Hans Grüneberg

Genetical studies on the skeleton of the mouse

SummaryCurly-tail is probably due to a single recessive gene whose manifestation is greatly influenced by the genetic background. The tail anomalies are produced mechanically either by spina bifida which persists, or by a rudimentary form of it (delayed closure of the posterior neuropore) which is transitory.

Genetical studies on the skeleton of the mouse: IV. Quasi-continuous variations

Summary1.The genetical behaviour of a number of skeletal characters which differentiate the pure lines CBA and C57BL is described in crosses between these two strains, between C57BL and A, and in some subsidiary experiments.2.The results indicate that the entities investigated are ‘quasi-continuous’ characters in the sense that the underlying genetic basis is a continuous variable (generally not yet identified) with multiple factor inheritance which is divided by a physiological threshold into normal and abnormal animals; the abnormality is usually itself capable of graded expression.3.The peculiar genetical properties of quasi-continuous characters are regarded as partly due to the fact that a continuous distribution may occupy any position in relation to a physiological threshold; and partly that they share with ordinary continuous variables the multiple gene basis and the sensitivity to influences of the environment, both prenatal and post-natal.4.It is suggested that additiveness of gene effects and sensitivity to the environment may trace back to the common cause that the so-called multiple genes of quantitative genetics are in fact remote gene effects. It is pointed out that arbitrarily chosen parameters will generally be influenced by genes only indirectly; and as every measurement involves a choice and is thus arbitrary, the multiple gene inheritance generally encountered in quantitative genetics may be due to the arbitrary choice of parameters rather than to inherent causes.

Two closely linked genes in the mouse.

(1) In heterozygous condition, the gene for Patch (symbol Ph ) produces spotting with sharply defined pigmented and white areas. The extent of the spotting is under the control of the genetic background. (2) The Ph/Ph homozygote is inviable and dies before birth. In 9-day embryos, clear liquid is found flanking the notochord; in addition, there may be excessive amounts of liquid in the pericardium, the circulation, the tissues, and under the epidermis. The more extremely affected Ph/Ph embryos die at about 10 days. About one-third survive to later stages of pregnancy. Such ‘cleft-face’ embryos have a large bleb of liquid in the middle of the face which interferes mechanically with the formative movements of the nose and palate, and many subepidermal blebs elsewhere. (3) Ph is closely linked to the gene for dominant spotting with macrocytic anaemia ( W, W v ) in linkage group III, the crossover percentage being 0·077. There is a striking interaction in the double heterozygote Ph + / + W v which is almost white, but nearly equally striking interactions occur with other spotting genes ( s, bt and Mi wh ). (4) By itself, Ph has no detectable effect on the coat colour, but in the double heterozygote with W v , it slightly increases the dilution effect of the latter in the regions which remain pigmented. Similarly, Ph by itself has no appreciable effect on the red-blood picture of 13–14-day-old animals, but in the double heterozygote with W v , it probably slightly increases the mild macrocytic anaemia produced by that gene. It remains unknown whether the Ph/Ph homozygote has an effect on the blood. Unlike W/W and W v / W v , Ph/Ph has no appreciable effect on the primordial germ cells. (5) The relationship between Ph and the W -series is discussed.

Two new mutant genes in the house mouse

Summary1. Fidget is a new recessive gene with regular manifestation and nearly normal viability under laboratory conditions. Affected animals shake their heads in the horizontal plane and often run in circles. A period of hypersensitivity to sounds early in life is followed by deafness or a condition approximating deafness. Lesions of the cornea are regularly found. Polydactylism of the hind feet was observed in fifteen out of eighty-six fidgets; its rare occurrence in normal segregants may be due to occasional semi-dominance of this trait. Fidget males usually breed well, while fidget females are unreliable mothers.2. Hydrocephalus-3 is a recessive gene which overlaps normal if classification is based on living animals. The onset of clinical signs is usually early in the second week, but occasionally much later. Heavily affected animals are greatly retarded in development and rarely reach the age of two months. A feature of hydrocephalic young is nasal discharge, which is also found in mild cases, which have no recognizable skull anomaly, though they are retarded in development. Such young often survive to reach full adult size; whether they may become sexually functional is unknown. The genetic relations ofhy-3 tohy-1 andhy-2 remain to be cleared up by crosses.

A ganglion probably belonging to the N. terminalis system in the nasal mucosa of the mouse.

SummaryIn mouse, rat and hamster there occurs in the nasal mucosa and far forward in the nose a somewhat diffuse ganglion of placodal origin. It persists throughout life. The identity of the associated nerve has not yet been established, but N. terminalis and N. ethmoidalis anterior may both be involved. Comparable structures seem to be present in some mammals, but not in others. The function of the ganglion is unknown.

Genetical studies on the skeleton of the mouse: VII. congenital hydrocephalus

SummaryThe development of the skeleton of the mutant congenital hydrocephalus in the mouse has been investigated. The condition is basically due to a disturbance of the mesenchymal skeleton which is generalized. The mesenchymal condensations are reduced in size, this being more marked in some parts of the skeleton than in others. Where reduction is not too drastic, cartilages of reduced size are laid clown, often with a delay of a clay or so as compared with the normal. Once laid down, cartilages grow at a normal rate and hence remain smaller than normal to about the same extent throughout. Though often some what retarded, the cartilage is histologically normal. In some places where the reduction of the mesenchymal condensations is too great, no cartilage is formed; the missing parts may, however, be represented by fibrous tissue. Anomalous fusions between neighbouring cartilages occur in several localities. While the extensive abnormalities of the cartilaginous skeleton are secondary to the reduction of the mesenchymal condensations, the more scattered abnormalities of the osseous skeleton are partly clue to those of the cartilaginous skeleton. Some bones are absent because their cartilaginous predecessors are absent.

Genetical studies on the skeleton of the mouse: XII. the development of undulated

SummaryThe anomalies produced by the gene for undulated in the mouse have been traced back to the 11-day stage of embryonic development. On that day, it can be seen that the condensations of mesenchyme cranial to the sclerotomic fissures are smaller than normal. Later on, these condensations continue to lag behind those of normal embryos and are not clearly demarcated from those caudal to the sclerotomic fissures. On the basis of sensenig’s view that, in normal development, the condensations cranial to the fissures fuse with the primitive centra in front of them and thus help to form the vertebrae, and that the fissures themselves correspond in position to the posterior ends of the vertebrae in the adult, the anomalies produced by the undulated gene can be interpreted as follows. The condensations cranial to the sclerotomic fissures, instead of being incorporated with the vertebral material in front of them, are (at least in part) retained by the condensations behind them which form the intervertebral disks. For this reason, the reduction of the vertebrae is accompanied by an increase in size of the intervertebral disks. The material absent from the undulated vertebrae is, in normal development, destined to help in the formation of the centrum, the neural arches, the spinous processes and the transverse processes and ribs; all these structures are reduced to a varying extent in the undulated mouse; the involvement of the ribs is but slight, but can be detected in a tendency of fusions between adjacent sternebrae. Following chondrification, the formation of hyaline matrix is slow at first in undulated embryos, but the cartilage ultimately becomes perfectly normal histologically.The work reported in this paper has been supported by grants from the Medical Research Council and from the Rockefeller Foundation, which are gratefully acknowledged. For assistance in various directions I am indebted to my colleague, Dr Gillian M. Truslove. My special thanks are due to Mr A. J. E. Munday (Galton Laboratory, University College) for the microphotographs which illustrate this paper.

The anaemia of flexed-tailed mice (Mus musculus L.)

SummaryThe anaemia of flexed-tailed mice is of a normocytic hypochromic type, that is, the mean cell size is normal, but the mean corpuscular haemoglobin concentration is reduced. The pathological process is confined to the embryonic mode of haemopoiesis; this persists during the first 2 weeks after birth in the anaemics, but has ceased at the beginning of the 3rd week. Pathological cells survive in the circulation for at least 2, but not more than 6 weeks. With the final disappearance of these surviving cells, the red blood picture of flexed mice becomes entirely normal. The disappearance of the anaemia takes place by the substitution of pathological by normal cells in such a way that cells of intermediate grades of abnormality are formed during the transition period.

The Tabby Syndrome in the Mouse

The tabby syndrome in the mouse (which is common to the sex-linked gene for tabby and autosomal genes for crinkled and downless) affects the coat, the sinus hairs, the teeth, many glands and some surface features like tail rings, plicae digitales and the papilla vallata of the tongue. All these structures develop by the downgrowth of solid epithelial buds into the underlying mesenchyme. Organs which arise by invagination (like the neural tube or the otic vesicles and certain glands) are not affected by the tabby syndrome. The rudiments of glands and sinus hairs are reduced in size, and if reduction goes beyond a critical point, stunted organs are formed or, more commonly, the rudiments regress altogether. The same is true for the teeth and apparently for the whole syndrome. Measurements show the same situation in Ta ♂♂(and Ta/Ta ♀♀) and in heterozygous Ta/ + ♀♀. As in Ta ♂♂ and Ta/Ta ♀♀ there cannot be any doubt that a threshold mechanism is involved, there is no reason to assume that, in Ta/ + ♀♀, the identical defects are derived clonally from ancestral cells in which the Xchromosome carrying the normal allele has been inactivated. Whereas the Ta/ + phenotype does not give any evidence that the Ta locus is involved in X-chromosome inactivation, the possibility cannot be ruled out that, if inactivation should actually take place on the cellular level, the macroscopic phenotype could be the result of intercellular interactions along with the effects of threshold mechanisms.

Genetical studies on the skeleton of the mouse xv. Relations between major and minor variants

Summary1.The mutant genesun, Sd, vt, Bn, se, fi andtk in the mouse have been tested for possible effects on a group of fifteen minor variants of the skull and vertebral column. Each of the mutants has been found to be associated with effects on some of these characters (as many as eight each in the case ofse andfi).2.The average effect on the minor variants associated with the mutant genes amounts to 1–16 standard deviations.3.Substrain differences which arose in the C57BL strain in the course of continued inbreeding and which affect a similar set of minor variants are believed to represent single gene differences. The average effect of these single gene differences amounts to 0–58 standard deviations.4.It is assumed that most or all of the effects associated with the major genes are pleiotropic effects of these genes themselves rather than effects of linked genes. This is based on the observation that genes (se, tk) which arose by spontaneous mutation in inbred strains and were studied on their original homogeneous backgrounds showed similar effects on the minor variants as genes segregating on heterogeneous backgrounds. Secondly, the effects associated with the major genes were greater than those which would have been expected in the case of linked genes (compare (2) and (3) above).5.There are instances in which major genes affect a minor variant on some genetic backgrounds, but not on others. While these cases might be explicable in terms of linked genes, it is concluded that they are due either to specific gene interactions, or to differential gene effects depending on the physiological situation in which the gene finds itself.6.On account of the facts mentioned under (5), genetic backgrounds must be regarded as unique, and experiments involving the genetic background as a variable as not accurately repeatable.7.The pleiotropic effects of the major genes on minor variants are of a kind which could not have been predicted from what is known about the major actions of these genes. They are clearly very remote gene effects and their causal connexion with the ‘main’ effects of the genes is completely obscure.8.It is concluded that the so-called polygenic variation is not due to a separate class of genes (the ‘polygenes’), but is best explained as clue to the pleiotropic effects of the normal alleles and iso-alleles of genes with major effects.