Paul E. Polani

Pairing of X and Y chromosomes, non-inactivation of X-linked genes, and the maleness factor

SummaryIn this paper observations are summarized and speculations discussed, and it is suggested that some loci on the distal short arm of the X chromosome (Xp) are not randomly inactivated in the female, because they are within the proximal part of the pairing segment between Xp and Yp. This peculiarity of gene expression may be a remnant of the evolutionary history of the sex chromosomes, the pairing segment of which may involve at least 27% of Xp and 95% of Yp. Crossing over seems to occur mostly in the terminal third of the X/Y pairing segment. However, crossing-over inhibition control may lapse, or may be on the X and Y (e.g. Xg, H-Y, STS, and perhaps others) might cross over with a variable frequency which is proportional to their distances from the telomeres of the short arms. It is postulated that the DNA of the pairing segment is composed in a way which may also permit unequal crossing over to occur between the X and the Y, thereby giving rise to exceptions to X-or Y-linked inheritance. The peculiarities of behaviour and the position of other loci on the sex chromosomes are also discussed briefly.

Neural-tube defects and vitamins: the need for a randomized clinical trial.

It has been suggested that taking extra vitamins around the time of conception may reduce the risk of fetal neural‐tube defects. We have examined the evidence for this and conclude that there is considerable doubt about the efficacy of such a regimen. Also, it cannot be assumed that the taking of extra vitamins has no adverse medical effects. We give reasons for our view that a large randomized clinical trial is ethical and the only satisfactory way of resolving the matter. The Medical Research Council is currently conducting such a study in centres in Britain and abroad, involving women who have already had a pregnancy with a fetal neural‐tube defect. The design of the Medical Research Council study is described briefly.

A test of the production line hypothesis of mammalian oogenesis

SummaryGerm cells in female mammals become committed to meiosis and enter its prophase sequentially in fetal life and, according to the Production Line Hypothesis, the oocytes thus generated are released after puberty as mature ova in the same sequence as that of meiotic entry in fetu. This hypothesis in its original and complete form has a subordinate proposition that concerns chiasma (Xma) frequency; it postulates that Xma number would decrease with fetal age. Consequently, univalents would increase, leading to errors of chromosome disjunction at the first meiotic division (MI), and thus to maternal age-dependent numerical chromosome anomalies. By using an in vitro/in vivo approach, we radioactively labelled the DNA of germ cells at premeiotic synthesis as they sequentially entered meiosis, while the fetal ovaries were in culture. At the end of this in vitro phase, pachytene/diplotene (P/D) stages were studied to determine their labelled fraction. The ovaries were then transplanted to spayed females and, after the in vivo phase, mature ova were harvested and the proportion of labelled first and second meiotic metaphases (MI/MII) determined. By marking the germ cells with label while in vitro during periods equivalent to early and late gestation, and by comparing the observed proportions of labelled MI/MII with those of oocytes labelled at P/D, we concluded that, in the mouse, ova do not mature at random for release, but are formed according to a production line system in which the time of release after puberty is related to the time of entry into meiosis in fetu.

Neural Tube Defects in Curly-Tail Mice. II. Effect of Maternal Administration of Vitamin A

Vitamin A, a known teratogen of the central nervous system, was administered in various doses, at the time of active neural tube closure, to pregnant curly-tail mice which have a genetic predisposition to neural tube defects (n. t. d. ), and to A Strong mice, which are not so predisposed. The curly-tail mice showed an enhanced susceptibility to the teratogenic effect of vitamin A given on day 8 of gestation, demonstrating a clear gene─environment interaction. There was a differential response by the two sexes. Females seemed to be more affected by the vitamin A than males. When vitamin A was administered on day 9, instead of day 8, of gestation, the incidence of n. t. d. decreased rather than increased. Furthermore, the number of mice affected by n. t. d. was markedly lower even than that found spontaneously in untreated curly-tail mice.

Neural tube defects in curly-tail mice. I. Incidence, expression and similarity to the human condition

The incidence of neurovertebral defects in mutant mice of the curly-tail strain was investigated and found to be similar to that observed in the same mice twenty-five years ago. The results of breeding experiments support the hypothesis of Grüneberg that the defects in these mice are probably caused by a recessive gene, the expression of which is markedly affected by the genetic background. Selection against the curly-tail phenotype for six generations did not affect the incidence of abnormalities. A marked excess of females was found among exencephalic mice, as among humans with neural tube defects. Similarly, polyhydramnios, hydrocephaly, high levels of amniotic fluid alphafoetoprotein and distinctive, rapidly adhering cells in the amniotic fluid also occurred in these mice, as in humans. The curly-tail mice thus provide a useful model for the investigation of neural tube defects in man.

The Little Club

During the past year and a half a number of interested people have rnet at the Little Club to discuss a memorandum on the terminology and classification of “cerebral palsy”. The memorandum in its present state* was put forward for discussion at the Oxford Study Group on Child Neuroloqy and Cerebral Palsy. The participants in the discussions were: Dr. N . S. Alcock, Dr. J . Bates, Dr. E. A. Carmichael, Dr. J . Crosland, Dr. P. R . Evans, Dr. M . C. Joseph, Dr. M . J . McArdle, Dr. A . D. McDonald, Dr. R . C . Mac Keith, Dr. I . C. K . Mackenzie, Prof. A. A. Moncriefl, Dr. P. E. Polani and Sir Charles Symonds. The memorandum gives a definition of “cerebral palsy”, notes the need for definition of clinical ierms and sugqests that at the present time clinical features offer the most useful basis for classification; the clinical features of hypertonus are discussed in detail and then Q clinical approach to diagnosis is put forward. This suggests thar the spastic cases should first be recognised and then, from among the remainin? cases, the dystonic and choreoathetoid cases, leaving a residue which will include mixed cases, ataxic caws and cases o f atonic diplegia.

Genetic control of H-Y synthesis. A hypothesis

SummaryIn view of the claimed serological H-Y positivity observed in patients with ovarian dysgenesis (for example, 45,X) and in XO mice (neither of whom have a Y chromosome), it is suggested that genetic control is exercised over the H-Y system by structural genes on the pairing segments of the X and Y chromosomes, acting on an autosomally coded H-Y precursor.

Incidence of developmental and other genetic abnormalities.

Possibly 6 per cent of all new born infants have a developmental anomaly— sometimes severe, sometimes relatively mild, at times treatable but often not. The commonest anomalies are those of the central nervous and of the cardiovascular systems and of mentation. Biochemically defined errors, though singly rare, are relatively frequent in the aggregate and chromosome disorders with variable degrees of developmental anomaly are even more frequent. In addition many conceptuses that are chromosomally abnormal are spontaneously aborted and quite a few die in the perinatal period.

Rôle of Sex Chromosome in the Determination and Differentiation of Sex in Mammals

This preview presents a general picture of prevailing thought in the field of sex development and describes some of the advances made over the last twenty years in the understanding of the genetic controls of sex development in man and mammals.

Prenatal diagnosis of genetic disorders in preimplantation embryos: invasive and non-invasive approaches

SummaryThe purpose of this article is to analyse the various non-invasive and invasive methods that offer the opportunity of prenatal diagnosis of selected inherited disorders at the preimplantation stages of human embryonic development and to discuss the advantages and ethical problems associated with such procedures. These investigations should also provide important information on the development of the human embryo and its hormonal and immunological relationship with the mother.