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Reproductive fitness of carriers of heterochromatic variants of the human karyotype was found to be normal. The method was based on a comparison between known carriers and known non-carriers from the same pedigree in respect of live births, generation time and survival of offspring to reproductive age. A subset of the data had been included in an earlier study in which reproductive fitness of carriers was found to be significantly reduced. Our analysis suggests that the result may have been fortuitous, since it was not supported by the additional data. There was no evidence of heterogeneity between carriers of different types of variant or of different sex. There were indications of increased fetal losses to carriers, but the number of spontaneous abortions was insufficient to produce a detectable effect on gross reproductive fitness.

The segregation of human phosphoglycolate phosphatase has been studied in 52 independent human-rodent hybrids and 69 subclones. The results suggest that human PGP is on chromosome 16. Family data suggest that PGP is not close to 16qh or alpha Hp. The most likely regional assignment for PGP would appear to be 16p13 or 16p12, but a site on 16q cannot be entirely excluded. New data on 16qh and alpha Hp suggest that the male recombination fraction between these loci is about 0.2.

A family is described in which the mother, her two live offspring, and a therapeutically aborted fetus each had a ring 14 chromosomes. The two children were mentally retarded and the mother's intelligence was at the lower end of the normal range. In addition, the mother had two spontaneous abortions, one of which was shown to be chromosomally normal.

The results of an IAEA coordinated programme on radiation induced chromosomal aberrations in human peripheral blood lymphocytes in vitro are presented. In a master experiment, a whole blood sample from one donor was irradiated with 200 R of X-rays. Different fixation times from 46 to 82 h were used. The progression of cells into mitosis was monitored by BrdUrd incorporation. 14 investigators took part in the scoring of chromosomal aberrations. The main conclusions of this study are: (1) The mean frequencies of aberrations changed with fixation time. (2) The number of cells scored as aberrant by different laboratories was very similar, but there was variability in the number of aberrations scored per aberrant cell. (3) The differences in the frequencies of aberrations between laboratories were minimal when the scoring was restricted to the first major peak of mitotic activity and sufficient cells were scored. It is concluded that using controlled experimentals conditions, human peripheral blood lymphocytes can effectively be used as a reliable biological dosimeter for absorbed radiation dose.

The incidence of chromosome aberrations in peripheral blood lymphocytes of 197 dockyard workers has been followed over a 10-yr period. These workers were exposed to mixed neutron-gamma radiation during the refuelling of nuclear reactors, but most exposures were below the internationally accepted maximum permissible level of 5 rem per yr. There was a significant increase in chromosome damage with increasing exposure; aberration frequency was a linear function of dose and was unfluenced by age and time of blood sampling after exposure.

We have failed to measure the recombination fraction between 9qh and the ABO:AK1 linkage group. Since the total male map distance along chromosome 9 is likely to be at least 120 cM, calculated from male chiasmata counts (Hultén, 1974) they may well not be within measurable distance of each other. ACONs does not lie between ABO and AK1, but there is so little information on this marker from family studies that it could lie almost anywhere else on chromosome 9 and might be within measurable distance of 9qh. The map of chromosome 9 based on studies on families with normal karyotypes is summarized in Fig. 1. We hope to improve this map in a subsequent paper based on observations on families with abnormal karyotypes.

A large family is described in which a (21q22q) Robertsonian translocation is segregating through three generations. The assessment of the risk of a translocation carrier producing an offspring with Down's syndrome is calculated from the data in this family and eight others reported in the literature. The risk when the translocation carrier is a female is approximately 6 in 100, or 0.06. For the male translocation carrier the risk can only be guessed, since the patients with Down's syndrome born to these parents were probands. The risk for Down's syndrome from the combined data of male and female translocation carriers in 3 is 100, or 0.03.

We present clinical, cytogenetic, and linkage data of four DNA probes from the terminal long arm of the X chromosome in ten new families with fragile X syndrome. A prior/posterior method of multipoint linkage analysis is employed to combine these results with published data to refine the linkage map of terminal Xq. Ten possible probe/disease orderings were tested. The order with the greatest posterior probability (0.78) of the five loci is 52a-F9-fragile X gene-DX13-St14, although the order with reversal of the positions of 52a and F9 has a posterior probability 0.15. The mean estimates of the distances between the probes and the fragile X gene are 38 cM and 33 cM for the proximal probes 52a and F9, and 8 cM and 12 cM for the distal probes DX13 and St14. Although the current method of choice in the prenatal diagnosis and carrier detection of the fragile X syndrome remains detailed cytogenetic analysis, consideration is given to the potential role of these DNA probes, both singly and in pairs.

G- and R-banded chromosome preparations from eight of twelve 46,XX males, with no evidence of mosaicism or a free Y chromosome, were distinguished in blind trials from preparations from normal 46,XX females by virtue of heteromorphism of the short arm of one X chromosome. Photographic measurements on X chromosomes and on chromosome pair 7 in cells from twelve 46,XX males, eight 46,XX females, and four 46,XY males revealed a significant increase in the size of the p arm of one X chromosome in the group of XX males, independently characterised as being heteromorphic for Xp. No such differences were observed between X chromosomes of normal males and females or between homologues of chromosome pair 7 in all groups. The heteromorphism in XX males is a consequence of an alteration in shape (banding profile) and length of the tip of the short arm of one X chromosome, and the difference in size of the two Xp arms in these 46,XXp+ males ranged from 0.4% to 22.9%. From various considerations, including the demonstration of a Y-specific DNA fragment in DNA digests from nuclei of one of three XX males tested, it is concluded that the Xp+ chromosome is a product of Xp-Yp exchange. These exchanges are assumed to originate at meiosis in the male parent and may involve an exchange of different amounts of material. The consequences of such unequal exchange are considered in terms of the inheritance of genes located on Yp and distal Xp. No obvious phenotypic difference was associated with the presence or absence of Xp+. Thus, some males diagnosed as 46,XX are mosaic for a cryptic Y-containing cell line, and there is now excellent evidence that maleness in others may be a consequence of an autosomal recessive gene. The present data imply that in around 70% of 46,XX males, maleness is a consequence of the inheritance of a paternal X-Y interchange product.

The distribution of satellite DNA and nucleolar organiser activity have been studied in a female with a new dicentric translocation chromosome derived from the maternal chromosomes 13 and 14. More than half the satellite DNA (60.5%) was lost in the translocation, together with both the nucleolar organiser regions (NOR'S). However, at least one NOR (chromosome 21) which was inactive in the mother (by the AgI reaction) is active in the subject, and this may be an example of functional compensation. The somatic cells of the mother of the subject, which do not have the translocation, show a high frequency of acrocentric associations, but these do not include any obvious excess of associations involving chromosomes 13 and 14, indicating that the high frequency of association in somatic cells is not in itself a predisposition to Robertsonian translocation in germ line cells. The father's chromosomes 9 both have more satellite DNA in the secondary constriction than normal, but this is not reflected in any obviously larger size of the C-band in this region.

Two families are described in which there is an inv(X) (p22q13) which has been transmitted for three generations. In one family (K482), no recombinants have been recovered and the inversion can be traced to a female born in 1839. In the second family (K491), a recombinant (X), dup q, has been recovered in a normal fertile woman. In both families the inverted X appears to be carrying the Xg allele. Despite extensive family studies no common ancestor has been found for the two families. The pattern of DNA synthesis has been studied in those individuals who are karyotypically 46,X,inv(X) (p22q13) and 46,X,rec(X)dup 1, inv(X) (p22q13); the selection of the abnormal as the late synthesizing X chromosome is random in the former and total in the latter. In some cells the two long arms of the recombinant X chromosome showed asynchrony of DNA replication.

The incidence of the various classes of C-band and Q-band polymorphisms on ten pairs of chromosomes in the human complement have been investigated in three Scottish populations, two from the mainland (newborn and 14 year olds) and one, of individuals over 65 years, from an island in the Outer Hebrides. Although there is an overall similarity between the populations, there are some differences, especially with the island group. For all populations, over 90% of the C-band size variants fall within the medium class. Rather more variation is found in the Q-band intensity polymorphisms: the island population appears to have fewer Brilliant and Intense variants than do the other two groups, 2-9 per person as compared to 4-2 and 3-9 for the newborn and 14 year olds respectively; this may be an age difference rather than a population difference.

Some families with abnormalities of chromosome 9 have been combined with others from the literature to show that AK1 and ABO must lie near the end of that chromosome. Current evidence suggests that both lie in band 9q34. MNSs, GPT and Gc can be excluded from chromosome 9.

The results of a chromosome survey of 3993 liveborn infants, the majority of which have been studied using G-banding, are reported. The frequency of all types of chromosome abnormalities detected was similar to that found in previous newborn surveys, which were carried out on different socio-economic structure, but the incidence of aneuploid chromosome abnormalities was comparable in the two localities.

The analysis of two rodent X human somatic cell hybrids, carrying different inborn translocations of the human chromosome 14 long arm, has permitted us to narrow down the localization of the structural locus for alpha-1-antitrypsin (PI) to band 14q32.1, proximally to the highly polymorphic DNA locus D14S1 which has been localized by previous studies between 14q32.1 and 14q32.2. These data, evaluated in conjunction with other published information, suggest that the D14S1 locus is cytologically equidistant from both the PI locus and the complex locus for the immunoglobulin heavy chains (IGH) but, genetically, it appears much closer to the latter since the recombination frequency reported between the IGH complex and PI is six times greater than that between the IGH complex and D14S1 (lod score peaks respectively at 26% and 4% with narrow fiducial limits). The present report adds further strength to the frequently proposed hypothesis of a nonlinear relationship between cytologic and genetic distances of human genes. The possibility that this phenomenon may be a feature of frequent occurrence throughout the entire human genome is discussed.

Chromosome analysis using G-banding was carried out on cells from 65 males and 102 females of all ages from a random sample of the population. The frequency of aneuploid cells showed a significant increase with age in both sexes, and in females the increase in hypodiploidy and hyperdiploidy was more marked than in males, and involved a high proportion of cells that had lost or gained an X chromosome, 45,X cells being much more common than 47,XXX cells. In females, the occurrence of a "fragment" of an X chromosome also correlated with increasing age, and this "fragment" appears to be an X chromosome that has simply divided prematurely at the centromere. The effects of time in culture and of repeating cultures of blood samples from the same individual on proportions of abnormal cells of various types were also investigated, and the results are discussed in the light of findings from several other "ageing surveys".

The segregation of the Q-band polymorphisms in 32 families have been studied. From 90 matings in these families, there were a total of 208 offspring. In one of these offspring it could be shown that there had been a change of a fluorescent polymorphism, resulting in the loss of fluorescent intensity in the satellite of a chromosome 21. The origin of such a 'mutation' and a consideration of mutation rates is discussed.

Unstable chromosome aberrations induced by in vitro irradiation with zero plus seven low doses of 14.8 MeV D-T neutrons in the range 3.55-244 mGy have been analysed in human peripheral blood lymphocytes. In order to obtain the required large numbers of scored cells for such low doses, fourteen laboratories participated in the experiment. The dose responses for dicentrics, excess acentrics and total aberrations, fitted well to the Y = alpha D model. The alpha coefficient of yield for dicentrics, 1.60 +/- 0.07 X 10(-2) Gy-1, compares well with the values obtained in previous studies with D-T neutrons at somewhat higher doses. Results from a previous collaborative study using 250 kVp X-rays over a comparable dose range indicated the possible existence of a threshold below 50 mGy. In the present study there is no clear evidence for neutrons for such a threshold. However, the data were insufficient to permit the rejection of a possible threshold below approximately 10 mGy.

A severely mentally subnormal child with many physical stigmata was shown to have the karyotype 46,XY,-2,+der(2),t(2;10)(q31;q24)pat. Full evaluation of this patient's karyotype depended on the family studies. It was shown that a balanced translocation t(2,10) was present in 4 normal males in 3 generations.

1. Malic enzyme has been examined by starch-gel electrophoresis in human cultured fibroblasts and in 60 brain samples. The polymorphism of MEM has been confirmed and the electrophoretic pattern suggests that this enzyme, like MES, is a tetramer. 2. The appearance of the soluble and mitochondrial malic enzymes in mouse and Chinese hamster is described, and the identity of the enzymes in man, mouse and hamster has been established from a study of interspecific somatic cell hybrids. In man and in hamster MES migrates anodal to MEM, whereas in the mouse MES is relatively less anodal than MEM. 3. Segregation of human enzymes in human--mouse and human--hamster somatic cell hybrids confirms the synteny of MES and PGM3. Data from human--mouse hybrids suggest that MEM is probably not syntenic with MES is probably not syntenic with MES in man, nor is it syntenic with GPI.

Frequency distributions of fluorescence intensity of ethidium bromide stained human chromosomes from nine phenotypically normal males are cross correlated and autocorrelated following repeated flow cytometric measurements. It is shown that each individual donor produces a fluorescence profile which is both visually and numerically different from those of other individuals in the set. The wide variety of chromosome heteromorphisms which occur to varying degrees for chromosomes 1, 9, 13, 14, 15, 16, 21, 22 and Y give rise to the uniqueness of a given fluorescence profile. Estimates of chromosome heteromorphisms for each individual in the set were made and then compared with parallel results obtained from inspection of Q-banded and C-banded conventional metaphase preparations. Fluorescence profiles identifiable with each individual were also obtained for Hoechst 33258 stained chromosomes.

Lymphocyte chromosomes were examined in 36 patients with Alzheimer's presenile dementia, 36 healthy, age and sex matched controls, and 36 sex matched, non-demented, elderly controls, approximately 20 years older than the Alzheimer patients. Increased chromosome aneuploidy was found in females with Alzheimer's disease but not in male subjects. Chromosome abnormalities observed in female patients were similar to those observed in elderly controls, though in this latter group there was an increase in the frequency of cells that had lost an X chromosome. In the female Alzheimer patients and the elderly controls, there was an increase in the frequency of autosomal aneuploid cells but no single chromosome was preferentially affected. Because the chromosome abnormalities found in Alzheimer's disease are similar in nature but not as extensive as those observed in senescence in the absence of dementia, it is argued that chromosome aneuploidy is more likely to be related to processes concerned with ageing rather than being specifically linked to the dementia of Alzheimer's disease.

The inheritance of C-band and Q-band polymorphisms have been investigated in 32 families. C-band inversion and size polymorphisms appear to segregate in a Mendelian manner, with the possible exception of the very large variant of chromosome number 9 which may be selectively inherited. There is some evidence to suggest a preferential segregation of Brilliant Q-band polymorphisms but it may be that this is an artifact caused by insufficient data and scoring error.

In a coordinated research programme sponsored by the International Atomic Energy Agency, the frequencies of chromosomal aberrations induced in peripheral blood lymphocytes (in vitro) by 250 kV X-rays at low doses (0.4, 1, 2, 3, 5, 10 and 30 rad) were determined. Blood from 2 donors was used to conduct one master experiment at these dose levels. The culture time used was 48 h and all samples including the controls were processed according to a standard protocol. The coded slides were scored by investigators from 10 participating laboratories. The main results are the following: (1) the frequencies of all types of chromosome aberrations at 0.4 rad are significantly lower than the control values; (2) there is no increase in the frequencies of dicentrics up to 2 rad and in those of terminal deletions up to 5 rad; (3) the mean frequencies of all aberrations considered together are not significantly different from one another at 1, 2 and 3 rad (P = 0.05); and (4) over the entire dose range the dose-effect relationship is clearly non-linear. A fit of these data to a linear quadratic model (E(D) = c + alpha D + beta D2) showed that the observed total aberration frequencies at doses 1, 2, 3 and 5 rad are below the curve defined by the model. The deviations can be explained by an altered kinetics of aberration production at very low doses probably due to DNA repair mechanisms operating these cells.

A translocation of genetic material involving the long arm of the X chromosome and the heterochromatic portion of the Y chromosome is reported in a young woman. The phenotypic effect of this translocation and loss of almost half of the long arm of the X chromosome is described.

Lymphocyte chromosomes were examined in 20 women with Alzheimer's pre-senile dementia, 42 non-demented women of similar age and 31 women 15-20 years older than the Alzheimer patients and who were not demented, living independently in the community. Increased chromosome aneuploidy was found in Alzheimer's disease compared to age-matched controls, and this aneuploidy was of a similar nature and degree as that observed in controls 15-20 years older than the Alzheimer patients, though in this latter group there was an increased loss of chromosomes. No single chromosome was preferentially affected in Alzheimer's disease. Because similar chromosome aneuploidy was found in females with Alzheimer's disease and in senescence in the absence of dementia, the 'premature ageing' hypothesis of Alzheimer's disease was preferred rather than the hypothesis that chromosome aneuploidy and dementia arise on the basis of the same biochemical defect.

A family with two nucleoside phosphorylase-deficient patients has been scored for the segregation of NP0 and the variable region 14p. The mose likely 14p:NP recombination fraction is 0.15 in males and 0.30 in females. There is no family data to assign the Pi:Gm linkage group to chromosome 14, but as immunoglobulin heavy chain has been assigned to this chromosome by somatic cell methods the most likely gene order is 14p:NP:Pi:Gm with Pi in 14q2 and Gm in 14(q23 leads to q32), but the order 14p:NP:Gm:Pi with Pi in 14(q24 leads to qter) and Gm in 14(q22 leads to q24) is not excluded. The available linkage data between biochemical markers on acrocentric chromosomes and their short arm markers suggest that there may be more recombination towards the ends of human chromosomes whether or not those ends carry centromeres.

Information is presented which has been obtained from an exhaustive examination of 44 probands with a supernumerary marker chromosome (mar) and their families. The data include the derivation of the mar, frequency in various populations, inheritance and possible effect on fertility, congenital abnormality, and mental ability. The practical problems in assessing the risk of abnormality in a foetus discovered during prenatal diagnosis to be carrying a mar, are discussed.

The segregation of human enzymes and chromosomes has been studied in more than 30 independent primary human-rodent somatic cell hybrids and a series of 64 subclones. The results strongly suggest that the locus determining AK1, 'red cell' adenylate kinase, is on chromosome 9 in man, and hence that the locus for the ABO blood groups and that for the Nail-patella syndrome may also be assigned to this chromosome. Evidence is presented indicating that another adenylate kinase, nucleoside triphosphate adenylate kinase, and also the soluble form of aconitase, are probably syntenic with AK1, and that the mitochondrial form of aconitase is probably not syntenic with these loci.

The aberrations seen in chromosomes of human peripheral-blood lymphocytes, X-irradiated in vitro, have been analysed in three types of preparations, treated to give G-banding; R-banding; and G-banding followed by R-banding on the same cells. The data from cells subjected to both banding techniques reveals that 30 per cent of the sites of chromosome breakage are situated at he interfaces between dark- and - light-stained bands. The results of all the analyses show that approximately 30 per cent of all breaks were located in either the telomere (19-5 per cent) or centromere (11-3 per cent) regions. Chromosomes rich in R-band material were not preferentially damaged, but chromosomes 12, 15, and particularly 17, were involved in aberrations more frequently than would be expected on the basis of their length. No breaks were found on the Y chromosome in the 114 male cells analysed, but the X did not appear to be spared from damage either in the male cells analysed, but the X did not appear to be spared from damage either in the male cell or the 136 female cells analysed. G and/or R-banding enables a much more accurate analysis of aberrations than can be obtained from the use of conventional staining techniques, and with these methods, it is shown that the numbers of induced asymmetrical and symmetrical exchanges are similar.

Data from seven families carrying rearrangements and variants of chromosome 2 have been analysed in relation to the assignment of ACP1 and MNSs. The data are consistent with the regional assignment of ACP1 to 2p23, but not with that of MNSs to band 2q14.