on cell surface.
Index
Adenosine monophosphate primer, 1–2
(AMP), 2 versus RNA, 2
Allergic responses replication, 1, 4–5
ethical, legal, social implications, template, 1
29–31 Dot plot, 8
evolution of, 23–31 Double-stranded DNA, 5
Antibodies, 23
antigen complex, 25 E. coli, 9, 10
first wave of, 27 pathogenic strain of, 13
primary response B cells,
produced by, 27 GC content, 12–13
producing B cells, 26 Gene duplication, 11
structure and function of, 24 and speciation, 17–19
Antigen-specific B cells, 25–26 Genetically modified organisms
(GMOs), 19–20
Baltimore, David, 1–2 Genetic disease, cause of, 4
Batteries, in landfills, 4 Genome duplication, 18
B cells, 23 Genomic research, 4
evolution of, 28–29 Gibberellin, 7
BLAST2, 8 Golden rice, genome of, 20
Cancer cells, 15, 16 Heavy chain proteins, 23

Chisholm, Sallie W., 13 Heterozygous cells, 8
Chlamydomonas, 12 Horizontal gene transfer, 12, 13
Copy number variation, 14–15 Human genome, 14
Cyanobacteria, 13–14
Jsmol interactive tutorial, 5
Deoxyadenosine monophosphate
(dAMP), 2 K-12 gene, 9, 10
Deoxyguanosine triphosphate
(dGTP), 1 Le gene, 7, 8
Deoxyribonucleotide triphosphates Light chain proteins, 23
(dNTPs), 1
DNA Memory B cells, 26
deletion, 11 Mutations, origins of, 1–5
insertion, 11
polymerase, 1–5, 16 New species, origins of, 7–8
activity comparison, 3 clinical whole genome, changes
E. coli, 1, 2 of, 14–17
ions on young human, ethical, legal, social implications
comparison of, 4 of, 19–20
38 INDEX
genome duplication and speciation, Secondary immune response, 25–26

17–19 Single nucleotide polymorphism
large scale genome, changes (SNP), 7–8
of, 9–14 Smoler, Donna, 1–2
safety of GMOs, 19–20 Somatic hypermutation, 27
Speciation, 9
O157:H7 gene, 9, 10 genome duplication and, 17–19
Stem cells, 26
Paralogs, 17 Survival signals, 26
Pea plants, height of, 7
Ploidy number, 15 US Department of Agriculture
Primary immune response, 25–26 (USDA), 31
Provirus, 13
Venter, Craig, 15
Rights of individual versus group,
balancing, 29–31
RNA versus DNA primer, 2
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Cellular Consequences of Evolution

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The Origins of New

the reaction, the investigators removed aliquots and quantified the

Table 1 DNA polymerase activity comparison.

Table 2 Comparison of old and young DNA polymerase

A few years later, a different group of biochemists wondered what

Table 3 Comparison of ions on young human DNA

Source: From Seal et al., 1979; their table 4.

From Table 1, it is clear that older DNA polymerases generate more

The Origins of New Mutations 5

exact copy. Regardless of whether the DNA polymerase produces a new

Linn S, Kairis M, Holliday R. Decreased fidelity of DNA polymerase

The Origins of New Species

nucleotide polymorphism (SNP, pronounced snip) at base number 685

following case studies will consider examples of genomics changes that

Large Scale Genome Changes

= DNA in the same orientation

Figure 1 Dot plot comparing the chromosome of E. coli strain K-12 on

A reference genome B reference genome C reference genome

Figure 2 Diagrams of dot plot patterns. These three panels show

Panel A of Figure 2 shows an inversion as has happened in E. coli

Return to E. coli O157:H7 as our example. Bioinformatics tools allow

viruses cannot photosynthesize. These cyanobacteria viruses must have

Clinical Whole Genome Changes

amount of DNA. Tetraploid cells in normal individuals have undergone

Genome Duplication and Speciation

If all vertebrates evolved from a common ancestor that had a genome

Ethical, Legal, Social Implications:

20 CELLULAR CONSEQUENCES OF EVOLUTION

Burds AA, Lutum AS, Sorger PK. Generating chromosome instability

Ethical, Legal, Social Implications: The safety of GMOs

Campbell AM, Heyer LJ. Discovering genomics, proteomics, and bioin-

In America and other countries, the number of people who have an

two heavy chains

Figure 3 Antibody structure and function. A, Antibody

Evolution of Allergic Responses 25

Figure 4 Primary and secondary response. The primary

have an unusual property—their antibody alleles mutate at a very high

Figure 5 Summary of long-term B-cell responses. Antigen stimulates

evolution, secondary antibody responses are more robust as a result of

Ethical, Legal, Social Implications:

30 CELLULAR CONSEQUENCES OF EVOLUTION

to quantify the inconvenience experienced by others. Without quantifi-

Ethical, Legal, Social Implications: Balancing the rights of the

independent variable. the variable manipulated by the investigator.

Cancer cells, 15, 16 Heavy chain proteins, 23

genome duplication and speciation, Secondary immune response, 25–26

• Cellular Structure and Function by A. Malcolm Campbell and Christopher J. Paradise

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