GENETICAL AND EMBRYOLOGICAL COMPARISONS OF
SEMILETHAL t-ALLELES FROM WILD MOUSE POPULATIONS
DOROTHEA BENNETT* AND L. C. DUNNf
MARY D. RYNERSON
WITH THE ASSISTANCE OF
Department of Anatomy, Cornell University Medical College, N e w York City,
and Nevis Biological Station, Columbia University,
Iruington-on-Hudson, N e w York
Received July 3, 1968
HE genetic variants at the complex T locus in the house mouse have been
Tmuch studied (see DUNN1964; BENNETT1964; and LYONand MEREDITH
1964, for reviews) because of their uniquely varied and interesting effects on
such diverse characters as embryonic development, sperm function, suppression
of recombination in their vicinity, and high level of conversion to new and different genetic forms. There is in addition the surprising fact that such variants occur
in most wild populations of house mice.
The situation with respect to these alleles as heretofore described in the literature is as follows. A dominant gene T (Brachyury) in linkage group IX serves as a
diagnostic marker for this locus. In heterozygous condition T produces a shorttailed phenotype, apparently by interference with the growth and maintenance
of the notochord during embryonic development. T is lethal when homozygous,
such embryos dying about halfway through gestation. In these the posterior part
of the body is missing, a situation apparently also due to defects in the primitive
streak or notochord.
In addition, there exist at this locus a whole series of different recessive variants. These so-called t-alleles are recognized solely by their interaction with T ,
the interaction being such that the genotype TJt has a tailless phenotype. Thus
the dominant gene T provides a means for detecting these interesting recessive
alleles which would otherwise in practical terms be unrecognizable.
The recessive alleles known at this locus have been garnered from two different
sources. Many of them have been isolated from wild populations of mice or
laboratory stocks in which they are apparently maintained as a natural polymorphism. Others have occurred as “mutations” to new and different form; of
t-alleles which have already been characterized and are maintained as balanced
inbred lines in the animal colony.
Although these recessive t-alleles have one constant factor in common, that is,
their tail-modifying effect when combined with T , they proved to be a heterogeneous group with respect to other effects mentioned above. In general, however,
Research performed under contract AT(30-1)1804 with U S Atomic Energy Commission+, and USPHS Grant GM
09912 * .
* Career Investigator, Health Research Council of the City of New York
Genetics 61: 411422 February 1969
412
DOROTHEA B E N N E T T A N D L. C. D U N N
the alleles so far described in detail have fallen into two relatively distinct categories on the basis of several of their properties.
First, is a category of alleles which, when homozygous, are lethal before birth.
SOfar five different groups of such alleles have been recognized. Each group is
composed of more than one member of independent occurrence; the members of
each group have apparently identical effects on embryogeny and lead to death at
a particular time and in a particular manner. The members of each group are by
definition non-complementary with one another, but show complementation with
all members of other groups. All of the alleles in the lethal category share one
other common property; they produce new and different t-alleles at a frequency
(about one variant per 500 gametes) which is too high for any known mutational
process.
Such new alleles are easily detected because stocks of lethal t-alleles are maintained as tailless balanced lethal systems T /tz.In such tme-breeding tailless stocks
a newly arisen t-allele different from that in the stock is detected when it comes
into combination t z / t n e wand because of the complementation eflect mentioned
above, an exceptional normal-tailed animal is produced.
Four members of the lethal category (to,t 1 2 , tW', tZo5)share two other common
properties. First, they completely suppress recombination in their vicinity over a
distance of at least 8 crossover units. Our stocks are routinely carried as T t f / t z
(+tufted being a marker about 8 units from T ) and no recombination is detected
between T and tf under such circumstances except in the event of the origin of a
new t-allele, when the tuftcd marker is commonly found to have undergone
recombination and to be on the chromosome with the newly arisen t-allele.
(DUNN,BENNETTand BEASLEY1962) Secondly, they all produce an altered
transmission ratio in male, although not in female, heterozygotes. Males transmit
their t-allele to a preponderance of their offspring ranging from about 80% to
almost 99% depending on the particular t-allele studied. This effect is apparently
based on sperm function, rather than on abxrant meiotic phenomena (YANAGISAWA, DUNN,and BENNETT1961). The fifth lethal group t9, however, demonstrates neither recombination suppression nor alteration of male transmission
ratio. An interesting additional observation is that although all different lethal
t-alleles, when combined as double heterozygotes, show complementation, the
degree of complementation is not complete and varies according to the lethal
alleles combined. Many embryos of such gmotypes die before or at birth, showing various degrees of an otocephalic type of abnormality, and all compound
males even though morphologically normal are completely sterile.
The second major category of t-alleles, heretofore described, are those which
are fully viable when homozygous. These form a relatively homogeneous category; they do not supprezs recombination; if they alter transmission ratio at all,
and many of them do not, they alter it in favor of the normal allele; and male
homozygotes are usually fertile.
When all these observations were taken together, the impression was gained
that there are two more or less typically different classes of t-alleles: a class of
lethal, recombination-suppressing, high-transmission-ratio alleles, and another
t-ALLELES IN MOUSE POPULATIONS
413
class of alleles which are viable and have none of these properties but only the
common element of interaction with T which is necessary if they are to be
detected in the first place. An interesting corollary is that the fully viable alleles,
as well as the atypical lethal t9, have been obtained only by “mutation” from
previously existing t-alleles; while the typical lethals have been found most often
as existing polymorphisms in wild or laboratory mice, and only occasionally as
“mutations” in the laboratory.
The purpose of this paper is to report genetic and gross embryological data on
a third major category of t-alleles not previously described in detail. These alleles
produce viable homozygotes, but in such reduced proportion as to justify designating them as semi-lethal (BRUCK1967). In all other aspects they resemble typical
lethal alleles, that is, they were all derived from wild populations, suppress crossing over completely and have very high transmission ratios. In addition, they
are completely male sterile as homozygotes or compounds with each other or with
lethal alleles.
MATERIALS A N D METHODS
Methods of testing: Detection of t-alleles: Tests for the presence of a t-allele in phenotypically normal mice are made by crossing them to +/T mates. Mice heterozygous for a t-allele
will reveal it by producing offspring of genotype T / t recognizable by their tailless phenotype.
Progeny tests of tailless offspring from any single-pair mating will determine lethality or
viability of the t-allele involved, since if it is lethal, the mating of T/t x T/t forms a balanced
lethal system and only tailless offspring will be produced. If the t is viable, then another class of
animals, phenotypi3cally normal tailed and genotypically t/t, will appear at birth.
Estimate of degree of uiability of t-homozygotes: Matings between two T/t animals should at
conception give the following classes of offspring: T/T, T/t and t/t. Regardless of any other
factors the tailless (T/t) class should represent one-half of the total litter. Thus an estimate of
original total litter sizes can be obtained by doubling the number of tailless offspring. Assuming
equal viability on the part of homozygotes for t, the number of t/t animals expected can be
calculated by multiplying the transmission ratio of the male by the female transmission ratio
( . 5 ) by total litter size. The expected number obtained in this way can be directly compared
with the number of normal tailed homozygotes observed, to give a viability estimate in percent.
Measurement of transmission ratio: A direct estimate of male transmission ratio is obtained
by mating male heterozygotes of genotype T/t to wild type (+/+)females; all offspring receiving the males’ T chromosome are short-tailed, all receiving the t-allele are normal-tailed.
Estimation of recombinah’on suppression: All tailless stocks of the semilethal alleles were
routinely maintained as T tf/tw+. Thus in the absence of crossing over between T and tf all
tailless animals are expected to be phenotypically non-tufted. Recombination would be detected
by the praduction of a t tf chromosxne and its subsequent union with the standard T tf to produce
a phenotypically tailless tufted animal.
Direct tests of recombination between T and tf are made by crossing T tf/tm+ animals to a
+tf/+tf tester stock. Parental types from this cross will be phenotypically short-tailed tufted
and normal-tailed non-tufted; recombinants would be detected as short-tailed non-tufted and
normal-tailed tufted animals.
Male fertility tests: Mature healthy males are caged with 4 or 5 females of proven fertility;
a sojourn of one m m t h with one such female is arbitrarily considered as one “mating unit”
(mu). A male is considered to be “mating sterile” if under these circumstances he produces no
offspring in 10 mating units.
Embryological obseruations: Since the breeding results at birth for the four semilethal alleles
under study indicated that many homozygotes must die before birth, a study of embryos from
414
DOROTHEA B E N N E T T A N D L. C. D U N N
the most severely affected genotype (tw49) and from one with intermediate viability (tWSG)was
undertaken at 14, 15 and 16 days of development.
This time period was chosen because embryos of these stages are roughly quite comparable
to one another with placentation and all major organogenesis completed In litters examined a t
these stages one is able to distinguish major externally visible abnormalities. Embryos which
had died previously but after implantation would still be expected to be at least detectable as
resorbing decidual capsules o r even classifiable for abnormality if death was more recent.
Source of alleles; Four samples widely separated in space and time taken from wild populations of mice have yielded alleles of the semi-lethal typel. The alleles derived and the origin of
the stocks are described below.
itus. A confined population of wild house mice captured in suburbs of Philadelphia and New
York was maintained at the Rockefeller Institute by Dr. HOWARD
SCHNEIDER
from 1946 to 1966.
1953) showed it to be polyTests of samples from this population in 1953 (DUNNand MORGAN
morphic f o r a viable allele which has now been reclassified as a semi-lethal tW2.
tt'J8. A sample of mice from a farmyard i n Rumford, Virginia, obtained by Dr A. B. BEASLEY
in 1955 was found to contain the allele tm8. (cf. also BRUCK1967).
t t " j 6 . A feral population of mice trapped by Dr. KEITHJUSTICE
in 1961 in the neighborhood
of Tucsm, Arizona was found to carry the allele tW".
P 4 9 . t-alleles were detected by Dr. PAUL
ANDERSON
in several samples of mice captured in
farm buildings in the vicinity of Calgary, Alberta Most of them P T O V C ~to belong to the tZu5
lethal group; but a few were shown by complementation interaction with P to belong t o another
group or groups These were referred to us by Dr. ANDERSON
for further testing. We detected a
Stryker 113) which at first appeared to produce
hitherto unrecorded allele as tw49 (ANDERSON'S
a balanced lethal system in the combination T tf/t"g. Later, however, three exceptional normaltailed offspring appzared. Three other alleles from adjacent farms appeared to be similar to twA9,
complementing t = j and giving a low frequency of normal-tailed offspring when bred inter-se or
crossed with tailless tw49.
A summary of breeding data from the four different samples is provided in Table 1. As can
be seen from the table, the four samples seem to contain the same allele, both genetically and as
TABLE 1
Results of crosses within and between tailless mice heterozygous for
independently derived members of the tW49 group
Stryker 113
81.2
1GO4
1687
Tailless Normal
Tailless Normal
Tailless Normal
=(twig)
Allele' designation
tau49
842
1604
1687
Tailless
251
Normal
3
247
161
94
4
0
244
..
2
..
..
..
88
84
4
1
81
0
6**
* Numbers refer to original capture numbers of ANDERSON.
** One normal was 'an exception i1*04/ie059 i f .
In addition to the four occurrences of semilethal alleles in wild populations, one case has been noted in an allele
DE.Jo ANN MUNGLEin a laboratory stock of the balanced lethal
line T/tm5. Matings of Ttj/i"34 by Tfj/Iw34 produced 392 tailless and 28 normal tailed offspring. The expected frequency
of tm34 homozygotes, computed from the male transmission ratio of t'34 (26.8%) would be 102. The actual frequency
(28) thus indicates a homozygote viability of 27%, clearly within the semilethal range. This allele differed from the
semi-lethals reported in this paper in not suppressing or even reducing recombination in the T-ff region. Recombination
was 6.4% (14/218) in male heterozygotes T t f / t w 3 4 , a relatively normal recombination value. No homozygous males
survived to provide fertility tests. Embryological observations were not made and the stock was lost so it is not possible
to compare this allele with the semi-lethals reported here. No other similar case of lowered viability of homozygotes was
found among 4 4 viable 2-alleles derived from exceptions found in balanced laboratory stocks.
1
P a d , derived from an exceptional gamete found by
415
t-ALLELES I N MOUSE POPULATIONS
TABLE 2
Offspring observed at birth from inter-se matings between tailless
animals (T/t) carrying semi-lethal alleles
Allele
tW*
tW8
tW56
tW4Q
Transmission
ratio
Tailless
T/t”
Normal-tailed
observed
.95
.76
.97
.95
861
2084
413*
754
14w
1210
19$
194**
ut
expected
818
1584
73 1
1150
Viability of f/t
in percent
51
12
20
1.7
* 4 described as “small” at birth, 1 as microphthalmic.
** 10 described as “small” at birth, 10 microphthalmic and 8 dead.
+$ 211described
described as “sm~a1l”at birth, 9 microphthalmic, 6 anophthalmic, 6 dead.
as “small,” 1 anophthalmic, 3 dead.
judged from degree of homozygote viability. These will henceforth be considered in a common
category as W 9 .
RESULTS
Breeding datu: Inter-se crosses
Table 2 presents data from inter-se crosses for the alleles twa,tW8,tWj6and tw4’
together with viability estimates for the homozygote of each allele. It is obvious
that viability is far from complete for any one of them, but also that there is a
large variation in degree of survival, ranging from 51’% viability for tWz,to the
extremely low figure of 1.7% for tw4’.
The results of matings of T/twzX T/twa(line 1, table 2) include offspring born
between 1952 and 1966. When first measured (1952) tw*/tws had a viability of
about 72% at birth (83 tailless: 57 normal). The results of matings T / t W 8X T/tW8
(line 2) cover the period 1956 through 1966. When first observed, tW8/tm8
had a
viability of about 13% at birth (422 tailless: 36 normal) and a male transmission
ratio of .87. Hence these “viable” alleles were semi-lethal when first extracted
from wild populations, although rlo viability estimates were made at the time.
It was noted that many of the surviving homozygotes were dead at birth or
classified as being small; they often were obviously microphthalmic or anophthalmic. The incidences of these abnormalities in the various genotypes were
closely correlated with the degree of lethality. These data thus establish all of
these alleles as semi-lethals. Quantitative differences in the degree of lethality
are obvious amongst the four alleles, but the types of abnormalities seen in the
newborn young of all genotypes appeared to be similar.
Transmission ratios: Table 3 presents data on the transmission ratio of semilethal t-alleles from tailless male heterozygotes ( T / t ). In all classes, the t-allele
is transmitted to significantly higher proportions of off spring than its alternative
allele. Three of the alleles have transmission values which are very high indeed,
approaching loo%, while one ( P )ratio is only moderately high. Transmission
ratios from females are normal (DUNN1960). Thus in this respect also the semilethal alleles form a relatively homogeneous group.
416
DOROTHEA B E N N E T T A N D L. C. D U N N
TABLE 3
Male transmission ratios of semi-lethal alleles
Offspring from matings of T / t males by
Normal
tail ( + / t )
Males tested
'
5 T/twP*
9 T/tw8
14 T/tW86
19 T/tW49
Brachyury
(+/TI
Total
319
449
15
139
1147
37
51
334
588
1184
920
+/+ females
Transmission ratio
(normal/total)
.95
.76
.97
.95
971
* Data from DUNNand SUCKLING
(1956).
TABLE 4
Results of tests for the occurrence of recombination between T and tf
in the presence of a semi-lethal allele
Offspring
Mating
T tf/tw'
T
+T
tf/tw36
tf/+ t f
tf/tW8
-tt f / + t f
T tf/P49
+tf/+
tf
x T tf/tw*
x T tf/tws6
x T tf/tw36
x T tf/tWB
x T tf/tw8
x T tf/tw49
x T tf/tw4g
Non-recombinant
recombinant
205
240
262
1*
699
2**
215
381
99
2101
4
* A tailless tufted exception, carrying a new tw allele (tw62tf)
** 2 tailless tufted exceptions: tw54tf and @057tf.
i.1 nt
tw@/tw59tf.
Recombination suppression: Table 4 records observations on 2405 off spring of
parents heterozygous for one of the semi-lethal alleles together with the two
marker genes T and tf near the t-region. The tailless offspring of T tf/tn by T tf/tn
matings were scored for tufted at 28 days when this phenotype can be reliably
classified. All were non-tufted except three. Each o i the tufted tailless exceptions
proved to carry a fully viable t-allele other than that present in the parents. One
normal-tailed exception from t w h g also carried a newly arisen viable t-allele together with the tufted marker. All four exceptions thus represented exceptional
recombinants like those reported from lethal t-alleles from wild populations
(DUNN,BENNETTand. BEASLEY1962). No recombinants were detected in other
tests. The exceptions occurred at about the same rate as in balanced lethal stocks,
that is, about 1/500. The tests leave no doubt that regular recombination is suppressed in the presence of semi-lethal t-alleles just as it is in the case of fully
lethal alleles.
Sterility of m a h hornmygous for semi-lethal alleles: Fertility tests for males
homozygous for alleles tWz,tZUs
and tWS6
and of selected compound genotypes were
t-ALLELES IN
41 7
MOUSE P O P U L A T I O N S
made. No homozygotes f o r twJ9are included because none survived to maturity
in sufficientlyhealthy condition for a valid fertility test. A total of 33 males were
tested, with a total of 421 mating units, and no offspring were obtained. Males of
these genotypes can thus be considered to be unequivocally mating sterile.
Comparisons among the semi-lethal alleles: The breeding tests show that the
semi-lethal alleles derived from different wild populations, like the wild lethal
alleles, resemble each other in having high male transmission ratios, in suppressing recombination in the vicinity of locus T , and in giving rise to exceptions
which in four cases contained viable alleles differing from the parent allele.
Other breeding experiments were carried out to elucidate the differences
amongst the semi-lethal lines in the degree of viability of homozygotes. These
consisted of intercrossing tailless animals from the different balanced semi-lethal
stocks and comparing the viabilities at birth of compounds such as tW2/tWS6
and
twor/twz
and tWS6/tWSG.
The offspring observed at birth from these cross tests are
shown in Table 5 together with estimates of relative viabilities of the normaltailed compounds, i.e. the percent of the expected viability which was realized.
For comparison, the viabilities of normal-tailed animals homozygous for each of
the semi-lethal alleles are repeated from Table 2.
Although the data are rather meager, there is a clear indication that the viability of compounds carrying alleles from different semi-lethal stocks is higher
than the viability of normal-tailed animals homozygous for the same semi-lethal
allele. Thus 65% of the expected number of tWS6/tWP
animals survive until birth
The viability of comas compared with 51% for twz/twzand 20% for tw366/tW86.
is strikingly higher than any of these
pounds containing twA9and either tW8or tWS6
when homozygous. Although individual differences are of doubtful significance,
statistically, there is a strong suggestion of some degree of complementary interaction amongst the semi-lethal alleles. The criterion of complementarity has
served to discriminate amongst lethal alleles of different origins and has been
confirmed by the finding of differences in embryological effects (BENNETT1964).
Thus complementarity if confirmed would suggest different origins for the semilethals.
Another set of comparisons amongst the semi-lethals was made by combining
each one with certain lethal alleles and estimating the viabilities of the different
compounds so formed. The results of these cross tests are shown in Table 6. The
TABLE 5
Offspring obserued at birth from crosses between different balanced semi-lethal tailless stocks
O t = tailless offspring; nt = normal-tailed offspring; v% = percent viability of nt.
Alleles
T/ZW*
T/iws6
T / P S
Ot
nt
Y%
51
13
5
. . . .
50
12
T/tw36
..
..
T/W9
..
T/tWz
T/W
. . . . . .
. . . . . .
Ot
nt
Y%
57 32 65
64 1 1 20
. . 20
. . . . . .
.,
Ot
8
38
14
T/t"r9
nt v%
3
..
10 28
8 57
. . . .
2
418
DOROTHEA BENNETT A N D L. C. D U N N
TABLE 6
Offspring observed at birth from crosses between balanced semi-lethal and lethal tailless stocks
O t = tailless; nt = normal; v% = percent viability of normal.
T/tO
Semi-lethal
alleles
Ot
50
220
175
51
T/tW2
T/tw8
T/tW36
T/W9
nt
v%
12 27
17 10
13 8
19 39
Ot
Lethal alleles
T/t9
nt v%
T/t”5
nt v %
Ot
50 23 48
69 45
68
T/tIZ
nt v%
ot
T/tW1
nt v%
146 34 31
23
42
15 71
15 47
Ot
24 22 100
28 24 89
most instructive comparisons are those in which each semi-lethal allele was combined with the same lethal, to. Here tm8and tW36interact similarly with to,the
compounds showing little complementation. A to allele seems to be roughly
equivalent in compounds to another tW8or tWS6allele. One should thence expect
to have similarly low viability. In fact (Table 5 ) it is as low
the compound tW8/tW36
as
(20% ) . The viability of tW2
is lowered by combining it with to,whereas that
of t1u49 is greatly increased, suggesting similarity of tW8and tW36but difference
and t w A 9 . The allele tWJgwas combined with each of the five
among these two, tW2
different lethals and showed strong complementation effects with each one, but
the different lethals, as might have been expected, showed quantitative differences
when combined with tW”.As judged by complementation interaction, tw49is most
unlike the other semi-lethals, and also differs from all the lethals.
Embryological observations: Table 7 presents data from 56 litters containing
tZUj6
homozygous, 122 litters from the t W h 9 stock and 54 litters containing t2056/tW49
compounds examined at 14-16 days of gestation.
TABLE 7
Embryological comparison at 1 4 , 1 5 , and 16 days gestation of embryos found on dissection of
litters from matings of animals heterozygous for semi-lethals
Mating
+/tw36
T/P6
+/tW49
X +/tWS6
number
x T/tw361 percent
x +/t“49 number
percent
+/tw36
x +/tw4g number
T/ttuS@x T/tW4Q percent
3
Embrvos
”ma1
hIoles
Placentae
630
325
52
489
51
326
60
128
20
286
30
93
17
37
6
36
4
46
954
547
8
Dead
abnormal
embryos
Living
abnormal
embryos
39*
113
18
67
7
70
13
5
76**
8
17**’
3
* 2 dead at 11 days, 19 at 12 days, 9 at 13 days.
* * 13 dead at 11 days, 43 at 12 days, 6 at 13 days, others later.
* * * 2 dead at 11 days, 8 at I2 days, 7 at 13 days.
Description of headings: “Moles”: resorbing decidual capsules, whose embroys have died after
implantation but before placentation, “Placentae”: placentae attached to necrotic embryonic
membranes, indicating that the embryo therein had survived at least to 10% or 11 days, the time
of placentation. “Dead abnormal embryos”: embryos which were dead but not yet too macerated
to prevent morphological description. “Living abnormal embryos”: embryos either retarded in
development, smaller than their litter mates, or grossly abnormal.
419
t-ALLELES I N MOUSE POPULATIONS
It is obvious that all three groups have suffered considerable mortality by this
time. Several interesting points emerge from this table. First of all, in litters
segregating for tw49or tWS6homozygotes, only 51% and 52% respectively of
embryos are classified as normal. This fits almost precisely the expected proportion of normal (+/+ or + / t ) genotypes expected from these matings. It is therefore probable that essentially all t-homozygotes are recognizably abnormal by
this time. However, it is interesting to note that the distribution of deaths in time
is different in the two genotypes, with tlUh9 homozygotes dying a t earlier stages.
There is thus correspondence between the quantitative degree of lethality and the
severity of effect in the embryo, although as will be shown below the types of
abnormalities found are qualitatively the same in the two genotypes. The crosses
between twh9 and tW56indicate some degree of complementation. Sixty percent of
embryos here are classified as morphologically normal; since only roughly 50%
are expected to be genotypically normal this group presumably includes some
tZVy6/tZ”49
compounds which are fully viable and normal. In all three crosses, however, it is remarkable that in the group of embryos which were dead but still
recognizable, the great majority appear to have died at about the 12-day stage.
This period obviously represents some critical point in development, for these
abnormal genotypes at least, but the reason for it is not obvious.
The types of abnormalities detected in the group of living abnormal embryos
express various degrees of otocephaly. The distribution of grossly evident abnormalities is given in Table 8.
Most of the malformations seem to be based on reduction of forebrain size. The
most extreme otocephalics seen had essentially no forebrain at all, with the brain
ending at the level of the midbrain and the head being jawless. I n these cases
there was ear migration ventrally, with occasional midline fusion of the external
ears. In some embryos there was a fleshy proboscis studded with vibrissa1follicles.
Otocephalics of lesser degree usually had a proboscis, apparently derived at least
in part from the diencephalon, since it usually contained elements of the eye,
fused into a single cyclopean structure. Anophthalmia and microphthalmia were
frequently seen, often without an extremely obvious reduction in brain size. A
number of embryos showed exencephaly, with failure of cranial neural fold
fusion anterior to the hind brain; this condition was usually found in brains of
apparently normal proportions although twice it was detected in embryos with
moderate otocephaly. Another anomaly irequently seen, but not obviously related
TABLE 8
Distribution
Genotype
tW36/t7036
tW49/tW49
/
t W 5 6 tw49
of
abnormalities in the “Living Abnormal” group at 14,15,16 days gestation
Total
observed
113
67
70
UniBi“Small”
lateral
lateral
and/or microph- microph- Anophretarded thalmia thalmia thalmia Cyclops
92
41
54
5
4
7
1
2
2
2
2
3
Exencephaly
Moderate Extreme
otootoVisceral
cephaly cephaly hernia
5
4
4
4
6
5
6
7
2
1
9
420
DOROTHEA B E N N E T T A N D L. C. D U N N
to the head abnormalities discussed above, was herniation of heart, liver, and
lungs through the open abdominal wall. With rare exception all embryos showing
major malformation were also small in size and often retarded in developmental
stage.
One other point emerges from table 8 which makes the basis for the complementation apparent between t2049and tW36difficult to assess. Both the breeding
records at birth and the embryological data indicate quite unequivocably that
tW36/tW49
animals are more viable than either twhgor tZuS6
homozygotes. Yet Table 8
embryos observed 30 had grossly visible
shows that of 70 living abnormal tW4g/t".U36
morphological abnormalities, compared to only 21/113 for the less viable genotype tw36/tWSG.
The former proportion is, in fact, almost exactly the same as the
very lethal genotype tW4gg/tW49
which had 30 morphologically abnormal out of a
total of 67 observed. In other words, although the genotype tw49/tW36
as a whole
is more viable than either homozygote, the embryos which do develop abnormally
seem to be more severely affected.
DISCUSSION
The first studies of a newly diagnosed category of alleles at the complex T-locus
have given the opportunity for reconsidering several questions about mutations
in this region (cf. also BRUCK1967). These concern (1) the genetical structure
of this region of the ninth linkage group within which some 100 changes have
been identified; (2) the relations among the semi-lethal alleles in their effects on
embryonic development; (3) the fate of semi-lethal variants in natural populations and their relation to the adaptive significance of this region.
The last-named question will be discussed elsewhere in connection with studies
of analog populations computed with assumptions concerning fitness of homozygotes like those reported here (cf. LEWONTIN
1968). Here it should be emphasized
that semi-lethal t-alleles with the properties of low viability, high male transmission ratio, recombination suppression and sterility of surviving male homozygotes have been found only in wild populations. Their persistence in wild populations is presumably due to their high male transmission ratios, as in the case of
the lethal alleles which they closely resemble.
A feature of special interest in relation to the first question above concerns the
differences and similarities found among the four semi-lethals. These bear on
the important problem whether they represent four different genetical changes.
The fact that each semi-lethal was found in a different wild population and that
these were as widely separated as New York, Virginia and the Canadian province
of Alberta does not by itself indicate independent origins of the four. Some lethal
t-alleles from distant populations have proved to be indistinguishable and those
may trace to the same genetic event with later dispersion of descendants of the
original variant. Whether the semi-lethals are to be considered as the same or
different will thus depend, as in the case of the lethals previously studied
(BENNETT1964), upon the comparison of their phenotypic effects and upon the
degree to which they complement each other's effects when combined in compounds tn/tx.
t-ALLELES I N
MOUSE POPULATIONS
421
The most striking differences are the quantitative ones in relative viability over
the range 1.7, 12, 20 and 51%. These are indeed wide differences but by themselves not decisive for the question since it is known that viability is subject to
variation by factors other than the particular combination of t-alleles. KLYDE(in
manuscript2) has shown that such factors may, by selection, alter viabilities over
a range of 20% or more when the t-allele combination is held constant.
In apparent contrast to these quantitative differences among the semi-lethals
are some general resemblances in the morphological abnormalities found in the
dead or dying homozygous embryos in each of the four lines. The defects seen in
each line and in compounds of alleles from different lines are largely restricted
to those which might be engendered by either reduced quantity of forebrain
material or by defects in inductive competence or inductive stimulus in that
region. (A detailed discussion of these abnormalities in one of the lines ( t W Bis) in
the dissertation of R. M. BRUCK1967.) I n this sense, the semilethal alleles may
be members also of the series formed by the lethal alleles already described at
this locus. The effects of each of these can be attributed, at least theoretically
(BENNETT1964), to failure to pass successfully through some critical period in
which there is a requirement for completion of a major step leading to increased
differentiation of ectodermal or neural tissues. The same defects seen in homozygotes of semi-lethal alleles have been regularly found in compounds of two different lethal alleles such as tO/tl* (SILAGI1962) and t o / P (KLYDEin manuscript).
The repeated finding of features of the syndrome known as otocephaly (WRIGHT
1934) in compounds of lethals (e.g. DUNNand GLUECKSOHN-SCHOENHEIMER
1939) and now in homozygotes and compounds of semi-lethals in this region, is
further evidence that the chromosomal aberrations responsible for all of those
mutants which suppress recombination within this region have some altered or
deficient region in common.
At the same time differences in effects of different lethals, and now differences
at least of degree, among the semi-lethals suggest a considerable complexity of
the many aberrations found in this region. No decisive indications of the nature
of this differentiation within the region is given by the analysis of the semi-lethals.
We hope to return to this problem in later publications.
SUMMARY
A category of semilethal t-alleles is described based on studies of four alleles
each derived from a heterozygote found in a wild population. The viabilities of
homozygotes until birth range from two to 51 percent. All suppress recombination
in the t-region, and have high transmission ratios through sperm from heterozygotes. The surviving male homozygotes are entirely sterile. The effects of all four
on embryonic development included otocephaly and failure to complete diff erentiation of ectodermal or neural tissues. It is assumed that they are caused by aberrations within a segment of chromosome IX having some defect in common with
each other and with lethal mutations in this region.
2
We are grateful to Mr KLIDE for pennission to quote from his unpublished results.
422
DOROTHEA BENNETT AND L. C. DUNN
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