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Deciphering primate phylogeny from macromolecular specificities.

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Deciphering Primate Phylogeny from
Macromolecular Specificities ’
Department of Anatomy, W a y n e Stute University
College of Medicine, Detroit, Michigan
A problem in deciphering primate phylogeny, morphological convergence between different evolutionary lines, can be overcome by species comparisons
of proteins, macromolecules with specificities closely linked to the genetic code in DNA.
Various chemical, electrophoretic, and immunological data on serum and tissue proteins in primates are reviewed with respect to their phylogenetic significance. Much of
this data deals with protein specificities in the Hominoidea and depicts a particularly
close genetic relationship between man and the African apes. Hominoidea, Cercopithecoidea, Ceboidea, and Lorisoidea are characterized by their proteins as monophyletic or natural taxa, even though the conventional subdivisions within several of
these superfamilies are not in complete accord with the protein analyses. The protein
evidence supports the conventional grouping of Cercopithecoidea with Hominoidea in
the infraorder Catarrhini and the grouping of Catarrhini and Platyrrhini (Ceboidea)
i n the suborder Anthropoidea. Lemuroidea and Lorisoidea appear to be closer to one
another than to either Tupaioidea or Anthropoidea and closer to the Anthropoidea
than to the Tupaioidea. Comparisons of primate DNA’s by Hoyer and coworkers are
demonstrating genetic affinities among primates which agree with those deduced from
the comparison of protein specificities.
Species differences and similarities in the relative amounts of different protein
macromolecules reflect the grade relationships of prjmates, but, unlike the comparisons
of amino-acid sequences or antigenic specificities, are not reliable indicators of phyletic
affinities. Data on the ratios of M(usc1e) to H(eart) type lactate dehydrogenase in a
series of primate brains provides a biochemical example of the concept that there are
“lower” (primitive) and “higher” (advanced) grades of evolutionary development
among the extant primates.
Several participants at this conference
have shown how the species of Primates
can be divided into groups on the basis of
locomotor behavior. Classifying these species in such terms focuses attention on a n
especially difficult problem in evolutionary
systematics : deciding whether resemblances between species in features of
functional morphology are due to nearness
to a common ancestor or to parallel or
convergent evolution. A clear example of
convergence is provided by the adaptations
for brachiation of spider monkeys and
gibbons. In this case the particular resemblances in functional morphology in no
way suggest close phylogenetic affinities.
However, there are cases in which the
taxonomic classification of certain species
have been influenced by parallel or convergent resemblances. For instance, among
the extant members of the Hominoidea, the
large-sized ape species are conventionally
placed i n the Pongidae while only m a n is
placed in the Hominidae. A key diagnostic
AM. J. PHYS. ANTHROP., 26: 255-276.
feature from the standpoint of functional
morphology for differentiating the two
families is the presence of brachiating
behavior in the various apes and the absence of such behavior in man. Yet the
fossil record suggests that the recent nonhuman hominoids had independently acquired i n evolution their elongate forelimbs
and other specializations for brachiation
(Simons, ’62). Furthermore, as emphasized at this conference, marked differences
i n locomotor behavior and ecological adaptations occur among the various apes.
Thus, while the locomotor and other data
on functional behavior provide a typological rationale for the respective placement
of great apes in Pongidae and m a n in
Hominidae, these data certainly do not provide a convincing phylogenetic rationale
for this arrangement. Nevertheless, the
view has been vigorously advocated in recent discussions of hominoid systematics
~ _ _ _ 1
Supported by N.S.F. grant GB-1241.
that the differences among organisms in
their structural-functional adaptations and
ecological zones constitute an important
basis for taxonomic classification. The
literal adoption of this view in taxonomic
practice would be a return, it seems to me,
to one of the oldest ways of classifying
animals, i.e., “according to their mode of
life, environmental adaptations, and associations” (Simpson, ’45, p. 3). Such criteria, which favor the creation of polyphyletic taxa, have, according to Simpson,
“long been abandoned for purposes of primary zoological classification or formal
nomenclature.” However, in subtler form
these criteria may have retained a hold on
taxonomic practice.
Even the authorities who believe it more
probable than not that the chimpanzee and
gorilla are less removed in descent from
man than from orangutan still support the
convention discussed above, which represents the chimpanzee and gorilla as closer
to the orangutan. It can be reasoned in this
case (see, e.g., Simpson, ’63) that the recent apes are termini of conservative lineages, whereas man is the product of a
radically divergent lineage. In other words,
one can look upon the Hominidae as a
young family arising by extensive adaptive
divergence from an older and more conservative family, the Pongidae. However,
I wonder if this conception of man’s taxonomic status does not have a subjective
bias to it. How can one be sure, for instance, that the orangutan’s arboreal ecological niche is less far removed from the
chimpanzee’s combined terrestrial-arboreal
niche than is man’s terrestrial habitat?
Or, to consider social relationships in naturalistic settings, might not it be possible
that chimpanzees and gorillas, which as a
rule live in large groups, are actually closer
in behavior to humans than to orangutans,
which have been observed only as solitary
travelers or in small family groups of no
more than a mother, inCant, and father.
Furthermore, the particular functionalmorphological features which indicate that
man has radically diverged from other
hominoids - such as his unusually large
brain, his unrivaled manual dexterity, and
his bipedal gait - do not in themselves
demonstrate that man’s genotype is markedly different from that of chimpanzee or
gorilla. Indeed, it is known that sometimes
small genetic changes can cause marked
morphological differences between organisms. Similarly, due to the dependence of
gene expression on environmental factors,
organisms with much the same genotype
can, under the influence of different environments exhibit marked phenotypic variations in their morphologies. These problems, along with the opposite problem of
convergent morphological similarities,raise
formidable difficulties in unraveling the
phylogenetic relationships of organisms.
Although giant strides toward a phylogenetic classification of the primates have
been achieved by the traditional methods of
comparative morphology, many questions
remain. In addition to the uncertainty about
whether the African apes are genetically
closer to man or to orangutan, there is
uncertainty about the phylogenetic position of the gibbons. Some authorities (e.g.,
Simpson, ’45; Le Gros Clark, ’59) place the
gibbons in a subfamily of the Pongidae.
Other authorities (e.g., Fiedler, ’56; Straus,
’49) consider the gibbons a separate family,
the Hylobatidae, distinct from Pongidae as
well as from Hominidae but still within
the Hominoidea. Recent chromosome analyses (Hammerton et al., ’63; Chiarelli, ’65)
have even provoked the thought that the
gibbons are closer to the Cercopithecoidea
than to the Hominoidea.
Another question in primate systematics
pertains to the ceboids or platyrrhine
primates. Although they are always placed
in the same suborder as the catarrhine primates, not all authorities assume that this
grouping represents the “clade” relationships of the two assemblages of higher
primates. It is felt that placing these
assemblages together in the Anthropoidea
represents their “grade” relationships, however. A common view is that the simian or
monkey-like grade, which can be defined
by a complex of functional-morphological
features, was attained independently in
Old and New World continents by parallel
or convergent advances in lineages which
cladistically were as close to lines leading
to modern prosimians as to each other.
Such ambiguity about phyletic relationships increases on approaching the lower
boundary of the order Primates, with systematists divided on whether or not this
order should include the Tupaioidea (tree
shrews). For example, Van Valen (’65)
argues from mounting paleontological data
on early eutherian mammals for the exclusion of the tupaoids from the order Primates. However, the question is far from
settled. It would seem that if we are
eventually to gain a detailed, authentic
picture of the phylogeny of the primates,
there is need for new sources of data as
well as for continued exploitation of the
old sources.
Data which closely reflect the genetics of
organisms would be especially useful, for
as Simpson (’45, p. 5) pointed out, complete genetic analysis would provide the
most priceless data for mapping the stream
of heredity which makes phylogeny. Although genetypic similarities and dissimilarities would have to be interpreted phylogenetically in much the same way as
phenotypic likenesses and differences, “the
advantage of genetics,” Simpson emphasized, “lies rather in the fact that the genes
(and some other genetic factors) are the
immediate physical continuants of phylogeny, while morphology is less direct, a
result of these hereditary factors as modified by other influences.” In 1945, when
Simpson set forth these germinal ideas
on genes and phylogeny, most scientists
were not yet convinced that the material
substratum of the genes was deoxyribonucleic acid (DNA). Nor had it yet been
proven that the genetic code in DNA determines with extremely high precision
the detailed structures of proteins. Thus
the potential significance for taxonomy of
the precipitin work of Nuttall (’04), Boyden
(’42), Wolfe (’39), and others, which
demonstrated the “species-specificity” of
proteins (Landsteiner, ’47), was not fully
grasped. A different situation exists today,
based on our growing understanding of the
molecular basis of heredity. Efforts to map
the genetic relationships of species by suitable serological and biochemical analyses
are gaining momentum. In addition, promising methods have recently been developed
for directly comparing DNA homologies
among species.
The purpose of my paper is to discuss
the picture of evolution in the order Primates as furnished by the data already
gathered on primate proteins and deoxy-
ribonucleic acids. When these molecular
data agree with the functional-morphological data in grouping certain species together, we can have confidence that such
assemblages are indeed phylogenetic ones.
But when the molecular data do not agree
with the groupings from the functionalmorphological data, we can suspect that
the species under comparison represent
convergent evolutionary lines stemming
from different adaptive radiations.
The evidence now seems overwhelming
for the model of the molecular geneticists
which depicts colinearity in primary structure between genes and proteins (Stretton,
’65; Khorana, ’65). According to this model,
the genetic code resides in the sequence of
nucleotide bases of long-chained DNA, with
each consecutive triplet of bases coding for
a correspondingly positioned amino acid in
a polypeptide chain. The mechanisms by
which the code in a gene is first transmitted into “messenger” RNA and then
translated into the sequence of amino-acid
residues of a polypeptide chain need not
concern us in this discussion. What does
concern us is the size and complexity of
the genetic message reflected in the polypeptide chain. Typically such a chain or
protein subunit as is found in the hemoglobin molecule consists of a sequence of
about 150 amino acid residues of up to
20 different kinds. Since the code “words”
for the different amino acids are different
triplets drawn from the four kinds of nucleotide bases in DNA, the structural gene
or section of chromosomal DNA coding the
amino acid sequence of the polypeptide
chain would consist of about 450 nucleotide residues. It is apparent that the theoretical permutations in structure for such
a gene or its corresponding protein product
are fantastically large. Thus the tiny fraction of the total coded information in a
genome represented by a single structural
gene is still of such complexity (and contains such a unique selection of information) that it could well exhibit properties
of phylogenetic specificity.
Pursuing this point, Zuckerkandl (’65)
and others distinguish two classes of organic molecules. One class consists solely
of nucleic acids and proteins, special substances which are termed semantides to
emphasize their richness in coded information. The other class consists of organic
molecules such as retinene which are synthesized under the control of proteinenzymes without the direct participation of
nucleic acid templates and are relatively
low in genetic information. The substances
in this class are called episemantic molecules. It may be fairly common for longseparated lineages to produce the same
members of this class by evolutionary convergence. Consequently, episemantic molecules are not nearly as useful as the semantides for phylogenetic studies.
Given the almost innumerable choices
€or mutations (changes in code letters)
within even a single genetic locus and the
random order in which mutations occur, it
is highly unlikely that proteins of the same
specificity can be produced by evolutionary
convergence. However, during periods of
phyletic evolution, any particular protein
may have been more conservative (i.e.,
changed less in specificity) in certain lineages than in others. Thus, if lineage A
diverged more from lineage B than from
lineage C in terms of a particular protein,
it would not necessarily mean that A has
a more recent common ancestry with C
than with B. On the other hand, this would
be a reasonable assumption to make if B
consistently showed the most divergence
in a series of proteins examined. At the
least, it would be fairly safe to conclude
that A has more genetical affinities with C
than with B. A priori reasoning and the
trend of results already observed in studies
of primate proteins suggest that when appropriate methods are employed, the data
from a relatively small sampling of proteins can produce valid inferences about
phylogenetic relationships.
The chemical determination of the actual
amino acid sequences in proteins can give
the most precise description of protein
homologies in different species. However,
the methods of analysis are painstakingly
slow and the data as yet are too meager to
have any impact on primate classification.
Perhaps the only relevant sequence data
are for cytochrome c (Smith and Margoliash, '64) and fibrinopeptide A (Blomback,
Doolittle and Blomback, '65). Even though
the results were obtained on only a handful of species, they demonstrate that, in
terms of cytochrome c and fibrinopeptide
A, man and Old World monkey barely diverge from each other while showing sizable divergencies from nonprimate mammals. A broader but less precise set of data
on hemoglobin structure in primates has
been obtained by fingerprinting various
primate hemoglobins and determining their
amino acid compositions. In fingerprinting
(Ingram, 'SS), peptide fragments with differing amino acid sequences are first produced by controlled tryptic digestion of a
protein or protein subunit and are then
separated into a complex pattern by
chromatographic and electrophoretic procedures. Differences between proteins in
their primary structure, i.e., in their amino
acid sequences, can be spotted by differences in their fingerprint patterns. Amino
acid composition data give the amounts but
not the arrangements of the different
amino acids in a protein substance. On the
whole, the fingerprint and amino acid
composition analyses provide minimum
estimates of differences in primary structure between proteins. From these analyses, human hemoglobin appears to be
almost identical with chimpanzee and
gorilla hemoglobins (Zuckerkandl, '63)
and to be more similar to orangutan
(Zuckerkandl, '63) and gibbon (Hill and
Buettner-Janusch, '64; Buettner-Janusch
and Hill, '65) hemoglobins than to Old and
New World monkey hemoglobins. The
correspondence in hemoglobin structure
appears to be much greater among these
higher primates than among lemurs and
other prosimians (Hill and BuettnerJanusch, '64; Buettner-Janusch and Hill,
'65). The various chemical data on cytochrome c, fibrinopeptide A, and hemoglobin all suggest that genetic correspondence
among higher primates may be relatively
By far the most extensive data on primate proteins are those being gathered by
electrophoretic and immunological procedures. A wide series of sera from primates
and certain related mammalian types have
been surveyed in my laboratory by the twodimensional electrophoretic method of
Poulik and Smithies (’58). The proteins
in a sample are separated by electrophoresis on filter paper followed by electrophoresis in starch gel. The proteins separate
in the second dimension on the basis of
molecular size as well as electrophoretic
charge, forming a complex pattern of about
19 to 25 components. Such discrete properties as a protein’s electrophoretic charge
or its polymer-forming tendencies can be
sharply altered by gene mutations, even by
a single-point mutation if the amino acid
substitution in the polypeptide chain is a
“radical” replacement (Zuckerkandl and
Pauling, ’65): e.g., a positively charged amino acid for a negatively charged one, or an
amino acid with an hydrophobic residue
for one with an hydrophilic residue, and
so on. It can be deduced that phylogenetic
branching need not be extensive for striking differences to appear in the two-dimensional electrophoretic serum patterns of
diverging species. The reasonableness of
this proposition becomes apparent on considering that there are at least 25 and
probably up to 100 or more gene loci which
control the amino acid sequences of the
different subunits of the proteins in serum.
Furthermore the actual two-dimensional
electrophoretic data gathered on a wide
range of taxa (including 50 species from
31 primate genera) demonstrate marked
divergencies in serum patterns between
samples from different subfamilies and
also in the large majority of cases from different genera within the same subfamily.
The major exception is in the Cercopithecinae, a subfamily of Old World monkeys.
Here fairly similar patterns are observed
between genera (Goodman, ’63b; Goodman,
Farris and Poulik, in press). In all groups
examined so far, the samples from different species within a genus (such as
Galago crassicaudatus and Galago senegalensis, or Pan troglodytes and Pan paniscus)
invariably have very similar but usually
not identical patterns (Goodman, ’62b,
’63b, ’65; Goodman, Farris and Poulik, in
press ) . Thus the two-dimensional electrophoretic serum data can best be used to
assess phylogenetic relationships at the
lower taxonomic levels. For example, these
data (Goodman, ’63b) do not favor the
proposal of Mayr (’50) and Simpson (’63)
that the taxonomic distinction between
gorilla and chimpanzee be only at the species level; instead the serum electrophoretic data suggest that there is sufficient
genetic divergence between gorilla and
chimpanzee to favor maintaining Gorilla
as a separate genus from Pan. On the other
hand, the serum patterns of Gol-illa, Pan,
and Homo have more features in common
with one another than with the patterns
of Pongo, Hylobates, or Symphalangus.
Conceivably, the conventional Ponginae,
which groups Gorilla and Pan with Pongo
while excluding Homo, is an artificial taxon
not reflecting the true phyletic affinities of
its members. This suggestion will be amplified later in the paper when we consider
the more definitive immunological data on
The two-dimensional electrophoretic serum patterns provide a small piece of evidence for the hypothesis that within the
Cercopithecinae Erythrocebus is closer to
Cercopithecus than to other genera ( M a caca, Cercocehus, Theropithecus, and
Papio) . Although these various cercopithecine genera have fairly similar patterns,
some obvious differences do occur among
them, especially in the positioning of the
protein components migrating both on filter paper and in starch gel between transferrin and albumin. In this area of the
two-dimensional electrophoretic patterns,
Erythrocebus least resembles Cercocebus,
Papio, and Theropithecus and most resembles Cercopithecus (Goodman, Farris
and Poulik, in press).
The taxonomic significance of starch-gel
(or other comparable) electrophoretic analyses can be enlarged by obtaining tissue
patterns of the multiple molecular forms of
particular types or classes of enzymes.
These patterns are called zymograms
(Hunter and Markert, ’57). Using starch
gel electrophoresis and the appropriate
histochemical reagents for demonstrating
five distinct types of esterases, Tashian
(’65) has compared the zymograms of
erythrocyte esterases in 23 primate species.
The patterns were similar in man, gorilla,
chimpanzee, and orangutan but were
sharply different in gibbon. On the other
hand, Syner and Goodman (unpublished
data), on examining the zymograms of
brain esterases in 24 primate species, found
that these esterase patterns were quite similar in human, chimpanzee, and gibbon
brains (gorilla and orangutan brains were
not available). In each study there was
little variation among different cercopithecoid species in their zymogram patterns,
which differed sharply from hominoid patterns and perhaps even more so from ceboid
and prosimian patterns. Within the small
limits of variation in erythrocyte esterase
patterns among the four cercopithecine
genera which were examined (Tashian,
'65), Erythrocebus showed more similarity
to Cercopithecus than to Papio or Macaca.
Among both ceboids and prosimians, in
contrast to cercopithecoids, the patterns
varied sharply from species to species.
The esterases are a broad class of enzymes and each tissue is likely to have its
own specific assortment of members of the
class. Thus more than a few gene loci are
represented by the amino acid sequences
of the various esterase components, though
probably not as many loci as control the
serum proteins. When more tissues and
additional classes of enzymes are surveyed
in a series of primates, the findings will
almost certainly have significance for primate systematics. Even the limited erythrocyte and brain data already gathered add
nicely to the serum electrophoretic data.
One gains the impression from the sum of
this electrophoretic data that the African
apes and man are closer to the orangutan
than to the gibbon but (taking into consideration the brain data) closer to the
gibbon than to Old World monkeys and
other primates. However, false impressions
can easily be gained from electrophoretic
data. In particular, estimations of the
magnitude of genetic divergence between
organisms from such data are likely to be
fallacious. Electrophoretic mobilities of intact macromolecules cannot be used to
measure the extent of the differences in
amino acid sequence between proteins. All
that can be assumed is that the more extensive the variation of amino acid sequences, the greater is the likelihood of
detecting some difference between proteins
in their electrophoretic mobilities.
Genetic polymorphisms of various proteins (hemoglobin, transferrin, haptoglobin,
carbonic anhydrase, lactic dehydrogenase,
etc.) within species are often detected by
electrophoretic analyses. Information obtained from population surveys of these
electrophoretically detectable polymorphisms could perhaps be useful in unraveling
the genealogical relationships of populations grouped together at quite low taxonomic levels and having only statistically
minimal genetic differences between them.
Such an approach, which would rely
heavily on the techniques of population
genetics, could be profitably used, for instance, to evaluate the systematics of the
macaques. There is reason to suspect that
among macaque groups, currently classified as distinct species, the degrees of speciation are actually not so complete as to
have prevented all gene exchange or introgression between these groups in their
zones of geographic contact and overlap
(Goodman et al., '65). If this were the
case, the frequencies of allelic genes in the
local populations of different groups would
tend to be more similar to one another in
the zones of geographic overlap than elsewhere. In such studies the number of
genetic loci that could come under inspection could be increased by using immunological procedures to type for the isoantigens on erythrocytes and on certain serum
To return now to questions of primate
systematics which pertain to genera and
higher taxonomic categories, the most informative data from primate proteins have
been obtained by immunological procedures. Comparative analyses by agar-gel
immunoprecipitin techniques are particularly effective. They allow attention to be
focused on single proteins and thus permit
a more accurate antigenic comparison of
these proteins to their homologues in other
animal sera. In contrast to an electrophoretic difference, the antigenic divergence
between a protein and its homologue in a
different species is related to the magnitude
of code-word differences in the corresponding genes. A strong antiserum produced
in a vertebrate host to a foreign protein
can detect a variety of different surface
configurations or antigenic determinants
on the foreign protein. Each such determinant would arise from the unique topographical features in a fairly small but still
exceedingly intricate cluster of amino-acid
residues. Due to the phenomenon of immune tolerance to self-substances, only
those stereochemical configurations not
found on the host's own circulating proteins would be antigenic. Tolerance would
automatically exist to the less intricate
configurations, which, being common to all
kinds of diverse proteins, are found in almost all organisms. Thus, due to the confluence of two factors - the phenomenon
of immune tolerance and the unrivaled
architectural complexity of protein molecules - the proteins exhibit an exquisite
degree of specificity at the antigenic level.
The field of this specificity can be either
broadened or sharpened in phylogenetic
comparisons of proteins by the choice of
antibody producer. The more closely related the host or antibody producer is to
the donor of the immunizing proteins, the
greater will be the similarity in the specificities of host and donor proteins and the
more selective will be the antibody response
of the host. Only the more species-specific
(more recently evolved) configurations on
the donor proteins will be antigenic to the
host. For example, Old World monkey
antisera to human proteins, being directed
to the more recently evolved configuratons
on the human proteins, would be able to
distinguish sharply the sequence of relationships of man to other members of the
Hominoidea but would be useless for studying the relationships of man to more distant species. On the other hand, antisera
produced in rabbits or chickens, while not
likely to draw as sharp distinctions within
the Hominoidea as the monkey-produced
antisera, could nevertheless provide valid
information about the phylogenetic relationships of man to species throughout the
order Primates and possibly even throughout the class Mammalia in the case of
chicken antisera.
Here it may be pointed out that only the
precipitins to proteins are likely to provide
such valid information. Other kinds of
substances, e.g., the carbohydrates of the
26 1
blood-group isoantigens, often have heterogenetic properties. Such substances, usually made up in each case of only a few
repeating units, are not nearly as complex
in chemical structure as the proteins yet
have an erratic appearance in nature. Although typically a heterogenetic substance
is synthesized by organisms in diverse species of animals, plants, and bacteria, not
all species or all organisms in a species
synthesize the substance. Thus, unlike the
case of the common (less intricate) configurations of proteins which are ubiquitous
in organisms, immune tolerance would not
be universal to a heterogenetic substance
despite its relatively simple configurations.
Consequently, the cross-reactions of antibodies to heterogenetic antigens could furnish misleading information about phylogenetic relationships, especially at the
higher taxonomic levels. On the other
hand, as indicated earlier, surveys of the
distribution of such antigens could contribute to studies concerned with the divergencies among population groups at the
lower taxonomic levels. As may be surmised, the proteins, with their particular
properties as antigens, either lack heterogenetic properties or possess them to a
weak degree. Thus, to reiterate an important point, the immunological comparisons
that can furnish the most reliable information on phylogenetic relationships are those
carried out on proteins.
Of the immunoprecipitin data on primate proteins, the most extensive set has
been gained with chicken, rabbit, and
monkey antisera to the proteins of human
serum. Many of the antiserawere produced
to purified protein fractions (albumin,
gamma globulin, transferrin, ceruloplasmin, etc.) and the rest to whole serum. In
my published (Goodman, '62a,b, '63a,b,
'64, '65) and as yet unpublished studies, a
minimum of 1 4 different human serum
proteins have been compared (some more
intensively than others) to their homologues in various primate sera. With respect to at least 9 to 13 of these proteins,
chimpanzee and gorilla showed less divergence from man than the orangutan
and gibbons, and in no case did the
chimpanzee and gorilla show more divergence than the Asiatic apes. Ever since
the classic study of Nuttall ('04) this same
trend of results has been found in the
species comparisons with antihuman serum
protein precipitins (Boyden, '58; Picard,
Heremans and Vandebroek, '63; Williams,
'65). As shown in figures 1 and 2, the
cross-reactions of an Old World monkey
antiserum to whole human serum very
Fig. 1 Agar-gel immunoelectrophoresis on glass
slides: the precipitin lines were developed by an
Old World monkey (Cercopithecus aethiops) antiserum (M-68) to human serum. Note that human
and chimpanzee sera gave much stronger precipitin reactions (number and intensity of lines)
than orangutan and gibbon sera.
clearly pictures man as being closer to the
African apes than to the Asiatic apes. The
immunological data which tend to demonstrate this relationship now include results obtained with rabbit-produced antiserum to human lense extract (Maisel and
Goodman, '65; Maisel, '65) and other rabbit- and chicken-produced antisera to
human thyroglobulin, the major protein
found in the thyroid gland. The former
antiserum detected a lens-specific protein
whjch was not as conservative in evolution
as the typical lens antigens. While its
chimpanzee homologue was indistinguishable from it, its gibbon homologue diverged
slightly. The antihuman thyroglobulin precipitins detected a small divergence of
chimpanzee thyroglobulin and a further,
more marked, divergence of gibbon thyroglobulin. Unfortunately the hominoid comparisons were incomplete since gorilla and
orangutan lenses and thyroids were not
available. In the additional comparisons
carried out with the various antisera to
human serum and tissue proteins, crossreactions decreased on going from gibbons
to cercopithecoids to ceboids to prosimians,
the decrease being steepest on leaving the
A sizable amount of data has also been
obtained with antisera to serum proteins
and, in a few cases, lens proteins on nonhuman primate species. However, not as
many antisera have been produced to proteins of each nonhuman primate as were
produced to human proteins. Nevertheless,
this additional precipitin data complement
very nicely the antihuman precipitin data.
So far no support is given the taxonomic
convention of classifying man as the sole
living representative of the Hominidae for chimpanzee, man, and gorilla barely
diverge from one another in their serum
antigens while clearly diverging from the
orangutan and gibbons. The latter diverge
from each other and from man, chimpanzee, and gorilla but show somewhat larger
divergencies from Old World monkeys.
Recent data with rabbit precipitins to
Hylobates serum proteins demonstrate apparent identity in serum antigens of Hylobates and Symphalangus and some divergence of these gibbons from other hominoids. To amplify my earlier proposal
(Goodman, '63a,b) : a serologically based
Fig. 2 Comparative analysis (Ouchterlony) reactions of hominoid sera in agar gel developed by the monkey
antiserum (M-68) to human serum. Man ( M ) formed small spurs against chimpanzee ( C ) and strong
spurs against orangutan ( 0 ) and gibbon ( G i ) . Chimpanzee formed only a slight spur against gorilla ( G )
but formed moderate to strong spurs against orangutan and gibbon. In this type of testing (Goodman, '62a),
a protein forms a spur against its homologue in another serum if it contains reactive antigenic sites that
its homologue lacks. Thus the divergence from the human proteins was greater for the orangutan and gibbon homologues of these proteins than for the chimpanzee and gorilla homologues.
classification would still place Pun, Homo,
and Gorilla in the Hominidae; Pongo could
remain in the Pongidae; and Hylobates and
Symphalangus would be placed in the
Hylobatidae. The three families would still
be grouped together in the Hominoidea.
The Old World monkeys (Cercopithecoidea) were found to be more similar in
their serum and lens proteins to the hominoids than to New World monkeys and
marmosets (Ceboidea) and the latter more
similar to the Hominoidea and Cercopithecoidea than to any prosimian or comparable mammalian group (tarsiers, lorises,
lemurs, tree shrews, etc.). These findings
support the primate classifications (Fiedler,
'56; Straus, '49; Hill, '57) which subdivide
the suborder Anthropoidea into infraorders
Platyrrhini (Ceboidea) and Catarrhini
(Cercopithecoidea and Hominoidea). At the
same time the protein findings are strong
evidence that a true phyletic l(i.e., cladistic)
relationship, not just a grade relationship,
exists between the platyrrhines and catarrhines.
The Cercopithecoidea, Ceboidea, and
Lorisoidea, like the Hominoidea, appear
from the precipitin data as true monophyletic assemblages or natural taxa. The
subdivision of the Cercopithecoidea into
Cercopithecinae and Colobinae is also in
good agreement with the serum precipitin
data. The three colobine genera examined
(Presbytis, Colobus, and Nasalis) showed
a high correspondence to one another in
serum antigens while diverging from cercopithecines (Erythocebus, Cercopithecus,
Cercocebus, Macaca, Papio, and Theropithecus). The latter in turn showed high
antigenic correspondence among themselves while diverging from the colobines.
Within the Cercopithecinae itself the clearest antigenic divergence - surprisingly, of
serum albumin - was between the patas
monkey ( E q t h r o c e b u s ) and the baboons
(Papio and Theropithecus). Thus this serological analysis agrees with aspects of the
functional-morphological analysis (Napier,
'66) which suggest that the adaptations of
the patas monkey and baboons for terrestrial existence were produced by parallel
or convergent evolution. But at the same
time the finding of serological divergence
between these ground-living cercopithecines helps demonstrate that similarities in
ecological adaptations and functional behavior are not necessarily indicative of
genotypic similarities.
Within the Ceboidea the subdivision of
genera into subfamilies in the conventional
taxonomic schemes has been largely an
arbitrary matter in that the morphological
differences between genera within a subfamily are often as marked as the differences between genera in different subfamilies. However, there is fairly strong evidence for the subfamily grouping of Ateles
(spider monkey) and Lagothrix (woolly
monkey) in Atelinae. These forms, which
are noted for the abilities to brachiate and
€or their prehensile tails, show a relatively
high degree of similarity in functional
morphology. Furthermore, the cross-reactions of rabbit precipitins to spider and
woolly monkey albumins (Goodman, ' 6 5 )
and gamma globulins (figs. 3,4) demonstrate that Ateles and Lagothrix correspond
more to one another than to other ceboids.
The cross-reaction data also suggest that
Ateles and Lagothrix are phyletically more
closely related to the howler monkey
Alouatta (another form with a prehensile
tail and ability to brachiate) than to other
ceboids. On the other hand, data obtained
with anticapuchin and antisquirrel-monkey
precipitins disagree with classifications
(Simpson, '45; Hill, '60) which group
Cebus and Saimiri in the subfamily Cebinae, since these two genera diverged as
much from each other as from other ceboid
genera. Nor is the grouping of Aotes and
Callicebus in the Aotinae (Simpson, '45)
supported by the cross-reactions of precipitins to night and titi monkey sera.
These and other data suggest that the differences between genera in serum proteins
are greater within the Ceboidea than within
either the Cercopithecoidea or Hominoidea.
Turning now to the Lorisoidea, the
serum protein precipitin data (examples of
which are given in figs. 5,6,7,8) show each
genus of the four examined diverging from
the others, with slightly less divergence
between Nycticebus and Galago than between Nycticebus and Perodicticus. On the
other hand, the divergence between Nycticebus and Galago may be slightly greater
than the divergence between Nycticebus
and Loris. These results would not appose
the conventional grouping in the Lorisinae
Fig. 3 Comparative analysis (Ouchterlony) reactions developed by anti-gamma globulin
precipitins of chicken antiserum (C-939) to spider monkey serum. The test antigens were
gamma globulins isolated (by paper electrophoresis and elution) from the sera of the
following primates: spider monkey (Sp), woolly monkey ( W ) , howler monkey (H), night
monkey ( N ) , squirrel monkey (Sq), man ( M ) , and slow loris (SI). With the exception
of the slow loris and man, the other animals were all ceboids. Spider monkey formed a
trace spur (not evident in the photograph) against woolly monkey, a moderate spur against
howler monkey, and strong spurs against night and squirrel monkeys. In turn, squirrel
monkey formed a medium to strong spur against man, and man a weak spur against slow
of Nycticebus and Loris but would appose
that of Perodicticus, since Galago is conventionally excluded. Conceivably, parallel evolution may have played a n important part
in bringing about the marked resemblance
between Perodicticus and Nycticebus in
their locomotor adaptations. The present
serological results, while not yet extensive
enough to encourage any categorical claims
do suggest that the phyletic distance be-
Fig. 4 Comparative analysis (Ouchterlony) reactions of gamma globulins developed by
anti-gamma globulin precipitins of chicken antiserum (C-946) to woolly monkey serum.
Woolly monkey ( W ) merged with spider monkey (Sp), formed a trace spur (perhaps not
evident in the photograph) against howler monkey ( H ) , and strong spurs against night ( N )
and squirrel monkeys ( S q ) . Squirrel monkey formed a strong spur against man ( M ) , and
man a moderate spur against potto (Po).
tween Perodicticus and Nycticebus is every
bit as great as the distance between Galago
and Nycticebus.
The serological results also apply to the
problem of the systematic relationships of
prosimian groups at the higher taxonomic
levels. While Lorisoidea and Lemuroidea
diverge markedly in serum antigens, each
nevertheless appears to be closer to the
other than to Tupaioidea, Tarsioidea, or
Anthropoidea. This would support the removal of the tree shrews from the Lemuriformes and the grouping of Lemuroidea
with Lorisoidea in the Strepsirhini (Hill '53).
So far the immunoprecipitin data tend
to affirm that the Anthropoidea is not quite
as f a r from Strepsirhini as from Tupaioidea. For example, precipitins (Goodman,
'63b) to human gamma globulin, ceruloplasmin, and alpha, macroglobulin, as well
as precipitins (Maisel and Goodman, '65;
Maisel, '65 j to the least conservative fraction of the higher primate lens proteins,
developed larger cross-reactions with lorisoids and lemuroids (lens could not be
tested in this case) than with Tupaia and
nonprimates. On the other hand, tupaiid
albumin resembles higher primate albumins slightly more than do the strepsirhine
albumins and distinctly more than do nonprimate mammalian albumins. However,
as discussed elsewhere (Goodman, '63a j ,
a marked evolutionary conservatism of both
tupaiid and higher primate albumins could
account for this resemblance.
In the initial study with antisera to
galago lens proteins ( Maisel, '65) lorisoids
corresponded much more to the Anthropoidea than to tree shrew and nonprimate
mammals. However, the lens results
neither distinguished the different lorisoids
(Galago, Perodicticus, and Nycticebus )
from one another, nor the lorisoids from
the tarsier. The latter result (which requires confirmation) is especially interesting since the Lorisoidea and Tarsioidea diverge very markedly from each other in
their serum proteins. Conceivably, since
the lorisoids and tarsier have remained in
nocturnal arboreal habitats, they may have
retained lens proteins having the ancestral
specificities of the early Tertiary primate
lens. In contrast, certain lens proteins in
the Anthropoidea clearly changed in speci-
Fig. 5 Comparative analysis (Ouchterlony) reactions of lorisoid sera developed by a
rabbit antiserum (R-85) to slow loris serum. Slow loris ( S l ) developed weak spurs against
slender loris (Sle); slender loris (Sle) developed a weak spur against galago (Ga), weak to
moderate spurs against potto (Po), and strong spurs against lemur (Le).
Fig. 6 Comparative analysis (Ouchterlony) reactions developed by anti-albumin precipitins of the rabbit antiserum (R-85) to slow loris serum. The test antigens were albumins
isolated (by paper electrophoresis and elution) from the sera of the following animals: slow
loris (Sl), potto (Po), galago (Ga), lemur (Le), chimpanzee (C), and the tree shrew (Tr).
Potto albumin diverged much more from slow loris albumin than did galago albumin, but
did not diverge as much as lemur albumin. In turn, lemur formed a spur against chimpanzee
and chimpanzee against tree shrew.
ficity during the evolution of higher primates (Maisel and Goodman, '65; Maisel,
'65). These results give credence from the
standpoint of molecular affinities to Simpson's classification (Simpson, '45), which
constructs two major grades of evolutionary development in the Primates and
places the tarsier along with lorisoids and
lemuroids in the lower grade, Prosimii.
However, the serum data suggest that a
determination at the molecular level of
over-all genetic similarities and differences
among extant primates may not necessarily
support such a grade classification.
A promising molecular approach for determining over-all genetic similarities and
differences among organisms has been de-
veloped by Bolton and McCarthy ( ’ 6 2 ) ;
(McCarthy and Bolton, ’63) and Hoyer
(Hoyer, McCarthy and Bolton, ’64). Their
procedure takes advantage of the tendency
to helical formation between the complementary strands of DNA in a genome and
measures the specific binding of radioactively tagged DNA fragments to long
single-stranded DNA embedded in agar.
The extent of “hybridization” obtained in
this system between the DNA’s of different
species can be considered a function of the
genetic correspondence between the species. Hoyer and co-workers are applying
their DNA method to primate materials.
So far the DNA results (Hoyer et al., ’65;
Hoyer, ’65) show extensive genetic similarities among higher primates and agree with
the protein data which would subdivide the
Anthropoidea into Platyrrhini and Catarrhini with man being closer to apes than
to Old World monkeys. In further agreement with the protein data, gibbon DNA
is not quite as similar to human DNA as is
chimpanzee DNA. In a series of comparisons which demonstrate the latter point,
the homologous DNA was human and the
percentages of correspondence of heterologous DNA’s to the human calculated in
the test system were as follows: chimpanzee, 100; gibbon, 94; rhesus monkey,
88; capuchin monkey, 83; tarsier, 65; slow
loris, 58; galago, 58; lemur, 48; tree shrew,
28; hedgehog, 21; mouse, 19; and chicken,
10 per cent (Hoyer, ’65). Such data whet
one’s appetite to apply this approach much
more extensively to primate and other
mammalian materials. One would want to
know the sequence of relationships to the
tree shrew, to the tarsier, and so on, using
a broad series of homologous and heterologous DNA’s. Undoubtedly the findings
Fig. 7 Immunoelectrophoretic patterns developed by a chicken antiserum (C-858) to slow loris
by the procedure of Weiner et al. (’64). Electrophoresis of the serum aliquot was carried out on
a n agar-covered glass strip. The strip, after being placed in the bottom of a glass chamber was
overlaid with agar, and the antiserum was then placed on top of the agar. Precipitin lines (the
white ones) formed as the antigens diffusing up from the bottom and the antibodies diffusing
down from the top met in the agar. The degree of cross-reaction (number and intensity of precipitin lines) decreased on going from slow loris ( S l ) to galago (Ga) to potto ( P o ) to the lemuroid
Propithecus (Pr ) .
Fig. 8 Comparative analysis (Ouchterlony) reactions of albumins developed by anti-albumin precipitins of chicken antiserum (C-796) to potto serum. Potto (Po) formed spurs against slow loris
(Sl) and galago (Ga), and galago formed a spur against lemur (Le). In turn, lemur farmed a spur
against baboon (B).
would help solve many of the questions
concerning the systematics of the Primates.
ilar organisms are in the specificities of
their semantides, the closer their proximity
to a common ancestor. Comparisons by
appropriate methods of either the proteins
or deoxyribonucleic acids should yield the
same sequence of probable phyletic relaThroughout this paper I have implied tionships. Furthermore, due to the inherthat protein and DNA data of the kinds dis- ent phylogenetic specificity of even single
cussed can more consistently reflect the structural genes, the comparisons should
genealogical relationships of organisms not have to involve the specificities of
than can the data of comparative morph- very many proteins or structural genes to
ology. My confidence in the molecular ap- reflect the same sequence of relationships
proach rests on the deduction, made from as would be revealed by the complete speciconsiderations concerning the nature of ficities of the total genomes. On the other
the genetic code, that evolutionary con- hand, there are numerous examples demonvergence in the detailed structural speci- strating that similar morphological features
ficities of proteins is extremely unlikely. have been produced in widely separated
The corollary follows that the more sim- phyletic lines by evolutionary convergence.
A morphological structure, of course, is
shaped by the quantities, relative proportions, and spatial positions as well as by
the intrinsic properties of the different
macromolecules making up its substance.
Thus it is not difficult to see that even if
two organisms had many amino-acidsequence differences in their proteins, or
code-word differences in their genes, a convergence in their locomotor or other functional adaptations could readily be achieved
by the independent emergence of morphological structures containing similar quantities and spatial arrangements of the
same sorts of macromolecules, thereby
showing similar macroscopic properties.
Of course, this situation would probably
require a similarity between the two organisms in genetic regulatory mechanisms.
But still there is no reason to suppose that
a convergence in morphological features
would increase the convergence between
the organisms in the code words of either
their “regulator” genes of their “structural”
genes. Indeed, evolution, whether convergent or divergent at the morphological
level, should still increase divergence of
genetic code words at the molecular level.
Organisms are said to show a “grade”
relationship to one another if they possess
a complex of similar morphological features irrespective of whether these features
were produced by evolutionary convergence or inheritance from a common ancestor. At the molecular level, similarities in
the differential expression of structural
genes could preserve or create morphological resemblances even in widely separated
phyletic lines and thus be responsible for
a grade relationship between these lines.
The concept of grades is also implicit in
the ingrained view that there are “lower”
and “higher” organisms, of which the
highest organism is man. Although one
should be wary of any tendency to pass
anthropomorphic judgments on an animal’s
status in nature, it is perfectly reasonable
to believe that phyletic evolution has increased the complexity of organisms in
certain lineages. Differences between organisms in their degree of complexity
might be defined in the following genetic
terms. Compared to a less complex - i.e.,
a ‘lower” or ‘primitive” organism - the
“higher” or “advanced” organism would
have a more extensive genetic code and a
more elaborate integration of gene actions
during ontogeny.
Several grades of Primates have been
distinguished at the morphological level
largely in relation to the state of evolutionary development of the central nervous
system, with the neocortex being much
more developed in the ‘%higher’ primates
than in the ‘lower.” Since the marked expansion and increased function of the
higher primate brain probably has a basis
in the differential activity of particular
genes and in the corresponding synthesis
of particular macromolecules, the grade
concept as applied to the Primates should
be evident at the molecular level as well
as at the morphological level. This point
may be illustrated by data obtained on lactate dehydrogenase isozymes in lower and
higher primate brains (Syner and Goodman, ’66; Goodman et al., ’66). The enzyme lactate dehydrogenase (LDH) was
chosen for study due to its relevance to
energy metabolism (an important parameter in brain function) and because much
is known about the significance of the molecular forms or isozymes of this enzyme.
Two basically different types of LDH
and three hybrids of these types are found
in many vertebrate tissues (Appella and
Markert, ’61; Cahn et al., ’62). One type
is a tetramer of a subunit termed A ( A p
pella and Markert, ‘61) or, alternatively,
M (Cahn et al., ’ 6 2 ) because this type predominates in adult skeletal muscle. The
other type is a tetramer of a subunit termed
B (Appella and Markert, ’61) or, alternatively, H (Cahn et al., ’62) since it predominates in adult heart. These two distinct subunits are encoded at separate
genetic loci (Shaw and Barto, ’63) and
have different electrophoretic mobilities,
amino acid compositions, and antigenic
structures (Vessel, ’65a; Kaplan, ’65).
Although both LDH types catalyze the
interconversion o f pyruvate and lactate,
they have different sensitivities under certain in vitro conditions to inhibition by high
pyruvate concentrations, with the heart
enzyme (H4)
being far more prone than
the muscle enzyme (M1)to inhibition. The
hybrids of these two enzymes (MIHs, M2H2,
and M,HI) have intermediate catalytic behaviors which are proportionate to their
H :M ratios (Dawson, Goodfriend and K a p
ence of LDH isozymes. These theories may
Ian,'64). Kaplan ('65) argues from a con- actually complement each other since the
siderable body of evidence that M LDH nucleus lacks mitochondria (on which the
suits conditions such as found in skeletal
muscle which favor anaerobic glycolysis
and sporadic energy production whereas
H LDH suits conditions such as found in
heart which favor respiration and sustained
efficient energy production. This theory
gives an attractive explanation for the finding (Markert, '63) that many more tissues
have higher proportions of M to H LDH in
the mammalian embryo than in the mammalian adult. The embryonic tissues, of
course, are better capable of withstanding
anaerobic conditions. Another piece of
circumstantial evidence for Kaplan's theory
is that the lamprey, one of the lowest
vertebrates, has LDH of the M type only
in all of its tissues. This correlates with
the lamprey's relatively anaerobic environment and has possible significance with
respect to the concept of grades of evolutionary development, since anaerobic metabolism is phylogenetically more ancient
than respiration (Oparin, '57).
Given the many facets of biological phenomena, it would be surprising if all the
LDH data conformed to Kaplan's theory.
In fact there are certain findings (Vessel,
'65b) which do not readily conform, such
as the reported lack of any difference between human M and H LDH with respect
to pyruvate inhibition when the analyses
were performed at 37". Vessel ('65a,c)
believes that the main significance of the
LDH isozymes has to do with differences
in their intracellular locations, and he
claims that LDH-5, the electrophoretic component which is the pure A or M tetramer,
is localized predominantly in the cell nucleus. It should be pointed out that the
two theories are concerned with different
aspects of the problem poised by the exist-
respiratory enzymes are organized) and
probably has a lower oxygen tension than
other cellular regions due to its deeper
distance from the cell surface. I am still
sufficiently impressed with the evidence
for Kaplan's theory to use it to interpret
in a provisional way the data obtained on
M and H LDH in primate brains.
These brain data, summarized in table 1,
demonstrate a drastic change from a preponderance of M to a preponderance of H
on ascending the phylogenetic scale of
Primates, going from lorisoid to tarsier to
ceboid to catarrhine brains. Of further
interest are the LDH differences between
particular brain regions in lower and
higher primates. The relative amounts of
M and H LDH in dissected regions of six
lorisoid (three galagos, three slow lorises),
six ceboid (three squirrel monkeys, one
capuchin, one night monkey, one marmoset), and four catarrhine (three macaques,
one human) brains were determined by
zymogram and reflectance-densitometric
analysis techniques (Goodman et al., '66).
To briefly summarize the results: in the
primitive primates (the Lorisoidea) three
to four times more M than H was found in
most cerebral cortical regions, whereas oneto-one amounts occurred in brain stem
(pons and medulla) and spinal cord. In
more advanced primates (the Ceboidea)
the H/M ratios showed a marked increase
in all central nervous system (CNS) regions, especially in the visual neocortical
region represented by occipital pole and
calcarine fissure. Three to four times more
H than M was found in this visual region,
a higher proportion of H to M than found
in any other ceboid CNS region. The substitution of H for M was carried further in
Percentage values of M LDH and H LDH in whok brains of primates
No. of
No. of
the most advanced primates (the Catarrhini), for in addition to occipital pole and
calcarine fissure, other neocortical areas,
such as precentral gyrus, also had three
times more H than M. Thus we may deduce that as an integral part of the extensive elaboration of the neocortex in the
evolutionary development of higher primates, a shift from synthesis of M to H
LDH occurred.
In terms of Kaplan’s theory, which associates M LDH with sporadic energy production and H LDH with sustained, efficient
energy production, the shift from M to H
LDH suggests that the advanced primate
neocortex operates continuously with a
much richer supply of energy than does the
primitive primate neocortex. To pursue
this speculation further, it would seem that
at the ceboid grade of higher primate development, biochemical evolution to a
more efficent form of energy metabolism
had been especially pronounced in the neocortical region concerned with the analysis
of visual sensations. Such biochemical
evolution, together with the marked morphological expansion of the visual neocortex, would constitute an important adaptation for arboreal existence.
The data on the proportions of H and
M LDH strongly indicate that the grade
concept as applied to primate evolution is
meaningful at the molecular level as well
as at the morphological level. However, it
must be emphasized that while such data
on the proportions of macromolecules have
a n evolutionary significance, they are not
reliable indicators of phyletic affinities.
For example, hedgehogs and soricoid
shrews have rich amounts of M LDH in
their brains, though not as much as lorisoids have. In terms of a grade classification based on these LDH result, it might be
proposed that the Lorisoidea shows a closer
relationship to certain groups in the Insectivora than to the Anthropoidea. Obviously such a classification would not reflect clade (phyletic) relationships. On the
other hand, if the amino acid sequences or
the antigenic specificities of either or both
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these various taxa, a closer relationship of
the Lorisoidea to the Anthropoidea would
be, I suspect, immediately apparent.
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deciphering, primate, macromolecules, specificities, phylogeny
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