Showing papers in "Annals of Human Genetics in 1971"

Developmental changes and polymorphism in human alcohol dehydrogenase

Abstract: Ann. H u m . Genet., Lond. (1971), 34, 251 Printed in Great Britain Developmental changes and polymorphism in human alcohol dehydrogenase BY MOYRA SMITH, D. A. HOPKINSON AND HARRY HARRIS M.R.C. Human Biochemical Genetics Unit, Galton Laboratory, University College London I n man, alcohol dehydrogenase (alcohol: NAD oxidoreductase E.C. 1 . 1 . 1 . 1 ) occurs princi- pally in liver, though low levels of activity have aIso been found in lung, kidney and the gastro- intestinal tract (Moser, Papenberg & von Wartburg, 1968). Evidence for at least three distinct isozymes has been obtained by chromatography of liver extracts on CM cellulose (Blair & Vallee, 1966) and also by electrophoresis (Moser et al. 1968; Pikkarainen & Raiha, 1969; Murray & Motulsky, 1970). Von Wartburg, Papenberg & Aebi (1965) reported that certain individuals have an atypical form of alcohol dehydrogenase associated with an increased level of activity. The usual and atypical forms of the enzyme were shown to differ markedly in pH activity curves with ethanol as substrate. The pH optimum for the usual form was found to be pH 10.8 and for the atypical form pH 8.5. The enzymes also differed in the relative rates at which they oxidized various other alcohols, and in the degree of inhibition produced by various metal binding agents. On the other hand no significant differences were observed in Michaelis constants for the substrates ethanol or acetaldehyde or for the corresponding coenzymes NAD or NADH. Also the pH activity curve with acetaldehyde as substrate was essentially the same for both enzymes, having an optimum at pH 6.0-6.5. A simple screening test to distinguish the usual from the atypical enzyme in crude liver homo- genates was designed (von Wartburg et al. 1965). This involves determining the ratio of the activity at pH 11.0 to that at pH 8-8 with ethanol as substrate under standard conditions. The usual enzyme gives a value for this ratio greater than 1.0, and the atypical enzyme less than 1.0. In a survey of 59 liver samples from different individuals in Switzerland, 12 were found to have the atypical alcohol dehydrogenase, and in another series of 50 individuals from London, 2 were found to be atypical (von Wartburg & Schiirch, 1968). The atypical enzyme occurred in indi- viduals varying from 16 to 82 years of age. Pikkarainen & Raiha (1967) reported that alcohol dehydrogenase activity in liver is low during foetal life and reaches adult levels about 5 years after birth. Changes in electrophoretic pattern have also been noted during development (Pikkarainen & Raiha, 1969; Murray & Motulsky, 1970). In the earliest stages only a single isozyme is observed but later further iso- zymes appear. I n adult liver individual variations in the relative contribution of the different isozymes to the total activity have been noted (von Wartburg & Schiirch, 1968), but no clear electrophoretic differences between the usual and atypical alcohol dehydrogenases as determined by the ratio of activity at pH 11.0 and pH 8.8 were detected. The present paper is concerned with a study of human alcohol dehydrogenase in which liver, lung, kidney and intestinal material from foetuses, infants and adults has been examined. The en- zyme has been investigated both by spectrophotometric assay at different pH’s and by starch-gel

Frequency in relatives for an all-or-none trait.

Abstract: The frequency of an all-or-none trait in the relatives of individuals possessing the attribute may be caIculated for a simple genetic model by the direct method of constructing frequency tables for all genotypes in index cases and their relatives. This is often tedious, and the systematic matrix method of Li & Sacks (1954) may be more convenient, as shown by Elston & Campbell ( I 970). Our purpose here is to present another approach and to consider some of its implications. Suppose individuals are taken at random from the whole population and given a score of 1 if they have the trait and 0 if they do not. Let the variable X denote the scores of these primary individuals. Suppose that the relatives of the primary individuals are scored in the same way, the variable Y denoting the scores on relatives. Then if K , is the proportion of the population which has the attribute, X and Y have the same mean, Kp, and they also have the same variance, K , ( 1 K,). Further, since X has only two values, the regression of Y on X must be linear, and the regression coeEcient is cov,lK, (1 K,), where covR is the covariance between relatives for the all-or-none trait, i.e. the covariance between X and Y. If K , denotes the frequency ofthe attribute in relatives of index cases, then K , is the mean value of Y at the point X = 1 . Thus it can be calculated from the regression equation as

Inherited variants of human nucleoside phosphorylase.

Abstract: SUMMARY 1. A method, for the starch gel electrophoresis of human nucleoside phosphorylase (NP) is described. Multiple NP isozymes were found in most human tissues and the best resolution of these isozymes was achieved by electrophoresis in a buffer system containing lithium ions. 2. Tissue to tissue variation in the complexity of the NP isozyme patterns and the examination of NP isozymes in relatively young red cells, suggest that a primary isozymic form of human NP is modified in vivo with generation of several secondary isozymes. The slowest isozyme is probably the primary form in all tissues, the secondary isozymes have greater anodal electro-phoretic mobilities. Storage experiments carried out with fibroblasts indicate that in vitro modification of the NP isozyme patterns may also occur. 3. Three electrophoretically different genetically determined variants of NP were found in a survey of red cell lysates from 2178 unrelated individuals; one of them was found twice. Family studies showed that these variants occur in individuals heterozygous for a common allele (NP1) and a variant allele (either NP2, NP3 or NP*) at an autosomal locus. 4. Examination of the NP isozymes in cultured fibroblasts and hair follicle cell extracts obtained from individuals with variant red cell phenotypes suggests that NP has a trimeric structure. In vitro hybridization experiments using a freeze-thaw-NaCl technique with mouse and human liver and with calf spleen and human liver NP support this view. 5. The molecular size of human NP by gel filtration chromatography is c. 84,000.

Adenosine deaminase isozymes in human tissues

Abstract: Several isozymes of adenosine deaminase (ADA) in human red cells can be detected by starch-gel electrophoresis and a number of inherited variants have been described (Spencer, Hopkinson & Harris, 1968). The phenotypes ADA 1, ADA 2-1 and ADA 2 occur in European populations with frequencies of about 0.9, 0.1 and 0.003 respectively, and are due to the two common alleles ADA1 and ADA2, phenotypes ADA 1 and ADA 2 representing the homozygotes and the ADA 2-1 phenotype the heterozygous genotype. Several less common phenotypes of red cell ADA have also been identified and in each case family studies have shown that the variant type represents the heterozygous combination of either ADA1 or ADA2 and a rare variant allele at the same locus (Hopkinson, Cook & Harris, 1969; Dissing & Knudsen, 1969; P. Gerald, 1969, personal communication; Detter et al. 1970). The present paper is concerned with the isozymes of ADA in human tissues other than red cells. The principal technique used was starch-gel electrophoresis and a wide range of tissues has been investigated. The sulphydryl group reactivities of the ADA isozymes in different tissues have also been compared, using the procedure of Hopkinson & Harris (1969)) and molecular size estimates of the various ADA isozymes have been obtained by gel filtration chromatography. I n most tissues isozymes similar to the red cell ADA isozymes were encountered but in many tissues additional isozymic forms were found which differed in electrophoretic behaviour, in sulphydryl group reactivity and also in molecular size from the red cell ADA isozymes. The results suggest that human adenosine deaminase may be determined by several different gene loci.

The estimation of admixture in racial hybrids

Abstract: When a racial hybrid population has arisen from the intermarriage of two or more parental populations, a problem of interest is to determine what the relative contributions are from each parental population to the hybrid. Various distance measures have been proposed whereby, on the basis of several traits, the distance between the hybrid and each of the parental populations can be estimated; these distances are then sometimes interpreted, as a first approximation, as being inversely proportional to the parental contributions (Pollitzer, 1964). In the particular case that all the traits considered are discrete in nature and each is determined by alleles at a single locus (or system of tightly linked loci), it is possible to estimate the parental contributions more directly. It is the purpose of this paper to reconsider two main methods of doing this when the traits involved are determined by a random set of independently assorting loci. Roberts & Hiorns (1962, 1965) proposed a least-squares solution to the problem, and Krieger et al. (1965) gave a maximum-likelihood solution. Both methods, as given by these authors, can be improved. We shall here restate both methods, using a common notation, and point out the improvements possible ; furthermore, some results of using these methods will also be presented, so that the methods may be compared empirically.

Unscheduled DNA synthesis, u.v.-induced chromosome aberrations and SV 40 transformation in cultured cells from xeroderma pigmentosum.

Abstract: Xeroderma pigmentosum (XP) is a rare autosomal recessive skin disease (El-Hefnawi, Maynard Smith & Penrose, 1965) characterized by extreme sensitivity to sunlight and a greatly increased susceptibility to carcinomas and melanomas of the skin. A severe deficiency or complete absence of DNA repair replication following 2537A. U.V. irradiation has been demonstrated in both cultured fibroblasts (Cleaver, 1968; Bootsma, Mulder, Pot & Cohen, 1970) and lymphocytes (Burk, Lutzner & Robbins, 1969) from these patients. Recent work has suggested that the initial step in the repair mechanism the recognition and excision of thymine dimers, is deficient in xeroderma cells (Setlow, Regan, German & Carrier, 1969; Cleaver, 1969; Cleaver & Trosko, 1970). The retention of pyrimidine dimers in the DNA of skin cells thus directly or indirectly predisposes the cells to neoplastic change. Normal human cells can be photosensitized to long-wavelength U.V. radiation by treatment with the furocoumarin trisoralen (Trosko & Isoun, 1971). Pathak & Kramer (1969) have demonstrated that furocoumarins form C 4-cycloaddition products with DNA, following prolonged irradiation, and postulated that this reaction is an important mechanism in photosensitization. Trosko & Isoun (1971) showed that cells treated with trisoralen and 3600A. wavelength light, showed markedly reduced DNA synthesis. These workers also demonstrated that trisoralen and 3600 d irradiation did not inhibit excision of pyrimidine dimers formed by short-wavelength U.V. radiation (2637 A), but they did not investigate repair synthesis following exposure of the photosensitized cells to 3600 d. U.V. Studies in bacteria, however, have suggested that DNA excision repair may occur (Igali, Bridges, Ashwood-Smith & Scott, 1970). A liquid scintillation assay, similar to that developed for leucocyte cultures (Robbins, Burk & Levis, 1970) has been used here to measure the amount of u.v.-stimulated thymidine uptake of normal and xeroderma fibroblasts. In this way the level of repair in different xeroderma patients can be compared. The fibroblasts of three xeroderma patients have been cultured and the amount of unscheduled DNA synthesis after short-wave U.V. (2537 B.) estimated both by autoradiography and liquid-scintillation counting. The same techniques have been used to find out whether there is any measurable repair synthesis after treatment with trisoralen and long-wave U.V. The liquid-scintillation assay technique has also been used to determine whether there is any change in the level of repair in fibroblasts from a xeroderma patient after these cells have undergone viral transformation.

Genetics of dermatoglyphic patterns on palms.

Abstract: SUMMARY Genetics of palmar dermatoglyphics have been investigated on the basis of a topological classification of dermal ridge patterns. A study was undertaken in a sample of 201 Polish families, comprising 187 pairs of parents and 666 children. Correlational analysis was performed using an IBM computer. The first step was to establish frequencies of dermatoglyphic characters in the sample and anatomical correlations between various patterns on palms and finger tips. Then, correlation coefficients between relatives were calculated for eighteen dermatoglyphic characters. Further genetical analysis of the data was performed, including estimates of heritability index (h2), dominance-recessivity index (dr)2 and search for the possible influence of sex-linked genes. The results obtained show that the dermatoglyphic characters on palms vary considerably with respect to the proportions of genetical and environmental components; some of them, like hypothenar H loop, interdigital loop II and triradius t and some quantitative characters, like pattern intensity, have high heritability indices, while the others, like hypothenar distal loop H, radial hypothenar loop Hr or z triradii, are almost entirely determined by environmental influences. It was further possible to examine the mode of inheritance of some of the pattern elements. It can be assumed, on a basis of results so far obtained, that some dermatoglyphic characters like loops Ĥ and II and presence of triradius t may be determined mainly by single genes those for the loops being in homozygous recessive form.

Fluorescent evidence for spermatocytes with two Y chromosomes in an XYY male

Abstract: SUMMARY A quinacrine fluorescent technique has been used to identify the presence and frequency of Y chromosomes at different stages of spermatogenesis in &n XYY male. Forty-five per cent of primary spermatocytes contained two Y chromosomes associated as a YY bivalent, and the patient exhibited an increased frequency of YY bearing spermatozoa as compared to three control males.

An inhertited X‐autosome translocation in man

Abstract: The inability to distinguish the human X chromosome from the autosomes in the C group in conventionally stained mitotic preparations has resulted in several translocations involving a C group chromosome being described as possible X-autosome translocations (Mann et al. 1965; Neuhauser & Bach, 1966; Thorburn, Martin & Pathak, 1970). The suggestion that the X chromosome is involved in the rearrangement has usually been made because the carrier has some abnormality of the primary or secondary sex characters. In addition, two X-autosome translocations have been reported in man where the identity of the X chromosome was established using autoradiography (Mukherjee & Burdette, 1966; German, 1967). In these latter two cases the X chromosome involved in the rearrangement was always found to be the one which completed DNA replication late in the S-period. However, autoradiographic techniques can only identify a structural abnormality involving the X chromosome where more than one X chroinosome is present and, furthermore, only when the structurally abnormal X is late replicating in all, or a significant proportion of, the cells examined. Recently Caspersson and his colleagues have demonstrated that it is possible to identify all the human chromosomes by utilizing the ability of quinacrine mustard to bind with specific regions of the chromosomes, so that when viewed under U.V. illumination each chromosome pair has a characteristic fluorometric profile (Caspersson, Zech & Johansson, 1970). It was shown that a similar discrimination can be made on the basis of differences in fluorescing banding patterns when chromosomes are stained with quinacrine dihydrochloride (O’Riordan et al. 1971). Using this technique we have demonstrated that a reciprocal translocation between a C group and a D group chromosome is a t ( X p ; 14g+ ). Our findings in the family in which this X-autosome rearrangement is segregating form the basis of the present report.

Tissue distributions, substrate specificities and molecular sizes of human peptidases determined by separate gene loci.

Abstract: SUMMARY 1. The distribution of seven different peptidases thought to be determined by separate gene loci has been examined in a variety of human tissues. Although most of them are widely distributed, their relative activities vary from tissue to tissue. 2. The enzymes have been characterized in terms of their electrophoretie mobilities, their patterns of specificity with thirty-five different substrates, and their molecular sizes as estimated by gel nitration. 3. One of the peptidases (peptidase S) which is not found in red cells but is present in most other tissues has not been previously described. It appears to hydrolyse a somewhat wider range of substrates than the other peptidases, and to have a larger molecular size (c. 245,000).

Prevalence and inheritance of congenital nystagmus in a Swedish population.

Abstract: In cormexion with the clinical study of congenital nystagmus, the results of which have briefly been summarized in a recent paper (Forssman, 1971), Forssman found recorded material of the disorder from a limited age-group and geographical area that could be used for an estimation of the frequency of the disturbance. He also made hereditary studies from 26 probands of congenital nystagmus by examining 815 persons. An analysis of this material seemed desirable to complete the investigation. In the present paper, an estimate of the frequency will be presented, followed by an analysis of the pedigree material.

The analysis of X-linkage.

Abstract: SUMMARY The estimation of the recombination fraction between pairs of loci on the X-chromosome is discussed, with special reference to the bias from defined forms of ascertainment. Tables are presented which give lods corrected for the common forms of ascertainment. The interpretation of lods is discussed, and the concept of equivalent observations introduced. A simple counting system is described for use in close linkage.

Glucose‐6‐phosphate dehydrogenase mosaicism: utilization in the study of hair follicle variegation

Abstract: Mosaic cell systems arising early in development may be used to investigate various developmental problems. The basic methodology involves observations of variegation within and variation among mosaics. The extent of variegation of a tissue is indicative of the degree of coherent clonal growth of that tissue and a comparison of the variegation of multiple tissues within mosaic individuals can yield information about cell lineage relationships. On the other hand, variations among mosaic individuals for particular tissues may be related to embryonic cell pool sizes. For optimal utilization of mosaic systems differences between cell types should be cell autonomous and detectable a t the cellular level. It is equally important that the differences between the cell types making up the mosaic should not lead to selective problems involving overgrowth of one cell type by another. Mammalian X-chromosome inactivation-derived mosaic systems approach these requirements : the initial X-chromosomal differentiative event occurs a t about the time of implantation and leads to permanent somatic clones with either the maternal or paternal X-chromosome active ; the mosaic populations differ only with respect to X-linked heterozygous loci (Lyon, 1968) ; and in humans the polymorphic X-linked glucose-6-phosphate dehydrogenase (G-6-PD) system is available for such studies and represents a cell autonomous system which can be detected in very small amounts of material (Davidson, Nitowsky & Childs, 1963; Nance, 1964; Gartler & Linder, 1964). We have utilized the G-6-PD mosaic system in man to explore various normal and abnormal developmental phenomena, including a recent paper on a study of hairfollicle development (Linder & Gartler, 1965; Gandini et al. 1968; Gartler et al. 1969). I n this report we extend our work to a study of variegation in hair follicles of the scalp and some further observations on hair-follicle development. Variegation results from any tendency of daughter cells to remain adjacent; such daughter cells form a patch, and the degree to which related cells remain adjacent (coherent clonal growth) determines the size of the patch or the extent of variegation. Patch size may be estimated directly by determining the area populated by like cells, and indirectly in a more general rnanncr from the proportion of samples of a tissue consisting of both cell types. A tissue sample will consist of both cell types only when it is taken at the junction of patches of different cell types. Consequently, the larger the patch size relative to the sample, the lower the proportion of samples containing both cell types. Utilizing this simple relationship of patch and sample size and limited direct observations, we have estimated the scalp hair-follicle patch size and coilsidered some aspects of follicle development.

Studies on the separate isozymes of red cell acid phosphatase phenotypes A and B

Abstract: SUMMARY Comparisons were made of some of the properties of the isozymes of types A and B red cell acid phosphatase. In each case, the more anodal isozyme had a higher pH optimum and a lower Km for ^-nitrophenyl phosphate. Thermostability tests indicated that this isozyme was also the least stable in both types. Evidence is also presented which suggests that the two isozymes within one type are interconvertible.

Relatives of probands: models for preliminary genetic analysis.

Abstract: 1 . INTRODUCTION In the genetic study of a particular trait it is common practice to summarize the data by stating the frequencies with which the trait occurs among the various types of relatives of probands. Thus we find reported in the literature the proportion of sibs, parents, first cousins, etc., of probands who are affected with the trait. One method of analysis is then to consider the question, under a variety of genetic models, ‘What is the probability that a relative of a proband be affected? ’ A comparison of these expected probabilities of being affected with the reported empirical proportions will then give a clue as to which genetic hypothesis is the most appropriate. Li & Sacks (1954) introduced three basic stochastic matrices for the purpose of deriving the joint distribution and correlation between relatives, appropriate for monozygotic twins, children (or parents) and unrelated individuals respectively. These same matrices and others of a similar nature can be used to answer the question posed above. Each of these matrices has dimensions k x k, where Ic is the number of genotypes involved in the particular genetic hypothesis. For example, if the trait is due to the segregation of two alleles at one locus, k = 3; if three alleles at one locus are involved, k = 6. For two alleles at one autosomal locus, the 3 x 3 matrices for monozygotic twins, children (or parents) and unrelated individuals respectively are given by Li and Sacks as 1 0 0 P P O P2 2Pq q2

A statistical and genetical study of diabetes. I. Prevalence and morbidity.

Abstract: SUMMARY 1. Records of current age and onset age of known diabetics resident in Edinburgh and alive at 1 January 1968 were obtained. Ascertainment was estimated to be between 90 and 95% complete. 2. The overall prevalence was 0–57% in males and 0–67% in females. 3. The age-specific morbidity risks were estimated by a new method which uses the information from all living diabetics by relating the frequency to the duration of the disease. 4. The morbidity risk increases continuously with age and reaches 2 % per annum at the age of 70, after which it levels off but does not decline. 5. Cumulation of the annual morbidity risks leads to estimates of the ‘potential prevalence’ at successive ages. This is the prevalence expected if the mortality of diabetics was the same as that of the non-diabetics and if the morbidity risks were the same as they are now. The potential prevalence increases with age faster than the actual prevalence; at 40 it is about twice as great and at 80 about eight times. 6. The difference between the actual and the potential prevalence may be due to higher mortality of diabetics or to the morbidity risk increasing with time, or to both. By analysis of the frequency of diabetics in relation to the duration of the disease and the date of diagnosis estimates were made of the rate of mortality or of the rate of increase of the morbidity risk. 7. Assuming constant morbidity risk, the additional annual mortality risk to diabetics is 1–2% at age 10, rising to 20% at age 80. Relative to the population, the mortality is 20 times at age 20 and 2 times at age 80. 8. Assuming no additional mortality, the morbidity risk would have to have increased by 1–2% per annum at age 10 and 8–10% per annum at age 60 to account for the difference between the actual and the potential prevalence. The number of registrations at the Clinic showed an increase of only 3 % per annum in males and no increase in females.

The incidence of triplets and higher multiple births in some rural and urban populations in Western Nigeria.

Abstract: SUMMARY In a study of triplets and higher multiple births in Western Nigeria, the incidence of triplets was found to be approximately 1–6 per 1000 maternities. The expected incidence calculated by Hellin's ‘law’ was higher than the observed incidence. The twinning and triplet rates in Western Nigeria were found to be approximately 4 and 16 (i.e. 42) times the corresponding rates in U.K. and U.S.A. Using data on sex the method described by Allen (1960) indicated that there was a relatively higher proportion of trizygotic triplets in the Nigerian population.

Patau's syndrome with D1 duplication-deficiency derived from a maternal D group pericentric inversion

Abstract: Pericentric inversions are detectable in somatic cells only if they result in a shift in centromere position which substantially alters the chromosome morphology so that the inverted chromosome can be distinguished from the other members of the group. For this reason, large-scale surveys are bound to give an underestimate of the extent of chromosome inversions in man. The population studies available suggest that detectable inversions are relatively infrequent and may show no adverse effect in individual carriers or their offspring (Court Brown et al. 1966; Jacobs et al. 1967). Inversions have also been ascertained through a wide variety of phenotypically abnormal individuals, but few of these have been causally implemented in the original disorders. They include two cases of an inversion in chromosome no. 1 (Lele, Dent & Delhanty, 1965), four involving chromosome no. 2 (Carr, 1962; De Grouchy et al. 1963; Miller, 1966; Breg, 1966), one involving a group-B chromosome (Morishima, Liu & Grumbach, 1964), four separate families with inverted C-group chromosomes (Jacobs et al. 1967 ; Ferguson-Smith, 1966) and two with D-group inversions (Cohen, Capraro & Takagi, 1967 ; Crandall & Sparkes, 1970). Other morphologically abnormal autosomes have been described which might represent either pericentric inversions or small duplications (De Grouchy et al. 1965; Prats & Moragas, 1967; Chandra & Hungerford, 1963; Gray, Mutton & Ashby, 1962; Ellis, Marshall & Penrose, 1962). The family presented here represents one of the few instances where a maternal autosomal pericentric inversion is thought to have given rise to duplication-deletion gametes resulting in congenitally malformed offspring.

Dermatoglyphic patterns and clinical diagnosis by discriminant function.

Abstract: Clinical diagnosis, based upon dermatoglyphic characters, can only be made in terms of probability because no dermatoglyphic sign is pathognomonic. The same peculiarities occur both in normal and abnormal samples but with different frequencies. In order to improve discrimination between each abnormal type and the normal, constituent characters can be combined ; even so, results indicate that there is considerable overlapping of normal and abnormal distributions. Nevertheless, an account of the construction of discriminants for distinguishing some well-known clinical types, dermatoglyphically, may be of interest. Three sources of information were available : patterns on fingers, palms and soles. All loops and certain triradii were recorded ; their identification did not involve measurement and their presence or absence is not dependent on age. For each clinical group the differences in frequency between normals and abnormals could be used as weighting factors for discriminant purposes, and this was done for a number of conditions with respect to each of the three pattern sources. Having established a weighting system for an abnormal condition, this can be used to test any given case in order to see how far the peculiarities present resemble those found in the specified condition. The resemblance can be measured against the difference between normal and abnormal on each specific discriminant and the answer can be given in terms of probability of belonging to the specified type. Discriminants for mongols have been worked out for palmar dermatoglyphics by Ford Walker (1957) and for a combination of anatomical traits by Beckman, Gustavsson & Norring (1965). In the present paper differences between normals and trisomies D, E and G and 4-5 shorter arm, or Bp, deletion, respectively, were established by combining data from the previous observations so as to construct four sets of discriminant weightings.

Assignment and map-positioning of human loci using chromosomal variation.

Abstract: A method owing much to Smith (1959) is given for obtaining a posterior distribution of mapposition of a gene locus, G, on a chromosome when the data concern heteromorphisms (variants, aberrations, etc.) of a pair of chromosomes and bear on the distances of G from a specific site of each of the heteromorphisms. This site will be called a mapping-mark, and may be a breakpoint of, say, a translocation or inversion, or it may be the site of control of a characteristically staining region (such as a prominent secondary constriction or a fluorescence polymorphism made visible by a fluorochrome. For the moment, it is assumed that the site of control of such a polymorphism is very close to the abnormal region itself). Pedigrees will often differ in the type or position of the heteromorphism or a t least in the position of the mapping-mark. Some mapping-marks are effectively unique to individual pedigrees. I n such a case the data bearing on the linkage of a locus, G, to the mark are relevant only to that particular pedigree. I n general, the value of the data for locating G and assessing the probability of its being on particular autosomes can be increased if we take into account what we know or can deduce about the distances of the various mapping-marks MI, M, . . . from a fixed reference point. We can imagine the autosomes laid out end to end in decreasing order of size, beginning with the free end of the short arm of chroniosome 1. The map-distance xt between this free end and the gene locus G will be called G’s map-position and it will not, presumably, vary from pedigree to pedigree. We may reasonably suppose that observed loci distribute themselves nearly uniformly over all chromosomes, so that before any linkage data are available, G will have a uniform (prior) distribution. The prior distribution of the mapping-mark is rather more complicated, and will be considered later. It is independent of the prior distribution of G. By taking into account linkage data and using Bayed Theorem (see Lindley, 1965) we obtain a (posterior) distribution of xt, representable by a distribution curve. We may then estimate xt. Further, the probability that G belongs to any one chromosome is equal to the area under the part of the curve corresponding to that chromosome. The evaluation of this distribution depends largely on the study of the distances between G and the mapping-marks. I n practice for each pedigree, data relate only to a special part of the range of xt, corresponding to, a t most, two chromosome pairs. We may think of this as the data-influenced part and only here will the posterior distribution of x, differ from its prior state. It is convenient to denote any xt value that refers to this data-influenced region by x. The need for this arises because, for certain types of mappingmark, namely those for inversions and translocations, the length, i, of the transposed material is an additional variable but only in the data-influenced region. It necessitates the opening up of another dimension (e.g. the length of the inversion) temporarily for this region which must therefore be distinguishable, but, as it is closed up again when the additional variable is

Hereditary studies of congenital nystagmus in a Swedish population.

Abstract: Congenital nystagmus is defined as a nystagmus of a pendular type existing from birth or early infancy. The disorder comprises two groups: an ocular and an idiopathic one. The former differs from the latter by the presence of obvious ocular defects (e.g. aniridia, microphthalmia, opacities of the media, albinism, dyschromatopsia). The present study is concerned only with the idiopathic group, investigated earlier by the author (Forssman, 1 9 6 4 ~ ) . That investigation comprised ninety cases, which were examined from different aspects. Above all, otoneurological considerations were stressed. That the vestibulo-ocular reflexes were abolished in about half the cases (absent in 44 yo and uncertain in 10 yo), although the vestibulo-spinal reflexes (Henriksson, Dolowitz & Forssman, 1962 ; Henriksson, Forssman & Dolowitz, 1962) were normal, prompted habituation studies (Forssman, Henriksson & Dolowitz, 1963; Forssman, 1964a) by which this reflex dissociation could be elucidated (Forssman, 1964b). Among other findings, the following can be noted. (1) The eye movements were pendular in a neutral zone and almost always became jerky on lateral gaze with the fast component in the direction of the deviation of the eyes. (2) I n 35% of the cases, the neutral zone was so eccentric that on fixation the patients turned their heads in the direction of the fast component of the nystagmus and the eyes contrariwise, thus bringing the neutral zone in front of the body and resulting in improved visual acuity. This turned position of the head seemed to be more obvious than the head nodding, which was infrequent and variable from one time t o the next in the same patient. (3) The nystagmus in the dark, as compared with that in the light, was almost always suppressed when the eyes were closed, but presented a very different pattern whcn the eyes were open, manifesting a decrease in 32 yo of cases, increase in 7 yo, and indefinite or variable changes in 61 yo. (4) Pigmentation of the fundus was found to be slightly subnormal in 17% of the cases. Higher degrees of depigmentation were never observed. ( 5 ) Ocular disturbances were more common than in the general population. (6) The corrected visual acuity of the better eye was normal or almost normal in more than one-third of the cases, and the refractive errors of the better eye were absent or small in one-half of the cases. (7) Squint was present in 16 yo. Hereditary studies of congenital nystagmus have been reported from Scandinavia, Denmark and Finland (Holm, 1926) and Finland (Forsius & Eriksson, 1964) with respect to the ocular form. As to the idiopathic group, no hereditary studies from this area have been made. Therefore, it seemed worth while to fill in this gap, namely to find out if some peculiarities, e.g. minor or micromanifested symptoms, are rare or not, to estimate the frequency of the disorder, and to analyse the inheritance.

A distinctive pigment of the skin in New Guinea indigenes.

Abstract: SUMMARY An unusual pigmentation of skin is described amongst indigenes of widely scattered areas in New Guinea. It is suggested that it is due to the accumulation of a red intermediary metabolite in the formation of melanin, and that it results from a metabolic error determined by an autosomal recessive gene. Pedigrees of thirty-three families with red skins are presented and analysed. The pigment could not be identified by histochemical studies of biopsy specimens and a portable reflectance spectrophotometer did not define its characteristics. The gene is present in high frequency in some areas in which it must possess a significant survival advantage.

Infant mortality from spina bifida, congenital hydrocephalus, monstrosity, and congenital diseases of the cardiovascular system in England and Wales

Abstract: SUMMARY The epidemiology of congenital abnormalities is reviewed and the data available in the Registrar General's Annual Reviews for England and Wales from 1848 to 1967 are analysed statistically. The time and place of reported epidemics of spina bifida and anencephalus are tabulated. It is concluded that the pattern of epidemics of dysraphism in time and place is inconsistent with a viral aetiology, and it is suggested that a proportion of embryos may be genetically susceptible to an antimetabolite present in a food under certain conditions of preservation, preparation or storage.

Y chromosome fluorescence in buccal mucosa cells: a study on a newborn population.

Abstract: It has been shown by Pearson, Bobrow & Vosa (1970), Caspersson, Zech & Johanson ( 1 9 7 0 ~ ) and Caspersson et al. (1970b) that it is possible to detect the presence of the Y chromosome in interphase cells from various tissues of the human male. I n metaphase cells the distal ends of the long arms of the Y chromosome fluoresce intensely when stained with quinacrine mustard or quinaarine dihydrochloride (Pl. 1 a , b ) ; a t interphase in 46,X Y males they appear as a single, or sometimes double, bright spot. I n cells from 47 ,XY Y males two such ‘Y bodies’ can be seen and i t would appear that the technique might be useful for (i) nuclear sexing in the same way as, and complementary to, the chromatin-positive Barr body, and (ii) providing a simple and reliable method for detecting males having two Y chromosomes. In an attempt to test the suitability of the technique, we have examined the fluorescent status of buccal mucosa cells in smears from a group of infants born in an Edinburgh hospital. Chromosome analysis from peripheral blood cells from these infants was already being carried out for routine diagnostic purposes and was quite independent of the present exercise. These studies provided a direct check on the reliability, or otherwise, of the fluorescent technique.

Further studies on the molecular size of red cell acid phosphatase

Abstract: SUMMARY Estimates of the molecular weight of red cell acid phosphatase have been made by gel filtration under denaturing conditions, i.e. in 6 M guanidine hydrochloride. The results suggest a figure of 14,800 which is almost twice as high as previous estimates obtained by gel filtration in the native form.

Properties for auromatic metaphase selection

Abstract: In the field of automatic chromosome analysis most published work (Hilditch (1970) contains a bibliography) has been concerned with the analysis of selected metaphase spreads, but relatively little attention has been paid to methods whereby such spreads might be selected. The task of finding suitable metaphases is usually considered more tedious than that of analysing them, once found, and hence if a computer is to be used at all there is a strong argument for using the machine to select the spreads as well as t o analyse them. Fig. 1 shows in great detail some examples of the things encountered on the slide when searching for metaphases. Here 1.1-1-6 show six stages of the nucleus from its undivided state to that of analysable metaphase spread, 1-7 and 1.8 show debris and 1.9 shows a cell in metaphase which could be analysed only with great difficulty even by a trained cytologist. The human operator finds no difficulty in distinguishing these patterns; our task is to find a machine-measurable property which will allow a machine to make this distinction. If several such properties can be found we may well ask which is best, but it is important to realize that this question is very difficult, perhaps impossible, to answer. First, our choice is not between the properties themselves but rather between the systems of automatic metaphase selection they allow us to construct. Although we can describe the performance of a given system in terms of cost, speed, accuracy of the selection process, reliability of the machinery and so on, these quantities are not comparable and any attempt to reduce the description to a single quant,ity such as ‘cost per analysable metaphase selected ’ must involve arbitrarily assigned exchange values between the different variables. Second, a system of automatic metaphase selection will usually form part of a system for automatic chromosome analysis and should properly be assessed in the context of that system. Third, systems of automatic chromosome analysis are themselves to be judged in terms of many non-comparable variables and the first problem reappears. Fourth, any ranking which could be established would reflect the state of technology at a given instant, for technical progress might make certain properties much ‘cheaper’ to measure and so alter the ranking, One feature of the problem is independent of the system employed. In the routine examination of one slide, in population studies for example, it is not usually necessary to examine more than 20 cells ; since there are, typically, 50 metaphases on the slide this is an average figure and there is wide variation between slides -it is not necessary for the automatic search to find every nietaphase. On. the other hand, if a non-metaphase is selected as a metaphase, then it will be submitted to analysis and time will be wasted in attempting to analyse the unanalysable. If we express the situation in a table, True value

Extension of the Hardy-Weinberg law to assortative mating.

Abstract: SUMMARY A relation is given between the degree of assortative mating in parents, which is measured by a weighted covariance, and the degree of departure from Hardy-Weinberg conditions in offspring.

A statistical study of the intrauterine selection factors related to the ABO system. II. The analysis of foetal mortality data.

Abstract: Foetal death rates by ABO‐mating type are presented for a Caucasian population. The rates are based on foetal deaths occurring while the women were participating in the Child Health and Development Studies, Oakland, California, as well as on data elucidated by interview. The rates for mating‐type Ox A were consistently higher than those for the other mating types. A‐O incompatibility is the most plausible interpretation of this finding.