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Dictionary of the History of Ideas

Studies of Selected Pivotal Ideas
  
  
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Molecular Homology. In the 1950's and 1960's the
notion of homology has begun to be extended to the
molecular level, to the comparison of nucleotide se-
quences in the DNA's of different organisms, and to
the comparison of amino acid sequences in proteins
from different organisms. If the work to establish mo-


240

lecular homology is great, so too are the conceptual
rewards. One of the most difficult handicaps of classical
genetics and evolutionary studies is, as we have noted,
the lack of a simple relation between the genotype
and phenotype of an organism. A consequence of this
complexity is that if two classes of organisms exhibit
a certain degree of phenotypic difference, one cannot
usually determine the extent of genotypic difference
between the two classes. Thus, from classical genetics
we can usually know neither the extent of genotypic
change underlying the observed phenotypic alterations
in evolution, nor, therefore, the rate at which the
genotype changes in evolution.

These difficulties are partially overcome by consid-
ering nucleotide sequences in DNA and amino acid
sequences in proteins. Since the nucleotide sequence
of the DNA is the genotype, comparison of nucleotide
sequences in different organisms is the most direct
means of assessing the extent of genetic change in
evolution, and genetic homology between species.
However, such an assessment is not as straightforward
as one might have hoped. In the first place, direct
analyses of truly long sequences of bases in DNA are
not currently available. Estimations of similarity of
nucleotide sequences between DNA's utilize indirect
techniques which only establish approximate ho-
mology, not identity of sequence. These techniques
will be described later.

Even were it possible to obtain quite detailed nu-
cleotide sequences for the DNA of two organisms, say
bacteria, estimation of the extent of genotypic differ-
ence between the two would remain difficult. The
concept of the extent of genotypic difference is ambig-
uous. Ambiguity resides in the dual reference of
“genotype” to the actual physical structure of the
DNA, the sequence of bases, and also to the DNA as
the carrier of genetic information. If one is referring
to the physical genotype, then the extent of difference
between two genotypes is simply the number of ho-
mologous loci at which the nucleotides differ. Alter-
ation in the informational genotype is related in rather
complex ways to alteration in the physical genotype.
Amino acids are coded for by triplets of nucleotides;
most amino acids are coded for by two or more codons.
Thus, some nucleotide substitutions change a codon to
a second codon for the same amino acid. Such a substi-
tution alters the physical genome, but leaves the infor-
mational genotype unaltered. Physical genotypes
different at many loci can be the same informational
genotype. Conversely, nearly identical physical geno-
types can be radically different informational geno-
types. This possibility is a consequence of the fact that
codons are triplets, and an amino acid sequence is
specified by a sequence of triplets in which the nucleo
tides are “read” from a specific starting point, three
at a time. A deletion of a single nucleotide can cause
a “reading frame shift” in which all codons downstream
from the deletion are misread and a large number of
incorrect amino acids are incorporated into the pro-
tein. A small change in the physical genotype yields
a large change in the informational genotype. If one
is concerned with the extent and rate of alteration of
the informational genotype in evolution, one must view
with caution data derived from estimates of physical
homology of the DNA's of various organisms.

Indirect physical techniques to study the extent of
base sequence homology of the physical genotype de-
pend upon the DNA's duplex structure whose comple-
mentary strands may be separated and caused to re-
combine. Since single-stranded DNA components from
different origins may also be induced to form “hybrid”
structures, a means is afforded by which to assess ge-
netic relationships among organisms. It can be shown
that duplex formation between single strands derived
from DNA of the same or nearly identical species
occurs readily, but fails to occur if the strands are
derived from very different organisms.

Results of such studies (Bolton, p. 77) indicate that
phenotypically similar animals have very similar DNA
base sequences. Furthermore, “... the similarities and
differences in polynucleotide sequences quantitatively
indicate the extent of the taxonomic category to which
the systematist refers. Thus, among the primates, a
superfamily distinction means that about one-quarter
of the polynucleotide sequences are different, half are
different for subordinal separation, and about three-
quarters for ordinal distinction.” Bolton also notes that
“the quantitative similarities in polynucleotide se-
quences among vertebrates can be related to the time
at which the lines of organisms in the present diverged
from one another in the geologic past according to
the paleontologist's judgment.” Bolton's figure shows
a linear decrease in the logarithm of DNA similarity
with time.

While Bolton's data gives a good indication of the
rate of alteration of a physical genome in evolution,
it remains difficult to relate the results to the extent
and rate of change of the informational genotype in
evolution.

A conclusion reached by Britten and co-workers
(1968, p. 529), is that many nucleotide sequences occur
repeatedly in the DNA of higher organisms, there being
many DNA families, each with many nearly identical
copies of one sequence. The existence of these homolo-
gous DNA sequences renders the relation between the
physical and informational genotype even more com-
plex, for the functional significance of the redundant
DNA is not known. Britten's data also casts doubt on


241

Bolton's conclusion about DNA homology among spe-
cies, for Bolton probably measured only highly re-
dundant DNA sequences.

In contrast to changes in nucleotide sequences which
may occur without alteration of the informational
genotype, changes in amino acid sequence are evi-
dence, by definition, of alteration of the informational
genotype. With the exception of substitutions of nu-
cleotides which do not change the amino acid specified,
substitution of a single nucleotide results in the substi-
tution of a single amino acid at a locus in the poly-
peptide. Since the assignment of codons to amino acids
is now fairly well established, it is now possible to say
which amino acid substitutions can occur by substi-
tution of a single nucleotide in a codon. Some amino
acid substitutions cannot be made by altering a single
nucleotide, but would require the simultaneous alter-
ation of two or three nucleotides; or else, since nucleo-
tide substitutions must usually occur one at a time,
intermediate proteins with an amino acid different
from both the first and final form, must have existed.

Partial or complete sequences of amino acids have
now been worked out for several sets of homologous
proteins in different organisms, for example, hemo-
globin and cytochrome C (Fitch and Margoliash, 1967).
By utilizing arguments about minimal possible changes
causing sequences of amino acid substitutions, coupled
with assumptions about nonreversal of changes, it is
possible to arrange contemporary proteins into pre-
sumptive branching phylogenetic sequences (ibid.).

Evidence supporting the deduced branching phylo-
genetic relations can be sought in the fossil record. The
form of argument utilized is closely similar to that
noted by E. O. Wilson in 1965 for deducing consistent
possible phylogenies based on gross phenotypes of
contemporary organisms. Utilizing such techniques on
cytochrome C, Fitch and Margoliash (1967) have pro-
duced a phylogenetic tree linking fungi, yeasts, nema-
todes, fish, birds, and mammals, which is very similar
to phylogenetic trees proposed by classical zoologists.
The number of amino acid substitutions, coupled with
time estimates derived from the paleontological record,
can give an estimate of the rate of mutation of the
informational genotype. It will be of particular interest
to compare the rates for proteins performing diverse
functions, for the rate must depend in part upon the
strictness of selective constraints on workable amino
acid sequences.

The extent of homology in amino acid sequence for
some proteins is enormous; neurohypophysial peptide
hormones hardly differ from man to shark (Acher,
1969). Other proteins exhibit far less homology, differ-
ing in many loci in many different ways. The occur-
rence of such proteins, all performing the same func
tion in different animals, has led some biologists to
suppose that some amino acid substitutions do not
affect protein function and are therefore not subject
to selection. By random drift, large numbers of such
substitutions are claimed to accumulate, so that these
homologous proteins differ at many loci but continue
to function.

Amino acid sequence homology is also utilized to
help establish possible common evolutionary ancestry
for different proteins. For example, the alpha, beta,
delta, and gamma chains of hemoglobin have long
identical sequences (Fitch and Margoliash, 1967). This
argues strongly that the four protein chains were de-
rived from some single gene, perhaps by its endorepli-
cation to form the sort of redundant DNA of which
Britten has spoken, and then the further evolution of
the four genes.

Clearly, the extension of the concept of homology
to the molecular level promises to be exceptionally
rewarding.