While doing some other research, I ran across a remarkable short paper by James Spuhler, "On the number of genes in man," printed in Science in 1948.
We've been hearing for the last ten years how the low gene count in humans -- only 20,000 or so genes -- is "surprising" to scientists who had previously imagined that humans would have many more genes than this.
So here's the next to the last line of Spuhler's article:
On the basis of these speculations there are then some 19,890-30,420 gene loci in man.
He actually estimated the total gene number in two ways. The first, based on estimates of chromosome length in Drosophila and humans, coupled with Bridges' estimate of fruit fly gene number (5000), led to an estimate of 42,000 genes in humans. This means of estimation was probably closer to those that later suggested a high gene number in humans.
Spuhler's second means of estimating gene number was a lot more interesting. He observed that among human pregnancies, more males than females are lost to miscarriages. Spuhler assumed that a high proportion of these fetal losses were caused by X-linked lethal mutations, and used that as a means of working out the total lethal mutation rate on the X chromosome.
Haldane had given an estimate of the mutation rate to X-linked hemophilia, based on its novel occurrence in pedigrees in the population. Taking this estimate for one locus, Spuhler could estimate the number of loci on the X. And then, the length of the X as measured cytologically could be used to estimate the total number of genes in the human genome.
His estimate on this basis, roughly between 20,000 and 30,000, is much like what we think today.
On the other hand, Spuhler's numbers were imprecise. Later, Frota-Pessoa revisited Spuhler's estimate. Frota-Pessoa found the means of estimation very attractive because they did not rely on extrapolation from other animals. However, there are other causes of fetal loss than lethal mutations, and we must recognize that the conception ratio is not 50/50, so that the proportion of male to female fetal losses can't estimate the X-linked lethal rate without some correction. Frota-Pessoa arrived at an estimate of human gene number less than a third that of Spuhler's range: only 5900 to 11,700 genes.
That estimate also gives the lie to the idea that geneticists always expected a very high gene count in humans. What's remarkable to me is that the entire means of estimation required no knowledge of gene sequences or DNA; the estimates required only epidemiology coupled with cytological estimates of chromosome lengths.
Frota-Pessoa O. 1961. On the number of gene loci and the total mutation rate in man. Am Naturalist 95:217-222.
Spuhler JN. 1948. On the number of genes in man. Science 108:279-280.