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Duplication with variation Metameric logic in evolution from genes to morphology.

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Duplication With Variation: Metameric Logic in Evolution
From Genes to Morphology
Department of Anthropology. and Graduate Program in Genetics,
Pennsylvania State University, lJniversit,y Park, Penns.ylvania
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dentition, morphological evolution, homeotic genes
This paper discusses the use of duplicated structures in
evolution. Duplication, followed by variation and modification of function,
has been a major strategy from the time of the early biological molecules to
the evolution of advanced morphological complexity. Evolution by duplication with variation produces a hierarchically structured organizational
logic based on nested segments, or metameres. The genome is itself largely
structured in this way by the process of gene duplication. Duplicate genes
often maintain related function and even chromosomal arrangement, and
the expression of those related genes may be coordinated, often by regulatory genes, which are themselves the products of gene duplication. The
morphology of complex metazoan organisms has evolved in a metameric
way from early in evolution, by the use of repeat units in histology and
repeated morphological segments. Recent advances in genetics have shown
that there is a direct correspondence between these morphological structures and metameric structures in the genome, suggesting how complex
morphology was produced by evolution at the gene level. Examples from
invertebrates and vertebrates show that homologous processes are involved
in morphogenesis in both groups, with strictly homologous developmental
genes retaining very similar function and regulation. These issues are
highly relevant to a n improved understanding of macroevol?*tion and to the
core questions of bioioglcal anthropology. The evolution of dental morphology is discussed as a n example.
The purpose of this paper is to summarize what I believe to be a deep and
unifying principle in biology, one at the same time of long standing yet only
recently confirmed. The phenomenon is metameric logic in euolution. I would like
to discuss how modern genetics has helped tie together classical comparative and
evolutionary anatomy with impressive new developments in developmental biology and genetics, that is, the control, evolution, and variation of complex morphological traits. It is becoming possible to relate the evolution of the structure of the
genome as a whole-not just DNA sequences-to the manner in which genes
control anatomical structure.
There is a tradition in biology, going back to Darwin's use of it a s a metaphor for
evolution, to organize the biosphere according to trees-phylogenetic ones. These
are schematic portrayals of the hierarchical structure of clades of organisms descended from a common ancestor, the basic metaphor in taxonomy. The charac6 1990 Wiley-Liss, Inc.
[Vol. 33, 1990
teristic of a biological tree is divergent branching as we move from the trunk
(known as the root in phylogenetic trees, but inappropriately so, because the root
of a real tree, but not of phylogenies, is a “convergent” branching structure as we
look upward). In a phylogenetic tree, characteristics are held in common, but
modified in detail, among the organisms along a branch and its sub-branches.
Indeed, that is how the branching is defined or determined. A phylogenetic tree is
“nested’ or hierarchical in that a set of traits in a major branch, or their derivatives, are included in sub-branches, whereas the latter have their own new set of
defining traits. At the morphological level, evolution sometimes seems “covergent”; but a t its underlying genetic level, evolution is divergent and unidirectional: Even if a trait is highly modified, its genetic origin is usually still discernable or inferrable.
These characteristics of phylogenetic trees are schematic, however, as it is biologists who group and classify. A given organism only has its own characteristics.
Here, however, I am interested in physical, not schematic, hierarchical structures,
specifically the repetition of nested segmental units found within individual organisms, although the origin and history of such structures can also be traced
phylogenetically. Comparative and evolutionary anatomists have long known of
the importance of such segmented, or metameric, structures. Recognition of the
importance of metameric morphological structures goes back to the 19th century,
if not earlier, and was a major aspect of some 20th century theories of evolution, for
example, W.K. Gregory’s theories of “polyisomerism” (Gregory, 1934). If Darwin’s
first theorem of evolution is Descent with Modification, a second should be Duplication with Variation, because we now know that metameric traits have been
produced by evolution from the level of the gene on up.
Life on earth is based on proteins, which are segmented molecules composed of
strings of units, the amino acids. A protein is a “chain” of such units, chosen from
the limited repertoire of 20 different amino acids. The function of the protein
depends on the order and number of these basic chemical metameres. The amino
acid string of course mirrors its counterpart in DNA, where there is a nucleotide
triplet, or codon, corresponding to each amino acid, plus some other metameric
subunits used for regulating the expression of genes. The DNA -+ amino acid
coding system is one of the earliest uses of segmented logic in evolution, although
RNA, a similar metameric molecule, probably came first as the main active biological molecule (e.g., Benner et al., 1989). Indeed, metameric logic predates these
macromolecules, at least insofar as the chemical parts of nucleotides, the nucleic
acids, are used in many other functions. These include the use ofcAMP in chemical
message transduction, and amino acids themselves are variants on a common
chemical core (e.g., Stryer, 1988).
We have traditionally defined genetic evolution as changes in these sequences
and their frequency over time and space; but the story is much more interesting
than that. The genome of higher organisms is metamerically structured at the
level of the whole gene, that is, where the units are not the nucleotides that make
up the genes, but the genes themselves. New functions typically arise by the
duplication of entire genes or even of blocks of genes.
A “family” of genes that have arisen in this way can be identified by their
nucleotide sequence similarity, and we can reconstruct their duplication history
with phylogenetic trees. These differ from traditional trees in that the members
are genes and often can be studied without regard to species or speciation. Faint
traces of macrolevel organization of genes on chromosomes suggest that there may
have been three duplications of the entire genome during the hundreds of millions
of years of chordate evolution. Gene duplication has been so ubiquitous in evolution that the entire genome can be viewed largely as one elaborate phylogenetic
tree of hierarchically structured gene families. By tracing these events back in
time, we can reconstruct the major branching structure of the Tree of Life itself.
Iiox-I C l u s t e r
Chromosome I
1.2 1.3
Ihx-4/5 Clustcr
Chromosome 2
Fig. 1. Chromosomal arrangement of Hox genes in the mouse. Each horizontal line represents a different mouse chromosome region. Vertical lines indicate sequence homologies of genes between chromosomal gene clusters. Figure illustrates evolution by duplication of entire clusters. (Reproduced from
Schughart et al., 1989, with permission of the publisher.)
One very interesting class of genes, known a s homeotic genes, contains sequences
highly preserved over deep evolutionary time. These genes are expressed a t critical
times to control the differentiation of metameric anatomical structures. Homeotic
genes were first identified in the fruit fly, Drosophila, but genes with homologous
sequences and similar function have been found in such diverse organisms a s
yeast, frogs, mice-and us. A stretch of about 61 amino acids, known as the homeobox, has evolved very little in that time. This region codes for a protein that has
a turned physical form that fits into the helical structure of DNA, because homeotic genes regulate development by activating the expression of other genes by
binding to specific DNA sequences upstream of those genes (e.g., Lewin, 1990). The
homeobox sequence is conserved because this is a fundamental mechanism for
differentiation in most if not all animals.
The fruit fly genome contains numerous homeobox genes. This includes two long
stretches of such genes on its third chromosome, known as the Antennapedia and
Bithorax complexes. The many genes in these blocks arose by duplication from a n
ancient ancestral homeotic gene long before the evolution of insects. Homeobox
genes are also found in vertebrates, and, almost incredibly, there are both specific
homologies between individual fly and mouse homeotic genes and between whole
blocks of contiguous homeotic genes in the mouse and fly.
Homeotic genes in the mouse are called Hox genes. Figure 1 is a sequence tree
showing the phylogenetic relationships of the Hox genes within the mouse
(Schughart et al., 1989). This shows their relative degree of relatedness. We know
from their chromosomal location that these genes have a hierarchical history involving not just simple gene duplication, but also the duplication of entire blocks
of Hox genes (Fig. 2). With some caveats, the most closely related Hox genes are
found in corresponding places in different homeotic regions, because the latter
have arisen by block duplication more recently than the events that created the
members within specific blocks.
Not all homologous genes are located in blocks in this way, but there must be a
reason for the highly conserved nature of those chromosomal arrangements that do
persist. That reason has to do with gene expression.
The use of contiguous gene organization to regulate gene expression was first
found in the production of individual proteins. We are accustomed to thinking of
[Vol. 33, 1990
Fig. 2. Sequence tree for mouse Hox genes. Genes close together in the tree are often from corresponding positions between (rather than from within) gene clusters. (Reproduced from Schughart et al.. 1989,
with permission of the publisher.)
genes as coding in a one gene-one protein way, but this is misleading. Even in the
simplest instances, a gene is expressed only when some other gene activates it. I n
fact, the logic of controlled gene expression is similar at many levels of complexity
and relies heavily on the organization of the genome into gene familes.
We can see this in the simple example of hemoglobin. Each molecule of hemoglobin consists of two polypeptide chains, called alpha and beta, coded by genes on
separate chromosomes. There are several genes in both the alpha- and beta- clusters; the genes themselves are homologous both within and between these clusters,
a s members of the globin gene superfamily that includes such distant relatives as
the genes for such other oxygen binding proteins as myoglobin and even leghemoglobin in plants (Lewin, 1990).
The beta-globin gene cluster, on chromosome 11, contains a string of related
genes. During development, a n individual's red blood cells first produce embryonic, then fetal, then adult forms of beta-globin. This order of expression is
largely sequential, according to the order of the genes on the chromosome. The
expression switching mechanism involves specific DNA regions around the individual genes, and specific regulatory proteins that recognize those sequences in a
complex, only partially understood way (Enver et al., 1990). Not all genes are
clustered with their relatives or expressed in so linear a way, but many are,
including important clusters of genes involved in the control of anatomical development.
At the level of morphology, the logic by which metazoan organisms arose was
metameric: Individual unicellular organisms aggregated from complex multicellular ones, eventually with specialized, interdependent component cells. In the
development of organs and their constituent tissues, cells become developmentally
committed to specific functions and physiology. This commitment is genetic in that
it is controlled by expression of a specified subset of the genome appropriate to the
cell type, and i t cannot be reversed under normal conditions. Moreover, the commitment is in a sense hierarchical or treelike in that all cells of a given type share
a t least some of the same genetic commitment, perhaps with genetically “cladistic”
subtype changes as cells mature or subspecialize.
Metameric logic is dramatically clear in the higher-level anatomical structure of
organisms in most if not all metazoan groups. At the level of gross anatomic
structures, organisms clearly are built by using the logic of repetition: leaves on a
tree, intestinal villi, papillae on the tongue, hair follicles, nephrons, pancreatic
islets, alveoli, and many other structures represent the repeated use of the same
structure within a given organ.
Thus, one-way complex organisms evolved in the first place was by the duplication of whole anatomical structures, just a s gene families arose by the duplication
of whole genes. Whole structures were duplicated or repeated in typiral !OWE)T
invertebrates, and radially or linearly arrayed.
Over time, the simple segmented structures became differentiated, with individual segments developing their own attached substructures, such as legs, and
these themselves are metameric, having repeated, modified, homologous parts
(Fig. 3). In the insect, for example, the different parts of the leg and of the antenna
can be shown to be homologous (e.g., Wilkins, 1986).
By the time vertebrates diverged from invertebrates, the commitment to this
metameric strategy was irrevocable. Early vertebrates are characterized by having large numbers of fairly similar segments, with whole metameric structuresvertebra, ribs, and related neural and soft structures-adjacently repeated many
times over (Fig. 4). As in invertebrates, the number of segments may reduce over
time, and they may become specialized to include other homeotic, segmented structures like limbs (Romer, 1966; Radinsky, 19871,just a s seen in invertebrates. This
has long been known in the study of evolutionary paleontology (Romer, 1966).
Fins, forelimbs, and hindlimbs are homologous metameres containing substructures that are homologous between (e.g., humerus and femur) as well as within
(e.g., femur, tibia, tarsals, etc.) them. In both invertebrates and vertebrates, these
detailed homologies suggest t h a t sometimes the same genes or homologous members of similar gene families are activated in the development of these substructures.
As I have tried to summarize, we find a Logically similar use of repeated hierarchrcai segmental structures--duplication with variation-on a grand scale a t
all levels from nucleotide codons to gross morphology: the Tree of Life as constructed by evolution. But is this just superficial similarity, or can we relate
metameric morphological structures directly to underlying metameric structures
in the genome? Do anatomic metameres have metameric genetic etiology? Can we
go from gene to form and back again? The answer appears to be yes.
What is emerging from recent research in developmental genetics is that segmentally arrayed genes are activated in a way that corresponds to, indeed that
determines, the differentiation of specific segmental anatomical structures. It appears t h a t this is accomplished because what homeotic and other similar developmental genes do is to recognize upstream DNA sequences around the genes those
homeotic genes regulate. The homeotic gene product physically binds to such sequence, enabling transcription enzymes to activate the downstream gene, in a
hierarchy of control.
Indeed, we are now catching such genes in the act and beginning to learn how
they work. To see this, we should first consider embryonic development in the fruit
fly, the organism from which most of our knowledge has come. The similarities we
find there with vertebrate development are a stunning testament to the unity of
Fig. 3. Segmented structure of invertebrates. A. Annelid worm; B: Various
arthropods. (Reproduced from Villee et al. 1958, with perizission of the publisher.)
pig. 4 .C.qppntedstFii&.T-.. ui'-aLz,,
a..=.377 ~~itcbratcs.
A: Fish; B: Ealiy reptiit>. Showing extent of segmentat
structure in the skeleton and dentition. (Reproduced from Romer, 1969, with permission of the publisher.)
Developmental genetics of invertebrates
In Drosophila, which is representative of higher invertebrates, segmented structures are apparent from early in embryonic life. The segmental structure seen very
early in the developing egg is modified to the segmental structure of the larva and
subsequently to corresponding segment-specific structures in the adult fly, with its
head, three thoracic, and eight abdominal segments. Special structures exist in the
most anterior and posterior segments.
Extensive experiments have identified genes that determine the number and
order of the segments in the early fly embryo. Mutations in these genes, known a s
segmentation genes because they determine the existence of segments, reveal their
domain of action. As shown in Figure 5, mutations in these genes may delete entire
blocks of segments, alternating segments, corresponding parts of every segment,
and so on.
segment p o l m f y
[Val. 33, 1990
Fig. 5. Control of segmentation by various mutations in Drosophila larva. Different types of mutation
cause patterned deletion of segments. Dotted lines are segment boundaries, dark shading are denticle
bands. Lightly shaded regions represent deleted segments. Arrows indicate lines of polarity reversal. On
the left, normal larva; on the right, resulting larva after deletion. (Reproduced from Nusslein-Volhard
and Wieschaus, 1980, with permission of the publisher.)
The two major blocks of homeotic genes referred to earlier control developmental
identity and segment specificity on a n anterior-posterior axis. The Antennapedia
Complex contains genes t h a t control the segments in the head and anterior thorax.
The Bithorax complex (BX-C) contains genes responsible for segments T2
through AS, the last abdominal segment. Each BX-C gene is responsible for details
of development within a given segment. This utilizes the contiguous arrangement
of these related genes, recalling mechanisms discussed earlier, namely, sequential
expression in chromosome order. In the case of the Bithorax genes, the identity of
succeeding segments depends on the total number of the genes whose products are
expressed and present in the cells of the segment. As we move down the developing
larva, each succeeding segment is associated with the added expression of the
succeeding gene in the Bithorax Complex, a cumulative-expression niodel first
suggested by Lewis (Fig. 6; Lewis, 1978; Wilkins, 1986; Lewin, 1990).
The second thoracic segment (T2) appears to be a base, or ground state, of which
later segments are modifications. Inactivating mutations cause the segment for
which the mutant gene is responsible to be modified toward the next most anterior
segment, and eventually toward the base T2 morphology.
Akam et al. (1988) have speculated about the gene duplication history of these
homeotic genes in the lineage leading from primitive preinsects, through myriapods (centipedes, etc.), to modern insects. Their ideas are shown in Figure 7. Initially there must have been specialized genetic instructions for the anterior part,
the posterior part, and a generic middle segment that were repeated many times
with little if any segment-specific differentiation. Successive gene duplication
events first appear to have permitted the differentiation of specialized anterior
(thoracic) structures and then specialization of the abdominal segments. The number may have become more rigidly fixed over time.
It is interesting to question whether there are differences in the control of structures with “open-ended” numbers of repeats that may vary in number from individual to individual, perhaps like early invertebrate and vertebrate segments, or
perhaps like intestinal villi or hair follicles, and structures with fixed numbers.
Fig. 6. Model, originally due to Lewis, of control of segment identity in Drosophzla by cumulative
sequential expression of Bithorax complex genes. (Reproduced from Lewin, 1990, with permission of the
Would such structures be encoded by a fundamentally different mechanism? This
would seem unlikely if open-ended systems can evolve into fixed-number ones
using Bithorax-like mechanisms.
Here I have only discussed segments. Before these become visible in the developing fly embryo, indeed early in the development of the egg, structures known a s
parasegments appear. These are precursors of the segments (which are formed from
parts o f adjacent parasegments) and are under the control of other genes, many of
which have been characterized The general principles described here appiy to the
Developmental genetics of vertebrates
If my statements about ground states and modifications toward adjacent structures are evocative of familiar patterns in vertebrate skeletal and dental anatomy,
that is no accident. A very similar story has been found in vertebrates. In all major
classes that have been studied, the early vertebrate embryo is clearly segmented.
The most clear and persistent series of segmental structures are the somites, which
lead to the formation of major structures like vertebral segments; (Fig. 8) but
before these appear the entire vertebrate embryo is composed of very rudimentary
segmental structures known a s somitomeres. Until recently, i t was not known how
extensive such development might be, but i t has now been shown that the somitomeres extend from the “tip o f the head to the tip of the tail” (Jacobson, 1988).
Structures of the central nervous system and the head and face derive from the
somitomeres. The structure of the veterbral column is eventually comprised of
unions of adjacent structures, a s with the parasegments and segments in the fly.
Genes homologous to the “engrailed” and “paired-box’’ genes in the fly, which are
related to the control of these kinds of boundaries, are involved in their development in vertebrates.
[Vol. 33, 1990
7 ‘ 1 II
Very ancient
Amp like
I ahial like 7 J
Ahd B l i k e
hl P
M yrinpod-like
/ \
Fig. 7 . Scheme for the origin of homeotic genes during the evolution of the myriapod (e.g., centipede!
millipede) insect lineage. Panel on left shows proposed set of Antennapedia-like genes existing a t each
stage. Black circles, shown only for the first two stages, indicate the existence of other homeobox genes
that probably arose prior to the isolation of this lineage. Arrows indicate potential gene duplication
events. Corresponding shading on the diagrams at the right shows the proposed expression domains of
each gene, corresponding to the progressive specialization of trunk segments. (Reproduced from Akam et
al., 1989, with permission of the publisher.)
The homeotic genes in the mouse, which are homologous to similar gene blocks
in the fly are, not unexpectedly, also involved in segmental differentiation in the
mouse. When the cells of a sectioned mouse embryo are exposed to antisense RNA
probes for specific Hox genes, the probes will bind to Hox mRNA in cells where the
Hox gene is expressed. Such studies show that these genes have highly constrained
tissue- and time-dependent expression in the mouse embryo.
Some Hox genes are expressed in relation to specific morphological segments,
some at certain stages in all segments, others only in some segments or some
stages, and still others in some segments and some developing soft organs. Homologous Hox genes have similar domains of expression, and some Hox regions have
expression restricted to certain organ systems. This burgeoning new literature also
shows that in the developing embryo there are striking similarities between mouse
and fly, and deeply homologous physiology has been found. Although there are
exceptions and the pattern is only incompletely known, several generalizations
have emerged: 1) expression domains are structured along an anterior-posterior
axis, with different genes in a Hox cluster expressed for different “lengths” along
the embryo; and 2) genes are switched on sequentially over time, along their linear
chromosome order, and with a summed-expression pattern relative to segment
specificity (e.g., Gaunt et al., 1988, 1989; Holland and Hogan, 1988; Dressler,
Specific mouse Hox genes, as well as gene regions, are homologous to those in
Drosophila, and many of the same genes are expressed in similar tissue in both
organisms. For example, some of the homologues of the fly abdominal segment
genes that are involved in the differentiation of neural tissue in the segments are
involved in neural tissue in vertebral segments; others are gut specific (e.g.,
Weiss I
A. George
A. 1.1Gmm.
B. 1.4 mrn.
c. 2.3 mm.
D. 2.0 mm.
E. 2 1 mm.
B. In
C. Sfernber$
D. Dandy
2.2 mm.
G. 3.0 mm.
E. Eternod
I? Fa
Drawn i-n
apprwima My
same length
G. Corner
Fig. 8. Sequential stages in human embryonic development. C: Somites begin to be grossly visible
(middle of figure); these become vertebral segments and other structures in the adult. G Gross divisions
of the central nervous system (CNS) are visible (anterior);CNS segmentation has been documented in
more detail than shown here (see text). (Reproduced from Schaeffer 1942, with permission of the publisher.)
IVOl. 33, 1990
2.5 2.4
2.3 2 . 2 2 . 1 2 . 6 2 . 7 2 . 8 2.9
Fig. 9. Schematic drawing of the mouse hindbrain (rhombencephalon), at 9.5 days postconception,
showing domains of expression of genes from the Hox-2 cluster. R1, r2, etc., are the rhombomeres. (OV,
optic vescicle; MB, midbrain; HB, hindbrain; SC, spinal cord; gv, gvi, etc. cranial ganglia). Gene expression boundaries are sharply defined by histological segment boundaries (see text). The Krox genes are
other developmental genes. (Reproduced from Wilkinson et al., 1989, with permission of the publisher.)
Dressler, 1989). But the similarities appear to go even farther. For example, a
dominant mutation, that is, one engineered arlificially l o be expressed wliieri it
would not normally be, tends to modify a structure in both Sly and mouse toward
a posterior segmental form. However, the deletion of both copies of a gene (i.e.,
recessive changes) cause anterior modification (Wilkins, 1986; Kessel e t al., 19901,
just as in the Lewis (1978) model for the fly and Akam et al.'s (1988) suggestion for
its evolutionary mechanism.
One recently documented example of these patterns is the embryonic mouse
rhombencephalon (hindbrain), where mouse Hox-2 complex genes are switched on
(i.e., their transcripts are found) in chromosome order, one new gene every two
segments (called rhombomeres) along the anterior-posterior physical axis, in a
summed-expression way (Fig. 9; Lewis, 1989; Wilkinson et al., 1989). Cells do not
move across rhombomere boundaries once they are established (but they can, before that time), showing that the brain is compartmentalized in a metameric,
segmented way (Fraser et al., 1990).
Another developing organ that has been studied experimentally for years is the
developing vertebrate limb bud. Although the geometry is more complex, the genetic story is similar. Genes of the mouse Hox-5 complex are expressed sequentially along a n anterior-proximal to posterior-distal axis. As before, regional identity appears to be defined, a t least in part, by the number of these contiguous genes
whose product is present. Figure 10 is taken from the original report of this work
Fig. 10. Domains of expression of genes from the mouse Hox-5 cluster in the developing mouse limb
bud, a t 10 days postconception. Left column, light micrographs showing horizontal section of the embryo; Center columns, hybridization radiographs of the same sections showing regions of the Hox-5.5
(left center) and Hox-5.2 (right column) genes representing the extremes ofthe gene cluster. Intensity of
exposure reflects intensity of mRNA for the specific gene present. Right column, schematic drawing
showing the pattern of expression for all genes in the cluster relative to the same sections. The key at the
bottom of the figure shows the position and orientation of the sections (which were somewhat asymmetric
on right and left), and key a t right shows that intensity of shading in the rightmost column reflects the
cumulative number of Hoxd genes expressed in a given part of the limb bud. For details, see the source.
(Reproduced from Dolle et al., 1989, with permission of the publisher.)
lV0l 33,1990
(Dolle et al., 1989a) and provides a partial suggestion of this complex, but rather
orderly, pattern.
Morphogenic gradients and development
These dramatic examples of evolutionary conservation of mechanism may illuminate another long-standing idea in morphogenesis, that of the morphogenic field
or gradient. This idea was first proposed by Huxley and de Beer in 1934 (Huxley
and de Beer, 1934) and has had an important but largely phenomenological history
in developmental biology (e.g., Wolpert, 1971). Embryologists have often noted
that developmental specificity seems to depend on where, along a linear axis,
equipotent primordial cells are located. The arrangement appears as if a morphogenic substance is secreted at one end of the axis and diffuses along it, so that the
diminishing concentration along the axis is the context-determining factor. Some
such gradients are well documented, such as microgradients of maternally produced proteins atid RNA, bpecifying the polarity 2nd early segmental development
of the Drosophila egg (Wilkins, 1986; French, 1988).
One of the best-known morphogens is retinoic acid (RA), the biologically active
form of vitamin A. Experiments have shown that RA can induce mouse Hox-1.1
gene expression in craniofacial development (Balling et al., 1989). Other Hox
genes have been shown to be related to RA as well. Aberrant concentrations of RA
in the limb bud, for example, cause developmental anomalies such as digits in the
wrong place. A small area known as the zone of polarizing activity (ZPA) has been
identified on the posterior margin of the limb bud, which appears to be the secretory source of an anterior-posterior development signal. It has been suspected that
a gradient of RA diffusing from this area acts as a morphogen in limb development
(Carlson, 1988).
Recent work suggests that this can be related to Hox gene expression (Dolle et
al., 198913; Lewis and Martin, 1989; Smith et al., 1989). Like steroid and other
hormones and other intercellular messengers, RA is recognized by and bound to
specific cell-surface retinoic acid receptors. The bound complex is transported to
the nucleus, where it expresses sequence-specific DNA binding and gene activation. In the the early limb bud, all mesenchymal cells express RA receptors and
have the potential to respond to RA. However, RA is secreted by the ZPA, which,
as it grows away from the body of the embryo, establishes a decreasing RA gradient along the posterior-distal to anterior-proximal limb axis. A corresponding increasing gradient of intracellular RA binding proteins has recently been found
along this axis. This protein binds free RA, making it unavailable to induce Hox
gene expression, perhaps helping t o establish the temporal-spatial distribution of
Hox-5 genes shown in Figure 10.
Suppose, for example, that when a gene is next in line to be switched on, the
switch mechanism (gene-regulating proteins binding upstream of the next gene to
be opened for expression) requires signals that depend on a high level of RA. As the
limb bud grows, the ZPA moves posterior-distally, taking its surrounding region of
high RA concentration with it, so that when it is the turn of a new Hox-5 to be
expressed, this occurs where the retreating ZPA (and its high RA concentration) is
at that time. Generally, it appears that the concentration gradient of free (unbound) RA is maintained by a coordinated “balance” between the concentrations of
RA receptors and RA binding proteins along this physical axis as a function of
distance from a source (the ZPA) (Smith et al., 1989).
The general pattern is consistent with current understanding about the induction and regulation of gene expression; to which reference has been made earlier.
A gene is expressed when a regulating protein or set of proteins recognizes nearby
sequences (or perhaps other regulator proteins bound to such sequences) and enables RNA polymerases to cause the gene to be transcribed (Mitchell and Tjian,
1989; Lewin, 1990). What causes the regulator protein to be produced? How is it
regulated? Essentially, I think the process can be described as being hierarchical.
Some “master” regulating gene recognizes and activates a set of genes, and these
themselves may be regulator genes that regulate a (perhaps larger) descendant
set, and so on. This is how stem cells differentiate and specialize (Hall and Watt,
1989). For example, different lineages of blood cells (erythrocytes and megakaryocites) share some transcription factors (Romeo et al., 1990). I n vertebrates, the
germ layers of the early embryo reflect some common branch points in which all
descendants are committed to a general extent, only to be further subdivided and
specialized. In fact, homologous genes are responsible for cell-lineage specificity in
nematodes as well a s vertebrates (Finney et al., 1988). To rephrase the famous
doggerel, “Main genes use little genes upon their backs to regulate ‘em, and these
genes use. . . . ”
One mechanism by which intercellular recognition works is the expression of
tissue- or context-specific receptors on the surface andlor specific binding proteins
inside the cell (e.g., Karin et al., 1990). Complexes of these with the messenger
molecule itself may constitute the active ingredient for gene regulation.
I would now like to attempt to relate these general concepts, which have been
documented broadly in selected experimental systems, to a n area in which the
level of knowledge is much less well developed, but where I believe extrapolation
is not inordinately far-fetched. The area is one of traditional interest to physical
anthropology, namely, the evolution of teeth.
The dentition is obviously a metameric, homeotic organ. We know that the
complex heterodont mammalian dentition in which different teeth have different
morphology evolved from a single-cusp homodont form in which all teeth have
essentially the same form (Fig. 11).A number of theories have been advanced over
the years to explain this evolution in terms of homologous structures. There is
variation and patterned evolution in incisors and even in canines, but most attention has been paid to molariform teeth.
The first major organizing theory of dental evolution was the tritubercular theory of Cope and Osborn, developed in the 1880s (Fig. 12; Osborn, 1888a, 1907;
Cope, 1883,1888).It was known early in evolutionary paleontology that the primitive mammalian tooth, or its prototype in reptiles, is typified by a three-cusped
structure (this applies to all tooth types, canine, incisor, and molariform teeth),
including one major cusp and two adjacent minor cusps (e.g., Hershkovitz, 1971).
The later, more complex, heterodont morphology evolved from this beginning by
elaboration of this pattern or by reduction of some of the elements. This was
Osborn’s basis for the standard nomenclature for the cusps (Osborn, 198813;but see
Hershkovitz. 1971, for a modern treatment).
One explanatinn fnr these tritubercular beginnings was that S U C C C S e~ reptiliaii
cone-teeth coalesced in triplets to form single teeth, a s they were crowded together
in the shortening mammalian jaw. However, Osborn noted that accessory cusps
had continued to arise during mammalian evolution, so that the original coalescence idea could not be totally correct, and he argued that new cusps had simply
developed from, and as additions to, existing cusps.
Mutations and variants affecting the teeth within species frequently, or even
typically, affect many or all teeth in a series (e.g., molars, incisors). Singly variant
teeth often resemble their neighbors in the series, and there is evidence that one
member of a series is the base, or ground state, to which variants are modified.
These generalizations are reminiscent of the patterns shown earlier in regard to
fly and mouse segments.
If teeth within a series are metameres of a common form, i t appears that so are
the cusps within individual teeth. Cusps appear and evolve as units rather than
simply as quantitative modifications of existing structures. This idea, based on
comparative morphology and paleontology, receives further support from studies
going back as far as the late 1800s, showing that cusps appear and calcify embryologically as units, in sequence roughly corresponding to their phylogenetic order
(Kraus, 1959, 1963; Kraus and Jordan, 1965; Kraus et al., 1969; Hershkovitz,
[Vol. 33, 1990
Cot hy r is
M yctewsburus
Fig. 11. Early vertebrate (theriodont therapsids) homodont upper and lower conical dentition. (Reproduced from Peyer, 1968, with permission of the publisher.)
1971). The data are generally consistent with a n anterior-posterior order of development, if one allows the developing sequence to “snake” its way around the
confines of the developing dental follicle (perhaps with some exceptions like secondary cusps, although the order of appearance can be misleading and difficult to
determine, depending on what material one has to work with). This is summarized
in Table 1.
There is even evidence (Fig. 13) that each mammalian cusp (including incisors
and canines) still passes a t least transitorily through a tritubercular developmental stage, subsequently enameling-over two of the cusps (Kraus et al., 1969;
Hershkovitz, 1971).One can speculate that the original entire tricuspid metameric
structure has duplicated a number of times in evolution, and we have seen that
this often means the sets of controlling genes have also duplicated or that the same
set of perhaps-contiguous genes are expressed in each major segment (cusp).
There have been decades of speculation as to how complex dental development is
2’1icoitodoii (Pi~iacodo~a).Upper Jurassic, Anicrica. Internal view.
External aud iiiternal views.
After 3farsh.
Upper Jurassic, America. After 3Iarsh.
Intcriial view.
Upper Juraauic, America.
x 8. After Xarsh.
Ftn. 11.
Spalacotkeiiwti. Upper Jurassic,
England. Internal view, etrlarged.
mh 8
Upper and lower teeth mid lower jam of Ti-ico~mloizfer~~a
from the Purbeck Beds,
Upper Juiassic (Lower Cretaceous), England. x 3.
Fig. 12. Triconodont early mammalian (Jurassic triconodontu) dentitions. (Reproduced from Osborn,
1907, with permission of the publisher.)
iV0l 33,1990
TABLE 1 Phylogenic and corresponding ontogenic order of mammalian dental cusps'
Upper cusps
Lower cusps
'Modified from Hershkovitz, 1971. Ontogenic order of appearance is variable in some instances (see the source for
details). Cusp nomenclature from Osborn, 1888h.
Fig. 13. Molars of fossil mammals compared with embryonic stages of human molars. A: Right lower
molar of Upper Jurassic pantothere, with three major cusps; B Developing human lower first primary
molar; C: Lower left molar of Eocine tarsier; D: Developing human lower left second primary molar; E:
Lower right third molar of Middle Eocene lemur; F Developing human lower right second primary
molar; G: Lower third molar of the most primitive triconodont mammal from Middle Jurassic, showing
central cusp with smaller mesial and distal cusplets; H typical developing human lower left second
primary molar, showing tendency to develop similar mesial and distal cusplets. See source for details.
(Reproduced from Kraus et al., 1969, with permission of the publisher.)
controlled. In a series of papers beginning in 1939, Butler (19411, suggested that
dental differentiation reflected morphogenic field gradients. He supposed t h a t
identical dental primordia, spaced along the developing dental lamina. are affected
by a n anterior-posterior (i.e., mesiodistal) gradient that determines within-set
morphological details and other gradients going in other directions to determine
the set itself.
A competing explanation subsequently developed by Osborn (1978) is that the
primary -differentiation of tooth types occurs in -a primordial clone of cells, from
which groups of cells separate, roman-candle fashion, and migrate along the growing jaw, developing tooth-specific details as they go.
As mentioned briefly above, even at the earliest, differentiation involves microgradients of maternal mRNA or of maternally produced morphogens in the early
embryo. At some point, a differentiation cascade appears to be triggered by some
form of chemical gradient, so t h a t there is likely to be some point in development
when a cell or group of cells becomes genetically committed to tooth-forming potential. Thus, the gradient and the field theories of dental morphogenesis may not
be as different a s they at first appear. But do we know enough to be more specific?
Not yet, I think, but we're getting there.
Figure 14 shows a dental Follicle, or tooth bud, taken from a classic paper by
Butler (Butler, 1956). The dark line in the center is the inner epithelium of the
enamel organ. The histogenesis of the tooth and its structures are well known a t
the microscopic level (e.g., Butler, 1956; Tonge, 1989). The enamel epithelium is
Fol Iicle
Scracum intermedi urn
Fig. 14. Structure of a dental follicle. (Reproduced from Butler, 1956, with permission of the publisher.)
derived from ectoderm and is responsible for enamel production. However, this
secretory activity is regulated by the underlying dental papilla, which is comprised
of cells of neural-crest origin. These migrate from the neural crest along the dental
lamina to combine with the ectodermal cells to form the follicle.
Experiments that combined ectoderm and papillary tissue from buds of different
types of teeth, or of teeth from different times in development, have shown definitively that the papillary cells control the crown morphology of the tooth and that
their commitment to potentiality for tooth-generation occurs before they migrate.
Because migration is not necessary, tooth-type specification must not be due to a
gradient along the dental lamina itself {Lumsden, 1979, 1988).
Little is yet known of the genetic determination of the neural crest tissue. However, i t appears that the neural crest is one area in which Hox genes are particularly important during development and specialization. For example, neural-crestspecific Hox-7 genes have been found in the mouse (Dressler, 1989). Other recent
experiments show that there must be a morphogenic signal of some kind in the
dental ectoderm, because although the potential to form teeth is determined before
migration, cells from various places along the neural crest can, when combined
with dental ectoderm, produce normal teeth (Lumsden, 1988).
These are only rudimentary facts, and much of the research in this area is quite
recent, but the results do have the scent of familiarity. They suggest that genes
like those discussed above are responsible for the critical events in neural crest
specialization that define the commitment to dental development, setting in motion the cascade of gene regulation that leads to morphological specialization of the
teeth. Perhaps each tooth series is a separate higher-level segment type (like
cervical and thoracic vertebrae are in mammals, or similar divisions in insects),
each controlled by its own gene block. Within tooth type, there is tantalizing
morphological suggestion that gene duplication events occur, perhaps involving
the entire tritubercular controlling system, to create new cusps. Probing the
IVOl. 33, 1990
enamel epithelium with Hox probes might help to localize their expression, a s in
the hindbrain and limb bud, and to elucidate these mechanisms.
I have discussed the developmental and evolutionary genetics of the dentition
because the latter has been of basic importance to physical anthropology from the
beginning. In particular, because teeth are the hardest and most durable structures, they are the core of the primate fossil record. Teeth take a central place in
all vertebrate taxonomy. We are always ready to make evolutionary reconstructions, taxonomic phylogenies, adaptive scenarios, and the like from fossil and
comparative dentitions. Would i t not be of some value to understand how the traits
are controlled, and to what extent genes are responsible for the patterns we see?
The same kinds of statements apply to the skeleton, which has a similar role in
paleontology and which has been one of the major sets of morphological traits used
in classifying human and other primate groups. Many or most mouse Hox genes
identified to date are closely linked to genes thal are involved in skeletal or other
morphological anomalies (Johnson, 1986; Fienberg et al., 1987; Griineberg, 1965,
Smith et al., 1989; Kessel et al., 1990). These indicate that we should expect that
evolution, which has to work with mutations in these same genes, will be patterned or constrained. Examples of homeotic developmental or evolutionary constraints abound in our anatomy and in the paleontological record.
After I discussed this paper with George Milner, in our Department, he performed a quick screen of about 100 Midwest Amerindian skeletons. Milner found
that about a third of them have vertebral anomalies involving segment-identity
changes, a scattering of variation that experimental studies will not notice, but
which anthropologists might expect to find. The anomalies included C7-TI and
L1-1’12 morphological shifts involving the rib or rib element and its facets, as well
as a number of partial changes of similar kinds.
I think that we can anticipate that behavioral traits, many of which have been
of long interest in anthropology and primatology, may also become tractable, once
we know how to define them in a developmentally structured way. Given the
pervasiveness of metameric logic in life, I believe that it basically must be true
that behavior is built of metameric, developmentally, or phylogenetically homologous components. Behavior is biological and must follow the “rules” of biology.
We now know that the central nervous system develops from a metameric, anatomically segmented organization of just the kind that is regulated by the developmental genes discussed in this paper. We also know that major behavioral
changes, such as manic depressive illness, Alzheimer’s, Parkinson’s and Huntington’s diseases, and other memory or behavioral traits like the Lesch-Nayan,
Tourette, or Prader-Willi Syndromes can be caused by single-gene mutations.
At the level of receptors, we know of patterned mechanisms in brain and neural
function, of gene families of neural receptors and transmitters. A possible example
of metameric structure might be that the biochemical-genetic mechanisms found
in the olfactory epithelium are similar in many details to those found in the retina,
suggesting (although evolutionary anatomy has not) that olfaction and vision are
homologous metameres of perception.
The challenge in behavior biology is to define traits properly.
Although I have discussed the basic function of developmental genes, little modern work has been done on the population genetics of such genes. Like all genes,
they do vary (e.g., Castiglione et al., 19901, but we know little about the effects
of such variation on morphology. There is a wealth of relevant classical genetic
data t h a t now might be meaningfully reanalyzed in this context. For example,
Wright (1968) has summarized the quantitative genetics of meristic (repeated)
structures. Classical comparative and evolutionary anatomical literature, vertebrate and invertebrate, based on expert pattern recognition, is abundant, and its
reinterpretation may be tremendously informative.
The details of our understanding of gene regulation are sure to change. Here I
have only covered a few of the known developmental genetic mechanisms (e.g.,
Dressler and Gruss, 1988). Nevertheless, this general conclusion seems secure: A
major strategy in evolution at all levels has been to add function by duplicating
structures or mechanisms formerly used in related ways. The detailed conservation of genetic controlling structure, a t the gene arrangement as well a s sequence
levels, suggests that much of vertebrate morphological evolution involves the use
of such structures and mechanisms.
The pervasiveness of metameric “duplication with variation” shows that i t is a
central principle of evolution. The footprints of hierarchical, segmented, developmental constraints are everywhere, if we but look for them, and they tell us about
the nature of the genes controlling everything from molecules to morphology.
Despite the cacophony of sequence variation, and the pattern-distorting effects of
selection and drift, this evolutionary strategy is essentially unidirectional, and its
irreversible commitments are pattern-generating.
Order is often found in complexity. once wc know what to look fix.
This lecture was given under the title “Odin’s Ravens”, and was the Luncheon
Address a t the Annual Meeting of the American Association of Physical Anthropologists, Miami, Florida, April, 1990. In Norse mythology, Odin, chief among the
gods, sits in his palace in Valhalla. Two ravens, Hugin and Munin, fly from his
shoulder each morning to survey the world and return later in the day to report to
Odin what they have seen. Hugin represents Thought, and Munin, Memory
(Sturluson, 1964; Evans and Millard, 1986). In this way, Odin keeps apprised of
events in the world.
I used this to serve the Association as its ravens, as Hugin to report what I see
as the state of the world of genetics, and a s Munin to show how t h a t applies to our
traditional past concerns about morphology and its variation. I also warned of the
danger (as a good raven should do) if anthropology a s a profession fails to take
advantage of the new methodologies and technology about which I reported.
I was honored to have been invited to give this lecture to the Association, and I
thank Dr. Yagar Igcan for the invitation and his logistical help. Whether this was
a good lecture or not, i t was probably a n historic event in that, through inadvertent
circumstances, i t had to be delivered during, rather than after, the Association
luncheon. I apologize to those whose lunch I ruined, and I thank the waiters whose
shadows, moving randomly across the screen, made the visual part of my presentation unique.
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