Showing papers in "Annals of Human Genetics in 1969"

Further data on the adenosine deaminase (ADA) polymorphism and a report of a new phenotype

Abstract: In a study of human red cell adenosine deaminase (ADA) three different types of isozyme patterns were identified (Spencer, Hopkinson & Harris, 1968). One phenotype designated ADA 1 was found in about 89 % of the English population, the second phenotype, ADA 2-1, was found in about 11 yo of the population and the third phenotype, designated ADA 2, was seen only once in a survey of 580 unrelated English people. Sixty-seven families were studied and the family data suggested that the three ADA phenotypes were determined by two autosomal alleles ADA1 and ADA2; phenotypes ADA 1 and ADA 2 corresponding to the homozygous genotypes ADAlADAl and ADAaADA2 respectively and phenotype ADA 2-1 corresponding to the heterozygous combination ADA1ADA2. This paper contains further family data and more extensive population data on the ADA polymorphism and also a description of a new phenotype.

Population subdivision with respect to multiple alleles.

Abstract: In view of the current interest in studying human isolated populations and the fact that many human gene markers have multiple alleles, the writer thought that it would be helpful to have the problem of population subdivision discussed in more detail and hence stimulate further investigation. Although the problem under consideration seems at first sight purely genetical, an appropriate change of a few technical terms will render the problem identical with those of epidemiologists and sociologists studying the association of certain traits or diseases in specific (homogeneous) groups and in the combined (heterogeneous) group. It may be said that these problems are ‘isomorphic’. Thus, an investigationin one area has similar implications in the others. We shall illustrate these ideas very briefly for the case of two alleles before introducing multiple alleles.

The relation of measured intelligence to birth order and maternal age.

Abstract: This article examines the relationhip of verbal reasoning scores recorded for 48913 Birminghan children born in 1950-1954 to birth order and maternal age. It is shown that the scores are negatively correlated with sibship size and positively with maternal age. It is concluded that the association of measured intelligence with maternal age and birth order in a general population of children is determined mainly by differences between rather than within families. Therefore the negative correlation between sibship size and intelligence cannot be attributed substantially to variation in intelligence according to birth order or maternal age within sibships. The population was divided according to occupation of fathers into 3 social groups. Since distribution of children by mothers age and birth order is a distribution by social class the relation of scores to the 2 variables in a population of births is largely a reflection of the social class difference.

The relation of measured intelligence to birth weight and duration of gestation

Abstract: There have been two main approaches to investigation of the relation of birth weight to intelligence. In one, birth weights of children of low intelligence are compared with those of children of average or high intelligence. Where the comparison has been between children in ordinary schools, as in Ascher & Roberts’s study (1949) in primary, grammar and secondary schools, birth weight differences have usually been unimpressive or absent ; but among the subnormal, mean birth weight appears to be reduced and the reduction is present even after exclusion of those whose low intelligence is associated with physical abnormalities (Barker, 1966). The more usual approach has been to measure the intelligence of children of different birth weights. Numbers investigated by this procedure are, as a rule, rather small and the methods of analysis sometimes make it difficult to assess the results. However, the general conclusion which has been reached is that when children with physical abnormalities-such as blindness, deafness and cerebral palsy-are excluded, the intelligence of the remaining children of low birth weight is about normal (McDonald, 1964). In children of very low weights, however, intelligence appears to be reduced (Drillien, 1964). The relation of intelligence to duration of gestation is even less well established, but the contemporary viewpoint is probably summarized in Baird’s conclusion (1959) that ‘there is no clear indication that within wide limits premature expulsion from the uterus does the foetus any serious harm ’. The data used in the present investigation were described in a preceding paper (Record, McKeown & Edwards, 1969). Briefly, they are derived from observations on all (86,630) Birmingham live births in the period 1 January 1950 to 1 September 1954. Verbal reasoning scores from the results of the eleven-plus examinations were matched for 50,172 children and birth weight and duration of gestation (estimated to the nearest week from the first day of the last menstrual period) were available from obstetric records for 41,534 single births.

The investigation of reactive sulphydryls in enzymes and their variants by starch gel electrophoresis. Studies on red cell adenosine deaminase.

Abstract: Electrophoretic studies of adenosine deaminase (ADA) in human red cells have shown that several distinct isozymes can be demonstrated when a freshly prepared haemolysate from a single individual is examined. Furthermore, there are consistent person to person differences in isozyme pattern. Among Europeans one type of pattern known as ADA 1 is found in about 90 yo of the population, another known as ADA 2-1 in about 10 yo of the population, and a further type known as ADA 2 occurs in about 1 in 400 people. These three types appear to be determined by two autosomal allelic genes, ADA 1 and ADA 2 representing the respective homozygotes, and ADA 2-1 the heterozygote (Spencer, Hopkinson & Harris, 1968). It has also been observed that when an haemolysate is stored for some days at 4’ C., a progressive change occurs in the isozyme pattern. The typical changes observed in ADA 1 haemolysates on storage are shown in Fig. 1. In the fresh haemolysate there are three electrophoretic zones which are regularly spaced and exhibit decreasing staining intensities in order of their electrophoretic mobilities towards the anode. With storage the slowest moving zone becomes progressively weaker while the others increase in intensity. After about ten days storage the slowest zone is almost undetectable, whereas the intermediate zone has about the same intensity as originally shown by the slowest zone. Also an extra even more anodal isozyme becomes visible. Thus the final appearance of the isozyme pattern in the stored haemolysate resembles the original pattern except that each of the main zones appears to migrate more rapidly towards the anode, so that the most intense zone of the ‘stored’ pattern has about the same mobility as the intermediate zone of the ‘fresh’ pattern. These ‘storage’ effects are greatly accelerated if oxidized glutathione is added to the fresh haemolysate. They may also be reversed by the addition of mercaptoethanol or reduced glutathione to the ‘stored’ haemolysate. It is known that the concentration of oxidized glutathione (GS-S-G) increases at the expense of reduced glutathione (G-SH) on storage of haemolysates. It has therefore been suggested that the changes in electrophoretic pattern of the ADA isozyme in stored haemolysates can be most simply accounted for if it is supposed that each isozyme in the ‘fresh’ haemolysate has at least one free -SH group capable of reacting with G-S-S-G to give a mixed disulphide according to

Peptidase D (prolidase) variants in man.

Abstract: A method for the detection of peptidases after electrophoresis on starch gel was described by Lewis & Harris (1967) and applied to the study of red cells obtained from different individuals. Five different peptidases, which could be distinguished in terms of their electrophoretic properties and their patterns of substrate specificity were found to occur, and were designated peptidases A, B, C, D and E. In the course of population surveys a number of inherited variants of peptidase A and also peptidase B were discovered (Lewis & Harris, 1967, and Lewis, Corney & Harris, 1968). In the present paper we describe some variants of peptidam D.

Glucose-6 phosphate dehydrogenase mosaicism: utilization as a tracer in the study of the development of hair root cells.

Abstract: Mammalian X-chromosome differentiation occurs early in development, leading in females heterozygous for sex-linked genes to the formation of two different cell populations which reproduce true to type throughout somatic growth (review by Lyon, 1968). The two cell types, if easily distinguishable, may be used as in vivo cell tags to trace various aspects of growth and development. Variants of the sex linked glucose-6-phosphate dehydrogenase (G-6-PD) locus fit this requirement and have already been used in development studies of normal and abnormal tissues (Gartler & Linder, 1964; Nance, 1964; Linder & Gartler, 1965; Linder & Gartler, 1965a; Fialkow, Gartler & Yoshida, 1967; Gandini et al. 1968). Two types of observations are possible : variegation within heterozygotes and variation among heterozygotes. The extent of variation is indicative of the degree of coherent clonal growth characteristic of a tissue. For example, studies of myomas of the uterus in G-6-PD heterozygotes have demonstrated, by the single phenotypes of these tumours, thab they exhibit an extreme coherent clonal growth pattern (single cell origin with all descendants remaining adjacent to one another) (Linder & Gartler, 1966). On the other hand, normal uterine tissue in these same individuals was shown to consist of a mixture of cell types even in very small biopsies adjacent to tumours, indicating a migrational rather than a coherent clonal growth pattern. Variation among heterozygotes may reflect the size of the embryonic cell population at Xchromosome differentiation or the size of the primordial cell pool from which a particular tissue is developed: the greater the variance the smaller the embryonic cell pool. We have recently shown that in Mediterranean G-6-PD heterozygotes selected for a deficient red blood cell (RBC) G-6-PD level, skin G-6-PD is not of a deficient level (Gandini et al. 1968). This result suggests that variation among heterozygotes reflects the size of tissue specific embryonic cell pools and not the total embryo a t X-chromosome differentiation. The present study is an extension of this work to another tissue, the cells of the hair roots.

The frequency of twinning in a rural community in Western Nigeria

Abstract: It is generally known that the incidence of twinning in Nigeria is very high and in fact the twinning rates in some parts of the country are the highest on record-45 per 1000 maternities compared with 11-12 per 1000 maternities in England and Wales and U.S.A. (RegistrarGeneral, 1967; Shipley, et al. 1967). Most of the information relating to the high twinning rate, however, is derived from the analysis of hospital statistics (Knox & Morley, 1960; Cannon & Hartfield, 1964; Cox, 1963; Nylander, 1967) and while such data may be very useful in many cases, they are, nevertheless, biased owing to selective factors in hospital populations. However, in some hospitals the twinning incidence agrees fairly closely with that in the general community, either because selection is minimal or some selection factors are offset by others (Nylander, 1967). It is hoped that analysis of data collected from a whole community in a rural area in Western Nigeria (Igbo-Ora) in which there is no selection, will provide valuable information to indicate the true incidence of twinning in Western Nigeria (where the main ethnic group is Yoruba).

Sex chromosome aneuploidy and parental age

Abstract: Most investigations of parental age and the attendant risk of the conception of an aneuploid zygote have related to maternal age and to zygotes trisomic for chromosome 21, although more recently interest has been aroused in other types of autosomal trisomy. The study of mongolism and parental age extends back for more than 30 years to the work of Jenkins (1933) and the early studies by Penrose (1933, 1934a, b). Recently Penrose (1966) has published the analysis of the distribution of maternal age for 2605 mongols, the mean maternal age being 35.1 years as compared with 28.3 years for a control population of mothers. He showed from an examination of the distribution of maternal ages that the mongols could be partitioned into two classes. Class A contained about one-third of the total and was made up of mongols whose abnormal chromosome complement was considered due to causes independent of maternal age, such as secondary non-disjunction, structural heterozygosity involving a no. 21 in one or other parent, or an abnormality of meiosis or mitosis due to a specific gene, or possibly some environmental factor such as ionizing radiations (Sigler et al. 1965). The distribution of maternal age for mongols in class A was indistinguishable from that for the controls. By contrast class B contained mongols, about two-thirds of the total, for whom it is assumed that their abnormal complement followed an age-dependent error in maternal gametogenesis. The mean maternal age in this group was found to be 3 8 4 years, about 10 years greater than that for the controls, and the evidence was in keeping with the incidence of mongolism among the children of these older mothers increasing approximately with the tenth power of the age of the mother. Lenz, Pfeiffer & Tunte (1966) and more recently Magenis, Hecht &Milham (1968), have shown that the distribution of maternal age in trisomy D and trisomy E shows a general similarity to that for mongols, and that there is evidence for an increased mean maternal age for spontaneous abortions where the abortus has been shown to be an autosomal trisomic, and these include types of trisomy not yet found in post-natal life (Kerr & Rashad, 1966; Carr, 1967). It seems, therefore, reasonable to assume that the same model used to analyse the distribution of maternal age in mongolism may well also be applicable to the other forms of autosomal trisomy. It may be anticipated that a single general model will be insufficient to account for the various forms of sex chromosome aneuploidy, for the range of viable individuals extends from monosomy (45,X females) to males and females with respectively 49,XXXX Y and 49,XXXXX complements, and includes males with two or more Y chromosomes. Furthermore, sex chromosome mosaicism is identified much more often than autosomal mosaicism and detectable mosaics form an appreciable proportion of males and females recognized to have sex chromosome aneuploidy. Any discussion, therefore, of parental age and the risk of the conception of aneuploid zygotes would not be complete without some reference to sex chromosome mosaicism. There is also a third class of individuals worth considering and these are those with double

The excretion of amino acids by cystinuric patients and their relatives

Abstract: Dent & Harris (1951) differentiated classical cystinuria with increased excretion of lysine and arginine from other conditions in which the urinary excretion of cystine is increased as part of a generalized amino aciduria. Harris, Mittwoch, Robson & Warren (1955) studied the genetics of the disorder and proposed that the affected families should be classified as ‘recessive ’ or ‘ incompletely recessive ’, there being no detectable abnormality in the presumably heterozygous individuals in the former group whereas the heterozygous members of the ‘incompletely recessive ’ families have detectable abnormalities in their excretion of cystine and/or the basic amino acids. Harris & Robson (1955) also concluded on the basis of genetic evidence that recessive cystinuria includes more than one genetic entity but that incompletely recessive cystinuria is genetically homogeneous. Rosenberg ‘and his colleagues classified cystinuric patients into types I, I1 and I11 on the basis of the ability of the patients’ jejunal mucosa to transport isotopically labelled amino acids in witro (Rosenberg & Segal, 1965; Rosenberg, Durant & Holland, 1965; Rosenberg, Downing, Durant & Segal, 1966). Type I cases correspond to recessive cystinuria and types I1 and I11 are subgroups of incompletely recessive cystinuria. Studies of the renal clearance of amino acids have also demonstrated heterogeneity in the disease. Thus, some patients have cystine clearance values which are signikantly greater than the simultaneously measured glomerular filtration rate, whereas in other patients the cystine clearance and glomerular filtration rate are approximately equal (Crawhall, Scowen, Thompson & Watts, 1967). Heterogeneity could be due to cystinuria including more than one patho-physiological entity which available diagnostic methods are not sufficiently sensitive to separate. Alternatively the condition might be a single genetic entity and the apparent heterogeneity might be due to different degrees of expression of the single defect. Crawhall, Saunders & Thompson (1966) studied the amino acid excretion by a small number of cystine stone formers and their parents. They concluded that arginine excretion was increased in the subjects who were homozygous for the abnormal gene causing cystinuria, but not in the corresponding heterozygotes. They also suggested that an increased lysine excretion was sometimes the only feature which differentiates cystinuria heterozygotes from normal subjects. In the present work, the excretions of cystine and the basic amino acids have been studied in cystine stone formers, their parents and in normal subjects. The cystine stone formers are regarded as being homozygous and their parents as heterozygous for the cystinuria gene. The results obtained for these three groups of subjects are compared with one another and with those obtained for the other blood relatives of the stone formers in order to determine if the members of the latter group could be classified as cystinuria homozygotes, heterozygotes or normal on * Present address : Royal Victoria Hospital, McGill University, Montreal, Canada. t Address after 1st January 1970: Medical Research Council, Clinical Research Centre, Northwick Park,

Translocation between both members of chromosome pair number 15 causing recurrent abortions.

Abstract: There have been many reports of carriers of translocations of the centric fusion type, in which the carriers show no phenotypic abnormalities. In most cases the chromosomes involved have not been the homologous members of the same pair, since normal children have been born to the carriers. In two families, however, in which only mongo1 children were born, the translocation was thought to be of pair no. 21 (Dallaire & Fraser, 1964; de Capoa et al. 1967). The present paper reports the case of a phenotypically normal woman with a D/D translocation who has had at least thirteen unsuccessful pregnancies all terminating before the Mteenth week, and no normal pregnancies. The translocation appears to involve both members of pair no. 15.

The linkage relations of the loci for benign (Becker type) X-borne muscular dystrophy, colour blindness and the Xg blood groups

Abstract: A relatively benign form of X-linked muscular dystrophy was first recognized by Becker (Becker, 1955, 1957, 1962; Becker & Kiener, 1955). In this type of muscular dystrophy, muscle weakness first becomes evident in the teens or early twenties and affected individuals usually become confined to a wheelchair only after about 20 years and the majority survive at least into middle age. Weakness begins in the pelvic girdle musculature, only later affects the upper limbs and in most cases there is pseudohypertrophy of the calf muscles. There is no clinical or biochemical feature specific for this type of muscular dystrophy; the diagnosis is made when several males affected with a limb-girdle form of muscular dystrophy occur in the same family and the pattern of inheritance is consistent with that of an X-linked recessive trait. The relationship of this to other forms of muscular dystrophy has been discussed in detail elsewhere (Emery & Walton, 1967). In a recent report Blyth and her colleagues (1965) in analysing two families with Becker-type muscular dystrophy were unable to draw any conclusions regarding the possibility of measurable linkage with Xg but the results suggested that more families should be tested: these two families are added to the analysis of three further families about to be described. A family originally reported by Philip, Walton & Smith (1956) in which deutan colour blindness and muscular dystrophy were segregating was restudied and the pedigree extended. Though originally reported as the severe Duchenne type of muscular dystrophy it is clear that the disease in this family would now be classified as Becker-type muscular dystrophy (Emery, 1968). The results of linkage studies in this family are reported in the present communication.

Effects of additive genes at many loci compared with those of a set of alleles at one locus in parent-child and sib correlations.

Abstract: The method of correlation was introduced by Galton (1889) for the study of hereditarylikeness. Pearson (1904~) was able to give a theoretical justification for it which was greatly expanded by Fisher (1918). In practice, the observations of Pearson & Lee (1903) on stature in the parentchild and brother-sister relationship and Holt’s (1956, 1957) on finger ridge-count are the only large scale and complete results on record. Nevertheless, the theory of multifactorial or polygenic inheritance is widely used in clinical applications (Roberts, 1961; Falconer, 1965; Carter, 1969). It is invariably implied in these studies that the parent-child (pc) and sib-sib (8s) correlation frequency surfaces are adequately represented by the bivariate normal surface as tabulated by Pearson (1900) and Everitt (1910). There are, however, very important differences between the (pc) and (8s) distributions which can be seen at once from the general formulae for one locus with 2 additive alleles.

Placentation and zygosity of twins in Ibadan, Nigeria.

Abstract: In recent years a number of studies of newborn twins have been made in the United States and in England (Benirschke, 1961; Potter, 1963; Edwards, Cameron & Wingham, 1967; Corney, Robson & Strong, 1968) in which details of placentation have been recorded together with information on zygosity using a variety of genetically determined characters. Whilst there has been some variation in the results from these studies, the overall pattern has been the same, the placentation of dizygotic twins was consistently dichorionic, the majority of monozygotic twins had a monochorionic placenta, and a minority (between 20 % and 30 %) had dichorionic placentae. All these reports have been on Caucasian populations. Potter (1963) did not define the composition of her sample at the time of publication, but has recently confirmed that this was entirely Caucasian. Reports of twinning in Negro populations have also been published (Bulmer, 1960; Heuser, 1967; Shipley et al. 1967 and Nylander, 1967), but none of these studies included details of placentation, nor was zygosity determined by the use of red cell antigens or other genetically determined characters in blood or placental tissue. The figures from Nigeria are taken from hospital statistics (Nylander, 1967) and from the total population of a rural community (Igbo-Ore) in Western Nigeria (Nylander 1969), since there are no national statistics available. A very high rate of twinning was found and appeared to be due to increased numbers of dizygotic twins. The proportion of monozygotic (MZ) and dizygotic (DZ) pairs was estimated from the sex distribution using Weinberg's formula (1902), which states that the number of dizygotic pairs equals twice the number of unlike-sexed pairs. It was felt therefore that a prospective study of twin births with determination of zygosity by blood group, biochemical and placental studies would be of interest. Such a survey was initiated from the Department of Obstetrics and Gynaecology, University of Ibadan in 1967.

Inherited pericentric inversion of chromosome number two: a linkage study.

Abstract: Pericentric inversion has been suggested as one possible explanation for an abnormally located, human somatic cell autosomal centromere in twenty-one instances (reviewed in Jacobs et al. 1967; see also Summitt & Atnip, 1966; Nance & Engel, 1967; Schmid, 1967; and Soudek, Laxovh & AdBmek, 1968). Five of these cases involved chromosome no. 2: three were found in individuals with various abnormalities (mild mental retardation and multiple congenital anomalies, DeGrouchy et al. 1963 ; mild mental retardation and hypogonadism, Miller, 1966, cited in Cohen, 1967; severe mental retardation and features of the de Lange syndrome, Breg, 1966, cited in Cohen, 1967) and two in normal individuals (Carr, 1962; Summitt & Atnip, 1966). Summitt and Atnip also reported that the abnormal no. 2 chromosome occurred in the normal mother of the propositus and in two of her five normal siblings. In this paper we report the occurrence, inheritance, segregation and genetic linkage relations of an abnormal number 2 chromosome. The most likely explanation for the abnormality is that it results from an asymmetric pericentric inversion, although formal proof of this is lacking. This is the &st report of a study in which a cytologically recognizable abnormality of the number 2 chromosome was used to determine whether any one of the genetic loci controlling a number of serum proteins, red cell enzymes and red cell antigens is located on this chromosome.

Congenital malformations; a detailed study of 2500 liveborn infants

Abstract: With the declining importance of other causes of perinatal mortality, increasing attention is being paid to the study of congenital abnormalities. It would seem probable that the incidence of congenital malformations is subject to many factors, including considerable geographic variability. Kennedy (1967), in a recent review of world literature, quoted published surveys reporting values ranging from 0.15 to 12.3%. He has, however, shown that the observed incidence depends to a large extent on the method used to collect the data. Consistently higher rates have been obtained in the few studies involving the direct examination of the infant by suitably trained observers, and these rates rise further where repeat examinations of the same infants have been carried out over a period of time. We have recently had the opportunity to examine in detail a population of 2600 consecutive live births in a hospital in south-east Scotland. This was part of a survey designed to show the incidence of chromosome abnormalities in unselected children with congenital malformations (Stewart et al. 1968). We report here our findings relating to the incidence of congenital malformations and factors likely to influence this incidence.

X-linked ichthyosis: linkage relationship with the Xg blood groups and other studies in a large Dutch kindred.

Abstract: Three propositi with probable X-linked ichthyosis were found from the files of the Dermatology Department of the Binnengasthuis (University Hospital, Amsterdam). These propositi and some of their relatives were seen at the Dermatology Clinic and they, together with the files of the Civil Registration Office, provided complete pedigrees. Preliminary tests showed the family of one of the propositi not to be informative with regard to the main purpose of the investigation : all those tested were Xg (a + ) and the mother, who is dead, had come from Germany. The other two propositi were both thought to have had an Italian great-great-great-grandfather and subsequently, as a result of the investigation, were shown to belong to one large kindred.

Colour vision deficiency in on of two presumably monozygotic twins with secondary amenorrhoea.

Abstract: BY J. PHILIP, C. H. VOGELIUS ANDERSEN, V. DREYER, E. FREIESLEBEN, H. GORTLER, M. HAUGE, F. KISSMEYER-NIELSEN, L. STAUB NIELSEN, M. PERS, E. B. ROBSON, A. SVEJGAARD AND B. SORENSEN From the Chromosome Laboratory, Department of Obstetrics and Gynaecology A-I, the Clinic of Aviation Ophthalmology, the Blood-Bank and the Department of Plmtic Surgery, Rigshospitalet, University of Copenhagen. And from the Department of Anthropology, Institute of Forensic Medicine and the Institute of Human Genetics, University of Copenhagen, and the Medical Research Council Human Biochemical Genetics Unit, University College London, and from the Blood-Bank and Blood Grouping Laboratory, University Hospital, Aarhzcs

Linkage relations of X‐borne ichthyosis to the Xg blood groups and to other markers of the X in Israelis

Abstract: A series of families in the counties around Oxford (Kerr, Wells & Sanger, 1964) gave the first indication that there was reasonably close linkage between the Xg blood groups and the X-borne type of ichthyosis. This stimulated the investigation in Israel of which the present paper gives the full account (it includes the data of an interim report by Adam et al. 1966). The Oxford findings also stimulated a survey based on London (Wells et al. 1966). These three publications established beyond any doubt that the locus for Xg is close to that for ichthyosis. The survey in Israel included tests for glucose-6-phosphate dehydrogenase (g-6-pd) aa well as for colour vision.

Evidence for X/X chromosome translocation in humans

Abstract: The phenotypic effects of an X/autosome translocation in mice were among the chief sources of evidence that led to the formulation of the single-active-X hypothesis (Lyon, 1961 ; Russell, 1961 ; Russell, 1963). Even though cytological examinations of such a stock of mice have shown an X-autosome insertion (Ohno & Cattanach, 1962) rather than a typical translocation, reports are available to suggest the occurrence of X/autosome translocations in humans (Mann, Valdmanis, Capps & Puite, 1965; Mukherjee & Burdette, 1966), as well as in other stocks of mice (Ohno & Lyon, 1965). Recent studies have also shown that, in the cow, the segments of an autosome may be translocated simultaneously to an X-chromosome and an autosomal member of the complement (Gustavsson, Fraccaro, Tupolo & Lindsten, 1968). The individual X-chromosomes of all these X autosome translocation bearing mammals do not suggest a random mode of differentiation in accordance with the single-active-X hypothesis. Whether or not this hypothesis is applicable to systems involving an X/X chromosome translocation has remained to be seen. I n this communication, cytological studies are presented from a human female who exhibited a few specific stigmata of Turner’s syndrome. She had two major populations of cells with respect to X-chromosome constitution. One population of cells conformed with 45, XO-chromosome distribution. The structural changes in the X-chromosomes of the other cell population were interpreted as 46 XjX translocation types. It is suggested that random differentiation of X chromosomes indeed takes place, even when the X-homologues appear structurally modified.

The investigation of reactive sulphydryls in enzymes and their variants by starch gel electrophoresis. Studies on the human red cell peptidase variant Pep A 5-1.

Abstract: Recent experiments on human red cell adenosine deaminase indicate that reactive sulphydryl ( 4 H ) groups in enzyme proteins may be conveniently studied by starch gel electrophoresis (Hopkinson & Harris, 1969). The general method is simple and involves preliminary treatment of the enzyme with one or other of several Merent specific thiol reagents followed by gel electrophoresis and comparison of the electrophoretic properties of the treated enzyme with the properties of freshly prepared untreated enzyme. In the case of adenosine deaminase for example each isozyme contains a free -SH group which is capable of reacting with disulphides to form mixed disulphides, with alkylating agents to form stable alkylation products and with organic mercurial compounds to form mercaptides. With each of these reagents the reaction product is found to exhibit a characteristic electrophoretic mobility which is either the same as the untreated enzyme when the added moiety is neutral, or faster-moving towards the anode when the added moiety is acidic or slower than the untreated enzyme when the added moiety is basic. Although no differences have been observed in the -SH group reactions of the isozymes determined by the common adenosine deaminase alleles (ADA1 and ADA2) the method appears to be potentially useful for the detection of genetically determined alterations in -SH group reactivity of other enzyme proteins such as structural gene mutations which lead to the acquisition or loss of cysteine residues. In order to test this notion the effects of the various thiol reagents which were found to be useful in the investigation of the adenosine deaminase isozymes have been examined on the peptidase isozymes characteristic of the rare peptidase A variant Pep A 5-1 (genotype Pep Al Pep As). This variant of peptidase A is of special interest since previous studies (Lewis, Corney & Harris, 1968) indicate that the variant polypeptide subunit determined by the Pep AS allele differs from the subunit determined by the Pep Al allele by the substitution of a cysteine residue.

Central nervous system malformation stillbirths, maternal age and birth order.

Abstract: Substantial literature but no consensus of opinion exists on the associations between central nervous system (CNS) malformations and birth order and maternal age. These notes may serve to emphasize this disunity providing possibly a representative survey. The Registrars General of England and Wales and of Scotland publish the number of anencephalic stillbirths spina bifida stillbirths hydrocephalic stillbirths and all stillbirths occurring annually. They classify the data by parity and by maternal age. In the data for both Scotland and England and Wales the proportion of stillbirths which are anencephalic and hydrocephalic diminishes with both maternal age and parity. In the data for Scotland the proportion of stillbirths which are due to spina bifida seems not to show such clear evidence of trend but when the data for Scotland and England and Wales are pooled a similar trend shows clearly. Several explanations can be offered to explain the decline in the proportion of stillbirths which are due to CNS malformations: there may be a positive maternal age (or birth order) effect among stillbirths which causes other than CNS malformations; a CNS malformation stillbirth may deter further reproductive effort to a greater extent than do other stillbirths; women prone to bear CNS malformation stillbirths may be less fertile than other stillbirth prone women; and there may really be a negative maternal age (or birth order) effect in each of the major CNS malformations. It is argued that the 1st 2 suggestions are inadequate to explain the decline in the CNS malformation stillbirth proportions. Regarding differential fertility Dr. H.B. Newcombe provided raw data on this point. The data refer to 2340 sibships in British Columbia which produced at least 1 stillborn infant during the 1953-58 period. Among these were 197 sibships which produced an anencephalic stillbirth 68 of which produced a hydrocephalic stillbirth and 37 in which spina bifida was recorded either as the primary or secondary cause of a stillbirth. From fthese data all sibships in which the last stillbirth occurred within 280 days of the end of 1958 and all sibships in which the stated birth order maternal age and duration of follow-up were not in conformity were eliminated. This left 2018 sibships. It is possible to calculate the frequencies of subsequent maternities "expected" to occur in the CNS stillbirth sibships on the hypothesis that overall fertility in these sibships does not differ from that in the sibships of all stillbirths. The figures were so small that one cannot conclude with any certainty that any fertility differentials exist at all.

Molecular size estimates of human peptidases determined by separate gene loci

Abstract: The presence in red cells of peptidases capable of hydrolysing diand tri-peptides was first reported by Adams, McFadden & Smith (1952). Using starch gel electrophoresis in conjunction with a new specific staining procedure Lewis & Harris (1967) obtained evidence for the occurrence of at least five distinct enzymes (referred to as peptidases A, B, C, D and E) which could be differentiated on the basis of their electrophoretic mobilities, and their patterns of substrate specificity. However, many of the Merent substrates tested could evidently be hydrolysed by two or more of the several peptidases. Electrophoretic surveys of individuals from various populations led to the discovery of a number of genetically determined variants of peptidases A, B, C and D (Lewis & Harris, 1967, 1969a, b ; Lewis, Corney & Harris, 1968). The different mutant alleles determining these variants appeared to alter in each case the electrophoretic characteristics of only one of the several peptidases and left the others unchanged. It seems probable therefore that each of the peptidase enzyme proteins is coded at a separate gene locus. Studies of certain families in which variants of more than one of the peptidases were found to be segregating suggest that the loci determining peptidases A and B are not closely linked (Lewis & Harris, 1967) and that the same is probably also the case for the loci determining peptidases A and D (Lewis & Harris, 1969a). In the present paper we report the results of molecular size determinations using the hethod of gel filtration. The results indicate that the various peptidases differ in molecular size, and the findings lend further support to the previous evidence that each of the peptidases A, B, C, D and probably also E, is the product of a separate gene locus, and that they represent distinct enzymes with Merent but overlapping patterns of substrate specificity.

Linkage relationships of the angiokeratoma (Fabry) locus

Abstract: Angiokeratoma corporis musum (AKCD ; Fabry's disease) has recently attracted attention since the recognition that it is a generalized disease with excessive storage of a normal glycolipid, ceramide trihexoside, detected more particularly in the walls of blood vessels and in the kidneys. The precise enzyme which is deficient may be ceramide trihexosidase. Its virtual absence has been demonstrated in small intestinal mucosa from mares with the disease, with some reduction in the concentration of this enzyme in one carrier female (Brady et al. 1967). The affected men complain of pains in the limbs and show a characteristic rash with dilated small blood vessels and some hyperkeratosis, distributed mainly over the spine, hips and genitalia. The fidl clinical features have been reviewed by Wise, Wallace & Jellinek (1962) and by Johnston, Weller & Warland (1968).