Extra Autosome Research Articles

Asynchronous replication of alleles in genomes carrying an extra autosome.

Transcriptional activity of genes appears to be highly related to their replication timing; alleles showing the common biallelic mode of expression replicate highly synchronously, whereas those with a monoallelic mode of expression replicate asynchronously. Here we used FISH to determine the level of synchronisation in replication timing of alleles in amniotic fluid cells derived from normal foetuses and from those with either of the trisomies for autosomes 21, 18 or 13, or for sex chromosomes (47,XXX and 47,XXY). Two pairs of alleles, not associated with the extra chromosome, were studied in subjects with each trisomy and three in normal subjects. In cells derived from normal foetuses and from foetuses with sex chromosome trisomies, each pair of alleles replicated synchronously; yet these very same alleles replicated asynchronously in cells derived from foetuses with trisomy for any of the three autosomes studied. The results suggest that the gross phenotypic abnormalities associated with an extra autosome are brought about not only by over-expression of genes present in three doses, but also by modifications in the expression of genes present in the normal two doses.

Cryptorchidism and Marker Chromosomes: Identification of Marker Chromosomes by Fluorescence in situ Hybridization

Identification of marker chromosomes by fluorescence in situ hybridization was performed in 2 cases of cryptorchidism. In case 1, the marker chromosome was derived from chromosome 22. In case 2, the origin of the marker was the centromere of chromosome 8. The extent of the congenital anomalies in these cases was milder than that in cases with complete trisomy of an autosome. These findings suggest that an incomplete extra autosome might influence clinical characteristics.

Gliogenesis and Myelination in the Optic Nerve of Trisomy 19 Mice

Trisomy 19 (ts19) of the mouse permits detailed studies on the influence of an extra autosome upon the postnatal development of the central nervous system. To examine gliogenesis and myelinogenesis, the optic nerves of 19 ts19 pugs aged 1-15 days have been examined by light and electron microscopy and compared to those of litter-mate controls. Differentiation of astrocytes and oligodendrocytes, myelinogenesis as well as the opening of the eyes are each delayed by about 2 days. Myelin sheaths are normally structured in ts19. There is a decrease in the percentage of myelinated fibres. The cross-sectional area of the ts19 optic nerve is reduced. The fibre density, which decreases with age both in ts19 and control mice, is higher in ts19 mice. Both with ts19 and control animals, the distribution of fibre diameters of myelinated axons overlaps with that of promyelinated and unmyelinated fibres, but myelinated axons cannot be observed below a diameter of 0.3 micron, and unmyelinated axons are always smaller than 1 micron. The mean diameter of promyelinated axons is identical in ts19 and control animals. Myelination is therefore not severely disturbed in the ts19 optic nerve. As retinal differentiation in ts19 is delayed by 2 days as well, reports on an asynchronous development of neurons and myelin sheaths cannot be confirmed for the visual system.

Anatomical analysis of the developmental effects of aneuploidy in man: the Down syndrome.

Detailed anatomical dissections of five Down syndrome (DS) bodies revealed a unique and consistent "internal phenotype" composed of: 1) variations in muscles, 2) peripheral artery variations, and 3) the presence of dilatations and nerve rootlets associated with the spinal accessory and first cervical nerves. Most of these variations may occur occasionally in the normal population, but their more frequent occurrence in the five DS cases provides further support for Shapiro's (1975) hypothesis that one effect of the extra autosome is to increase the instability of normal developmental processes. Three of the variations: 1) the presence of an extra facial muscle, 2) multiple vertebral arteries, and 3) the presence of dilatations and nerve rootlets associated with the spinal accessory and 1st cervical nerves, may be the result of a failure of regression of otherwise transient embryonic structures. A variation of the midfacial muscles of expression, explained as an arrest in development, has not been described previously and, to date, remains a manifestation unique to the trisomy 21 phenotype. Aside from their use in developmental speculation, the sum of these variations may be useful for corroborating diagnoses of suspected post-mortem cases of the DS without cytogenetic confirmation.

Partial trisomy 14q-- and pseudoxanthoma elasticum.

An adolescent mentally retarded child with short stature is described. Clinical and histological features of pseudoxanthoma elasticum (PXE) were present in the skin. Karyotype examination revealed an extra autosome roughly comparable in size to a G group chromosome. Detailed fluorescent and Giemsa banding analysis identified the extra chromosome as a 14q‐. It is probable that many other reported cases of non mongoloid trisomy involving G‐sized autosomes are similar to this case and are associated with partial trisomy of D group chromosomes. Viability and severity of abnormalities will depend on how much euchromatin has been deleted.

A 61,XY Cell Line in a Calf with Extreme Brachygnathia

Cells from kidney and adrenal tissues of a male calf with extreme brachygnathia inferior were grown in tissue culture for a chromosome study of this birth defect. Six of 17 metaphases with a 61,XY complement were karyotyped. The extra autosome was a large acrocentric of the A group. This finding provides further evidence that a chromosomal defect is associated with some forms of brachygnathia inferior in cattle.

Trisomy C in an infant with polycystic kidneys and other malformations

A female infant of non-consanguineous, healthy 40-year-old parents without family history of renal disease died one hour after birth following a 38 week gestation. She had a peculiar facial appearance with a flattened nasal bridge, epicanthic folds, micrognathia, and low-set ears. She also had a midline cleft palate, hyperextensible joints, and bilateral hip dislocation. The most significant finding at autopsy was bilateral polycystic disease of the kidneys, shown to be Potter's type II. The ovaries were also multicystic. Leukocyte culture showed the presence of 47 chromosomes, with an extra autosome in group C; there was no evidence of mosaicism. This is the first report of a viable infant with non-mosaic trisomy for a group C autosome.

Two generations of 13-15 chromosomal mosaicism: possible evidence for a genetic defect in the control of chromosomal replication

An identical nontranslocation autosomal mosaicism occurring in two consecutive generations is presented. A mother and two of her four daughters have been demonstrated to be 46/47 mosaics. The trisomic cells have an extra autosome in the 13–15, or D, group. The proband and one of her sisters reveal varying phenotypic expressions of the trisomic state. The mother and her two other daughters are phenotypically normal. The observation of 46/47 chromosomal mosaicism in man in a pattern which suggests that it is under genetic control necessitates the introduction of a new theory since it cannot be explained by earlier hypotheses which are directed towards understanding the chance occurrence of an individual mosaic. The rapidly accumulating evidence of the nonrandomness of chromosomal abnormalities points towards a possible defect in primary gene control of DNA replication. It is theorized that a gene which regulates the replication of a chromosome in the 13–15, or D, group is defective and that, as a result, this chromosome replicates twice instead of once during some, but not all mitoses, producing a mosaic of trisomic and normal cells. Presumably, the postulated mutant gene is present in the heterozygous state in the affected individuals and behaves as a dominant, with half of the children of an affected parent being abnormal.

CHROMOSOMAL ABNORMALITIES AND ORAL ANOMALIES.

W ITH the discovery that man has not fortyeight but forty-six chromosomes [I], interest in human chromosomes and the conditions that arise from their abnorma1 behavior has mushroomed.. (The reader is referred to severa exceIlent reviews of the present status of the knowledge of human chromosomes [~-IO].) There are severa autosoma1 and sex chromosome syndromes in which there is at Ieast some evidence of ora anomaIies and, in a11 probabiIity, more wiI1 be discovered. It had been thought unti1 recentIy that the presence of an extra autosome in the chromosoma compIement of forty-six wouId be IethaI; but with the discovery that mongoIism was associated with an extra autosome in the 21 to 22 group, this concept was shown to be erroneous [II]. Now that technics for chromosome counting have become considerabIy easier and are more frequentIy performed on periphera1 bIood {rz-141 or skin [r5,r6], use of the various technics is becoming widespread. SeveraI surveys, such as that of Gustavson and ikesson [17], have shown that many of these syndromes are more common than heretofore supposed. In newborns, the XXY or KIinefeIter syndrome is present in 0.3 per cent of the cases, the X0 chromatin-negative Turner syndrome* in 0.03 per cent and the XXX syndrome in 0.13 per cent. In institutionaIized individuaIs the incidence is 1.0, 0.05 and 0.4 per cent, respectiveIy [IS]. Trisomy 21 (mongoIism) accounts for at Ieast IO per cent of institutionaIized individuaIs.

The 18-trisomy syndrome -- two new clinical variants. One with associated tracheoesophageal fistula and the other with probable familial occurrence.

THE autosomal trisomy syndrome of numerous congenital anomalies associated with a modal chromosome number of 47, the extra chromosome being either number 17 or 18, is now well established.1 Rece-t reports1 2 3 4 have differed in the identification of the extra autosome, some favoring a designation as, number 181 , 2 and some favoring, number 7.3 , 4 Although precise identification is difficult if not impossible, analysis of the idiograms reported below suggested the extra autosome to be number 18. This symptom complex is therefore referred to asromy 18.The sources cited above have agreed, however, on the major systems involved in most of the . . .

Chromosomal Abnormalities and Their Relation to Disease

When human chromosome anomalies were first described in 1959, it appeared that specific abnormalities might be correlated with specific syndromes. Mongolism and the D and E syndromes are examples of specific syndromes associated with the presence of an extra autosome. Klinefelter's syndrome may be associated with a variety of different sex chromosome anomalies including XXY, XXYY, XXXY and XXXXY. The lastnamed variant is the only one that frequently presents features distinguishing it from the others. An XO sex chromosome complex is found in many women with gonadal dysgenesis. However, a variety of mosaicisms have been described in association with this condition, including XO/XX, XO/XXX, XO/XX/XXX, XO/XY and XO/XYY. Extra X chromosomes in phenotypical females do not seem to impair fertility or be consistently associated with congenital anomalies. Two families are described in which chromosome anomalies were found, but the association with defects was irregular. In one family the abnormality involved one of the number 16 chromosomes and in the other it involved one of the small acrocentric chromosomes.

An apparently identical extra autosome in two severely retarded sisters with multiple malformations.

Two female siblings, aged 5½ years and 7½ years, with similar clinical and apparently identical cytological findings are presented. They had marked mental deficiency, severe retardation in growth and development, microcephaly, cleft palate, micrognathia and low-set malformed ears. The younger one expired during the course of the study and autopsy revealed an atrial septal defect of the secundum type. Cells from peripheral blood cultures of both patients and cells from cultures of several different organs of the deceased patient consistently had 47 chromosomes. The extra small autosome could not be identified with certainty. It closely resembles one of the small acrocentrics, but the signs and symptoms of the two patients were quite different from those reported to be associated with trisomy for chromosome 21 (mongolism) or 22. Alternatively, it could be a deleted member of another group. As there are some clinical and pathological similarities to the syndromes associated with trisomy in groups 13–15 and 17–18, it is possible that this extra autosome is a deleted member of one of these groups. This is the second report of an extra autosome occurring in siblings except in mongolism.

MULTIPLE CONGENITAL ANOMALY ASSOCIATED WITH AN EXTRA AUTOSOME

MULTIPLE CONGENITAL ANOMALY ASSOCIATED WITH AN EXTRA AUTOSOME

MULTIPLE CONGENITAL ANOMALY CAUSED BY AN EXTRA AUTOSOME

MULTIPLE CONGENITAL ANOMALY CAUSED BY AN EXTRA AUTOSOME

The nature of the influence of x-translocations on sex of progeny in Sciara coprophila.

1. A reciprocal translocation between chromosomes X and II in S. coprophila was used to elucidate the occurrence of exceptional sons and daughters among the progeny of females heterozygous for any one of several X-translocations. 2. The studies support the view that the exceptions result from non-disjunction of sex chromosomes during oogenesis and not from genetic change induced by rearrangement on the X. 3. The percentage of exceptions was found to increase when chromosomal rearrangements were used to decrease synapsis of the sex chromosomes. Conversely, when the barrier to sex chromosome pairing was removed, by making the translocation homozygous, the exceptions did not occur. 4. The studies support the view that (1) the X′ influence on sex of progeny is one on sex chromosome elimination from the embryonic soma, and (2) sex of the individual fly is determined by the chromosome complement which remains in the soma after elimination. 5. Provided there are two sex chromosomes in the somatic complement, differentiation of the ovary is normal even when an extra sex chromosome is present in the germ line. Likewise, the testis differentiates normally provided the somatic complement is XO (maternal X) even when an extra autosome is present in the germ cells. 6. When an additional sex chromosome is transmitted to the zygote (i.e., 4 sex chromosomes present), errors may occur in the kind or the number of chromosomes eliminated from the embryonic soma. No errors in elimination of chromosomes from the germ line have been detected.

Half-and-half mosaics in the Fowl

1. A half-and-half mosaic pullet (case N) from the cross Rhode Island Red ♂ x Light Sussex ♀ is described. The right side of the bird shows all the characters to be expected in a pullet from this cross. The left side is abnormal in the following ways: (i) The shank is yellow instead of white. (ii) The plumage is a darker shade of reddish brown. (iii) The feathers, especially the flight feathers of the wing, have a frayed appearance, due to imperfectly formed barbules. (iv) The whole of the left side of the body is very much smaller than the right, and the limb bones, in particular, are abnormally proportioned. 2. Two females are described which are asymmetrical only in respect of the length of the legs. One of these had originally been regarded as a mosaic, but it now appears that in both cases a copper ring accidentally left too long on the right shank of the young chick hss been the cause of hypertrophy of the right tarsometatarsus and tibiotarsus. 3. The twenty-three known half-and-half mosaic fowls are discussed in relation to the theory of Crew & Munro, which postulates that all such cases are due either to elimination, or to non-disjunction, of a single autosome at first cleavage. The following objections to this theory are pointed out: (i) The data available on the proportions of the limb bones in several cases are inconsistent with the requirements of the theory. (ii) At least five cases, and probably six, are mosaic in respect of a sex-linked character. (iii) Three cases are mosaic in respect of more than one autosomally inherited character (apart from size). In no case do linkage data support the idea that the genes concerned are all situated on the same chromosome, and it is unlikely that this could be true in all cases. (iv) The theory requires unsupported assumptions about the dosage relations between alleles at two loci. (v) The theory assumes that an extra autosome above the normal diploid number will tend to swing the sex in a male direction; this is the reverse of what is to be expected on the sex-chromosome: autosome balance theory of sex determination. 4. An attempt is made to find plausible and consistent explanations for as many as possible of the known cases. These are clearly due to a diversity of causes, and fall into two main types: (i) Those in which somatic segregation has occurred at first cleavage in an otherwise normal zygote. In some, the somatic segregation has taken the form of maldistribution (elimination or non-disjunction) of a single pair of autosomes, or possibly of somatic crossing-over. Simple somatic gene-mutation may account for a few cases. In others (gynandromorphs) elimination of an X-chromosome has occurred. In yet others, multiple irregularities in the distribution of the autosomes seem to have occurred; to this cause are assigned only those cases (of which N is one) which cannot be satisfactorily explained in any other way. (ii) Those originating from a compound zygote; more specifically, in which one side of the body is of purely paternal origin (and diploid), the other side being of normal bisexual origin. This may, or may not, lead to gynandromorphism. 5. The explanations suggested for individual mosaics are all open to some degree of doubt. Certain other difficulties remain, notably the absence of any gynandromorphs genetically female on the right side. There is also some difficulty in reconciling the irregular type of mosaic found in some species of bird (pigeon, turkey) with the bilateral half-and-half characteristic of other species (fowl, finches).