¶ See Acknowledgments.
The author has declared that no competing interests exist.
As early as 1912, Wilhelm Weinberg, the visionary human geneticist, noted that infants with achondroplasia (short-limbed dwarfism) tended to be born late in their sibship
Yet there were exceptions. Some chromosome changes, including small duplications and deletions, seemed to have different rules of inheritance. And there were a few conditions, notably those associated with the genes
The first major breakthrough came from the work of Andrew Wilkie, Anne Goriely, and their colleagues
Definitive proof came with a study of the location of the mutants on one or the other of the two members of a chromosome pair, identified by marker genes. Rather than a binomial distribution, these showed a large excess of identical alleles. The authors inferred that there must be some sort of pre-meiotic selection favoring mutations. This was a remarkable result, considering the rarity of such a process in various species and the prevailing dogma that no such thing occurs in mammals. Such selection immediately supplied an explanation of the high “mutation rate” and the paternal age effect.
An attractive idea for the nature of the selection is that among the asymmetrical spermatogonial divisions, producing one daughter cell like the parent and one that develops into a sperm cell, occasional symmetrical divisions (two daughter cells like the parent) occur (
In the asymmetrical divisions each cell produces one daughter like itself and one that, after 6 divisions, develops into a sperm cell. Since there are many more asymmetrical divisions, especially in older men, most of the mutations occur during the period of asymmetrical divisions.
This beautiful result immediately leads to several questions. How many more loci are there that use this device? There are a number of examples in biology of easy transition between symmetrical and asymmetrical division. Why are examples, especially in higher vertebrates, so rare? The symmetrical type may cause a harmful effect. If the zygotic property of a gametically favored trait is harmful, the harmful effect may well prevail. As Haldane once said: “Clearly a higher plant species is at the mercy of its pollen grains”
The MEN2B system offers a promising way to approach this and other equally interesting problems because so much is known in the mouse: for example
Asymmetrical division is one of nature's cleverest devices. In a human male it yields a constant daily supply of sperm. Yet mutation to symmetry occurs in a number of biological systems. The process of asymmetrical division is in constant danger of sabotage by mutants waiting to beat it.
By Bret Payseur: Jim Crow passed away shortly after he finished writing this piece. Jim's infectious engagement with science lasted his entire life. This commentary marks the end of a storied career of research, teaching, and service that visibly advanced the field of population genetics. Jim considered the training of his many remarkable students to be his greatest gift to science. This collection of notable geneticists represents a living legacy of Jim Crow and his ideas.