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Morphogenetic studies of the rabbit XXXVI. Effect of gene and genome interaction on homeotic variation

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Morphogenetic Studies of the Rabbit
XXXVI. EFFECT OF GENE AND GENOME INTERACTION
ON HOMEOTIC VARIATION
P. B. SAWIN AND MARYANN GOW
The Jackson Laboratory, Bur Harbor, Maine
ABSTRACT
Study of the homeotic shifts of vertebral borders as affected by the
D a gene when on two different genetic backgrounds shows that the effects of both
gene and genome are distinguishable. The Du in either one or two doses shifts both
thoracolumbar and lumbosacral borders forward, particularly the former. The effect
of the DA genome is in the same direction, but significantly greater, and the two combined are additive. The effect of the IIID, genome, by contrast, is in the posterior
direction and epistatic. It suppresses and tends to shift the localization of D a effect
posteriorly. Significant differences between borders when considered separately and in
relation to each other indicate differences of interaction between gene and genome.
The fact that the only signacant difference in the three way comparisons of border,
genotype, and genome is between the Du/+ genotypes of IIIoa and DA as a manifestation of overdominance can be discounted because of the differences i n border interaction. As reference points defining the relative size and position of the thoracic and
lumbar regions, these borders reveal the activity of gene and genome to be a n alteration of the relative size and position of the growth gradients of these two regions
rather than a direct gene specific morphology.
The importance of genic interaction in
morphological genetics has been demonstrated (Wright, '63). One of its most signiiicant features is the dmculty of isolating specific genes and defining the
limits of their action, due to the fact that
morphology is by nature a differential
growth phenomenon. Mammalian growth
as revealed by study of the rabbit was
demonstrated to have a polygenic basis
subject also to extrinsic and other intangible factors (Castle, '31, '41) and control
in time by developmental rate (Castle and
Gregory, '20). Studies of many of the
effects of major mutant genes in mice have
also shown the influence of numerous
minor so-called modifying genes affecting
both external (Wright and Chase, '36;
Dunn and Charles, '37; Dunn, '42) and
internal morphological variations (Dunn
and Gluecksohn - Schoenheimer, '45 for
short tail; Green and Green, '46, McNutt,
'54, and Green, '57 for the short ear gene)
indicating that these mutations are also
under polygenic influence. Viewed in this
way, analysis of morphological variation
and malformation requires an approach
formulated in terms of the possible interaction of a number of genes acting by way
ANAT. REC., 157: 425-436.
of growth processes rather than specificity
of gene per discrete morphological unit.
The importance of gene number, if not
the entire genome (gene milieu), was recognized by Landauer ('58). The importance of developmental processes at particular times and places was emphasized
by Willier ('54) in discussion of morphogenesis in the chick and by Gruneberg
('57) in the mouse, both of whom have
shown the importance of the continuum
or sequence of events, a characteristic also
beginning to be recognized by the teratologists (Lash, '64). Few investigators, however, have associated these facts with the
species pattern of gradient growth as outlined by Child ('25).
The rabbit species pattern of gradient
growth of the axial skeleton as illustrated
by strain I11 was described qualitatively
and quantitatively by Sawin and Crary
('64) and discussed with reference to malformations. The manner in which the
pleiotropic effects of the Da (chondrodystrophy) gene arise through retarded
growth and are expressed by deficiency in
number of skeletal units, compensatory induction of accessory centers of ossification,
and overgrowth of adjacent normal units
425
426
P. B. SAWIN AND MARYANN G O W
was described by Sawin and Trask ('65).
Collectively, these lead to homeotic shifts
in position of regional borders (Bateson,
1894) and to crowding or fusion of units.
These observations, together with those of
Sawin and Crary ('57), Lamb and Sawin
('63), and Crary ('64), show that the Da
genotypes Da/+ and Da/Da may be distinguished from the normal and make it
possible to study the relative effects of
gene and genome upon the rabbit gradient
growth pattern.
This communication is concerned with
the effects of the Da gene upon the thoracolumbar (ThL) and lumbosacral (LS)
borders and the extent that they are
shifted by association of Da with two unrelated genomes. The borders serve as cartographic reference points, determining
the limits of thoracic and lumbar regions
and of the relative anteroposterior position
of the lumbar growth gradient.
MATERIALS AND METHODS
Skeletons of 1555 rabbits were studied.
They were obtained, with seven exceptions, during the first five postnatal days
and were examined either roentgenographically or as alizarin-stained preparations
(Crary, '62).
Seven populations were involved (fig.
2). The two unrelated parental strains
were of New Zealand White origin, DA,'
which was the origin of the Da mutant,
and 111' which does not transmit Da but
which has been partially inbred and selected for the 7C/13Th/7L/3s/18cd vertebral formula (VF). The IIIDa (transfer)
strain was synthesized by outcrossing I11
to DA with subsequent continued backcrossing of the D a / + genotype to race I11
for at least five generations. Both DA and
IIIo, were maintained under forced heterozygosity for the Da gene by selective breeding of tested heterozygotes ( D a / + ). Within each of these two strains, the three
genotypes (+/+, D a / S , and D a / D a ) are
readily identified by discrete variation at
the base of the external ear (Sawin and
Crary, '57; Lamb and Sawin, '63; Crary,
'64). This permits evaluation of 0, 1, or 2
doses of the gene upon each of the pleiotropic characters induced by the gene.
These six populations and parental strain
I11 provided tests of the differences between
Da genotypes and normal genomes. The
IIID, populations studied were derived by
intercrosses among the 5-7 backcross generation offspring. Many of the young of
populations on which the tabulations were
based were sacrificed at 33 days post coitus
to provide satisfactory information on initial appearance of the vertebral epiphyses,
to be reported later. AU potential breeders
(females and males) necessary for the
succeeding generations were typed roentgenographically for vertebral formula. Chisquare tests of the variation in VF between
the five age groups (30 to 34 days) and
generations revealed no significant differences, hence the data could be pooled irrespective of age and generation. As described by Sawin ('45) the VF of both
alizarin preparations and roentgenograms
were read with reference to the relative
thirteenth rib expressivity on each side. A
scale of 0-4 with relation to the size of
the twelfth rib was used. Similarly the expressivity of sacro-pelvic attachment was
recorded on a scale of 1-6. Type I involved
only the twenty-seventh vertebra, type 5
the twenty-eighth only, type 3 both 27 and
28 equally, and 2 and 4 were intermediate
classes (fig. 1 ) . A sixth type, similar to 5,
involved a very small part of the twentyninth in one case.
1 The DA strain of the Da gene was obtained from
California i n 1950 (Crary and Sawin, '72; Sawm and
Crary '57. Sawm Ranlett and Craw, 59, '62; Lamb
and dawid, '63; &win and Trask, '65).
2 Strain I11 was first descrlbed by Sawin ('37) with
reference to the homeotic variations of the axial
skeleton. It was also studied in connection with malformation of the vena cava (McNutt and Sawin, '43),
vanations of the ventral spinous processes of the
lumbar vertebrae (Sawin and Hull '46) aortic arch
( Sawin, and Edmonds, '49), gall blhdder' ( Sawin and
Crary, 51), growth of vertebra! centra (Tanner and
Sawin, '53; Crary and Sawin 57). growth and maturation (Crary and Sawin, '6'0).adult body size and
size of prgans and skeletal parts (Latxmer and Sawm,
'571 h
58 '59a.b. '60a.b. '61. '62. '63a.b: Sawin and
&a-:'
'56.' CraG'and Bawi?' '57) growth and body
w e i g k (drary and Sawin 60), h d malformations
(Sawin and Crary, '64). ks reported by .Sawin ('37).
strain I11 tended to produce a much hlgher proportinn of Droeenv of the vertebral formula 7C/13Th/7L
( 1 3 pa& 6f fibs and 27 presacral vertebrae, PSV)
than any other race. As close inbreeding as possible
consonant with maintenance of reproductive capaclty
plus select!on has materially increased the proportion unul in two sublmes the penetrance appears to
be 100%. One other subline,
was much more
variable in vertebral formula but was assigned for
inbreeding and maintenance. of the ep gene (audiogenic seizures) without selection for vertebral formula.
Since the Da gene had already been introduced without reference to sublme differenbatlon the experiment
was conducted with due attentlon only to secure sufficient progeny from each subline to permit adequate
test of the genetics of possible subline differences.
427
GENE AND GENOME INTERACTION
1
NORMAL
THORAX
12 17
2
NORMAL
LUMBAR
(7)
13/6L
REDUCED
LUMBAR
(61
3
13/6H
ENLARGED 4
THORAX
4
13/7H
NORMAL
LUMBAR
(71
SHIFTED
POSTERIOR
5
13/7L
Fig. 1 For the purposes of this paper, expressivity of rib (H and L ) and presacral vertebrae were ignored and classification was confined to an all or none basis, presence or
absence of extra ribs and grades 1-3 considered as 26, and 4, 5, and 6 as 27 presacral
vertebrae.
428
P. B. SAWIN AND MARYANN G O W
OBSERVATIONS
1 . Effect of genome differences on ver-
tebral formulae. In using the skeletal
pattern of growth and development to portray the true effect of any one gene it is
essential first to consider possible genetic
differences in that background. Figure 2
shows the difference between the normal
genome effects on VF of race 111, which
segrelacks the Da gene, and the
gates of the DA race. Race I11 has over
twice as many individuals of type 7/13/7
as does the DA and relatively few of the
other three types. The DA race has significantly larger proportions of 7/12/7 and
7/13/6 classes (P < 0.005).
The segregating
genotypes of
strain I&, however, do not differ from
race I11 (P > 0.05), indicating that the
genetic background is essentially similar
to that of race 111. The race I11 genome
tends to shift the vertebral border in such
manner as to increase the proportion of
individuals in the two classes to the right
(posteriorly) and the DA to decrease them
or shift the border to the left. When the
Da gene is present in either heterozygous
or homozygous state (fig. 2), the shifts
are complementary and the genome differences, DA vs I&., likewise are highly
significant ( P < 0.005, see table 2).
+/+
+/+
Genotype
2. Gene effects on vertebral formulae.
The effects of one and two doses of the
Da gene may be compared similarly as
shown in figure 2. The differences between
the DA race normals and both heterozygous and homozygous dachs (Da/+ and
D a / D a ) are signilkant (P < 0.01 and
< 0.005 respectively). The shift effected
by one dose of the Da gene appears to be
very little different from that of two doses
as indicated by the fact that the difference
between the two Da genotypes is not statistically significant (P > 0.05). The same
comparisons within the III,, race (fig. 2 )
show that the X2 between normal and
heterozygote is significant at the 0.02-0.01
level, but not between normal and dachs
or between heterozygote and dachs. In
general, the Da effect is manifest in both
DA and III,, as a reduction of penetrance
of extra ribs and PSV resulting in a n anterior shift of the borders. The effect, however, is greatest in the DA and expressed
more anteriorly than in IIIo,. Since these
borders determine the relative size of the
thoracic and lumbar regions, reduction of
rib number represents a decrease in size
of the thoracic area in the DA, whereas in
the I11 and IIID. the greater proportion of
individuals with 13 ribs indicates that
these strains actually have a relatively
Race
x2
df
P
Total
.3-.2
132
DaDa
DA
4.0
3
Da+
DA
18.4
3
.005
241
+I-
DA
12.1
3
.01
116
DaDa
IIIDa
2.0
3
.7-.5
131
Da+
IIIDa
7.2
4 .2-.1
190
$+
IIIDa
i+
111
621
/%
20
40
60
80
100
1555
Fig. 2 Bar graphs show the distribution of individuals according to vertebral type in each of the
three Da genotypes for the DA, 111, and IIIoa races, with significance and number of progeny at the
right. Blank bars are normal (12 thoracic/7 lumbar) vertebral formula, diagonal lined 13/6, black
13/7, and stippled 12/8. Significance of intrastrain differences are shown by brackets. Interstrain
differences of (+/+) phenotypes are significant between I11 and DA ( p 0.005), but not between
111 and IIID,. Actual numbers of each vertebral type are shown in table 5 by strain and genotype.
<
GENE AND GENOME INTERACTION
W
4
2
iij
B
4
Y
;i
W
s
Fr;
al
PI
,x
d
d
429
larger thoracic region. The question arises
as to whether the Da gene and DA genome
affect both borders and both regions in the
same way, or whether regional differences
of effect exist and, if so, how they are
localized.
3. Gene and genome effects upon the
separate vertebral borders. To test more
precisely the localization of gene and genome effect on the two regions the racial
differences at the two vertebral borders
have been compared separately. As shown
in table 1, the differences in both borders
between I11 and DA in the absence of the
Da gene are significant, race I11 having a
greater proportion of individuals with both
13 ribs and 27 PSV than does the DA
(P<O.O05). The same is true of DA vs
I I L , although the X2 is not as great. Although race I11 and IIL, are not significantly different from each other in rib
number (P>O.O5), a 6% reduction in
PSV suggests the possible existence of
some minor genetic differences, reducing
the proportion of PSV in the transfer
strain .
The effects of the genome on distribution of position of the individual borders
within the two Da genotypes are shown in
table 2. Considered independently, all are
highly significant at both borders, showing again that there is a difference between the two regardless of the genotype.
The largest between-strain chi-squares are
found in the proportion of PSV of the two
Da/Da populations and in the number of
ribs of the two Da/+ populations. Further
evidence of this is found in comparison of
the separate borders in the Da genotypes
as found in the DA (table 3) and IIID,
(table 4 ) genomes.
4 . Gene effects on the separate borders.
In the DA race (table 3) the chi-squares
for the thoracolumbar border (ThL) are
significant between both Da genotypes and
normal (+/+) (P<O.O05), and not between the Da/Da and D a / + (P=O.30.2). Those for PSV also are significant
though at lower levels (P < 0.05), thus
showing some, though perhaps less, effect
on the lumbar border.
In the IIIDa (table 4), however, the
effects of the Da gene separately on the
borders are not significant at the thoracolumbar in any case, but are significant
430
P. B. SAWIN AND MARYANN GOW
at the lumbosacral ( P < 0.01) between
Da/+ and + / C and (P<O.O5) between
Da/Da and
5 . Relation of thmacolumbar and lumbosucral borders. To test the possible relationship of the two borders, the data for
+/+.
the seven populations were assembled as
shown in table 5 and tested by Xa. All were
significant ( P < 0.005), indicating a high
degree of dependence or interaction of the
borders within each genotype of both
strains. The most obvious differences between the two strains was the relative proportion of the minority types, 12/8 and
13/6, and that which is the modal (12/7
in DA vs 13/7 in I I L ) , indicating some
degree of interaction between the Da gene
and its associated genome.
To test this, the method devised by
Bartlett (described by Snedecor, '46) for
the combined interaction of three attributes, in this case regional borders, strain,
and genotype, was applied. As shown in
table 5, of the groups tested the only ones
showing significant differences are the
heterozygous groups (Da/+) of the DA
and 111,. races (p = 0.05-0.02). Since no
significant differences between the genotypes were found, those of both DA and
IIID, were pooled, and similar 3-way tests
of the three genomes (DA, 111, and 1110,)
were made. Again no significant differences were found. Therefore, the only significant difference in the dependent relationship of the borders is that arising in
the two Da/+ groups. Hence, we may
conclude that it is interaction of the Da
gene with the two genomes which creates
the difference. It is supported by the fact
that the effect of Da is greater on the posterior border when associated with the I11
genome than when with DA (tables 3
and 4).
DISCUSSION
The results of this study clearly show
that the homeotic shifts of the ThL and
LS borders which were first regarded as
pleiotropic effects of the Da gene are not
in any sense exclusive to specific skeletal
units. Instead, as parts of the metameric
organization of the species, addition or
deletion of ribs or presacral vertebrae can
result from the cumulative effects of some
greater or lesser portion, if not the entire
genome, in much the same sense that
431
GENE AND GENOME INTERACTION
TABLE 3
Significant effects of Da on the thoracolumbar and lumbosacral borders of the
DA race considered inddpendently
Thoracolumbar
Genoqpe
companson
+ + vs. DA+
+ + vs. DaDa
Da+ vs. DaDa
Lumbosacral
XZ
df
P
xa
df
P
12.1
16.2
1.2
1
1
1
0.005
0.005
0.3-0.2
4.5
5.6
0.3
1
1
0.05-0.02
0.02-0.01
0.7-0.5
1
TABLE 4
Significant effects of Da on the thoracolumbar and lumbosacral borders of the
HI,, race considered independently
Thoracolumbar
Genotype
cornpanson
+ + vs. Da+
+ + vs. DaDa
Da+ vs. DaDa
Lumbosacral
XZ
df
P
X2
df
P
1.73
1.06
0.05
2
2
0.5-0.3
0.7-0.5
0.9-0.8
7.6
5.1
0.1
1
1
1
0.01
0.05-0.02
0.8-0.7
1
TABLE 5
Shows the populations (portrayed by bar graphs) of figure 1 arranged with Telationship o f anterior
(ribs) to posterior (PSV) borders for tests of significance between borders and f o r interaction of
the three attributes. Significances of all tests are based on 1 degree of freedom
Strain DA
Strain 111,
PSV
PSV
Ribs
26
12
13
71(54)
21(16)
92
Ribs
T
27
~~
14(11)
26(20)
40
x2 = 21.8
p=
0.005
85
47
132
15(6)
65(27)
80
77.9
141
100
241
5(4)
47(41)
52
33.9
0.005
45
71
116
DaDa
12
13
12
13
126(52)
35(15)
161
x2
p
12
13
=
x2
p
Da
+
=
=<
X=
21 vs. 24
22 vs. 25
23 vs. 26
21 vs. 22
21 vs. 23
22 vs. 23
24 vs. 25
24 vs. 26
25 vs. 26
23 vs. 27
26 vs. 27
1.10
5.167
0.236
0.09
1.08
0.097
2.58
0.056
2.58
0.342
0.479
22
109
131
16(8)
121(64)
137
14.7
0.005
35
155
190
9(7)
96(77)
1
18
106
x2 = 31.4
P = 0.005
20
103
1
124
=<
19(10)
34(18)
53
x2=
p=<
+f
12
13
14
11(9)
7(6)
<
Significance of tests between
3 attributes
Groups 4
~~~~~
7(5)
90(69)
97
24.6
0.005
15(11)
19(15)
34
p
12
13
= < 0.005
40(34)
24(21)
64
~~
x2=
<
T
27
26
P
0.3 -0.2
0.05-0.02
0.7 -0.5
0.8
0.30
0.8 -0.7
0.3 -0.2
0.9 -0.8
0.3 -0.2
0.7 -0.5
0.5 -0.3
12
13
Strain I11
32(5)
52(8)
24(4)
513(83)
56
565
x2=
100.10
84
537
621
P = < 0.005
*.Groups of genotypes for DA and IIID. are numbered 21-23 and 24-26 respectively, from top to bottom and
III is 27.
432
P. B. SAWIN AND MARYANN GOW
growth when measured by body size is
polygenic. The fact that both genotypes
and genomes appear capable of producing
at least some proportion of all four vertebral types, but in different proportions, indicates that the skeletal units are affected
by more than one genetic factor. Although
the Da gene does have an effect upon the
homeotic shifts, those shifts are varied by
other elements in the genome, and furthermore the apparent effect of Da in the one
genome can be altered or suppressed by
interaction with a different genome.
Furthermore, it is clear that in spite of
this interaction the effects of both the Da
gene and the DA genome can be distinguished from each other and can be within rough limits defined. The significant
differences in proportion of individuals
manifesting one or the other or both border shifts show that Da in either one or
two doses tends to shift both borders anteriorly, but that the effect on the ThL
border is the greater. The DA genome has
a similar directional effect but of greater
magnitude and the effects of Da and DA
when combined are complementary. The
effect of 111,. upon the borders is in the
posterior direction. It tends to be epistatic,
suppressing or masking the effects of Da,
and what is more significant, to alter its
localization. The significant effects of Da
in the III,, genome are more apparent at
the LS border. In general, between genome
and between genotype, the significant differences in VF and in the two borders considered separately indicate differences of
interaction between several genetic components. This is supported by the highly
significant Xz tests for independence of the
two borders within genotypes and strains
and by significant evidence of strain difference between the interaction of the two
borders when the Da heterozygote of the
two strains is compared. Accordingly,
these variations are in harmony with the
concept of a major gene (Da) plus modifiers as the most likely and presently
accepted interpretation for the range of
expression and penetrance which is usual
in morphological variations.
When the overall pattern of significant
differences in homeotic border shifts is
considered, it is apparent that the actual
effect is either (1) to alter the size of
thoracic and lumbar areas in relation to
each other by some fraction of one vertebra, or (2) in those cases where both borders are shifted in the same direction to
shift the position of the entire lumbar
region by that amount. These two effects,
size and position, are essentially integrated in determining the borders and
together are determined by genome entities acting on basic growth processes.
Previous measurement of the lengths of
centra of race I11 has shown that ( 1 ) the
thoracolumbar border is almost identical
with the peak of gradients 3 and 4 and
that the lumbosacral border coincides with
the valley between gradients 4 and 5, and
(2) these reference points are relatively
constant from beginning ossification to
well after birth (Sawin and Crary, '64) at
which time they are undoubtedly permanently established. In the same communication, certain significant relationships
between skeletal malformation and the
species gradient pattern were shown.
When considered in relation to that pattern, these border shifts are understandable as reference points portraying the
interactions of adjacent gradients in response to genetic changes in relative
growth capacity. Because of the broad
distribution of effects of the dachs gene,
Gruneberg ('63) has classified Da under
the systemic disorders of the cartilaginous
skeleton and the study of these border
effects of the axial skeleton of Da constitutes further substantiating evidence.
Time is being widely recognized as a
critical factor in determining induction of
malformation both experimentally and
genetically. The effect of Da being greatest
at the anterior border in DA, its reduction
of ribs (or anterior shift) may indicate an
earlier genetic growth retardation in the
cartilaginous skeleton, possibly even in the
late membranous stage, and hence on
the primary anteroposterior gradient. The
effects of either genome, however, are
more extensive than are Da's and particularly that of I&, which is exerted more
posteriorly. This may indicate a slightly
later origin in the metameric process,
actually perhaps effects of the differentiating secondary (thoracic and lumbar)
gradients. However, the fact that the Dd
anterior border shift (as observed in the
GENE AND GENOME INTERACTION
DA) when transferred to the III,, appears
more posteriorly suggests that it is not exclusively a “spuriously” pleiotropic effect
of Da (Gruneberg, ’63), nor solely an expression of its generalized retardation
(Sawin and Crary, ’57), in which case it
would be a “genuine” pleiotropic effect,
but is a manifestation of the interaction
of several gene-induced growth processes
best described at present with reference to
the primary and secondary gradients. Although of all the effects, those of genome
appear much greater than those of the Da
genotypes, it seems reasonable to assume
that this is due to the number of genes involved which have been concentrated by
selection and inbreeding in race I11 and
transferred to IIID,.As a single gene in the
DA background Da’s effect is prominent
in both one and two doses and although
less so in IIL, the shift in localization of
effect is highly indicative of the mechanism involved, i.e., the gradient being a
result of the cumulative contribution of
both a mutant gene and multiple units of
the genome. Such difference in timing and
localization could account for the irregularity revealed graphically in figure 2 and
statistically in the heterozygous interstrain
difference (table 5), where the effects of
the gene ( D a ) and genomes are both most
clearly expressed and effective in alteration of the vertebral type.
Logically, it may well be questioned
whether specific units of the modifier genome can ever be identified with more precision than those determining body size.
However, the fact that some degree of
identification has been achieved here by
use of these border units suggests that
closer examination of adjacent skeletal
units may in a similar way reveal the contour of others of the localized gene determined processes. In this paper, no consideration has been given to either the
parental phenotype or genotype insofar as
the VF or separate borders are concerned.
Furthermore, thus far no attention has
been given to other reference points either
between these borders or in either direction beyond them which would help to
define the gradient limits. Nor has attention been given to precise chronological
aspects of the gradient growth processes.
Each of these could be closely associated
433
in the gradient pattern and thus contribute
additional knowledge of the gradient
mechanism. Although the possibility of
overdominance or one gene heterosis as
an explanation for the interstrain difference in heterozygous effect cannot be
ruled out, the suggestion that “overdominance may be a function of the background genotype rather than a characteristic of a given locus,” (Wallace and Madden, ’65) at present seems the more
applicable and tenable for this variation.
It can be explored by breeding tests of the
interaction of these racial gradients using
( 1 ) matings of specific vertebral phenotype and genotype, and ( 2 ) other reference points in the skeleton to portray the
limits of gradient activity and points of
interaction. The latter would portray in
more detail the magnitude and characteristics of the gradients. Such projects are
in progress, some of which are approaching completion. As indirect interaction
products effected by way of the species
growth gradients rather than direct gene
induced malformations, these border shifts
and other spontaneous differences arising
in relation to gradient borders merit further intensive genetic investigation. They
have a bearing upon several major clinical
problems, particularly those of spontaneous malformation of the teratologist (Wilson, ’65; Sawin, Crary, Fox and Wuest,
’65), and the quantification of morphological differences of the anthropologist
(Haronian and Sugarman, ’65). Of most
value to the first is the knowledge of specificity of effect of one gene Da (as one experimental insult) and how its effects may
be modified in the society of two different
genomes or as Leck (’65) has suggested,
by “fortuitous mismatching of quantitative
factors that in other combinations would
contribute to normal development.” To the
second, is the cartographic use of the skeleton as a substitute or supplement to
present methods of quantifying morphological differences.
Although these specific homeotic variations are usually of minor clinical significance and therefore this information
may seem irrelevant to the malformation
problems generally, the same homeotic
variation when asymmetrical becomes scoliosis. When it involves an articulation
434
P. B. SAWIN AND MARYANN GOW
such as the occipitovertebral border it becomes functionally handicapping. It is anticipated that this knowledge of gradient
interaction gained from relatively simple
homeotic shifts will be helpful in analysis
of mechanisms involved in more complex
malformations and syndromes of malformation (see also Sawin and Trask, ' 6 5 ) .
CONCLUSIONS
Study of the homeotic shifts of vertebral
borders as affected by the Da gene when
on two different genetic backgrounds
shows that the effects of both gene and
genome are distinguishable. The Da in
either one or two doses shifts both thoracolumbar and lumbosacral borders forward, particularly the former. The effect
of the DA genome is in the same direction,
but significantly greater, and the two combined are additive. The effect of the III,,
genome, by contrast, is in the posterior
direction and epistatic. It suppresses and
tends to shift the localization of Da effect
posteriorly. Significant differences between
borders when considered separately and
in relation to each other indicate differences of interaction between gene and
genome. The fact that the only significant
difference in the three way comparisons
of border, genotype, and genome is between the Da/+ genotypes of IIIn. and DA
as a manifestation of overdominance can
be discounted because of the differences
in border interaction. As reference points
defining the relative size and position of
the thoracic and lumbar regions, these
borders reveal the activity of gene and
genome to be an alteration of the relative
size and position of the growth gradients
of these two regions rather than a direct
gene specific morphology.
ACKNOWLDGMENTS
This study was supported in part by
Public Health Service grant C281 from the
National Cancer Institute and in part by
grant E40 from the American Cancer
Society.
Our thanks are due to Dr. R. R. Fox,
Dorcas Crary, Adelaide Cousens, Esther
Clark, Eugene Farrin, Bruce Plummer and
Marjorie Muehlke who assisted in various
ways in analysis and collection and preparation of specimens or roentgenograms.
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