CONSEQUENCES
OF CHROMOSOMAL
IN MAMMALS
ABERRATIONS
N. S. FECHHEIMER
The Ohio State University, 1 Columbus
time at which to view the chromosomes; the
development of facile cell and tissue culture
techniques, particularly one developed by
Moorhead et al. (1960) enabling the study of
an animal's chromosomes from a sample of
blood; the discovery by Barr and Bertram
(1949) of a heterochromatic mass (sex
chromatin) in the nuclei of interpbase cells
of females in some mammalian species that
was subsequently shown to be associated with
a second X chromosome in a cell (Lyon,
1962). More recent innovations have made it
possible to distinguish between pairs of
chromosomes that are morphologically similar
by enhancing the appearance of secondary
constrictions (Saksela and Moorhead, 1962)
or by distinguishing on the basis of the time
in the DNA synthesis period at which individual chromosomes replicate (German,
1964; Chicago Conference, 1966).
E F O R E the rediscovery of Mendel's principles of the breeding behavior of genetic
factors at the turn of the 20th century, cytologists had already described how chromosomes
behave at mitosis and meiosis. The very careful pattern of chromosomal distribution at
meiosis, their particulate and duplex nature,
and universal occurrence were the characteristics that made them easily recognizable as
the vehicles in which hereditary factors are
transmitted from one generation to the next.
With this insight, the science of cytogenetics
had its birth. Some idea of its growth is obtained when one realizes that by 1950 the
chromosomes of over 3,000 species of animals
had been studied (Makino, 1951). Critical
observations of mammalian chromosomes were
precluded for technical reasons so that only
154 mammalian species had been studied by
1950.
None the less, the very extensive study of
cytogenetic phenomena in plants (Burnham,
1962) and the lower animals (White, 1954)
demonstrated that variation in chromosome
number and morphology both within and between taxa was widespread. Such variations
would appear to indicate that alterations of
the chromosomal set by aberration must be of
importance in evolutionary changes in the
long run and must be responsible for a good
deal of reproductive inefficiency in the short
run.
During the last 15 yr. certain technical
achievements have made it a relatively simple
matter to prepare mammalian cells so that
critical observations of their chromosomal
complement can be made. Notable among
these achievements are those of Hsu and
Pomerat (1953) who discovered that prefixation treatment of cells in a hypotonic solution
enlarged the cell so that the metaphase
chromosomes were more widely dispersed;
adaptation of the method of treating cells
with certain drugs, most notably colchicine
and its derivatives, in order to arrest the
mitotic cycle at metaphase, the most suitable
B
Classification of C h r o m o s o m a l
Aberrations
Before proceeding with a discussion of the
etiology and effects of aberrations it is necessary to describe the phenomena that give rise
to them and the results of the various phenomena on the chromosomal complement of
a cell, cell line or organism. Set out in figure
1 is a classification of the types of aberrations that are most likely to be encountered
among mammals, the more complex types having been left out of the classification because
they would be extremely difficult to diagnose
and would in all probability lead to death
very early in ontogeny.
Heteroploidy
Employing the terminology adapted by
Beatty (1957) heteroploidy refers to any deviation from the orthoploid number of whole
chromosomes, i.e. diploid somatic cells and
haploid gametes. Euploid cells are those that
contain a chromosome number that is a whole
number mvltiple of the basic or haploid number. Polyploidy constitutes whole number
Department of Dairy Science, Animal Reproduction Teaching and Research Center.
27
FECHHEIMER
28
OF
CLASSIFICATION
CHROMOSOMAL
ABERRATIONS
NUM ERICAL ABERRATIONS
~ "
(HETEROPLOl DY)
EUPLOI DY
I-tAPLOIDY
AN EU PLOI DY
POLYPLOIDY
HYPODIPLOIDY HYPERDIPLOIDY
ODiy ~ T ~ E r
TR,PL
I
~
C
MONOSOM,C
TR,SOM,C
TETRAP LOI DY
I
DOUBLE
I
DOUBLE
HYPO-AND
HYPER POLY PLOIDY
tETRASOM,C
MONOSOMIC TRISOM IC
STRUCTURAL ABERRATIONS
(CHROMOSOMAL REARRANGEMENTS)
ONE BREAK
DELETION
TWO BREAKS
ISOCHROi~,OSOME
IN SAME CHROMOSOME
MORE THAN TWO BREAKS
IN SEPARATE CHROMOSOMES MANY POSSIBILITIES
(TERM, NAL)
DELFTLCN
(1NT ERSt ITIAL)
f
PARACENTR,C
I N V E R S I O N R,NG
~
CHROMOSOME
l
AND FRAGMENTS
PERICENTR'C
RECIPROCAL
TRANSLOCATION
~ ~ _
OTHER MORE
COMPLEX CONSEQUENCES
J
EACH NEW CHROMOSOME
WITH CENTROMERE
DICENTRIC CHROMOSOME
PLUS ACENTRIC FRAGMENT
MULTIPLE ABERRATIONS
IN SAME CELL LINE
TWO OR MORE
H ETEROPLO~ D
ABERRATIONS
IN SEPARATE CELL LINES
TWO OR MORE
NUMERICAL AND
STRUCTURAL
STRUCTURAL
ABERRATIONS ABERRATIONS
DIFFERENT
H ETEROPLOI D
ABERRATIONS
DIFFERENT
STRUCTURAL
ABERRATIONS
NUMERICAL AND
STRUCTURAL
ABERRATIONS
MIXED CELL POPULATIONS
J
J
J
MOSAICS
(CELL LINES DERIVED FROM
TWO GAMETIC PRODUCTS)
NORMAL AND
ABERRANT LINE
TWO
ABERRANT LINES
CH I M ERAS
(CELL LINES DERIVED FROM
TWO OR MORE ZYGOTES)
MORE THAN
TWO LINES
TWO NORMAL
CELL LINES
NORMAL AND
ABERRANT LINE
TWO
ABERRANT
LINES
Figu e 1. Classification cf ch.omosomal aberlations.
multiples of three or more; thus a cell can be
triploid (contain three of each of the haploid
set), tetraploid, etc. Polyploidy can be brought
about in a number of ways, the most common
apparently being the production of diploid
gametes, polyspermy and endomitosis of
somatic cells.
Aneuploidy is any chromosomal complement
that is not euploid. It is composed, therefore,
of all deviations in numbers of whole chromo-
CHROMOSOMAL ABERRATIONS
somes that are fractional multiples of the
haploid number. Dealing only with aneuploid
types that are near the diploid complement,
i.e. peridiploids, one can categorize them into
hyperdiploid, those with no more than a few
elements in excess of the diploid, and hypodiploid, those with one or two elements
less than a diploid. The categories that appear to be of p r i m a r y importance in mammals
are those that have one excess chromosome,
called trisomics because they will contain
three representatives of one particular chromosome, and monosomics which have a deficiency of one whole chromosome. Trisomics
can arise as a result of non-disjunction at
either of the two meiotic divisions or at a
mitosis. A disomic gamete would be the outcome of non-disjunction at one meiotic division and when the disomic gamete engages in
s y n g a m y with a normal gamete, a trisomic
zygote results. The complementary cell product from a non-disjunctional event will lack
one whole chromosome and consequently will
result in a monosomic condition. Monosomy
can arise also b y the lagging of a chromatid
at anaphase so that it does not beceme included in the nucleus of one of the daughter
cells following cell division.
Structural Aberrations
Rearrangements of the chromatin material
within or between chromosomes and semet~mes
involving the duplication or deletion of parts
of chromosomes must ultimately be preceded
by breaks in the chromosomes. If only one
break occurs and if the break is not through
the centromere, the segment that is acentric
will lag at a subsequent cell division and the
resulting cell line will contain a chromosome
with a deletion, i.e. it will be p a r t i a l l y monosomic. Should the break occur in such a w a y
that both fragments contain a piece of centromere sufficiently large to direct their anaphase
movement, isochromosomes will be formed.
An isochromosome is one composed of two
arms that are genetically identical. A cell
containing one isochromosome but not the
complementary one will be trisomic for the
genes on the duplicated arm and monosomic
for the genes on the complementary arm.
W h e n two chromosomal breaks occur simultaneously in the same cell the outcome depends upon where the breaks are located and
how the four broken ends fuse with one another. If both breaks are in the same chromosome the two terminal segments m a y fuse
and if one of these contains the centromere
29
a deletion will result. Another possible outcome is that the interstitial segment becomes
reversed 180 ~, and its two broken ends then
fuse with the broken ends of the terminal
segments. The result is a chromosome with
an inverted segment. The third possibility is
fusion of the two end,s of the interstitial segment to form a ring.
W h e n one break occurs in each of two different chromosomes, fusions of broken ends
can take place in two new ways. The most
interesting in terms of its genetic consequence
is exchange of segments between two chromosomes, i.e. a reciprocal translocation, in such
a w a y that each of the new chromosomes contains a centromere. Although it m a y seem
that the p r o b a b i l i t y of the occurrence of three
or more breaks in one cell would be extremely
low, such would not necessarily be the case
if a cell is in contact with an agent that
causes breaks. T h u s in neoplastic tissue, the
indications are that manifold events are taking place and all the expected consequences
are to be seen.
A n y of the aberrations discussed so far can
occur at any time in the life cycle of the
organism. The proportion of cells in an organism that will contain an a b e r r a n t genome
depends upon when in the life cycle the aberration producing event occurred and, of
course, the viability of the a b e r r a n t cell line.
When carried in a gamete, the aberration will
be found in all the cells of the zygote. On t h e
other hand, when the aberration has its origin
at a mitotic division, the organism will be composed of at least two distinct cell lines and in
those cases where, as in the case of non-disjunction, complementary cell products arise,
three or more cell types m a y be found in the
same zygote. An organism composed of two
or more different cell lines all of which were
derived from one fertilized ovum are called
mosaics and should be distinguished from
chimeras, a term that refers to a zygote also
composed of more than one cell line b u t in
which the different lines were derived from
separate products of fertilization.
V a r i a b l e E f f e c t s of A b e r r a t i o n s
The effect t h a t a given chromosomal aberration will have on an organism is dependent
upon a number of factors, some of which are
interdependent. Quite obviously, aberrations
that involve the loss of a large amount of
chromatin from all the cells of a zygote in all
probability would cause a serious disruption
in its ontogenesis. F o r this reason, monosomy
30
FECHHEIMER
for an autosome in mammals is a very rarely
seen event even in young embryos, and trisomy of a large autosome ordinarily results in
embryonic death. Polyploidy too, when it involves all the cells of the zygote so interferes
with normal development that death by midterm of pregnancy is the usual, if not invariable outcome. Duplication or deletion of a
small proportion of the genome is less lethal,
depending upon the importance of the
processes directed by the genes that have been
added or removed. Removal of segments of
heteroehromatin, relatively genetically inactive chromosomal material, can be tolerated
to a greater extent than the removal of chromosomal segments of equal size but containing, per unit length, more genetic loci. The
degree to which a given aberration gives rise
to a major switch in the epigenetic pattern
depends upon its magnitude and genetic activity.
Some aberrations, while they involve no
changes in the genome of the original bearers,
cause irregularities of meiosis so that secondary and more severe aberrations are contained in some of the gametes produced. Two
non-homologous chromosomes that have been
involved in a reciprocal translocation for instance may form a tetravalent with their
homologues at the first meiotic division. Four
kinds of gametes are then produced; two of
which will contain a complete haploid genome
and two of which will each contain a duplication and a deletion. In similar fashion polysomics, polyploids, inversions, deletions and
duplications in addition to translocations, all,
under some circumstances, can be the direct
cause of secondary aberrations. For this reason the over-all effect of an aberration on
the fitness of a population cannot be totally
assessed without a great deal of work with a
number of generations.
The later in embryogenesis that an aberration first appears, the more attenuated will
be its effect on the organism. If organogenesis
is well under way or nearly completed, the
genome of only a few cells may be affected
and these may be confined to only one tissue.
Conversely if the event occurs very early,
perhaps even in the fertilized ovum, it will
be transmitted, by mitosis, to all the cells of
the developing organisms and its full effect
upon epigenesis will be observed. In fact,
by looking at the degree of mosaicism in
tissues derived from the three embryonic germ
layers, it should be possible to ascertain at
about what stage of development the aberra-
tion had its origin. In the case of those events
that are so severe that they render the cell
in which they are found incapable of subsequent mitosis, it is also clear that the phenotypic effects will vary with the time of occurrence.
There are a number of mechanisms in the
ontogenetic process that in some circumstances will vitiate some of the effects of a
chromosomal aberration. Beatty
(1957)
pointed out that only a very small proportion
of the cells in the inner cell mass in fact contribute to the embryo itself; most of them
contribute only to embryonic membranes
and placenta. Therefore an aberrant cell line
could well develop and yet not play a direct
part in infll;encing embryonic development.
While little effect is to be expected from
deletions containing little genetic activity, i.e.
heterochromatic regions, a number of mechanisms are known that regulate the amount of
product prodt'.ced by a given locus regardless
of whether the locus is represented once, twice
or even more frequently in the genome. One
of these so-called dosage compensation
mechanisms, the condensation and partial inactivation of all X chromosomes in excess of
one per diploid genome (Lyon and Meredith,
1966), can be viewed as a device by which
the otherwise harmful effects of some X
chromosome aberrations are vitiated in mammalian females. The Lyon hypothesis as
originally stated posited that at the time of
inactivation of the excessive X chromosome(s), whether the matroclinous or patroclinous one was inactivated in given cell (and
subsequently in all descendants of each), was
a random event. However, it now appears
that when an aberrant X is present it is preferentially inactivated leaving the majority of
cells with the normal X chromosome fully
functional. Individuals monosomic or trisomic
for the X chromosome are not nearly so handicapped as those possessing comparable aberrations of other elements of the same length.
Indeed, both XO mice and X X X wemen are
phenotypically normal, fertile females.
Many types of aberrations cause difficulty
only at meiosis, mitosis proceeding normally.
Obviously those organisms that can propagate
asexually can accommodate these much more
easily than those that are obligatorily sexual.
Another biological device that tends to protect
against secondary aberrations particularly is
the dispersal of centromere activity to more
than one short region of the chromosome. In
species where this has been accomplished,
CHROMOSOMAL A B E R R A T I O N S
chromosomal breaks and fusion of ends producing dicentric and acentric elements need
produce little harmful subsequent consequence.
Finally, it should be pointed out, the effect
and therefore the eventual fate of any given
aberration depends upon the extent to which
it influences the fitness of its bearer. Newly
created chromosome complements, for the
most part, do not increase the fitness of the
organism in which they appear because the
full line of all the ancestors of any individual
have been subjected to the forces of natural
selection, preserving and increasing those
genomes that are best adapted. As the environment changes, however, the genetic requisites
required to preserve fitness also change so
that occasionally a chromosomal aberration
will be of aid in the adaptation of a species in
a new environment. In this circumstance it
will increase in frequency to an equilibrium
value also determined by natural selection.
It is clear from this that one factor determining the effect of a given aberration depends
upon when and where it is produced.
Etiological A s p e c t s
Many genetic and environmental factors
have been more or less implicated as agents
that influence the frequency of occurrence
of chromosomal aberrations. Although the list
discussed here, and summarized in table 1, is
not all inclusive, it is sufficiently extensive to
suggest that the situation is a complex one,
particularly if one is thinking in terms of
finding the means to reduce the incidence of
aberrations in a given population. On the
other hand those investigators who wish to
use aberrations for genetic studies of mammalian species will see that they can be produced experimentally in a number of ways.
Parental Genotypes
That both mitosis and meiosis, being complex biological processes, relatively stable yet
subject to evolutionary modification, are under
genetic control has been demonstrated many
times in plants and lower animals (Riley,
1966). Examples of the evidence available
are the studies of Gowen (1933) of a recessive gene in Drosophila merlanogaster that
restricted the amount of crossing over in
primary oocytes, allowing bivalents to separate precociously and resulting in a high frequency of nullosomic and disomic or diploid
ova. A recessive gene in D. ttydei blocks the
31
formation of the mitiotic spindle thereby giving rise to polyploid cells (Gloor and Staiger,
1954).
In mice, it has been shown by Fischberg
and Beatty (1950) that the incidence with
which heteroploid embryos were produced was
dependent upon genetic differences in parental
(particularly maternal) strains. Descendants
of the group that had the highest incidence
of heteroploid embryos, when subsequently
studied for other purposes, were found to
possess a significantly higher incidence of
polyploid spermatogonia than other lines
(Fechheimer, 1961). When the frequency was
ascertained of different types of aneuploid
cells derived from inbred and outbred sons
of seven inbred Hereford sires, it was seen
not only that sire lines differed in the type
of heteroploidy that predominated, but when
the inbred groups alone were compared, the
differences were enhanced (Zartman and
Fechheimer, 1967). Anomalies of fertilization
leading to triploidy of embryos also appear
to be under partial genetic control. The evidence, consisting of strain differences, in mice
and rats, of incidence of polyandry, polygyny
and aneugamy was reviewed by Austin
(1960). Among the large number of recent
cytogenetic studies of human families are
some in which it is indicated that there exists
a tendency for the clustering within families
of zygotes bearing chromosomal aberrations
(Dekaban et al., 1963; Miller et al., 1961;
Hauschka et al., 1962). Even more s t r i k i n g
is the report of German and Archibald (1965)
wherein they show that chromosomal breaks
occur with high frequency in individuals afflicted with a rare and probably simply inherited syndrome. It can be concluded that
genes play an important role in determining,
within populations, the rate with which
chromosomal aberrations occur. Although too
little work has so far been done with mammals
to ascertain the importance of genetic variation as an etiological factor, certainly enough
is known to indicate that it must be taken
into account in cytogenetic investigations.
Ionizing Radiation
One well known effect of radiation is that
it causes chromosomal breaks. After chromosomes are broken the broken ends have a
propensity to fuse. When fusions occur they
frequently bring together chromosomal segments in new combinations. As a consequence,
many kinds of aberrant chromosomes are
formed including inversions, translocations,
32
FECHHEIMER
TABLE 1. SUMMARY OF ETIOLOGICAL AGENTS OF CHROMOSOMAL ABERRATIONS
Agent
Effect
Reference (review or key)
1. Genes
Breakage of chromosomes
Non-disiunction
Aneuploidy
Polyploidy
Meiotic events controlled
German and Archibald (1965)
I-lauschka et al. (1962)
Zartman and Fechheimer (1967)
Beatty (1957)
Riley (1966)
2. Ionizing radiations
Breakage of chromosomes
Polyploidy
Non-disjunction
Kihlman (1961)
Millard (1965)
Griffen and Bunker (1964)
Polyploidy
Polyploidy
Polyploidy, others
Breakage of chromesomes
Breakage, somatic pairing
Breakage of chromcsomes
Eigsti and Dustin (1955)
Jackson and Lindahl-Kiessling (1963)
Ingalls et al. (1963)
Cattanach (1961a, 1965)
Cohen et al. (1967)
Kihlman (1961)
4. Viruses
Breakage of chromosomes
Non-disiunefion
Loss of chromosome
Nichols (1966)
Nichols (1966)
Burdette and Yoon (1967)
5. Maternal age
Meiotic non-disjunction
Cohen et al. (1963)
6. Age and physiological state
Polyploidy of somatic cells
Chromosomal breakage
Loss of sex chromosome
Swartz (1960)
Crowley and Curtis (1963)
Court Brown et al. (1964)
7. Temperature shock
Polyploidy
Beatty (1957)
Polyploidy
Aneuploidy (non-disjunction)
Uncertain-indirect evidence only
Austin (1960)
Witschi and Laguens (1963)
Salisbury (1965)
Non-disjunction
Day (1966)
Non-disjunction
Day (1966)
10. Autoimmunity
Non-disj unction
Engel and Forbes (1963)
11. Primary aberrations
Chromosome breakage
Aneuploidy
Burnham (1962)
3. Drugs and other chemicals
(a) alkaloids
(b) metabolites
(c) teratogens
(d) mutagens
(e) psychodelics
(f) many compounds
8. Aging of gametes
(a) ova
(b) sperm
9. General environment
(a) non-randomness
in time
(b) non-randomness in
geographical area
dicentric chromosomes, acentric fragments and
ring chromosomes. I t appears that there is
no threshold below which no breaks are produced, b u t that the number of breaks is directly related to the dose applied (Brewen,
1962).
Certain types of aberrations caused by
breaks and fusions are not stable in that they
bring about severe alterations in the process
of cell division. When aberrations of this
kind are produced, no cell lines containing
them can develop. However, aberrations with
less severe effects are propagated and in fact
some may even possess a selective advantage,
reproducing at a more rapid rate than normal
cells. Individuals that were subjected to irradiation have been studied for months and
years following cessation of treatment in order
to ascertain the cause of events. Immediately
following irradiation, there is a short interval
during which the proportion of cells exhibiting chromosomal damage at mitosis decreases.
Presumably this decrease reflects the selection against the most severe types of aberrations (Chelebovsk39 et al., 1966). The frequency of aberrant cells, except in embryos
CHROMOSOMAL A B E R R A T I O N S
(Soukup et al., 1965), then appears to increase
for time periods extending to months (Chlebovsky et al., 1966; Millard, 1965).
Apart from their direct effects on the chromosomes, ionizing irradiations also appear to
affect other parts of the cell, thereby interfering with the normal course of mitosis. Accordingly, the frequency of polyploidy increases following irradiation (Millard, 1965).
Perhaps the frequency of non-disjunction at
meiosis is also affected (Griffen and Bunker,
1964). For the geneticist, radiation of the
gametogenic cell line to produce aberrations
can be a powerful tool in helping elucidate
their consequences (Lyon and Meredith,
1966).
Drugs and Other Chemicals
A multitude of chemical agents have been
shown to influence the rate of occurrence of
chromosomal aberrations. One large group,
the radiomimetic drugs exhibit effects similar
to ionizing irradiation. Colchicine and its
derivatives act on the spindle to inhibit the
anaphase movement of chromosomes, inducing
the production of polyploidy (Eigsti and
Dustin, 1955). Other, unrelated compounds
have been used to produce a similar effect;
some are even normal metabolites of mammalian cells (Jackson and Lindahl-Kiessling,
1963). Some teratogenic substances produce
a high rate of aberrations both in embryos
and in some tissues of the dams carrying the
embryos (Ingalls et al., 1963). Cattanach
(1961b, 1964, 1965) has used one mutagenic
compound to treat male mice subsequently
used as breeders. He has recovered from
among their progeny a number of translocations and autosomal trisomics.
The primary action of some of the most
effective herbicides in common use today is
mitogenetic and although little appears to be
known about the cytological effects of pesticides, other herbicides, food preservatives and
many components of industrial wastes found
so abundantly in air and water, it is safe to
predict that many will be found to possess
aberration producing properties.
Viruses
A rapidly growing body of evidence, recently reviewed by Nichols (1966) clearly
implicates viruses from many groups as etiological factors in the production of chromosomal aberrations. Interest in the role of
viruses stems not only from their appearance
33
in neoplastic tissue that also exhibits a high
incidence of aberrations (Nichols et al.,
1964), but also in their possible role as producers of aberrations causing congenital malformations of infants (Valenti, 1965). It has
been well established that the presence of some
virus lines causes chromosomal breaks when
assayed either in vivo or in vitro and may
also be associated with non-disjunction or
events causing chromosomal loss from cell
lines. Of perhaps greater importance is the
finding of Burdette and Yoon (1967) that
Drosophila raised on a medium to which has
been added concentrations of Rous sarcoma
virus, sired progeny among which a significantly increased frequency of aberrations was
found. Aberrations for which their system
tested were loss of the Y chromosome, nondisjunction and translocations. No virus could
be isolated from afflicted offspring, indicating
that the aberrations were probably contained
in the sperm.
Maternal Age
Particularly in respect to the incidence of
trisomy in man, a striking association with
the age of the mother exists. While the over-all
frequency of trisomy-21 is about 0.15%
among human neonates, (Cohen et al., 1963;
Miller and Dill, 1965) its frequency among
those born to mothers at age 40 yr. and over is
in excess of 1.0%. Similar but less striking
findings have been reported for the other
autosomal and sex chromosome trisomies of
man. Goodlin (1965) was unable to demonstrate increased aneuploidy in mice born to
older dams. Whether this species difference
is real or reflects only the attribute of the
stock used by Goodlin remains to be established.
Age and Physiological State
Ris and Mirsky (1949) and Swift (1950)
established that some mammalian tissues including the liver and pancreas contained nuclei with amounts of DNA equivalent to that
expected in tetraploid and octaploid cells.
Although such multiple DNA class cells are
absent or infrequent in the very young animal,
tetraploid cells begin to accumulate at the
age of puberty and octoploid ones at sexual
maturity (Swartz, 1956). The development of
polyploidy can be retarded by castration
(Swartz et al., 1960), thyroidectomy (Swartz
and Ford,
1960), hereditary pituitary
dwarfism (Leuchtenberger et al., 1954) as
34
FECHHEIMER
well as other factors that alter the physiological state of the animal (LeComte and
De Smul, 1952). The appearance of polyploid
classes of cells in some frogs is correlated with
the onset of the breeding season (Bachmann
et al., 1966).
Intrachromosomal aberrations in somatic
tissues increase with age and it was shown
by Crowley and Curtis (1963) that they increase more rapidly in strains of mice with
long life expectancies than in those with
shorter life spans. From these and other data,
Curtis (1963) hypothesized that the accumulation of aberrations in tissues with low mitotic rates is an important causative factor in
the aging process. In man, the process of agin~
appears to be accompanied by an increased
frequency of aneuploid leukocytes attributable primarily to a loss of one X chromosome
in females and to the loss of the Y from male
subjects (Court Brown et al., 1966). The
phenomenon was reported to be detectable at
an earlier age in the females and to achieve
a higher frequency than in males.
Temperature Shock
Although temperature shock has been used
experimentally with plants and lower animals
to induce heteroploidy, it has not been very
extensively used with mammals. Heat shock
of mice eggs (Beatty and Fischberg, 1949;
Fischberg and Beatty, 1952) did induce a
relatively high rate of heteroploidy and there
was some indication that cold shock might
have a slight effect. Although the most effective treatment was at almost 45 ~ C. for
2 ~ to 4 ~ hr. the possibility remains that less
extreme temperatures such as those produced
by fever, if sustained over longer periods may
produce some aneuploidy or polyploidy.
General Environmental Factors
From both retrospective and prospective
studies of human populations, it has been ascertained that births of individuals with certain chromosomal aberrations are not randomly distributed in time or over geographical
areas (see Day, 1966, for review). An analysis
of the sex chromatin pattern in a continuous
sequence of neonatal babies was made by
Robinson and Puck (1965) who found higher
frequencies of X chromosome monosomv and
polysomy in one period of 5 mo. than in the
preceding or succeeding periods. During the
critical 5 mo. period there also occurred a
disproportionately high number of births of
babies with Down's syndrome. Others (Coilman and Stoller, 1962; Heinrichs et al., 1963;
Hecht et al., 1964) have also found a nonrandom distribution of individuals with
autosomal aberrations in various human populations. Collman and Stoller (1962) also reported a significantly higher frequency of
Down's syndrome in urban than in rural areas.
Although it has been suggested (Robinson and
Puck, 1965) that clustering of aberrations
may be a function of viral epidemics, other
factors are probably also involved.
Aged Gametes
As time elapses between ovulation and
fertilization, ova apparently lose their protective mechanism for excluding supernumerary
sperm (Austin, 1960). Eight to ten per cent
of rats and rabbit eggs in dams subjected to
delayed mating were found to be polyspermic
by Austin and Braden (1953). In the
dispermic eggs both sperm appeared to engage
in syngamy and it was presumed that triploid
embryos would have been the result. Pik6
(1961) has made extensive studies of polyandry and has confirmed that in the rat, delayed mating markedly increases its frequency. Hancock ( 1 9 5 9 ) a n d Hunter (1967)
have made similar observations on the pig.
Polygyny, resulting from the suppression of
the second meiotic division may also be influenced by delayed mating. Quite apart from
polyploidy, Witschi (1960) has postulated
that overripe eggs may be susceptible to a
variety of cytological variations giving rise to
aneuploidy and has shown (Witschi and
Laguens, (1963) that delayed fertilization of
frog eggs was a major cause of non-disjunction in mitotic as well as meiotic divisions.
Data presented by Salisbury and Flerchinger (1961) from which it was shown that
storage of ejaculated bull sperm prior to its
insemination into females effected greater subsequent embryo death than the use of fresh
or one day old semen, might also be attributable to changes in the chromatin that render
it more susceptible to aberration.
Autoimmunity
Although the situation is not at all clear,
indications do appear in the literature that
mothers afflicted with autoimmune diseases,
particularly those affecting the thyroid gland,
have a higher risk of producing a child with
sex chromosome monosomy, i.e. XO (Engle
and Forbes, 1965) or other chromosomal
CHROMOSOMAL A B E R R A T I O N S
complement resulting in gonadal dysgenesis
(Valloton and Forbes, 1967). In the patients
themselves, the incidence of autoantibodies
was significantly higher than in controls.
Primary A berratlons
Secondary effects of primary aberrations
are produced when the new chromosome or
chromosome set is either incapable of undergoing normal mitosis or meiosis or alters the
capacity of the entire cell to replicate itself
faithfully. When breakage events result in
chromosomes that are dicentric or acentric
they are unlikely to be reproduced and distributed equally to daughter cells through
subsequent mitoses. The acentrics are excluded by their inability to migrate at anaphase and the dicentrics ordinarily are
stretched at mitotic anaphase forming a
bridge between the two telophase nuclei.
There appears to be no difficulty, however,
with the mitotic transmission of inversions,
translocations, polysomics, monosomics or
polyploids except when the genome of the
cell is modified to the extent that the genetic
control over cell division itself is altered or
lost.
At meiosis, because of the point nature of
synapsis and crossing over, complications are
more likely. Both inversions and translocation,
when they are carried as heterozygotes in
gametocytes cause difficulties that result in
the formation of gametes with new chromosomal complements. The extent of alteration of the gametic genome depends upon the
nature of the primary aberration and the number and position of chiasmata formed at the
first meiotic division. Distribution of polysomic chromosomes at meiosis I may be irregular and depends upon how synapsis occurred. In the case of a tetrasomic, for
instance, two bivalents may be formed, a
trivalent and univalent, or a quadrivalent.
Each possibility has its own array of consequences, some of which, in each case, are
gametes with altered genomes. For a complete discussion of the meiotic complications
of the various types of chromosomal aberrations, see Burnham (1962).
Evolutionary Implications
of A b e r r a t i o n s
Interspecific Variations
No known type of chromosomal aberration
is capable, in itself, of bringin~ about the
35
process of speciation. While related species
have karyotypes that can be shown to differ
in respect to one or a series of aberrations,
each can also be shown to exist within species
as chromosomal polymorphism. Nonetheless,
as segments of a population become isolated
from the main group, spread into new ecological niches or are subjected to the exigencies
of a changing environment where the genuine
becomes altered by natural selection, chromosomal aberrations frequently are advantageo,s
in aiding the adaptation and enhance the
process. Very small aberrations, i.e. those involving the duplication or deletion of one or
only a few loci are in many respects similar
to gene mutations and, except in those organisms where genetic fine structure can be
analyzed or in dipteran species with large
polytenic salivary gland chromosomes, cannot
be differentiated from them.
Recently, it has become possible to make
relatively detailed analyses of the genetic determiners of some mammalian proteins. The
hemoglobins, particularly , have been subjected
to a careful scrutiny. To account for the differences in hemoglobin structure within and
between the species that have been studied, it
is necessary to postulate that duplications,
deletions, unequal crossing over, translocations
and perhaps other aberrations, as well as a
number of mutations have occurred (Baglioni, 1966).
A block of genes situated on a given chromosome that, as a group, are advantageous
can be held together by inversions or some
types of translocations having the effect of
suppressing crossing over within the block.
How important these mechanisms have been
in the evolution of mammals is not yet known
but certainly in some of the lower organisms
whose chromosomes have been more amenable
to analysis, inversions and translocations are
a widely employed mechanism to aid in the
adaptation to different environments and are
frequent concomitants of speciation (see John
and Lewis, 1966, for review). From a study
of 17 species and subspecies of deer mice
(Peromyscus), all with the same diploid number of chromosomes but with much variation
in chromosome morphology, Hsu and Arrighi
(1966) concluded that the observed differences in karyotypes were probably accomplished by reciprocal translocations and
pericentric inversions. Perhaps, then these
mechanisms are of equal consequence in
vertebrate evolution as they have been shown
to be among some of the invertebrates.
36
FECHHEIMER
Structural changes in chromosomes, most
notably one or a series of interchanges of
segments between chromosomes can cause
changes in the number of chromosomes present as well as their morphology. Should a
translocation occur such that the two tong
arms of separate acrocentric chromosomes
form one new mediocentric or submediocentric
chromosome and the two short arms are lost
at a subsequent mitosis, there will have been
a diminution, by one, of chromosomes present
but practically no loss of genetic material.
Such an event has been called a centric fusion.
Perhaps because such events are so easily
detected there are frequent reports in the
literature of their presumed occurrence in
mammals. Thus in gerbils (Wahrman and
Zahavi, 1955), shrews (Sharman, 1956; Ford
et al., 1957; Meylan, 1964), a number of
rodents (Matthey, 1963b, 1965), domestic
cattle (Gustavsson, 1966; Herschler and
Fechheimer, 1966), wild pigs (McFee et al.,
1966a) and goats (Soller et al., 1966) intraspecific polymorphism of the karyotype explainable on the basis of a centric fusion has
been reported. I t is possible that a fusion of
centromeres of two acrocentric chromosomes
can give rise to a result similar to the one
described above via the mechanism proposed
by Robertson (1916). Matthey (1963a) has
shown that this event can happen frequently
in at least two related rodent species and its
occurrence may be related to cytoplasmic elements. By whichever method centric fusions
arise, it appears that they do so relatively
frequently in mammals and in a number of
cases balanced polymorphisms are established.
Perhaps then it is to be expected that in the
process of speciation, karyotypic changes accompanying it have been noted to involve
types that probably involved centric fusions.
Such has been found to be the case in the
Hominidae (see Hamerton et al., 1963) and
the Muridae (Matthey, 1958) for example.
I t is possible that chromosome fragmentation, i.e. the division of a centromere of a
biarmed chromosome to form two single armed
ones, may also occur although there would
appear to be some difficulties in the process.
Perhaps the most striking case in mammals
of what may have involved chromosome fragmentation is that of the hamsters. While the
Chinese and European species possess 22
chromosomes, the Syrian or golden hamster
has 44 (Sachs, 1952). Moses and Yerganian
(1952) were able to show, however, that the
D N A content of nuclei from the three groups
was q-antitatively similar thus ruling out allopol)ploidy as a rational cause of the difference in chromosome number. Galton and Holt
(1964) on the basis of their evidence are unwilling to discount polyploidy as possible
cause of the chromosome number difference
in the three species. That polyploidy is an
unlikely evolutionary development in mammals is indicated by other evidence. The most
compelling evidence is, that although polyploidy is frequently observed in embryos
(Beatty, 1957; Carr, 1965; McFeely, 1966)
and occasionally in neonatal babies (Bi56k
and Santesson, 1960), a very high proportion
do not come to term and those that do are
severely malformed, indicating that ontogeny
is misdirected by the polyploid state. Such
is not the case in plants (Stebbins, 1966) or
in some of the invertebrates or lower vertebrates (Bungenberg de Jong, 1957). There
are complications that are caused by polyploidy in species that are obligatorily sexually
reproducing and in which hermaphroditism
and parthenogenosis are precluded. These have
been discussed by Beatty (1957).
Some elucidation of the complex, step by
step process of karyotypic evolution in mammals is being made by study of the equine
species and their hybrids. The two most
closely related species Equus caballus and E.
przewalskii, when crossed, produce fertile
hybrids (Koulischer and Frechkop, 1966).
The autosomal complements differ by two
chromosomes, cabaUus having 62 plus X and
Y sex chromosomes and przewalskii 64 and
XY. By inspection of the karyotypes, Benirschke et al. (1965) were able to conclude that
other chromosomal differences had developed.
The cabatlus karyotype has 88 chromosomal
arms composed of 26 two-armed chromosomes
and 36 acrocentric elements while the przewalskii one also has 88 arms, 24 metacentrics or
submetacentrics and 40 acrocentric elements.
In spite of the differences, meiosis and gametogenesis apparently are not seriously disrupted.
E. asinus possess 60 autosomes (two less than
caballus) but 98 arms, of which only 22 are
acrocentric chromosomes. Asinus, therefore,
has 12 more metacentric chromosomes than
cabalhts (Benirschke et al., 1962). The more
extensive rearrangement of the genome that
has occurred during the divergence of caballus and asinus precludes normal meiosis in
the hybrid so that meiosis is disrupted at its
onset.
Benirschke and co-workers (1964) have
also shown that although other species in
CHROMOSOMAL A B E R R A T I O N S
37
TABLE 2. CHROMOSOME EVOLUTION AND SPECIES DIVERGENCE IN EQUIDAE
No. of autosomes a
Species
Metacentric
Acrocentric
Total
No. of
arms
24
40
(64)
88 1
26
36
(62)
88
38
22
(60)
98
46
6
(54)
100
32
12
(44)
70
36
6
(42)
78
26
4
(30)
52
Hybrids b, c
E. przewalskii
Mongolian wild horse
E. caballus
Domestichorse
J
J 1i
E. asinus
Donkey
E. hemionus onager
Persian wild ass
E. grevyi
Grevy zebra
E. burchellii b6hmi
Grant's (common) zebra
E. zebra hartmannae
Hartman's mountain zebra
Data from Hsu and Benirschke (1967); Mutton et aL (196~).
b Data from Gray (1954).
e Lille connecting two species indicates that hybrid has been produced.
the genus have very different chromosomal
composition than asinus, e . g . E , grevyi has
2 n ~ 4 4 and E. burchelli b6hmi has 2n~42,
the basic genome is still sufficiently similar
that hybrids can be produced.
Intraspecific Variations
Quite obviously any chromosomal aberration that can become a concomitant of species
divergence must also be occurring within
species. In fact it is to be anticipated that
many more aberrations are to be seen within
than between species because only those that
enhance the adaptation of emerging species to
their new environments will be incorporated
into their genome, so that for the occasional
one to have this potential, many must be occurring. Those aberrations arising, which do
not enhance the genetic fitness of a species,
will be eliminated and thus be counted as
part of the genetic load of the population;
those which are advantageous in heterozygous
form will reach an equilibrium frequency and
be found in the population as chromosomal
polymorphisms.
Sex Chromosomes. Among the mammals as
well as many other groups of plants and animals, one chromosomal polymorphism, that
involving the sex chromosomes is universal.
The advantages of sex, namely giving rise to
new combinations of genes in each generation,
and the selective effects whereby the cell lines
most seriously altered by aberration are unable to produce gametes, are so great that it
is widespread, and at least in the mammals,
the only mechanism for reproduction. Its
evolution, while no doubt different in the various taxa has led, in many cases, to specialized
chromosomes on which are concentrated the
genes directing sexual differentiation. They
have been uniquely molded by natural selection to perpetuate themselves and therefore
the chromosomal polymorphism. The evolutionary steps necessary to fashion such a system all involve chromosomal changes and very
briefly are as follows. By a series of mutations
and chromosome segment rearrangements,
genes for the differentiation of the homogametic sex became localized on one chromosome, the X. Simultaneously, genes fo( the
differentiation of the heterogametic sex' became localized on the homologue of the primitive X. The new gene combinations were held
FECHHEIMER
38
intact by some mechanism, perhaps inversion,
that restricted crossing over between at least
those segments of the two in which the genes
directing sexual separation were accumulated.
Each, not then being subjected to crossing
over in each generation, followed its own
evolutionary course.
Once genetic isolation of the sex chromosomes had occurred, a functional degeneration
of the isolated segment could be expected
because mutation pressure in the monosomic
regions would favor such an outcome. The
degeneration could be ac:omplished either by
its function being replaced by autosomal loci
as the sex chromosome becomes heterochromatic or by interchanges in which those portions of the sex chromosome not involved with
sexual differentiation become attached to
autosomes. Either process leads to a further
modification of the karyotype and both have
apparently occurred in some groups of animals. Thus from a simple XX, XY system
many variations can arise, including XO,
X1X2Y (Matthey, 1965), XY1Y2 (Wahrman
and Zahavi, 1955) systems (for a description
of sex chromosomes of mammals see Mittwoch
(1967) and for a general discussion of their
evolution see White (1954)).
Secondary adaptations to sex chromosome
polymorphisms develop, presumably in response to the genetic difficulties that arise as
a result of the specialization of activity of
some sex chromosomes and to the distinctly
different genomes with which members of the
sexes are accordingly endowed. The sex chromatin seen in mammalian female somatic cells
but absent from those of males is presumably
composed of one condensed and relatively inactive X chromosome so that each cell of
females has, as in males, only one active X
chromosome, (Lyon, 1962). Equalization of
genetic activity in somatic cells in males and
females has gone even further in some marsupials studied by Hayman and Martin
(1965). They found that one X in females
and the Y in males is completely eliminated
from at least some somatic tissues so that the
chromosome number is one less than in germ
line cells. Ohno et al. (1963) have described
an entirely different adaptation in the creeping vole where the females are XO and the
males XY. Thus each has an X chromosome
in somatic cells. However, the male X is excluded from the germ line leaving them a YO
constitution. Meiosis in the female has been
modified so that each ovum contains an X
chromosome in spite of the XO complement
of the oogonia.
Variations
in
Chromosome
Morphology.
Heteromorphic homologues, varying in length,
relative arm lengths, and placement and size
of both primary and secondary constrictions
have all been observed in human subjects
lacking gross phenotypic manifestations. Some
TABLE 3. INTRASPECIFIC CHROMOSOMAL POLYMORPHISMS OBSERVED TO BE
SEGREGATING IN MAMMALIAN POPULATIONS
Polymorphism
Species
Sex chromosomes
All mammals
Chromosomemorphology
Length of the Y
Man
Rat
Hamster
Length of autosomes
Enchanced constrictions
Centromere placement
Chromosomenumber
Authors
Mittwoch (1967)
London Conference (1963)
Court Brown et al. (1966)
Cohen and Shaw (1966)
Hungerford and Nowell (1963)
Lehman et al. (1963)
Pig
London Conference (1963)
Court Brown (1966)
McConnell et al. (1963)
Rat
Guinea pig
Peromyscus
Yosida and Amano (1965)
Manna and Taludar (1964)
Sparkes and Arakaki (1966)
Gerbil
Shrew
Wahrman and Zahavi (1955)
Sharman (1956)
Meylan (1964)
Matthey (1963c)
Soller et al. (1966)
Gustavsson (1966)
McFee et al. (1966a)
Man
African mice
Goat
Cattle
Wild pig
CHROMOSOMAL A B E R R A T I O N S
of the variations have also been reported to
occur in other species. So long as the variations affect chromosomal regions that do not
possess a great deal of genetic activity, it
would not be expected that they would cause
gross phenotypic effects and accordingly may
not reduce the fitness of their bearers. The
argument was made earlier that on a priori
grounds one would expect much of the genetic
activity of the Y chromosome to become
transferred to autosomal loci, leaving it relatively inert. Furthermore there is a good deal
of evidence that the Y chromosome of many
mammals does not carry many genes other
than those that influence testicular differentiation. Perhaps then it is not surprising that in
man, at least, variation in the length of the
Y chromosome has been noted by a number
of investigators (London Conference, 1963).
Almost 2% of a sample of males studied by
Court Brown et al. (1966) were seen to have
a Y chromosome of unusual length. Linear
measurements of the Y chromosome and
selected autosomes of 100 subjects representing five different racial and ethnic groups
were made by Cohen et al. (1966). Significant
differences in length of the Y were found both
among individuals within the groups and
among ethnic groups. Although the chromosomes of man have been more extensively
studied than those of any other mammal,
polymorphism of the Y chromoseme has been
noted in the Syrian hamster (Lehman et al.,
1963) and the rat (Hungerford and Nowell,
1963).
Unequal length of members of some autosomal pairs of chromosomes is not an unusual
occurrence in apparently normal human subjects (London Conference, 1963; Court Brown
et al., 1966). The observed polymorphisms
are not randomly distributed among all 22
autosomal pairs but are seen most frecluently
in acrocentric chromosomes and usually involve the enhancement of secondary constrictions. Lengthened primary constrictions in
two metacentric chromosomes of the pig
karyotype is a frequently observed variation
(McConnell e't al., 1963) that alters chromosomal length and other morphological features. I t has been postulated (Court Brown
et al., 1966) that variations in chromosome
length attributable to an increase in the length
of constrictions are not brought about by
breakages and rearrangements but are caused
by a genetically determined anomaly of the
coiling phenomenon restricted to a particular
region.
39
Polymorphism of autosomal pairs that had
their origin in structural rearrangements have
been seen in many laboratory and wild species
of mammals. Among the former, inbred strains
of rats have been noted to differ in respect to
the morphology of one pair of autosomes. In
some, the pair in question was subtelocentric
while in others it was seen to be telocentric.
In a wild l~opulation of rats both forms appeared (Yosida and Amano, 1965). In the
guinea pig, a difference in the relative length
of the members of one pair of chromosomes
has been reported (Manna and Talukdar,
1964). Individuals within subspecies of Peromyscus, while they contain the same number
of chromosomes, have differing karyotype
patterns that apparently were shaped by
pericentric inversions (Sparkes and Arakaki,
1966). Other murine species with multiple
chromosomal polymorphisms, many of them
involving translocations of autosomes and of
the sex chromosomes onto autosomes have
been reported (see for instance, Matthey,
1963b, c; 1965; Meylan, 1964). Established
polymorphisms involving centric fusions in
which two autosomes become joined into one
new one, give rise to a change in the chromosome number in the cells bearing the fusion.
As the new type spreads through the population other new karyotypes will appear bearing
the new chromosome singly, or doubly, and
in either case accompanied by the old homologues in single or double dose. Thus individuals in the same population are seen with
different numbers of chromosomes.
The same questions are pertinent in respect
to chromosomal polymorphisms as are asked
in regard to gene polymorpbisms. First one
wishes to know is the situation a transient
one. Has a new genome spontaneously developed that in a particular ecological niche
gives to its bearers (or to the population) an
increased fitness so that eventually it will
replace the older form? Alternatively the polymorphism may be a stable one in that the
fitness of the population is maximum when the
two (or more) forms coexist. There are a
number of circumstances that can lead to the
establishment and maintenance of stable genetic polymorphisms (for a discussion of each
see Ford, 1965). Heterozygote advantage is
the most obvious way in which stable p o l y morphisms may be maintained and has been
demonstrated by Dobzhansky (1951) and coworkers to be an important mechanism for
maintaining a series of inversions in populations of Drosophila (see Ford, 1965, for a
40
FECHHEIMER
review of the evidence). Another mechanism
that is employed to maintain polymorphisms
in populations is selective mating, whereby
individuals of unlike genotype mate more frequently than expected on the basis of chance.
Recently there appeared the first suggestion
that complex chromosomal variations may be
maintained in vertebrate populations in this
way (Thornycroft, 1966).
Until a great deal more knowledge is at
hand regarding the implications of the presence of chromosomal polymorphisms in mammalian populations, it is necessary to study
extensively the normally occurring karyotypic
variations of species before a significance can
be attached to any aberration. Except in
clearly exceptional cases this is true even when
a given aberration is accompanied by visible
malformations of zygotes that bear the
aberration.
duplications then are not seen. Also difficult
to ascertain with presently used methods
are paracentric inversions and reciprocal exchanges of approximately equally long chromosomal segments. Mosaicism may also remain cryptic unless many cells from a variety
of tissues are critically examined.
Within the confines imposed by these and
other restrictions, a number of abberafions
have been discovered, some of their effects
ascertained and their incidences estimated.
Much of the work so far accomplished with
mammals has been done with man and with
the laboratory mouse. Work with other species
is however now underway and promises to be
rewarding in helping to gain an understanding
of complex genetic phenomena in mammals.
In what follows an attempt is made to st, mmarize briefly the types of aberrations that
have been studied and to discuss what has
been learned from these stuides.
H a r m f u l Effects of Aberrations
Although occasionally a spontaneously occurring chromosomal aberration may, because
it increases the fitness of a population at the
particular time and place of occurrence, become incorporated into the genome, either as
a transient or stable polymorphism, most are
not beneficial and are eliminated. For those
situations when the effect is a severe reduction
in fitness, the elimination will occur quickly
and the frequency of the aberrant form in the
population will be no higher than the recurrence rate of the aberration. Others will not
reduce the fitness of their bearers absolutely
and, depending upon the severity of the effect,
may rise to equilibrium frequencies somewhat above their recurrence rates.
The manner in which chromosomal aberrations act to reduce fitness is as varied as are
the components of fitness. Some are known
which reduce the fertility of the individuals
that carry them. Others bring about embryonic or fetal death, while some cause only
slight modifications in the ontogenetic process so that an increased risk of premature
death may be the only effect. Congenital malformation is not uncommon among neonates
that bear aberrations. What must be kept in
mind is that, at present, what can be studied
is limited by the resolving power of the light
microscope so that any estimates of the occurrence of aberrations and their fitnessreducing effects on mammalian populations
are very probably minimal estimates. They
do not include those aberrations of a size less
than about half a micron. Small deletions or
Sex Chromosome Aberration's
A great number of aberrations of the sex
chromosomes have been seen in mammal~,
especially in mice and men where the search
has been more intensive than in other species.
That so many extensive chromosomal alterations are compatible with life and in some
cases even with fertility may be accounted
for on two bases. In the female, all but one
X chromosome per diploid cell is rendered inactive (Lyon, 1962) and there is some evidence that aberrant X's are preferentially inactivated so that the majority of cells of an
individual heterozygous for an aberrant X
will have the normal X maintained in an
active state (Mittwoch, 1964, reviewed the
evidence). Secondly, the Y chromosome in
many mammals is genetically relatively inert
(Dronamraju, 1965) so that changes in the
number of Y's per cell or in the structure of
a Y does not have such a widespread effect
as would similar alterations to an autosome.
(For general reviews of sex chromosome anomalies, see Beatty, 1964; Mittwoch, 1967:
Jacobs, 1966; Ford, 1967; Russell, 1962.)
Then too, sex chromatin screening tests can
be made on large samples of the population
making it more likely that some types of sex
chromosome aberrations will be found.
Monosomy and Partial Monosomy. The XO
state was first seen in man by Ford et al.
(1959b). It has been subsequently studied by
many workers (Ferguson-Smith, 1965) and
is the underlying cause of profound phenotypic malformations referred to as Turner's
CHROMOSOMAL A B E R R A T I O N S
syndrome. One of its manifestations is the
presence of hypoplastic, "streak" gonads that
render afflicted individuals sterile: The genitalia are distinctly female. The X-monosomy
condition is frequently seen in spontaneously
aborted human feti (Carr, 1965), indicating
that only a small proportion of XO early
zygotes survive to term. In the mouse however, XO individuals (Welshons and Russell,
1959; McLaren, 1960; Cattanach, 1962) are
phenotypically unremarkable and usually fertile. Although it would be expected that XO
females when mated with XY males would
yield equal numbers of XX, XY and XO
young (the YO being inviable), Cattanach
(1962) observed a deficiency of the XO type,
but not a reduction in normal litter size. Apparently preferential segregation occurs at
meisosis so that the X chromosome remains
in the ovt, m. According to Russell (1962) the
X pre~ent in XO mice it usually matroclinous.
Therefore, either the X chromosome is excluded from .~permatids b y non-disjunction
or lagging dvring m,iosis or the patroclinous
X is more liable to loss in early cleavage divisions than the maternally contributed one.
The more fr"o'-~nt occurrence of XO individuals than ef X X Y ones (Russell and Ch~,
1961) that wo'-ld have their origin in XY
gametes (the cemplementary gametic product
of meiotic non-disjunction) is an indication
that exclusion of an X chromosome at an
early cleavage may occur. Another indication
that mitotic errers may be involved are the
numerous report~, in man, of mosaics containing both X X and XO sex chromosome complements (see Ferguson-Smith, 1965, for
review).
Structural aberrations of the X chromosome
of man have been observed by many investigators (see Mittwoch, 1967, for review).
Among those seen have been deletions of both
the long (Jacobs et al., 1960b) and short arm,
isochromosomes composed of two long arms,
and ring chromosomes. Patients bearing such
aberrations usually exhibit seine but not all
of the stigmata of Turner's syndrome. Mosaics
composed of cells with XO and X aberrant-X
cell types, as well as mosaics with two or
more cell lines, also occur (Court Brown et
al., 1964; Ferguson-Smith et al., 1964; Engel
and Forbes, 1965).
Although the XO condition is at least compatible with life, the YO condition appears
not to be, there being no reports in the literature of individuals with this complement.
Deletions of the Y chromosome have however
41
been seen and when the deletion includes the
short arm, may result in the appearance of
some of the stigmata of Turner's syndrome.
Also reported (Jacobs and Ross, 1966) have
been an isochromosome for the Y long arm,
a Y with pericentric inversion, and a dicentric
Y.
Polysomy. Phenotypically normal females
with three or more X chromosomes can be
initially detected by the presence of more
than one sex chromatin body in their somatic
cells. The first report of a X X X woman was
made by Jacobs et al. (1960a). While some
of such individuals are fertile (Close, 1963)
others have abnormalities attributable to
faulty sexual development (Johnston et al.,
1961). Among the children of fertile X X X
women, most are normal indicating that some
mechanism exists to preclude secondary nondisjunction at meiosis. Mentally retarded patients with X X X X and X X X X X as well as
mosaics of these with X X and XO have been
described (see Mittwoch, 1967, for review).
Patients afflicted with Klinefelter's syndrome (see Overzier, 1963, for description)
were shown by Jacobs and Strong (1959) to
have an X X Y sex chromosome complement.
Such individuals are undoubted males but, the
testes are small, spermatogenesis is lacking
and somatic malformations are concomitantly
seen. In mice, though they appear to be without phenotypic malformation, X X Y individuals are also sterile males (McLaren, 1960;
Russell and Chu, 1961; Cattanach, 1961b).
Thuline and Norby (1961) were able to show
that male cats, suspected on genetic grounds
of being heterozygous for a sex-linked gene,
were XXY. Many variations have by now
been reported in man, including X X X Y (Ferguson-Smith et al., 1960), X X X X Y (Fraccaro
et al., 1962), X X Y Y (Court Brown e't al.,
1964) and mosaics with two-, three- and occasionally even four-cell lines.
Males with X Y Y (Hauschka, 1962;
Jacobs et al., 1965) and XYYY (Townes et
al., 1965) are not notable for any consistent
set of abnormalities except perhaps an increased height (Jacobs e't al., 1965). Hauschka's patient was fertile.
Sex Chromosome Chimerics. It is quite apparent that meiotic disorders of both male and
female (McLaren, 1960; Bateman, 1962) as
well as mitotic non-disjunction are involved
in the production of the amazing array of sex
chromosome aneuploids that are seen. Another
series of mechanisms must however be invokeJ
42
F E C H H E I M ER
to account for X X / X Y chimeric individuals
which are frequently found to be intersexes.
In cattle, it has been known for some time
that anastomosis of chorionic bleod vessels of
twins leads to a mutual exchange of blood
between dizygotic twin embryos (Lillie, 1916;
Owen, 1945). That a number of tissues are
rendered chimeric by the vascular connections,
presumably via the exchange, implantation,
and subsequent proliferation of embryonic
migratory cells has more recently been established (Ohno et al., 1962; Fechheimer ct al.,
1963; Kanagawa et al., 1965). Chimerism is
established in marmosets in a similar fashion
(Benirschke and Brownhill, 1963). In man,
it has been postulated that observed cases of
intersexuality in which chimerism was established had their origin in the fertilization, by
separate sperms, of two products of meiosis
derived from one oogonium (Gartler et al.,
1962; Jasso et al., 1965; Bain and Scott,
1965). Exceptions are the cases reported by
Uchida et al. (1964) of an intersex, chimeric
twin and of Manuel et al. (1965) where the
most reasonable explanation was two successive mitotic errors in an XY zygote. Naturally
occurring X X / X Y chimeric intersexes have
been reported for the goat (Padeh et al.,
1965), the pig (McFee et al., 1966b), the
cat (Thuline, 1964) and the sheep (Alexander
and Williams, 1964). Tarkowski (1964) has
produced experimentally X X / X Y chimeric
hermaphroditic mice by fusing two zygotes
which subsequently develop as one embryo.
It is interesting to note that with the exception of the marmoset and some reported
cases in man, X X / X Y chimerism is associated
with an intersexual state. From those cases
where cell cultures were made from the gonads
of such individuals, (Gartler et al., 1962;
Br0gger and Aagenaes, 1964) it seems appropriate to generalize that testicular differentiation can occur even when a fairly high
proportion of XX cells are present but as few
as perhaps 10~ XY cells influence gonadal
differentiation toward the male type (see
Herschler and Fechheimer, 1967, for discussion). It may also be instructive to note that
in the chicken, where the female is heterogametie and where chimerism can be found in
the twins contained in double-yolked eggs
(Moore and ()wen, 1965; Jaffe and Fechheimer, 1966), the male's gonad is modified
while the ovaries of the female twin develop
normally (Lutz and Lutz-Ostertag, 1959) and
at maturity are fully functional (Fechheimer
and Jaap, unpublished data).
A utosomal Aberrations
M o n o s o m y . This condition, i.e. the complete
exclusion of an autosome from a zygote is
either an extremely rare event or results in
very early embryonic death of mammals (Russell, 1962). Possible exceptions to this rule
may be found in those species where centric
fusions are found in a polymorphic state and
all the expected products of meiosis in carriers are seen to be represented in the population (e.g. Matthey, 1963b: Meylan, 1964).
Whether or not the evolution of these polymorphisms has been accompanied by the development of some special compensatory
mechanism is not known. However, the complex nature of the chromosomal variation observed would lead one to suspect that such
may be the case.
Partial M o n o s o m y . Deletions of autosomal
segments can be brought about in a number
of ways (vide supra). Ring chromosomes,
formed by the fusion of two broken ends of
a chromosome with a terminal deletion at
each end have been detected in some malformed babies (Gordon and Cooke, 1964;
Lucas et al., 1963). Individuals heterozygous
for a translocalion will produce some gametes
containing deletions, as well as duplications.
Zygotes composed of such unbalanced gametes
will have both a partial monosomy and a
partial trisomy (Edwards et al., 1962). They
are grossly malformed. Mice with similar
types of aberrations also appear to be afflicted
with malformations (Cattanach, 1965). Symptoms sufficiently uniform to be grouped as a
syndrome accompany a deletion of the short
arm of chromosome five of man (Lejeune et
al., 1964). Another deletion, this one of a
small acrocentric element, was found by Nowell and Hungerford (1960) in patients with
chronic myelogenous leukemia. Translocations
of the Robersonian type are presumed to involve the loss of short segments of the chromosomes. Yet aberrations of this type are
frequently seen in mammals. It is presumed
that the lost segments are not heavily endowed
with genetic activity because other partial
monosomics large enough to be seen cytologically, or studied genetically, cause sterility at
the very least (Russell and Russell, 1960).
On the other hand, relatively large amounts
of heterochromatin can be lost without marked
effects. Evidence of this is to be found in the
normal appearance and fertility of XO mice.
Trisomics and Partial Trisomy. An additional whole chromosome added to a zygote's
genome can be brought about by meiotic non-
CHROMOSOMAL A B E R R A T I O N S
disjunction, mitotic non-disjunction in an
early cleavage division or by transmission of
the extra chromosome by an existing trisomic
individual. Trisomics for the majority of the
human chromosome set have been shown to
occur. Most are infrequent occurrences and
result in embryonic death and abortion. The
first to be described (Lejeune et al., 1959;
Jacobs et al., 1959) was a trisomy of chromosome 21, a small acrocentric element, that was
found present in babies with Down's syndrome. Some cases whose karyotypes had
only 46 chromosomes were found (Polani
et al., 1960) but it was possible to show in
almost every case that a translocation of one
number 21 onto another autosome was involved (see Miller and Dill, 1965, for a review). A phenotypically normal parent who
carries such a translocation in its balanced
form will produce gametes of four kinds, only
two of which contain a balanced haploid
genome. Even more serious are those cases
when a 21/21 translocation is involved. Such
an individual produces only two types of
gametes, one with both number 21 chromosomes and one with none. Among new born
babies other trisomics are occasionally seen.
Trisomies for a chromosome in the numbers
13-15 group (Edwards et al., 1960) and of
nt,,mber 18 (Patau et al., 1960) have been
reported and both have characteristic stigmata. When larger autosomes are present in
the trisomic state, they disburb embryogenesis to the extent that abortion is the invariable outcome (Kerr and Rashad, 1966).
Trisomy has been reported in the mouse
by Griffin and Bunker (1964) and Cattanach
(1964). The animals were sterile but had no
gross deformities. Lyon and Meredith (1966)
reported finding partially trisomic mice among
the progeny of irradiated sires. They postulated that the previously reported viable trisomics were perhaps only partially trisomic.
Although viable, the animals studied by Lyon
and Meredith were sterile or semi-sterile.
Males were more seriously affected than females. Partial trisomics have been reported in
man also. These result either from the transmission of an isochromosome for one arm of
an autosome or, more frequently by the transmission of a translocation (see Hamerton,
1962, for discussion). Severity of the symptoms shown by patients with partial trisomy
is associated with the length of the superfluous segment. Attenuated symptoms are also
exhibited frequently by individuals mosaic
for a trisomic condition (Clark et al., 1961).
43
A number of individuals have been observed
who are mosaics for the 21-trisomy, having
both normal and trisomic cells. Mosaicism of
this nature must develop by chromosome lagging during one of the cleavage divisions of
a trisomic zygote. If it developed by nondisjunction in a normal zygote, three-cell lines
ought to be present.
Reports of trisomy or partial trisomy in
species other than man and mouse are beginning to appear in the literature. One interesting one described a short translocation that
was seen to be segregating in guinea pigs. It
was not producing any apparent loss of fitness
in the heterozygous state (Cohen and Pinsky,
1966).
The only mammal in which double trisomics
have been seen is in man. An individual with
X X Y and trisomic-21 was reported by Ford
et al. (1959a). Other cases are those of
Uchida and Bowman (1961) with trisomic-X
and 18, and Gagnon et al. (1961) with 18and 21-trisomies.
Translocations and Inversions. Examples of
the occurrence and effects of these chromosomal rearrangements in mammals have been
given in other sections of this paper and
therefore need not be discussed separately in
detail. Both types of aberrations, when present in heterozygous form, complicate meiosis
and frequently result in gametes that are genetically unbalanced. Progeny composed of
these unbalanced gametes will be partially
trisomic, partially monosomic or both. Accordingly, it is to be expected that heterozygous
males will be infertile and females may be
infertile or show a history of prolonged estrous cycles following undetected embryo
deaths or abortions. I t is too early to tell
to what extent reduced fertility in mammals
is attributable to chromosomal aberrations.
Kundsen (1956) in screening bulls of low fertility found three heterozygous for a translocation and two for an inversion. A boar carrying a translocation produced litters about half
the normal size when mated to 50 sows
(Henricson and B~ikstrSm, 1964). The karyotspes of a sample of 130 childless men were
determined by Kjessler (1~)65) who found
that while 12 contained chromosomal aberrations, most of these were aberrations of the
sex chromosomes. A number of translocations
have been experimentally produced and analyzed in mice. In general it can be said that
heterozygous males are sterile and the females
are sterile or exhibit a reduced fertility (Lyon
and Meredith, 1966). (For a full discussion
44
FECHHEIMER
of the implications of translocation heterozygosis in man, see Trujillo et .2l., 1966).
Polyploidy. The cytological mechanisms for
the development of polyploidy have been completely discussed by Beatty (1957). Its spontaneous occurrence, in one form or another
has been demonstrated in man (Carr, 1965),
mouse (Beatty, 1957), pig (Hunter, 1967),
cat (Chu et al., 1964), rat (Pik6, 1961). The
most extensive studies of the phenomenon
were those of Beatty and Fischberg in the
mouse. The predominant form that was observed in the absence of experimental treatment was triploidy, probably resulting from
a failure of the ova to extrude a second polar
body. In spite of a relatively high frequency
of embryos in some special stocks, no triploid
individual developed to term while most died
sometime after mid-gestation. In man, similarly, while triploid and occasionally tetraploid embryos are found among series of
abortuses (see Geneva Conference, 1966, for
review), in live born babies, the only triploids
reported have been triploid-diploid chimeras
with multiple malformations (B6tik and Santesson, 1960; Ellis et al., 1963; Edwards et
al., 1967). A similarly composed chimeric cat,
apparently normal phenotypically, was studied by Chu et al. (1964). One can conclude
that for the most usually studied animals,
polyploidy is a lethal condition, most if not
all polyploid embryos dying in utero.
Quantitative Considerations
Not enough information is available to attempt accurate estimates of the loss of fitness
in any mammalian species attributable to
chromosomal aberrations, either spontaneously occurring ones or polymorphic variations. Even for man, estimates having been
made on some large samples, certain limitations of the data must be recognized. Perhaps
the most important limitation is a lack of
complete knowledge, in many studies, of the
population that is being sampled. Much of
the cytogenetic knowledge that has been published about man comes from hospital patients
or other institutional inmates. It is doubtful
that such samples represent a random segment of a population of man. Then to, the
techniques that are used to screen large samples for the presence of aberrations possess
inherent difficulties. The sex chromatin method
for the detection of sex chromosome aberrations is inadequate for the finding of some
types of mosaicism as well as abnormal Y
chromosomes. Even when karyotypes are carefvlly studied, mosaicism or chimerism may
remain cryptic. Aberrations such as paracentric inversions and small rearrangements of
other types cannot be detected in any case
when only mitotic preparations are viewed.
Finally it should be kept in mind that a given
aberration may have extremely debilitating
effects on organisms in one species and none
at all in those of another. The differential effect
of the XO condition in man and mice is a
case in point.
In spite of these and other qualifications
it seems worthwhile to review the available
estimates of frequency of fitness reducing
aberrations if only to get a very rough idea
of their effect on the fitness of mammalian
populations.
Embryo Death and Abortion. In assessing
the embryo loss caused b y the presence of
lethal aberrations, it is not possible, with presently used techniques to detect the very early
deaths, i.e. those occurring at the first few
cleavage divisions. The most extensive series
of studies on any species were those of Beatty
and Fischberg (summarized by Beatty, 1957)
on 3400 non-treated, 3 ~ day mouse embryos.
Of those about 2 I ~ % were found to contain
aberrations, the most frequent of which was
triploidy.
If one summarizes 11 reports (Clendenin
and Benirschke, 1963; Thiede and Salm,
1964; Sato, 1965; Hall and K~llen, 1964;
Carr, 1965; Szulman, 1965; Kadotoni and
Pergament, 1966; Kerr and Rashad, 1966:
Smith, et al., 1966; Bowen and Lee, 1966)
dealing with cytogenetic analysis of products
of spontaneous abortion in man, it is seen that
22 to 23% of 518 abortuses were found to have
aberrations. From a series of 21 studies, many
not individually published, the incidence of
chromosomal aberrations in 788 cases of spontaneous abortion was seen to be 19% (Geneva
Conference, 1966). Assuming that 15 to 20%
of human pregnancies terminate in abortions
(see Carr, 1965, for basis), the over-all frequency of abortions brought about by the embryos with aberrations would be about 3 ~ %.
In classifying the aberrations, it was seen that
about 40% were autosomal trisomics and
other autosomal anomalies, about 22% XO
monosomics, 29% polyploidy of which the
majority were triploid and the remaining 9%
exhibited a variety of aberrations.
Pronucleate pig eggs have been observed by
Hancock (1959) and Hunter (1967), both
of whom reported a sharp increase in those
45
CHROMOSOMAL ABERRATIONS
containing more than two pronuclei when
mating of the sow was delayed past the calculated time of ovulation. M c F e e l y (1966) is
making a karyological s t u d y of 10-day pig
embryos and has found two blastocysts carrying aberrations among the first 98 examined.
F r e q u e n c y O] Aberrations D e t e c t e d in
Neonates. Screening of large samples for the
detection of sex chromosome aberrations can
be accomplished quite easily b y comparing
phenotypic sex of a subject with sex chromatin findings from smears of buccal cells.
Examinations of over 20,000 consecutively
born children were made b y Maclean et al.
(1964). The detectable sex chromosome aberration incidence was 0.2% in males and
0.16% in females. The most frequently found
aberrations involved, trisomy, X X Y in males
and X X X in the female sample. Autosomal
trisomy has been estimated to be present in
0.20 to 0.25% of new born babies. About
two-thirds of these are trisomy-21 (Penrose,
1963) and most of the remainder trisomies of
the 13 to 15 group and 17 to 18 group ( M a r den et al., 1964). Court Brown et al. (1966)
have made estimates of the frequencies of
autosomal rearrangements found in a sample
of over 1,000 adults. Such an estimate m a y
be used as a minimal estimate of that proba b l y present in a population of new born
babies. T h e y found 0.5% of their sample to
be carriers of pericentric inversions or translocations of autosomes. An additional 3% had
autosomal anomalies involving changes in
chromosomal morphology. A b o u t 3 % of the
males possessed Y chromosomes of remarkable morphology. The last two categories of
anomalies are presently not known to have
an effect on fitness. Omitting theses the remaining frequency of aberrations among
neonatal babies is estimated to be about
1.0%.
Estimates of a similar nature appear not
to have been made in a n y other species. The
only exception is estimation of spontaneously
occurring sex chromosome aberrations in mice,
TABLE 4. FSTIM~TES OF FREQUENCY OF CHROMOSOMAL ABERRATIONS
CAUSING REDUCED FITNESS IN MAMMALIAN POPULATIONS
Species and stage
Type of aberrations
Embryos and feti
Man
Autosomal trisomy
Tripolidy
X monosomy
Assorted miscellaneous
Mouse
Pig
Neonatal young
Man
Mouse
Author
20% of abortions
3.0%-4.0% of
pregnancies
Combined data from 21 studies
Geneva Conference (1966)
Polyp!oidy, primarly triploidy
Aneuploidy
Mosaics
2-2~/~% of embryos
Beatty (1957)
Polyploidy from polyspermy
0-15% of ova
Hunter (1967)
Sex chromosome aberrations
Autosomal trisomy
0.2% of males
0.16% of females
0.20-0.25%
Maclean et al. (1964)
Penrose (1963)
Marden et al. (1964)
Autosomal rearrangements
Translocations and
pericentric inversions
Morphological alterations
--of autosomes
--of Y chrc mosome
0.5%
Court Brown et al. (1966)
3.0%
3.0%
Court Brown et al. (1966)
Sex chromosome aneuploidy
--XO females
--XXY males
0.6%
0.6%
0.02 %
McLaren (1960)
No accurate estimate
Schmid (1962)
Rowley et al. 1963)
Kjessler (1965)
Lyon and Meredith (1966)
Knudsen (1956)
Henricson and Bakstrom (1964)
Reduced fertility and sterility
Man
Various aberrations
Mouse
Cattle
Estimate of frequency
Trisemy, partial trisomy
Translocations and inversions
Transtocation
No accurate estimate
No accura~:eestimate
No accurate estimate
Russell and Saylors (1961)
46
FECHHEI MER
XO females and X X Y males, made postnatally. McLaren (1960) estimated the frequency of occurrence to be about 0.67~. Russell and Saylors (1961) found XO females
to be more frequent than X X Y males, their
respective incidences being 0.79~ and 0.02~..
Fitness-Reducing Effects in Adult Population's. Should an aberration not produce malformations detectable at birth, it is none the
less possible that it may result in sterility or
reduced fertility of its carrier. Sex chromosome aneuploidy, particularly XXY, does not
produce recognizable abnormalities in mice
but does result in sterility. Translocations carried in the balanced state are not expected
to exhibit phenotypic deviations in their
bearers. However, half the gametes produced
by such individuals will contain deletions or
duplications. When the aberrant gametes participate in syngamy the zygote will contain
an aberration and may very well be seriously
hampered in its development. Schmid (1962)
searched for chromosomal aberrations among
couples whose reproductive history included
several spontaneous abortions. The male member of one of 10 such couples was carrying
an apparent translocation. A similar study by
Rowley et al. (1963) revealed another aberration, this one an unusually large Y. Trisomic
and partially trisomic mice are relatively infertile (Lyon and Meredith, 1966; Griffen and
Bunker, 1964). A semi-sterile boar was shown
by Henricson and B~ikstr6m (1964) to carry
a structural rearrangement. Perhaps the most
extensive study was that of Kjessler (1965)
who made cytological examination of 130
childless men, finding 12 with chromosomal
anomalies.
While it is possible that a number of noncongenital diseases have their origin with
chromosomal aberrations occurring in somatic
tissue, not enough is known about cause and
effect relationships to permit a discussion or
assessment of incidence. Although a good deal
has been written about the occurrence of aberrant chromosomes in neoplastic tissue (see de
Grouchy, 1966, for review) even in this area
it is too early for quantitative assessment of
damage.
L i t e r a t u r e Cited
Alexander, G. and D. Williams. 1964. Ovine freemartins. Nature 201:1296.
Austin, C. R. 1960. Anomalies of fertilization leading
to triploidy. J. Cell. Comp. Physiol. 56:1.
Austin, C. R. and A. W. H. Braden. 1953. Polyspermy
in mammals. Nature 172:82.
Bachmann, K., D. B. Goin and J. Goiu. 1966. Hylid
frogs: Polyploid classes of D N A in liver nuclei. Science 1.54:650.
Baglioni, C. 1966. Molecular evolution in man. Proc.
III Intern. Congr. H u m a n Genet. (In press.).
Bain, A. D. and J. S. Scott. 1965. Mixed gonadal
dysgenesis with X X / X Y mosaicism. Lancet i:1035.
Barr, M. L. and E. G. Bertram. 1949. A morphological distinction between neurones of the male and
female, and the behavior of the nucleolar satellite
during accelerated nucleoprotein synthesis. Nature 163:676.
Bateman, A. J. 1962. Maternal and paternal nondisjunction as the source of sex chromosome u n balance. Lancet ii: 1383.
Beatty, R. A. 1957. Parthenogenesis and Polyploidy
in M a m m a l i a n Development. Cambridge University
Press, Cambridge.
Beatty, R. A. 1964. Chromosome deviations and sex
in vertebrates. In C. N. A r m s t r o n g and A. J.
Marshall [ed.] Intersexuality in Vertebrates Including Man. Academic Press, London and New
York.
Beatty, R. A. and M. Fischberg. 1949. Spontaneous
and induced triploidy in preimplanation mouse
eggs. Natu re 163 : 807.
Benirschke, K., L. E. Brownhill and M. M. Beath.
1962. Somatic chromosomes of the horse, the donkey and their hybrids, the mule and hinney. J.
Reprod. Fertil. 4:319.
Benirschke, K. and L. E. Brownhill. 1963. Heterosexual cells in testes of chimeric m a r m o s e t monkeys.
Cytogenetics 2:331.
Benirschke, K., R. J. Low, L. E. Brownhill, L. B.
Caday and J. de Venecia-Fernandez. 1964. C h r o m o some studies of a donkey-grevy-zebra hybrid.
C h r o m o s n m a 15:1.
Benirschke, K., N. Malouf, R. J. Low a r d H. Heck.
1965. Chromosome complement: Differences between Equus caba!lus and Equus przewalskii, Poliakoff. Science 148:382.
BiSiik, J. A. and B. Santesson. 1960. Malformation
syndrome in m a n asseciated with triploidy (69
chromosomes). Lancet i:857.
Bowen, P., and C. S. N. Lee. 1966. Karyotypes of
cell strains derived from aborted h u m a n fetal
tissues. Proc. IlI Intern. Congr. H u m a n Genet.
11. (Abstr.).
Brewen, J. G. 1962. X - r a y - i n d u c e d chromosome aberrations in the corneal epithelium of the Chinese
hamster. Science 138:820.
BrCgger, A. and O. Aagenaes. 1964. Role of Y chromosome in development of testicular structures.
Lancet ii:259.
Bungenberg de Jong, C. M. 1957. Po]yp]oidy in animals. Bibliogr. Genet. 17 : l ] 1.
Burdette, W. J. and J. S. Yoon. 1967. Mutations,
chromosomal aberrations and tumors in insects
treated with oncouenic virus. Science 155:340.
B u r n h a m , C. R. 1962. Discussions in Cytogenetics.
Burgess Publishing Co., Minneapolis, Minnesota.
Carr, I). H. 1965. Chromosome studies in spontaneous
abortions. Obstet. Gynecol. 26:308.
Cattanach, B. M. 1961a. A chemically induced variegated-type position effect in the mouse. Z. Vererb.
Lehre. 92 : 165.
Cattanach, B. M. 1961b. X X Y mice. Genet. Res.
2:156.
Cattanach, B. M. 1962. XO mice. Genet. Res. 3:487.
Cattanach, B. M. 1964. Autosomal trisomy in the
mouse. Cytogenetics 3:159.
Cattanach, B. M. 1965. Snaker: A d o m i n a n t abnor-
CHROMOSOMAL ABERRATIONS
mality caused by chromosomal imbalance. Z.
Vererb. Lehre. 96:275.
Chicago Conference. 1966. Standardization in Human
Cytogenetics. Birth Defects: Original Article Series.
The National Foundation, New York. II:2.
Chlebovsk~, O., M. Prasli~ka and J. Horak. 1966.
Chromosome aberrations: Increased incidence in
bone marrow of continuously irradiated rats. Science 153:195.
Chu, E. H. Y., H. C. Thuline and D. E. Norby. 1964.
Triploid-diploid chimerism in a male tortoiseshell
cat. Cytogenetics 3 : 1.
Clarke, C. M., J. H. Edwards and V. Smallpiece. 1961.
21-Trisomy/normal mosaicism. Lancet i:1028.
Clendenin, T. M. and K. Benirschke. 1963. Chromosome studies on spontaneous abortions. Lab. Invest.
12:1281.
Close, H. G. 1963. Two apparently normal triple X
females. Lancet ii: 1358.
Cohen, B. H., A. M. Lilienfeld and A. T. Sigler. 1963.
Some epidemiological aspects of mongolism: A
review. Am. J. Public Health 53:223.
Cohen, M. M., M. J. MarineUo and N. Back. 1967.
Chromosomal damage in human leukocytes by
lysergic acid diethylamide. Science 155:417.
Cohen, M. M. and L. Pinsky. 1966. Autosomal polymorphism via a translocation in the guinea pig.
Cavia #orcellus L. Cytogenetics 5 : 120.
Cohen, M. M., M. W. Shaw and J. W. MacCIner.
1966. Racial differences in the length of the human
Y chromosome. Cytogenetics 5:34.
Collman, R. D. and A. Stoller. 1962. A survey of
mongoloid births in Victoria, Australia, 1942-1957.
Am. J. Public Health. 52:813.
Court Brown, W. M., K. E. Buckton, P. A. Jacobsl
I. M. Tough, E. V. Kuenssberg and J. D. E. Knox.
1966. Chromosome Studies on Adults. Cambridge
University Press, London.
Court Brown, W. M., D. G. Harnden, P. A. Jacobs,
N. Maclean and D. J. Mantle. 1964. Abnormalities
of the sex chromosome complement in man. M.R.C.
Special Report Series No. 305, H.M.S.O., London.
Crowley, C. and H. J. Curtis. 1963. The development
of somatic mutations in mice with age. Proc. Nat.
Acad. Sci. 49:626.
Curtis, H. J. 1963. Biological mechanisms underlying
the aging process. Science 141:686.
Day, R. W. 1966. The epidemiology of chromosome
aberrations. Am. J. Human Genet. 18:70.
de Grouchy, J. 1966. Chromosomes in neoplastic
tissue. Proc. III Intern. Congr. Human Genet. (In
Pressl).
Dekaban, A. S., M. A. Bender and G. E. Economos.
1963. Chromosome studies in mongoloids and their
families. Cytogenefics 2:61.
Dobzhansky. T. 1951. Genetics and the Origin of
Soecies. Columbia University Press, New York.
Dronamraju, K. R. 1965. The function of Y chromosome in man, animals and plants. Adv. Genet.
13:227. Academic Press, New York and London.
Edwards, J. H., M. Fraccaro, P. Davies and R. B.
Young. 1962. Structural heterozygosis in man:
Analysis of two families. Ann. Hum. Genet. 26:163.
Edwards, J. H., D. G. Harnden, A. H. Cameron, O.
N. Wolff and V. M. Cross. 1960. A new trisomic
syndrome. Lancet i: 787.
Edwards, J. H., C. Yuncken, D. I. Rushton, S. Richards and U. Mittwoch. 1967. Three cases of triploidy in man. Cytogenetics 6:81.
Eigsti, O. J. and P. Dustin, Jr. 1955. Colchicine in
Agriculture, Medicine, Biology and Chemistry.
Iowa State College Press, Ames.
47
Ellis, J. R., R. Marshall, I. C. S. Norman and L. S.
Penrose. 1963. A girl with triploid cells. Nature
198:411.
Engel, E. and A. P. Forbes. 1965. Cytogenetic and
clinical findings in 48 patients with congenitally
defective or absent ovaries. Medicine 44:135.
Fechheimer, N. S. 1961. Poikiloploidy among spermatogenic cells of Mus musculus. J. Reprod. Fertil.
2:68.
Fechheimer, N. S., M. S. Herschler and L. O. Gilmore.
1963. Sex chromosome mosaicism in unlike sexed
cattle twins. Proc. X I Intern. Congr. Genet. 1:265.
(Abstr.).
Ferguson-Smith, M. A. 1965. Karyotype-phenotype
correlations in gonadal dysgenesis and their bearing
on the pathogenesis of malformation. A review. J.
Med. Genet. 2 : 93.
Ferguson-Smith, M. A., D. S. Alexander, P. Brown,
R. M. Goodman, B. N. Kaufmann, H. W. Jones
and R. H. Heller. 1964. Clinical and cytogenetical
studies in female gonadal dysgenesis and their bearing in the cause of Turner's syndrome. Cytogenetics
3:355.
Ferguson-Smith, M. A., A. W. Johnston and S. D.
Handmaker. 1960. Primary amentia and microorchidism associated with an X X X Y sex chromosome constitution. Lancet ii:184.
Fischberg, M. and R. A. Beatty. 1950. Anfiinge einer
genetischen Analyse der spontanen Heterop!oidie bei
Mausen. Arch. Klaus Stiff. Vereb. Forsch. 25:22.
Fischberg, M. and R. A. Beatty. 1952. Heteroploidy
in mammals. II. Induction of triploidy in preimplantation mouse eggs. J. Genet. 50:455.
Ford, C. E. 1967. Inborn sex chromosome disorders.
Proc. III Intern. Congr. Human Genet. (In Press.).
Ford, C. E., J. L. Hamerton and G. B. Sharman.
1957. Chromosome polymorphism in the common
shrew. Nature 180:392.
Ford, C. E., K. W. Jones, O. J. Miller, U. Mittwoch,
L. S. Penrose, M. Ridler and A. Shapiro. 1959a.
The chromosomes in a patient showing both mongolism and the Klinefelter syndrome. Lancet i:709.
Ford, C. E., K. W. Jones, K. W. Polani, J. C. C. de
Almeida and J. H. Briggs. 1959b. A sex~chromosome anomaly in a case of gonadal dysgenesis.
Lancet i:711.
Ford, E. B. 1965. Genetic Polymorphism. Faber and
Faber Ltd., London.
Fraccaro, M., H. P. Klinger and W. Schutt. 1962. A
male with X X X X Y sex chromosomes. Cytogenetics 1:52.
Gagnon, J., N. Katyk-Longtin, J. A. de Groot and
A. Barbeau. 1961. Double trisomie autosomique
/t 48 chromosomes (21 & 18). Un. M~d. Can.
90:122. (Cited by Penrose, 1966).
Galton, M. and S. F. Holt. 1964. DNA replication
patterns of the sex chromosomes in somatic cells
of the Syrian hamster. Cytogenetics 3:97.
Gartler, S. M., S. H. Waxman and E. R. Giblett. 1962.
An X X / X u human hermaphrodite resulting from
double fertilization. Proc. Nat. Acad. Sci. 48:332.
Geneva Conference. 1966. Standardization of procedures for chromosome studies in abortion. Bul.
World Health Org. 34:765.
German, J. 1964. The pattern of DNA synthesis in
the chromosomes of human blood ceils. J. Cell.
Biol. 20:37.
German, J. and R. Archibald. 1965. Chromosomal
breakage in a rare and probably genetically determined syndrome in man. Science 148:506.
Gloor, H. and H. Staiger. 1954. Lethal polyploidy--
48
FECHHEIMER
A po!yploid gone in Drosophila hydei. J. ttered.
45:289.
Goodlin, R. C. 1965. Non-disjunction and maternal
age in the mouse. J. Reprod. Fertil. 9:355.
Gordon, R. R. and P. Cooke. 1964. Ring-1 chromosome and microcephalic dwarfism. Lancet ii:1212.
Gowen, J. W. 1933. Meiosis as a genetic character
in Drosophila melanogaster. J. Exp. Zool. 65:83.
Gray, A. P. 1954. Mammalian hybrids. Commonwealth Agricultural Bureaux. Farnham Royal,
EnT~land.
Griffen, A. B. and M. C. Bunker. 1964. Three cases
of trisomy in the mouse. Proc. Nat. Acad. Sci.
52:1194.
Gustavsson, I. 1966. Chromosome abnormality in
cattle. Nature 211:865.
Hall, B., and B. K~illfn. 1964. Chromosome studies in
abortuses and still born infants. Lancet i:ll0.
Hamerton, J. L. 1962. Cytogenetics of mongolism.
In J. L. Hamerton [ed.] Chromosomes in Medicine. National Spastics Soc. and Heinemann Medical Books, London.
Hamerton, J. L., H. P. Klinger, D. E. Mutton and
E. M. Lang. 1963. The somatic chromosomes of
the Hominoidea. Cytogenetics 2:240.
Hancock, J. L. 1959. Polyspermy of pig ova. An.
Prod. 1: 103.
Hauschka, T., J. E. Hasson, M. N. Goldstein, G. F.
Koepf and A. A. Sandberg. 1962. An XYY man
with progeny indicating familial tendency to nondisjunction. Am. J. Human Genet. 14:22.
Hayman, D. L. and P. G. Martin. 1965. Sex chromosome mosaicism in the marsupial genera Isodon and
Perameles. Genetics 52:1201.
Hecht, F., J. S. Bryant, D. Gruber and P. L. Townes.
1964. The non-randomness of chromosomal abnorma!ities. New England J. Med. 271:1081.
Heinrichs, E. H., S. W. Allen, Jr. and P. S. Nelson.
1963. Simultaneous 18 trisomy and 21 trisomy
cluster. Lancet ii:468.
Henricson, B. and L. Biikstri]m. 1964. Translocation
heterozygosity in a boar. Hereditas 52:166.
Herschler, M. S. and N. S. Fechheimer. 1966. Centric
fusion of chromosomes in a set of bovine triplets.
Cytogenefics 5:307.
Herschler, M. S. and N. S. Fechheimer. 1967. The role
of sex chromosome chimerism in alterning sexual
development of mammals. Cytogenetics 6:204.
Hsu, T. C. and F. E. Arrighi. 1966. Chromosomal
evolution in the genus Peromyscus (Cricetidae,
Rodentia). Cyto~enetics 5:355.
Hsu, T. C. and K. Benirschke. 1967. An Atlas of
Mammalian Chromosomes. Springer-Verlag, Inc.,
New York.
Hsu, T. C. and C. M. Pomerat. 1953. Mammalian
chromosomes in vitro II. A method for spreading
the chromosomes of cells in tissue culture. J. Here&
44:23.
Hungerford, D. A. and P. C. Nowell. 1963. Sex
chromosome polymorphism and the normal karyotype in three strains of the laboratory rat. J.
Morph. 113:275.
Hunter, R. H. F. 1967. The effects of delayed insemination on fertilization and early cleavage in
the pig. J. Reprod. Fertil. 13:133.
Ingalls, T. H., E. E. Ingenito and F. J. Curley. 1963.
Acquired chromosomal anomalies induced in mice
by injection of a teratogen in pregnancy. Science
141:810.
Jackson, J. F. and K. Lindahl-Kiessling. 1963. Polyploidy and endoreduplication in human leukocyte
cultures treated with /? mercaptopyruvate. Science
141:424.
Jacobs, P. A. 1966. Abnormalities of the sex chromosomes in man. In A, McLaren [ed.] Advances in
Reproductive Physiology. Vol. I. Logos Press Ltd.,
London.
Jacobs, P. A., A. G. Baikie, W. M. Court Brown,
T. N. MacGregor, N. Maclean and D. G. Harnden.
1960a. Evidence for the existence of the human
"super female." Lancet ii:423.
Jacobs, P. A., D. G. Harnden, W. M. Court Brown,
J. Goldsteiu, H. G. Close, T. N. MacGregor, N.
Maclean and J. A. Strong. 1960b. Abnormalities
involving the X-chromosome in women. Lancet
i:1213.
Jacobs, P., A. G. Baikie, W. M. Court Brown and
J. A. Strong. 1959. The somatic chromosomes in
mongolism. Lancet i: 710.
Jacobs, P. A., M. Brunton, M. M. Melville, R. P.
Brittain and W. F. McClermont. 1965. Aggressive
behavior, mental sub-normality and the XYY
male. Nature 208:1351.
Jacobs, P. A. and A. Ross. 1966. Structural abnormalities of the Y chrcmosome in man. Nature
210:352.
Jacobs, P. A. and J. A. Strong. 1959. A case of
human intersexuality having a pessibIe X / X / Y /
sex-determining mechanism. Nature 183:302.
Jaffe, W. P. and N. S. Feshheimer. 1966. Cell transport and the bursa of Fabricius. Nature 212:92.
Jasso, N., J. de Grouchy, J. Auvert, C. Nexelof, M.
F. Jayle, J. Moullec, J. Frezal, A. de Cassaubon
and M. Lamy. 1965. True hermaphroditism with
X X / X Y mosaicism, probably due to double fertilization of the ovum. J. Clin. Endocr. 25:114.
John, B. and K. R. Lewis. 1966. Chromosome variability and geographic distribution in insects. Science 152:711.
Johnston, A. W., M. A. Ferguson-Smith, S. D. Handmaker, H. W. Jones and C. S. Jones. 1961. The
triple X syndrome. British Meal. J. ii:1046.
Kadoteni, T. and E. Pregament. 1966. The nature and
implications of chromosome aberrations observed
in an abortion population. Proc. III Intern. Congr.
Human Genet. 53. (Abstr.).
Kanagawa, H., J. Muramoto, K. Kawata and T.
Ishikawa. 1965. Chromosome studies on heterosexual twins in cattle. I. Sex chromosome chimerism ( X X / X Y ) . Japan J. Vet. Res. 13:33.
Kerr, M. and M. N. Rashad. 1966. Chromosome
studies on spontaneous abortions. Am. J. Obstet.
Gyn. 94:322.
Kihlman, B. A. 1961. Biochemical aspects of chromosome breakage. Adv. Genet. 10:1.
Kjessler, B. 1965. Karyotypes of 130 childless men.
Lancet ii:493.
Knudsen, O. 1956. Chromosomen-Untersuchen bein
Bullen. Fortpflanzung, Zuchthygiene and Haustierbeiamung. 6, No. I.
Koulischer, L. and S. Frechkop. 1966. Chromosome
complement: A fertile hybrid between Equus
przewalskii and Equus cabaT,lus. Science 151:93.
LeComte, C. and A. De Smul. 1952. Effect du r6gime
hypoproteique sur la teneur en acide d~soxyribonucl~ique des noyau hfipatique chez la rat jeune. C.
R. Acad. Sci. (Paris) 234:1400.
Lehman, J. M., I. MacPherson and P. S. Moorhead.
1963. Karyotype of the Syrian hamster. J. Nat.
Cancer Inst. 31:639.
Lejeune, J., M. Gautier and R. Turpin, 1959, Etude
CHROMOSOMAL ABERRATIONS
des chromosomes somatiques de neuf enfants m o n goliens. C. R. Acad. Sei. (Paris) 248:1721.
Lejeune, J., J. Lafcurcade, R. Berger and R. Turpin.
1964. S@r6gation familiale d'une translocatinn .-5-13
d61erminant une monosomie et une trisomie partielles du bras court du chromosome 5. Maladie
du "cri flu chat" et sa "reciprnque." C. R. Acad.
Sci. (Paris) 258:5767.
Leuchtenberger, C., H. F. Helweg-Larsen and L.
Murmanis. 1954. Relationship between hereditary
pituitary dwarfism and the formation of multiple
desnxyribose nucleic acid (DNA) classes in mice.
I,ab. Invest. 3:24.-5.
Lillie, F. R. 1916. The theory of the free-martin. Science 43:611.
London Conference. 1963. The normal h u m a n karyotype. J. Hered. 54:158.
Lucas, M., N. H. Kemp, J. R. Ellis and R. Marshall.
1963. A small autosomal ring chromosome in a
female infant with congenital malformations. Ann.
H u m . Genet. 27:189
Lutz, H. and Y. Lutz-Ostertag. 1959. Free-marfinisme
sonntam? chez les oiseaux, l)evelop. Biol. 1:364.
Lyon, M. F. 1962. Sex chromatin and gene action in
the m a m m a l i a n X-chrnmosome. Am. J. t t u m a n
Genet. 14:135.
Lyon, M. F. and R. Meredith. 1966. Autosomal
translocatinns causing male sterility and viable
aneuplnidy in the mouse. Cytogencties 5:335.
Makino, S. 1951. An Atlas of the Chromosome N u m bers in Animals. Iowa State College Press, Ames,
Iowa.
Manna, G. K. and M. Talukrlar. 1964. C h r o m , s n m a l
polymorphism in the guinea pig, Carla porcellus.
Exoerientia 20:324.
Manuel, M. A., A. Allie and W. P. U. Jackson. 1965.
A true hermaphrodite with X X / X Y chrnmosomc
mosaicism. S. A. Medical J. 411.
Marden, P. H., 1). W. Smith and M. J. McDnnakt.
1964. Congenital abnormalities in the newborn infant including minor variations. J. Paediatrics
64:357.
Matthcy, R. 1958. Lcs chromosomes des mammifcrbs
euth~rians lisle critique et cssai sur l'dvolutinn
chromosomique. Arch. Klaus. Stiff. Vercb Fnrsch.
33:253.
Matthey, R. 1963a. Intraspeciflc and int,'aindividual
chromosomal polymorphism in Acomys ruinous
bate ( M a m m a l i a - R o d e n t i a - M u r i d a e ) . Cytological
studies of Acomys minou.~ X Acomys cahirinus
hybrids. The mechanism of centric fusions. Chromosoma 14:468.
Matthey, R. 1963b. Intraspecific chromosomal polvmorphism in a m a m m a l , Leggada minutoides Smith
(Rndentia-muridae~. Rev. Suisse Znol. 70:173.
Matthcy, R. 1963c. Cytologic co,npar6e et poly m o r phisme chrnmosomique chez des Mus africains
apartcnant aux ~roupes Bu/o-triton et Minutoides
( M a m m a l i a - Rodentia ). Cytogenetics 2 : 290.
Matthey, R. 1965. A new type of multiple sex chromosomes in an African mouse of the Mus (Leggada) minutoides ( M a m m a l i a - R o d e n t i a ) group.
Male:X~X~Y. Fcmale:X,X._./X,X=. C h r o m o s o m a
16:351.
Maclean, N., D. G. Harnden, W. M. Court Brown,
J. Bond and D. J. Mantle. 1964. Scx chromosome
abnormalitics in newborn baltics. Lancet i:286.
McCnnnell, J., N. S. Fechheimer and L. O. Gilmore.
1963. Somatic chromosomes of the domestic pig.
J. Animal Sei. 22:374.
McFee, A. F., M. W. Banner and J. M. Rary. 1966a.
49
Variation in chromosome n u m b e r a m o n g European
wild pigs. Cytogenetics 5:75.
McFee, A. F., M. Knight ami M. W. Banner. 1966b.
An intersex pig with X X / X Y leucocyte mosaicism.
Canada J. Genet. ('ytnl. 8:.-502.
McFeely, R. A. 1966. A direct method for the display
of chromosomes from early pig embryos. J. Reprod.
Fertil. 11:161.
McLaren, Anne. 1960. New evidence of unbalanced
sex-chromosome constitutions in the mouse. Genet.
Res. 1:253.
Meylan, A. 1964. l,e polymorphisme chromosomique
dc Sorex araneus I,. Rev. Suisse de Zool. 71:903.
Millard, R. E. 1965. Abnormalities of h u m a n chromosprees following therapcutic irradiation. Cytogenetics 4:277.
Miller, J. R. and F. J. Dill. 1965. The cytogenetics of
mongolism. Intern. Psychiatry Clinics 2:127.
Miller, O.. J. Breg, R. D. Schmiekel and W. Tretter.
1961. A family with an X X X X Y male, a leukaemic
male and two 21-trisomic mongoloid females.
Lancet if: 78.
Mittwnch, U. 1964. Sex chromatin. J. Med. Genet.
1:50.
Mittwoch, U. 1967. Sex Chromosomes. Academic
Press, New York.
Moore, M. A. S. and J. J. T. Owen. 1965. Bovine
freemartins and true hermaphroditism. Lancet
i:1163.
Meorhead, P. C., P. C. Nowell, J. Mellman, D. M.
Battips and D. A. Hungerford. 1960. C h r o m o s o m e
preparations of leukocytes cultured from peripheral
b h o d . Exp. Cell. Res. 20:613.
Moses, M. J. and G. Yerganian. 1952. Desoxypentose
nucleic acid (DNA) content and cytotaxonomy of
several cricetinae (hamsters). Rec. Genet. Snc. Am.
21:.51. (Abstr.).
M u t t o n , D. E., J. M. King and J. I,. Hamerton.
1964. ( ' h r c m c s o m e studies in the genus Equus.
M a m m a l i a n Chromosome Newsletter. No. 13.
Nichols. W. W. 1966. T h e role of viruses in the
etiology of chromosomal abnormalities. Am. J.
14uman Genet. 18:1.
Nichols, W. W., A. Levan, L. L. Coriell, H. Gnldner
and C. G. Ahlstr~im. 1964. Chromosome abnormalities in vitro in h u m a n leukocytes associated with
Schmidt-Ruppin Rous Sarcoma Virus. Science
146:248.
Nowell, P. C. and D. A. Hungerford. 1960. A minute
chromosome in h u m a n chronic granulocytic leukemia. Science 132 : 1497.
Ohnn, S., J. Jainchill and C. Stenius. 1963. The creeping vnle (Microtus oregonia) as a gonosomic
mosaic. I. The O Y / X Y constitution of the male.
Cytngenetics 2:232.
Ohnn, S., J. M. Trujilln, S. Stenius, L. C. Christian
and R. I,. Teplitz. 1962. Possible germ cell chimeras
a m o n g newborn dizygntic twin calves. (Bos taurus).
Cytngenetics 1 : 258.
Overzier, C. 1963. The so-called true Klinefelter's
syndrome. In C. Overzier ]ed.] Intersexuality
Academic Press, London and New York.
Owen, R. D. 1945. Immunogenetic consequences of
vascular anastomoses betwecn bovine twins. Science 102:400.
Padch, B., M. Wvsoki and M. Snllcr. 1965. An
X X / X Y hermaplarodite in the gnat. Israel J. Med.
Sci. 1 : 1008.
Patau, K., D. W. Smith, E. T h e r m a n , S. L. Inhorn
and tl. P. Wagner. 1960. Multiple congenital
50
FECHHEIMER
anomaly caused by an extra autosome. Lancet
i:790.
Penrose, L. S. 1963. The Biology of Mental Defect.
Sidgwick and Jackson, London.
Penrose, L. S. 1966. H u m a n Chromosomes, Normal
and Aberrant. Proc. Roy. Soc. (B). 164:311.
Pik6, L, 1961. Polyspermy in animals. Ann. Biol. An.
Biochim. Biophys. 1:323.
Polani, P. E., J. H. Briggs, C. E. Ford, M. Clarke
and J. M. Berg. 1960. A mongol girl with 46
chromosomes. Lancet ii: 721.
Riley, R. 1966. Genetics and the regulation of meiotic
chromosome behavior. Sci. Prog 54:193.
Ris, H. and A. E. Mirsky. 1949. Quantitative cytochemical determination o1 desoxyrihose nucleal reaction. J. Gcn. Physiol. 33:125.
Robertson, W. R. B. 1916. C h r o m o s o m e studies. I.
Tax(~nomic relationships shown in the chromosomes
of Tettigidae and Acridiae: V-shaped chromosomes
and their significance in Acridiae, Locustidae, Gryllidae; chromosomes and variation. J. Morph.
27: 179.
Rohinson, A. and T. T. Puck. 1965. Sex chromatin
in newborns: Presumptive evidence for external
factors in h u m a n non-disjunction. Science 148:83.
Rowley, P. T., R. Marshall and J. R. Eliis. 1963. A
genetical and cytological stud)" of repeated spontaneous abortion. Ann. H u m . Genet. 27:87.
Russell, L. B. 1962. Chromosome aberrations in experimental mammals. Progr. Med. Genet. 2:230.
Russell, L. B. and E. H. Y. Chu. 1961. An X X Y
male in the mouse. Proc. Nat. Acad. Sci. 47:571.
Russell, I,. B. and W. L. Russell. 1960. Genetic analysis o1 induced deletions and of spontanet~us nondisjunction involving chromosome 2 o1 the mouse.
J. Cell. Comp. Physiol. 56:169.
Russell, L. B. and C. L. Saylors. 1961. Spontaneous
and induced abnormal scx chromosclme n u m h e r in
the mouse. Genetics 46:894. (Abstr.).
Sachs, Let). 1952. Polyph)id evolution and m a m m a l i a n
chromosomes. Heredity 6:357.
Saksela, E. and P. S. Monrhead. 1962. E n h a n c e m e n t
o1 secondary constrictions and the heterochromatic
X in h u m a n cells. Cytogenetics 1:225.
Salisbury, G. W. 1965. Aging phenomena in gametes.
A review. J. Geront. 20:281.
Salisbury, G. W. and F. H. Flerchinger. 1961. In vitro
aging of spermatozoa and evidence for embryonic
or early fetal m~)rtality in cattle. Proc. IV Intern.
Congr. An. Reprod. III:601.
Sato, H. 1965. Chromosome studies in abortuses.
Lancet i: 1280.
Schmid, W. 1962. A familial chromosome abnormality
associated with repeated abortions. Cytogenetics
1:199.
Sczulman, A. E. 1965. Chromosomal aberrations in
sonntaneous h u m a n abortions. New England J.
Med. 272:811.
Sharman, G. B. 1956. C h r o m o s o m e s of the c o m m o n
shrew. Nature 177:941.
Smith, J. B., S. H. W a x m a n and I). Arakaki. 1966.
Cytogenetics of early fetal cteath in Hawaii. Proc.
III Intern. Congr. H u m a n Genet. 93. (Abstr.).
Soller, M., M. Wysoki and B. Padeh. 1966. A chromosomal ahnormality in phenotypically normal Saanen
goats. Cvtogenetics 5 : 88.
Soukup, S. W., E. Takacs and J. Warkany. 1965.
C h r e m o s o m e changes in rat embryos following
X-irradiatinn. Cytogenetics 4 : 130.
Sparkes, R. S. and D. T. Arakaki. 1966. Intrasubspecific and intersubspecific chromosomal polymorphism in Peromyscus maniculatus
(Deer
mouse). Cytogenetics 5:411.
Steblfins, G. L. 1966. Chromosomal variation and
evolution. Science 152 : 1463.
Swartz, F. J. 1956. The development in the h u m a n
liver of multiple desoxyribose nucleic acid ( D N A )
classes and their relationship to the age of the
individual. C h r o m o s o m a 8:53.
Swartz, F. J. and J. D. Ford, Jr. 1960. Effect of
thyroidectomy on development of polyploid nuclei
in rat liver. Proc. Soc. Exptl. Biol. Med. 104:756.
Swartz, F., B. F. Sams and A. G. Barton. 1960. Polyploidization of rat liver following castration of
males and females. Exp. Cell. Res. 20:438.
Swift, H. H. 1950. The desoxyribose nucleic acid
content of animal nuclei. Physiol. Zool. 23:169.
Tarkowski, A. K. 1964. True hermaphroditism in
chimaeric mice. J. Emryol. Exp. Morph. 12:735.
Thiede, H. A. and H. B. Salm. 1964. Chromosome
studies of h u m a n sl~ontaneous abortions. Am. J.
Ohstet. and Gyn. 90:205.
Thornycroft, H. B. 1966. Chromosomal polymorphism
in the white-thrnated sparrow, Zonotrichia albicollis (Gmelin). Science 154:1571.
Thuline, H. C. 1964. Male tortoiseshells, chimerism
and true hermaphroditism. J. Cat Genet. 1(4):2.
Thuline, H. C. and 1). E. Norby. 1961. Spontaneous
occurrence of chromosome abnormality in cats.
Science 134: 554.
Townes, P. L., N. A. Ziegler and L. W. l,enhard.
1965. A patient with 48 chromosomes ( X Y Y Y ) .
Lancet i: 1041.
Trujillo, J. M., R. S. Zeller, R. A. Plessala and B.
IAst-Young. 1966. Translocation heterozygosis in
man. Am. J. H u m a n Genet. 18:215.
Uchida, I. A. and J. M. Bowman. 1961. X X X 18
trisomy. Lancet ii: 1094.
Uchida, I. A., H. C. W a n g and M. Ray. 1964. Dizygotic twins with X X / X Y
chimerism. Nature
204:191.
Valenti, C. 1965. Cytogenetic analysis of abortuses
following maternal rubella. Am. J. Obstet. Gyn.
91:1141.
Valloton, M. B. and A. P. Forbes. 1967. A u t o i m m u nity in gonadal dysgenesis and Klinefelter's syndrome. Lancet i:648.
W a h r m a n , J. and A. Zahavi. 1955. Cy*ological contributions to the phylogeny and classification of
the rodent genus Gerbillus. Nature 175:600.
Welshons, W. J. and L. B. Russell. 1959. The Y
chromosome as the bearer of male determining factors in the mouse. Proc. Nat. Acad. Sei. 45:560.
White, M. J. D. 1954. Animal Cytology and Evolution (2rid ed.). Cambridge University Press, Cambridge, England.
Witschi, E. 1960. Sex reversal in animals and in man.
Am. Sci. 48:399.
Witschi, E. and R. Laguens. 1963. Chromosome aberrations in embryos from overripe eggs. Develop.
Biol. 7 : 605.
Yosida, T. H. and K. Amano. 1965. Autosomal polymorphism in laboratory bred and wild Norway
rats, Rattus norvegicus, found in Misima. Chrom o s o m a 16:658.
Z a r t m a n , D. L. and N. S. Fechheimer. 1967. Somatic
aneuploidy and oolyo~oidv in inbred and linecross
cattle. J. Animal Sci. (In Press.).