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44200_21_p679-706 3/12/04 3:58 PM Page 696

696 Chapter 21 • Evolutionary Genetics

the ␤-globin gene. The results are quite consistent with TABLE 21-5 Synonymous and
the claim that nucleotide substitutions have been effec- Nonsynonymous Polymorphisms
tively neutral in the past 500 million years. Two sorts of and Species Differences
nucleotide substitutions are plotted: synonymous substi- for Alcohol Dehydrogenase
tutions that are from one alternative codon to another, in Three Species of Drosophila
making no change in the amino acid, and nonsynony-
mous substitutions that result in an amino acid change. Nonsynonymous Species Polymorphisms
Figure 21-13 shows a much lower slope for nonsynony- Synonymous differences
mous substitutions than that for synonymous changes, Ratio 2
which means that the mutation rate to selectively neu- 7 42
tral nonsynonymous substitutions is much lower than 17 0.05 : 0.95
that to synonymous ones. 0.29 : 0.71

This is precisely what we expect. Mutations that Source: J. McDonald and M. Kreitman, Nature 351, 1991, 652 – 654.
cause an amino acid substitution should have a deleteri-
Number of amino acid substitutions per 100 residuesous effect above the threshold for neutral evolution peptides are merely a nonmetabolic safety catch, cut out
more often than synonymous substitutions that do not of fibrinogen to activate the blood-clotting reaction.
Mammalschange the protein. It is important to note that these ob- From a priori considerations, why hemoglobins are less
insVBRCMeiereacarrtdtptspmsie//llrbmeraeasal/ptmftsii/eplsrrse/heesyptilesservations do not show that synonymous substitutionssensitive to amino acid changes than is cytochrome c is
have no selective constraints on them; rather they show less obvious.
that these constraints are, on the average, not as strong as
those for mutations that change amino acids. MESSAGE The rate of neutral evolution for the amino
acid sequence of a protein depends on the sensitivity of a
Another prediction of neutral evolution is that dif- protein’s function to amino acid changes.
ferent proteins will have different clock rates, because
the metabolic functions of some proteins will be much The demonstration of the molecular clock argues
more sensitive to changes in their amino acid sequences. that most nucleotide substitutions that have occurred in
Proteins in which every amino acid makes a difference evolution were neutral, but it does not tell us how much
will have a smaller effectively neutral mutation rate of molecular evolution has been adaptive. One way of
because a smaller proportion of their mutations will be detecting adaptive evolution of a protein is by compar-
neutral compared with proteins that are more tolerant ing the synonymous and nonsynonymous polymor-
of substitution. Figure 21-14 shows a comparison of the phisms within species with the synonymous and nonsyn-
clocks for fibrinopeptides, hemoglobin, and cytochrome onymous changes between species. Under the operation
c. That fibrinopeptides have a much higher proportion of neutral evolution by random genetic drift, polymor-
of neutral mutations is reasonable because these phism within a species is simply a stage in the eventual
fixation of a new allele; so, if all mutations are neutral,
220 the ratio of nonsynonymous to synonymous polymor-
phisms within a species should be the same as the ratio
200 of nonsynonymous to synonymous substitutions be-
tween species. On the other hand, if the amino acid
180 changes between species have been driven by a positive
adaptive selection, there ought to be an excess of non-
160 synonymous changes between species. Table 21-5 shows
an application of this principle by J. MacDonald and
140 M. Kreitman to the alcohol dehydrogenase gene in three
closely related species of Drosophila. Clearly, there is an
Fibrinopeptides excess of amino acid replacements between species over
what is expected from the polymorphisms.
21.8 Genetic evidence
100 of common ancestry in evolution

Hemoglobin When we think of evolution, we think of change. The
species living at any particular time are different from
80 their ancestors, having changed in form and function by


Cytochrome c
40 Separation

of ancestors
20 of plants

and animals

0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300

Millions of years since divergence

Figure 21-14 Number of amino acid substitutions in the
evolution of the vertebrates as a function of time since
divergence. The three proteins — fibrinopeptides, hemoglobin,
and cytochrome c — differ in rate because different proportions
of their amino acid substitutions are selectively neutral.

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21.8 Genetic evidence of common ancestry in evolution 697

the mechanisms reviewed up to now in the discussion of Bat
the genetics of the evolutionary process. But there is a
second feature of the diversity of life, one that Darwin Humerus
took as an important argument for the reality of evolu-
tion. Not only have present organisms descended from Radius
previous, different organisms; but, if we go back in time, Ulna
organisms that are currently very different are de-
scended from a single ancestral form. Indeed, if we go Carpals
back far enough in time to the origin of life, all the or- Metacarpals
ganisms on earth are descended from a single common Phalanges
ancestor. Thus we expect to find that apparently differ-
ent species have underlying similarities, attributes of Human Bird
their common ancestor that have been conserved
through evolutionary time despite all the changes that Figure 21-15 The bone structures of a bat wing, a bird wing,
have taken place. and a human arm and hand. These bone structures show the
underlying anatomical similarity between them and the way in
Before the tools of modern biochemistry and genet- which different bones have become relatively enlarged or
ics were available, the chief evidence of underlying simi- diminished to produce these different structures. [After W. T.
larity of apparently different structures in different
species was taken from anatomical observations of adult Keeton and J. L. Gould, Biological Science. W. W. Norton & Company,
and embryonic forms. So, the similar bone structures of
the wings of bats and the forelimbs of running mammals 1986.]
make it evident that these structures were derived evo-
lutionarily from a common mammalian ancestor. More- larity between the corresponding components of the
over, the anatomy of the wings of birds points to the two pathways indicated by similarly shaped objects in
common ancestry of mammals and birds (Figure 21-15). the diagrams. We do indeed know that DL and NF␬B
It is even argued that the basic segmentation of the bod- participate in some equivalent developmental decisions.)
ies of insects and of vertebrates are evolutionary variants Indeed, as can be seen from a selection from the known
on a common ancestral pattern derived from the com- examples, such evolutionary and functional conservation
mon ancestor of invertebrates and vertebrates. Although seems to be the norm rather than the exception. What
this argument may seem to push the claim of evolution- has made developmental genetics into an extraordinarily
ary conservation too far, it turns out, as we have seen in exciting field of biological inquiry is the demonstration,
the discussion of the Hox and HOM-C genes in Chapter by means of genetic analysis, that basic developmental
18, that genetic analysis of patterns of development pro- pathways and their genetic basis have been conserved
vides a powerful demonstration of the common ancestry over hundreds of millions of years of evolution.
of animals as different as insects and mammals.

We saw in Chapter 18 that such disparate organisms
as the fly, the mouse, and human beings have similar se-
quences for the genes controlling the development of
body form. (The same is true for the worm C. elegans.)
The simplest explanation is that the Hox and HOM-C
genes are the vertebrate and insect descendants of a
homeobox gene cluster present in a common ancestor
some 600 million years ago. The evolutionary conserva-
tion of the HOM-C and Hox genes is not a singular oc-
currence. Many examples have been uncovered of
strongly conserved genes and even entire pathways that
are similar in function. For example, the pathways for
activating the Drosophila DL and mammalian NF␬B
transcription factors are essentially completely con-
served from a common ancestral pathway (Figure
21-16). The Drosophila protein at any step in the DL ac-
tivation pathway is similar in amino acid sequence to its
counterpart in the mammalian NF␬B activation pathway.
(Don’t worry about what the particular proteins do; just
appreciate the incredible conservation of cellular and
developmental pathways as demonstrated by the simi-

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698 Chapter 21 • Evolutionary Genetics

Drosophila SPZ Mammalian IL-1
embryo ligand lymphocyte ligand

Plasma membrane TOLL receptor Plasma membrane IL-1 receptor

Activated Activated PLL-like
protein kinase protein kinase

CACT DL PLL CACT I␬B NF␬B Phosphorylation I␬B
+ +


Nucleus Import Nucleus Import

Figure 21-16 Two parallel signaling pathways. The signaling pathway for activation of
the Drosophila DL morphogen parallels a mammalian signaling pathway for activation of

NF␬B, the transcription factor that activates the transcription of genes encoding antibody
subunits. There are structural protein similarities between SPZ and IL-1, TOLL and

IL-1R, CACT and I␬B, and DL and NF␬B. [After H. Lodish, D. Baltimore, A. Berk, S. L. Zipursky,
P. Matsudaira, and J. Darnell, Molecular Cell Biology, 3d ed. Copyright Scientific American Books, 1995.]

MESSAGE Developmental strategies in animals are quite the loss of any observable similarity in genes or proteins
ancient and highly conserved. In essence, a mammal, a between different species, even if they were descended
worm, and a fly are put together with the same basic genetic from a common ancestor. In fact, even the time since the
building blocks and regulatory devices. Plus ça change, plus common ancestor of present-day vertebrates and inverte-
c’est le même chose! brates has not erased the similarity of DNA and amino
acid sequences between Drosophila and mice. Not only
At a second, deeper level, we can observe the com- are mutation rates not high enough to cause complete
mon evolutionary origin of organisms in the structure of loss of similarity even over hundreds of millions of years,
their proteins and of their genomes. The advantage of di- but also most new mutations are not preserved, because
rect observation of the protein and DNA sequences is they cause a deleterious loss or change in function of a
that we do not have to depend on observing similarity of protein or in the control of the time and place of protein
function among the proteins or anatomical structures production. Thus the amount of divergence that has been
that result from the possession of particular genes. We preserved in evolution has been limited.
have already seen that replacing a single amino acid can
change the function of a protein from an esterase to an 21.9 Comparative genomics
acid phosphatase. Yet, despite this change in function, and proteomics
we have no difficulty in determining that the two en-
zymes are produced by reading genes that are virtually As we saw in Chapter 12, a major effort of molecular
identical, one of which was derived by a single muta- genetics is directed toward determining the complete
tional step from the other as resistance to insecticides DNA sequence of a variety of different species. At the
evolved by natural selection. time at which this paragraph was written, the genomes
had been sequenced from more than forty species of
Over evolutionary time, genes that have descended bacteria; two species of yeast; the fungus Neurospora
from a common ancestor will diverge in DNA sequence crassa; the nematode, Caenorhabditis elegans; two
and in their physical position in the genome, as a result of species of Drosophila; two plants, Arabidopsis and rice;
mutations and chromosomal rearrangements. If enough the mouse; and humans. By the time you read these
time elapsed and there were no counteracting force of
natural selection, this divergence would finally result in

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21.9 Comparative genomics and proteomics 699

lines, many more genomes of many more species willNumber of proteinshaps as a manifestation of the many cell types that dif-
have been sequenced. The availability of such data ferentiate in humans, the size and distribution of the
makes it possible to reconstruct the evolution of the families of specific transcription factors in humans far
genomes of widely diverse species from their common exceed the numbers for the other sequenced eukaryotes,
ancestors. Moreover, it is now possible to infer the simi- with the exception of mustard weed (Arabidopsis
larities and differences in the proteomes of these species thaliana, see Figure 21-17).
by comparing the gene sequences in various species with
gene sequences that code for the amino acid sequences The distribution of proteins described in the pre-
of proteins with known function. ceding paragraph is a description of only half of each
proteome. What about the other half? It can be broken
Comparing the proteomes down into two components. One component, compris-
among distant species ing about 30 percent of each proteome, consists of pro-
teins that have relatives among the different genomes,
With our current state of knowledge, we can suggest but none have had a function ascribed to them. The
functions for about half the proteins in the proteome of other component, comprising the remaining 20 percent
each of the eukaryotes whose genomes have been se- or so of each proteome, consists of proteins that are un-
quenced, by using the similarity of their sequences with related by amino acid sequence to any protein known
proteins of known function. Figure 21-17 depicts the in another branch of the eukaryotic evolutionary tree.
distribution of this half of each proteome into general We can imagine two possible explanations for these
functional categories. Strikingly, the group of proteins novel polypeptides. One possibility is that some of
engaged in defense and immunity have expanded greatly these polypeptides first evolved after the sequenced
in humans compared with the other species. For other species having a common ancestor diverged from one
functional categories, though there are greater numbers another. Because none of these species are evolutionar-
of proteins in the human lineage, there is no case in ily closer than a few hundred million years, it is per-
which the differences between humans and all other eu- haps not surprising to find this frequency of newly
karyotes are as pronounced. As discussed in Chapter 10, evolved proteins. The other possibility is that some of
gene expression is often controlled through regulation of these proteins are very rapidly evolving, and so their
transcription by proteins called transcription factors. Per- ancestry has been essentially erased by the overlay of
new mutations that have accumulated. It is almost
4500 Mustard
4000 Worm
3500 Human

3000 Figure 21-17 The
distribution of eukaryotic
2500 proteins according to broad
categories of biological
2000 function. [Reprinted by

1500 permission from Nature 409
(15 February 2001), 902,
1000 “Initial Sequencing and Analysis
of the Human Genome,” The
500 International Human Genome
Sequencing Consortium.
0 Copyright 2001 Macmillan
Magazines Ltd.]

44200_21_p679-706 3/12/04 3:58 PM Page 700

700 Chapter 21 • Evolutionary Genetics

Prokaryotes only gene orders between diverged species. As an example of
<1% this approach, we will compare the genomes of the hu-
man and the mouse, two species that diverged from a
Vertebrates only Eukaryotes common ancestor about 50 million years ago. The mouse
22% and prokaryotes genome has now been sufficiently sequenced that relative
gene orders can be determined. It turns out that large
Vertebrates and 21% blocks of conserved gene order are easily recognized.
other animals Through systematic comparisons of this type, one can
24% Animals and make synteny maps, which show the chromosomal origin
other eukaryotes of one species essentially painted onto the karyotype of
the other. Figure 21-19 depicts a color representation of
32% the syntenic mouse – human genome. In this figure, 21 dif-

No animal Human chromosomes


Figure 21-18 The distribution of human proteins according to
the identification of significantly related proteins in other species.
Note that about one-fifth of human proteins have been
identified only within the vertebrate lineage, whereas, at the
other extreme, one-fifth have been identified in all of the
major branches of the evolutionary tree. [Reprinted by

permission from Nature 409 (15 February 2001), 902, “Initial
Sequencing and Analysis of the Human Genome,” The International
Human Genome Sequencing Consortium. Copyright 2001 Macmillan
Magazines Ltd.]

certain that both possibilities are correct for a subset of 1 2 3 4 5 6 7 8 9 10 11 12
these novel polypeptides.
13 14 15 16 17 18 19 20 21 22 X Y
Finally, we can ask, Where do the protein-coding Key: Mouse chromosomes
genes in the human genome come from? Figure 21-18
depicts the distribution of human genes in other species. 1 2 3 4 5 6 7 8 9 10
About a fifth of the known human genes have been 11 12 13 14 15 16 17 18 19 X Y
found only in vertebrates. Another fifth seem to be ubiq-
uitous in eukaryotes and prokaryotes. About a third are Figure 21-19 A synteny map of the human genome. The map
found throughout eukaryotes but not in bacteria. Curi- uses color-coding to depict regional matches of each bloc of
ously, a few hundred genes (less than 1 percent) appear the human genome to the corresponding sections of the
to be found only in humans and in prokaryotes. Either mouse genome. Each color represents a different mouse
these genes were present in a common ancestor of chromosome, as indicated in the key. [Reprinted by permission
prokaryotes and eukaryotes and have disappeared from
most other eukaryotes in the course of their evolution or from Nature 409 (15 February 2001), 910, “Initial Sequencing and
else these genes that we and prokaryotes have uniquely Analysis of the Human Genome,” The International Human Genome
in common have been passed on to us from prokaryotes Sequencing Consortium. Copyright 2001 Macmillan Magazines Ltd.]
through horizontal gene transfer.

Comparing the genomes
among near neighbors:
human – mouse comparative genomics

Genomes are thought to have evolved in part by a
process of chromosome rearrangement — that is, the
breaking and rejoining of the backbones of double-
stranded DNA molecules, thereby producing new gene
orders and new chromosomes. (See Chapter 15 for a dis-
cussion of chromosome rearrangements.) The extent to
which chromosome rearrangements have accumulated
during evolution can be assessed by looking for common

44200_21_p679-706 3/23/04 10:54 AM Page 701

Key questions revisited 701

ferent colors represent the mouse X and Y sex chromo- arrangements have occurred between human beings and
somes and the 19 autosomes. For example, most of mouse the mouse, but not enough to have completely scrambled
chromosome 14 can be found in three blocks on human the two genomes relative to one another.
chromosome 13, but, in addition, small segments can be
found on human chromosomes 3, 8, 10, and 14. Similar MESSAGE Comparative genomics is a source of insight
block-by-block distributions in the human genome are into gene-level and chromosome-level changes that occur
observed for each of the other mouse chromosomes. in the process of evolution.
Thus, we can conclude that many chromosomal re-

KEY QUESTIONS REVISITED the bulk of the population, these new genotypes will in-
crease in frequency and may eventually become the
• What are the basic principles of the Darwinian characteristic type in the population. Even if a new
mechanism of evolution? genotype is selectively advantageous, it may not spread if
the population is so small that random genetic drift
The Darwinian explanation of organic evolution is based causes the chance loss of the new type.
on a population variation model in which individuals in a
population vary from one another and some variants in- • How do different species arise?
crease in number while others decrease. A variational
mechanism for evolution is based on three principles: Different species arise from populations that are sepa-
(1) the principle of variation, that among individuals rated by some geographical barrier that prevents the ex-
within any population there is variation in morphology, change of genes between them. When such a separation
physiology, and behavior; (2) the principle of heredity, that exists, then each population will acquire mutations not
offspring resemble their parents more than they resemble shared by the other populations, random genetic drift
unrelated individuals; (3) the principle that some variants will cause the fixation of mutations in one population
are more successful at surviving and leaving offspring than and their loss in others, and ecological differences be-
other variants in a given environment. Taken together, tween the geographical localities may result in some
these three principles provide a mechanism for changes genotypes being favored by natural selection in some
over time in the properties of a population and for the di- populations but not in others. All these forces result in
vergence of different populations from one another. an increasing genetic difference between the isolated
populations. Eventually, the populations may become so
• What are the roles of natural selection and other genetically different from one another that no offspring
processes in evolution, and how do they interact with can be produced by matings between indiviual members
one another? of the different populations even when the geographical
separation disappears. Such reproductively isolated pop-
Evolution is a consequence of several processes operat- ulations are new species.
ing within and between populations and interacting with
one another. The heritable variation required by the • How different are the genomes of different kinds of
Darwinian theory arises by mutation and chromosomal organisms?
changes and by the introduction of new DNA into the
genome by duplication of DNA already present or by The genomes of different kinds of organisms may differ
transposition of DNA from other organisms. In the ab- greatly in the total amount of DNA and in the organiza-
sence of natural selection, the frequencies of different tion of the genes on the chromosomes, but there is a re-
variants change erratically, and eventually populations markable similarity in the proteins that are encoded by
will differentiate from one another by this process genomes of very divergent forms. Among eukaryotes,
because some populations become fixed for a new mu- which include organisms as different as yeasts and hu-
tation, whereas in others the mutation may never have mans, about half the proteins are similar enough to as-
occurred or may be lost by chance. Migration of individ- cribe a similar function to them. Another 30 percent
uals between populations increases the variation within have DNA coding sequences that are similar enough
populations and decreases the differences between pop- among different organisms to recognize that they are de-
ulations. One of the effects of migration is to introduce rived from some common ancestral state even though
new mutations into a population and so make it possible no function has yet been assigned to the proteins for
for more rapid evolution than would occur if popula- which they code. The remaining 20 percent of the cod-
tions were totally isolated and had to wait for the ing DNA has no detectable similarity among organisms
chance occurrence of a new favorable mutation. If the and encodes proteins of unknown function.
carrriers of a new mutation have a greater survival or re-
productive rate than that of the genotypes that make up

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702 Chapter 21 • Evolutionary Genetics

• How do evolutionary novelties arise? velopment of an organism. The result may be novel
changes in shape and function of the parts of the or-
Evolutionary novelties arise from three kinds of ganism, as when legs in reptiles evolved into wings in
change in the genome. First, mutations in already ex- birds. Third, novelties may arise from the evolution of
isting coding DNA may result in the substitution of extra DNA that has been added to the genome by du-
amino acids that completely alter the function of the plication or transposition. The extra DNA is free to
protein. Second, changes may occur in regulatory evolve to new functions while the old functions are
DNA sequences such that the genes that they regulate still served by the original genes.
are transcribed at new rates, times, or places in the de-

SUMMARY species be reproductively isolated from one another. In-
deed, we define a species as a population of organisms
The Darwinian theory of evolution explains the changes that exchange genes among themselves and are repro-
that take place in populations of organisms as being the ductively isolated from other populations. The mecha-
result of changes in the relative frequencies of different nisms of reproductive isolation may be prezygotic or
variants in the population. If there is no variation within postzygotic. Prezygotic isolating mechanisms are those
a species for some trait, there can be no evolution. that prevent the union of gametes of two species. These
Moreover, that variation must be influenced by genetic mechanisms may be behavioral incompatibility of the
differences. If differences are not heritable, they cannot males and females of the different species, differences in
evolve, because the differential reproduction of the dif- timing or place of their sexual activity, anatomical differ-
ferent variants will not carry across generational lines. ences that make mating mechanically impossible, or
Thus, all hypothetical evolutionary reconstructions de- physiological incompatibility of the gametes themselves.
pend critically on whether the traits in question are, in Postzygotic isolating mechanisms include the inability of
fact, heritable. The processes that give rise to the varia- hybrid embryos to develop to adulthood, the sterility of
tion within the population are causally independent of hybrid adults, and the breakdown of later generations of
the processes that are responsible for the differential re- recombinant genotypes. For the most part, the genetic
production of the various types. It is this independence differences responsible for the isolation between closely
that is meant when it is said that mutations are “ran- related species are spread throughout all the chromo-
dom.” The process of mutation supplies undirected vari- somes, although in species with chromosomal sex
ation, whereas the process of natural selection culls this determination there may be a concentration of incom-
variation, increasing the frequency of those variants that patibility genes on the sex chromosome.
by chance are better able to survive and reproduce.
Many are called, but few are chosen. If new functions are to arise in evolution without
the sacrifice of previously existing functions, new DNA
The evolutionary divergence of populations in space must be made available for the evolution of added
and time is not only a consequence of natural selection. genes. This new DNA may arise by duplication of the
Natural selection is not a globally optimizing process entire genome (polyploidy) followed by a slow evolu-
that finds the “best” organisms for a particular environ- tionary divergence of the extra chromosomal set, which
ment. Instead, it finds one of a set of alternative “good” has been a frequent occurrence in plants. An alternative
solutions to adaptive problems, and the particular out- is the duplication of single genes followed by selection
come of selective evolution in a particular case is subject for differentiation. Yet another source of DNA, recently
to chance historical events. Random factors such as discovered, is the entry into the genome of DNA from
genetic drift and the chance occurrence or loss of new totally unrelated organisms by infection followed by in-
mutations may result in radically different outcomes of tegration of the foreign DNA into the nuclear genome
an evolutionary process even when the force of natural or by the formation of extranuclear cell organelles with
selection is the same. The metaphor usually employed is their own genomes. Mitochondria and chloroplasts in
that there is an “adaptive landscape” of genetic combina- higher organisms have arisen by this route.
tions and that natural selection leads the population to a
“peak” in that landscape, but only to one of several alter- Not all of evolution is impelled by natural selective
native local peaks. forces. If the selective difference between two genetic
variants is small enough, less than the reciprocal of pop-
The vast diversity of different living forms that have ulation size, there may be a replacement of one allele by
existed is a consequence of independent evolutionary another purely by genetic drift. A great deal of molecu-
histories that have occurred in separate populations. For lar evolution seems to be the replacement of one protein
different populations to diverge from one another, they sequence by another one of equivalent function. The ev-
must not exchange genes; so the independent evolution
of large numbers of different species requires that these

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Solved problems 703

idence for this neutral evolution is that the number of for proteins such as fibrinopeptides, in which the amino
amino acid differences between two different species in acid composition is not critical for the function, and this
some molecule — for example, hemoglobin — is directly difference in clock rate is, in fact, observed. Thus we
proportional to the number of generations since their di- cannot assume without evidence that evolutionary
vergence from a common ancestor in the evolutionary changes are the result of adaptive natural selection.
past. Such a “molecular clock” with a constant rate of
change would not be expected if the selection of differ- Overall, genetic evolution is a historical process that
ences were dependent on particular changes in the envi- is subject to historical contingency and chance, but it is
ronment. Moreover, we expect the clock to run faster constrained by the necessity of organisms to survive and
reproduce in a constantly changing world.

KEY TERMS directional selection (p. 685) phyletic evolution (p. 681)
adaptive landscape (p. 686) diversification (p. 681) postzygotic isolation (p. 690)
adaptive surface (p. 686) founder effect (p. 684) prezygotic isolation (p. 690)
allopatric (p. 690) molecular clock (p. 695) species (p. 689)
allopatric speciation (p. 690) natural selection (p. 681) synonymous substitution (p. 696)
balancing selection (p. 685) nonsynonymous synteny map (p. 700)
canalized characters (p. 688)
substitution (p. 696)

SOLVED PROBLEMS A skeptical population geneticist reads about
the case in a textbook and she immediately has
1. An entomologist who studies insects that feed on some doubts. It seems to her that, given the evi-
rotting vegetation has discovered an interesting case dence, an equally plausible explanation is that these
of diversification of fungus gnats on several islands populations of gnats are not species at all but just lo-
in an archipelago. Each island has a gnat population cal geographical races that have become slightly dif-
that is extremely similar in morphology, although ferentiated morphologically by random genetic drift.
not identical, to those on the other islands, but each Moreover, the different electrophoretic forms of the
lives on a different kind of rotting vegetation that is alcohol dehydrogenase protein may be physiologi-
not present on the other islands. The entomologist cally equivalent variants of a gene undergoing neu-
postulates that these populations are closely related tral molecular evolution in isolated populations.
species that have diverged by adapting to feeding on
slightly different rot conditions. Outline a program of investigation that could
To support this hypothesis, he carries out an distinguish between these alternative explanations.
electrophoretic study of the alcohol dehydrogenase How could you test whether the different popula-
enzyme in the different populations. He discovers tions are indeed different species? How could you
that each population is characterized by a different test the hypothesis that the different forms of the
electrophoretic form of the alcohol dehydrogenase, alcohol dehydrogenase have diverged selectively?
and he then reasons that each of these alcohol dehy-
drogenase forms is specifically adapted to the partic- Solution
ular alcohols that are produced in the fermentation
of the vegetation characteristic of a particular island. To test the species distinctness of the different gnats, it is
There is, in addition, some polymorphism of alcohol necessary to be able to manipulate and culture them in
dehydrogenase within each island, but the frequency captivity. If they cannot be cultured in the laboratory or
of variant alleles is low on each island and can be greenhouse, then their species distinctness cannot be es-
easily explained as the result of an occasional muta- tablished. The mating-behavior compatibility of the dif-
tion or rare migrant from another island. These fun- ferent forms can be tested by placing a mixture of males
gus gnats then become a textbook example of how of two different populations with females of one of the
species diversity can come about by natural selec- forms to see whether there are any female mating pref-
tion adapting each newly forming species to a differ- erences. The same experiment can then be repeated
ent environment. with mixed females and males of one form and with

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704 Chapter 21 • Evolutionary Genetics

mixtures of males and females of both forms. From such demonstrate that this divergence is a result of nat-
experiments, patterns of mating preference can be ob- ural selection rather than neutral evolution?
served. Even if there is some small amount of mating of
different forms, it may occur only because of the unnat- Solution
ural conditions in which the test is being carried out. On
the other hand, no mating of any kind may occur, even a. Obtain DNA sequences of the gene from a number
between the same forms, because the necessary cues of separate individuals or strains from each of the two
for mating are missing, in which case nothing can be species. Ten or more sequences from each species would
concluded. be desirable.
b. Tabulate the nucleotide differences among individuals
If matings between different forms do occur, the sur- within each species (polymorphisms), and classify these dif-
vivorship of the interpopulation hybrids can be compared ferences as either those that result in amino acid changes
with that of the intrapopulation matings. If hybrids sur- (replacement polymorphisms) or those that do not change
vive, their fertility can be tested by attempting to back- the amino acid (synonymous polymorphisms).
cross them to the two different parental strains. As with c. Make the same tabulation of replacement and syn-
the mating tests, under the unnatural conditions of the onymous changes for the differences between the
laboratory or greenhouse, some survivorship or fertility of species, counting only those differences that completely
species hybrids is possible even though the isolation in na- differentiate the species. That is, do not count a poly-
ture is complete. Any clear reduction in observed sur- morphism in one species that includes a variant that is
vivorship or fertility of the hybrids is strong presumptive seen in the other species.
evidence that they belong to different species. d. If the ratio of replacement differences between the
species to synonymous differences between the species
To test whether the different amino acid sequences is greater than the ratio of replacement polymorphisms
underlying the electrophoretic mobility differences are to synonymous polymorphisms, then select for amino
the result of selective divergence, a program of DNA se- acid change.
quencing of the alcohol dehydrogenase locus is neces- e. Test the statistical significance of the observed greater
sary. Replicated samples of Adh sequences from each of ratio by a 2 ϫ 2 ␹ 2 test of the following table:
the island populations must be obtained. The number of
such sequences needed from each population depends Species Replacement Polymorphisms
on the degree of nucleotide polymorphism that is pres-
ent in the populations, but results from many loci in Differences Synonymous Replacement Synonymous
many species suggest that, as a rule of thumb, at least 10
sequences should be obtained from each population. ab
The polymorphic sites within populations are classified cd
into nonsynonymous (a) and synonymous (b) sites. The
fixed nucleotide differences between populations are ␹2 ϭ (a ϩ b ϩ c ϩ d ) (ad Ϫ bc)2
classified into nonsynonymous (c) and synonymous (d) (a ϩ c) (b ϩ d) (a ϩ b) (c ϩ d)
differences. If the divergence between the populations is
purely the result of random genetic drift, then we ex- 3. How could the molecular evolution of a set of dif-
pect a/b to be equal to c/d. If, on the other hand, there ferent proteins be used to provide evidence of the
has been selective divergence, there should be an excess relative importance of exact amino acid sequence to
of fixed nonsynonymous differences, and so a/b should the function of each protein?
be less than c/d. The equality of these ratios can be
tested by a 2 ϫ 2 contingency ␹2 test of the form Solution

Polymorphisms Obtain DNA sequences from the genes for each pro-
tein from a wide variety of very divergent species
Nonsynonymous Synonymous whose approximate time to a common ancestor is
known from the fossil record. Translate the DNA se-
Population a b quences into amino acid sequences. For each protein,
Differences c d plot the observed amino acid difference for each pair
of species against the estimated time of divergence for
␹2 ϭ (a ϩ b ϩ c ϩ d ) (ad Ϫ bc)2 those species. The line for each protein will have a
(a ϩ c) (b ϩ d) (a ϩ b) (c ϩ d) slope that is proportional to the amount of functional
constraint on amino acid substitution in that protein.
2. Two closely related species are found to be fixed for Highly constrained proteins will have very low rates of
two different electrophoretically detected alleles at substitution, whereas more tolerant proteins will have
a locus encoding an enzyme. How could you higher slopes.

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Problems 705

PROBLEMS Calculate the mean fitness, W, of the population if
the allele frequencies are p(A) ϭ 0.8 and p(B) ϭ
BASIC PROBLEMS 0.9. What direction of change do you expect in al-
lele frequencies in the next generation? Make the
1. What is the difference between a transformational same calculation and prediction for the allele fre-
and a variational scheme of evolution? Give an ex- quencies p(A) ϭ 0.2 and p(B) ϭ 0.2. From inspec-
ample of each (not including the Darwinian theory tion of the genotypic fitnesses, how many adaptive
of organic evolution). peaks are there? What are the allele frequencies at
the peak(s)?
2. What are the three principles of Darwin’s theory of
variational evolution? 9. Suppose the genotypic fitnesses in Problem 8 were:

3. Why is the Mendelian explanation of inheritance es- A/A A/a a/a
sential to Darwin’s variational mechanism for evolu-
tion? What would the consequences for evolution B/B 0.9 0.8 0.9
be if inheritance were by the mixing of blood? What B/b 0.7 0.9 0.7
would the consequence for evolution be if heterozy- b/b 0.9 0.8 0.9
gotes did not segregate exactly 50 percent of each of
the two alleles at a locus but were consistently Calculate the mean fitness, W, for allelic frequencies
biased toward one or the other allele? p(A) ϭ 0.5 and p(B) ϭ 0.5. What direction of
change do you expect for the allele frequencies in
4. What is a geographical race? What is the difference the next generation? Repeat the calculation and pre-
between a geographical race and a separate species? diction for p(A) ϭ 0.1 and p(B) ϭ 0.1. From inspec-
Under what conditions will geographical races of a tion of the genotype fitnesses, how many adaptive
species become new species? peaks are there and where are they located?

CHALLENGING PROBLEMS 10. What is the evidence that polyploid formation has
been important in plant evolution?
5. If the mutation rate to a new allele is 10Ϫ5, how
large must isolated populations be to prevent 11. What is the evidence that gene duplication has been
www. chance differentiation among them to develop in the source of the ␣ and ␤ gene families in human
the frequency of this allele? hemoglobin?

6. Suppose that a number of local populations of a 12. The human blood group allele I B has a frequency of
species are each about 10,000 individuals in size and about 0.10 in European and Asian populations
that there is no migration between them. Suppose, but is almost entirely absent in Native American
further, that they were originally established from a populations. What explanations can account for this
large population with the frequency of an allele A at difference?
some locus equal to 0.4. Show by approximate
sketches what the distribution of allele frequencies 13. Drosophila pseudoobscura and D. persimilis are now
among the local populations would be after 100, considered separate species, but originally they were
1000, 5000, 10,000, and 100,000 generations of classified as Race A and Race B of a single species.
isolation. They are morphologically indistinguishable from
each other, except for a small difference in the geni-
7. Show the results for the populations described in talia of the males. When crossed in the laboratory,
Problem 6 if there were an exchange of migrants abundant adult F1 progeny of both sexes are pro-
among the populations at the rate of (a) one duced. Outline the program of observations and ex-
migrant individual per population every 10 gen- periments that you would undertake to test the
erations; (b) one migrant individual per population claim that the two forms are different species.
every generation.
14. Using the data on amino acid similarity of the ␣-, ␤-,
8. Suppose that a population is segregating for two al- ␥-, ␨-, and ⑀-globin chains given in Table 21-3, draw
leles at each of two loci and that the relative proba- a branching tree of the evolution of these chains
bilities of survival to sexual maturity of zygotes of from an original ancestral sequence in which the or-
the nine genotypes are as follows: der of branching in time is as consistent as possible
with the observed amino acid similarity on the as-
A/A A/a a/a sumption of a molecular clock.

B/B 0.95 0.90 0.80
B/b 0.90 0.85 0.70
b/b 0.90 0.80 0.65

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706 Chapter 21 • Evolutionary Genetics

15. DNA-sequencing studies for a gene in two closely Does this result support a neutral evolution of the
related species produce the following numbers of gene? Does it support an adaptive replacement of
sites that vary: amino acids? What explanation would you offer for
the observations?
Synonymous polymorphisms 50
Nonsynonymous species differences 2
Synonymous species differences
Nonsynonymous polymorphisms 18

EXPLORING GENOMES A Web-Based Bioinformatics Tutorial

Measuring Phylogenetic Distance
Sequence data allow us to estimate the evolutionary distance among organisms
on the basis of the extent of sequence divergence. In the Genomics tutorial at, we will use sequence comparisons to generate or
support our conclusions regarding the structure of the evolutionary tree.

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