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One of the major results of the Human Genome Project (HGP) was that humans have far fewer separate genes than previously thought. From a 2004 article about the HGP:

Francis S. Collins, director of the National Human Genome Research Institute (NHGRI), said, "Only a decade ago, most scientists thought humans had about 100,000 genes. When we analyzed the working draft of the human genome sequence three years ago, we estimated there were about 30,000 to 35,000 genes, which surprised many. This new analysis reduces that number even further [to 20,000-25,000] and provides us with the clearest picture yet of our genome."

What was the old estimate of 100,000 based on? I assume that in 1994 no one had sequenced the entire proteome...

Edit:

As Remi.b points out, the 100,000 gene estimate is probably based on the One gene–one enzyme hypothesis. But that raises another question (which I guess is what I was really trying to ask originally): pre-HGP, did people think that there were 100,000 distinct enzyme activities? If so, what experiments/data were used to establish that number?

The estimate of 100,000 genes is probably caused by the one gene - one enzyme/protein ideas

The one gene–one enzyme hypothesis is the idea that genes act through the production of enzymes, with each gene responsible for producing a single enzyme that in turn affects a single step in a metabolic pathway.

The idea that genes are affecting cell functions via the protein that they code for is not so outdated. However, the idea that a gene codes for a single unique protein is a little outdated.

In reality a single gene can code for several different proteins via a mechanism called alternative splicing.

Alternative splicing, or differential splicing, is a regulated process during gene expression that results in a single gene coding for multiple proteins. In this process, particular exons of a gene may be included within or excluded from the final, processed messenger RNA (mRNA) produced from that gene. Consequently, the proteins translated from alternatively spliced mRNAs will contain differences in their amino acid sequence and, often, in their biological functions [..]. Notably, alternative splicing allows the human genome to direct the synthesis of many more proteins than would be expected from its 20,000 protein-coding genes.

The original estimate of the number of genes was hence probably alined with the observed number of proteins by assuming that there is a one-to-one function from gene to protein (as by the one gene - one protein hypothesis).