Mammalian developmental genetics in the twentieth century

Abstract

This Perspectives is a review of the breathtaking history of mammalian genetics in the past century and, in particular, of the ways in which genetic thinking has illuminated aspects of mouse development. To illustrate the power of that thinking, selected hypothesis-driven experiments and technical advances are discussed. Also included in this account are the beginnings of mouse genetics at the Bussey Institute, Columbia University, and The Jackson Laboratory and a retrospective discussion of one of the classic problems in developmental genetics, the T/t complex and its genetic enigmas.

Figure 1

Institutions that served as incubators of genetics and mammalian genetics in the first half of the 20th century. A name within a circle or in overlapping circles shows that the scientist was present at that institution at a critical time. A blue arrow points to a student or post-doc, a red double arrow indicates collaborators, a single asterisk indicates a Nobel Prize winner, a red asterisk indicates a National Medal of Science winner. George Snell was also a post-doc of H. J. Muller.

Figure 2

Tail phenotypes and genotypes in Tt-complex crosses. (A) Tail phenotypes and genotypes are indicated. (B) The balanced lethal cross. It appears that taillessness breeds true because the other two genotypes die as embryos. (C) Complementation between t-lethals. Now a class of normal-tailed compounds t^x/t^y appears. The numbers of each phenotype will not resemble Mendelian ratios because the male transmits the t-haplotype to 99% of the progeny. The female has normal transmission. Thus one can expect ∼50% normal tails and 50% tailless offspring. Male normal tails are sterile. A variation of C is when the cross involves two parents carrying a semilethal (t^sl). In this case, the phenotypes of the pups would be the same.

Figure 3

The cytologically invisible inversions in a t-haplotype. The left chromosome is a normal one. The chromosome bands are indicated as they would have been seen with the techniques available in the 1970s. The inversions in a t-haplotype occur between bands A2 and D as indicated by arrows, highlighted with a light gray box. Without modern cytological techniques, these would not have been detectable. (This diagram has been modified from Lyon et al. 1988.)

Figure 4

The cross that allowed measurement of recombination between t-haplotypes. Dark gray represents t-chromatin; light gray represents normal chromatin. The arrows represent the three possible intervals where recombination can be detected using the outside markers T and tf. Exactly which interval is involved must be determined by progeny testing for the lethals involved.

Figure 5

Transplantation experiments with sl and W genotypes. Both mutants are severely anemic. In the case of sl/sl, the microenvironment is bad. Thus, no transplanted bone marrow, regardless of genotype, can survive. There is no ligand in the environment. In the case of W/W^v, the environment is good and those cells that have a normal c-kit (+/+ and sl/sl) can survive and rescue the mouse.

Figure 6

Making a knockout mouse. (A) Anatomy of the blastocyst. (B) KOed ES cells are injected into the blastocyst and (C) are allowed to mix naturally with the host inner cell mass cells. (D) After returning the embryos to a pseudopregnant female, some mice are born with patches of black from the manipulated cells.

Figure 7

Phenotypes and genotypes of Qk mice.

Figure 8

The qk hypothesis. The deletion leaves the qk gene and its embryo enhancer intact but, removes an enhancer for the myelinating cells. The separate gene for male sterility is now known to be Pacrg (Lorenzetti et al. 2004).