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The Human Genome Project was famously declared complete in 2003, and to date there are 6000 genes discovered/annotated. What was the first one discovered and annotated?

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    $\begingroup$ Some human genes (cancer related) were sequenced already by 1982, see Van Straatenet al., and about 500 were sequenced by 1987 (Kanigel). The HGP only started in 1990 and sequencing was not completed in 2002 when it ended, despite media announcements. The "final completion" was announced in April 2022 by the T2T consortium, HGP's successor. $\endgroup$
    – Conifold
    Commented Mar 13 at 6:41

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Answer

Although the original publication makes no claims to this effect, I suggest that the first human gene sequence to be reported was that of β-globin in 1980.

The reference to the publication is Lawn et al. (1980) Cell 21, 647–651.

Historical context

Following the acceptance of the messenger RNA (mRNA) hypothesis in 1959/1960 (reviewed by M. Cobb in Current Biology 25, R523–R548, 2015) there were two main requirements/obstacles to determining the sequence of a particular mRNA or of the gene encoding it:

  • Isolation and purification
  • Sequencing methodology

The combination of these problems meant that most initial work was done on the small RNAs, transfer RNA (tRNA) and the various components of ribosomal RNA (rRNA), and in bacterial or yeast systems. Sequencing was of radioactively labelled RNAs by laborious chemical techniques.

It was for the reasons of isolation and purification that the first animal mRNAs sequenced by these means were the globin mRNAs which dominate the spectrum of mRNAs in reticulocytes. At that time there was no way of isolating pure genes, and no methods of sequencing DNA.

The purification problem was overcome by the introduction of molecular cloning in plasmid vectors (e.g. pBR322, introduced in 1977), made possible by the previous discovery of type II restriction endonucleases. This could be applied to mRNA by copying to complementary DNA (cDNA) using the enzyme, reverse transcriptase. The discovery (1971) that eukaryotic mRNAs were polyadenylated at their 3′ ends greatly facilitated their cDNA cloning.

The availability of cDNA clones for specific eukaryotic mRNAs allowed screening of genomic DNA by hybridization. Thus the genes for the mRNAs which were easiest to purify because of their abundance in particular tissues were also the first to be cloned and mapped. The various haemoglobins were obvious candidates, and the shift to the human genome was natural because of the extensive interest in human haemoglobinopathies, and the corresponding genetic knowledge. Other genes that were relatively easy to clone included those of muscle proteins, such as actin. The first human actin gene sequence was not, however, published until 1982. It should also be noted that identification of these genes was also facilitated by the fact that the sequences of their protein products had been determined directly.

The sequencing problem was overcome by the introduction in 1977 of the Maxam/Gilbert (chemical) method of sequencing DNA, allowing over 100 nucleotides to be determined at a time.

It was the combination of these two technologies that was important. Ironically, The first human globin mRNA sequence, published in 1977, used cDNA cloning, but then transcribed the cDNA into radioactive RNA, and employed the laborious chemical methods already mentioned (ribonuclease digestion and 2D chromatography, followed by fragment identification).

Conclusion

Considering the time of introduction of Maxam/Gilbert sequencing method (1977) and that of publication of the sequence of the human β-globin gene (1980), together with the other historical factors mentioned above, I doubt that there are any other contenders for the claim for the first human gene sequence.

What I feel is more important than “which was first?” is “why?” and “why then?”, questions which I hope have also been answered by the historical context described above. This also suggests the further methodological problems that needed to be solved before the Human Genome Project was considered feasible ten years later.

Appendix

Annotated 2060 nucleotide sequence from Lawn et al. (1980)

Beta Globin gene sequence

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  • $\begingroup$ I tentatively thought that Orkin et al. (also Orkin) were "the first" in 1978, although it is hard to tell from their descriptions if they actually sequenced a gene. Antonarakis, History of the methodology of disease gene identification is also informative, but I do not think it gives a straight answer either. He does say "The HBB gene cluster was cloned and sequenced in the late 1970s (Fritsch et al., 1979)". $\endgroup$
    – Conifold
    Commented Mar 18 at 20:54
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    $\begingroup$ @Conifold — Clearly the Lawn paper was not written in isolation, but was the culmination of work on mapping the human globin genes, some of which was published in the Fritsch paper, which was by the same group under Tom Maniatis, later author of the famous molecular cloning manual. Orkin was using the tools and information that had been generated in studies of haemoglobinopathies. But the actual sequence was not established in any of the previous mapping papers. $\endgroup$
    – David
    Commented Mar 19 at 8:08

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