The 20th anniversary of the human genome sequence: 6. Nature doubles down on ENCODE results

Nature has now published a series of articles celebrating the 20th anniversary of the publication of the draft sequences of the human genome [Genome revolution]. Two of the articles are about free access to information and, unlike a similar article in Science, the Nature editors aren't shy about mentioning an important event from 2001; namely, the fact that Science wasn't committed to open access.

By publishing the Human Genome Project’s first paper, we worked with a publicly funded initiative that was committed to data sharing. But the journal acknowledged there would be challenges to maintaining the free, open flow of information, and that the research community might need to make compromises to these principles, for example when the data came from private companies. Indeed, in 2001, colleagues at Science negotiated publishing the draft genome generated by Celera Corporation in Rockville, Maryland. The research paper was immediately free to access, but there were some restrictions on access to the full data.

The 20th anniversary of the human genome sequence: 5. 90% of our genome is junk

This is the fifth (and last) post in celebration of the 20th anniversary of publishing the draft sequence. The first four posts dealt with: (1) the way Science chose to commemorate the occasion [Access to the data]; (2) finishing the sequence; (3) the number of genes; and (4) the amount of functional DNA in the genome.

Back in 2001, knowledgeable scientists knew that most of the human genome is junk and the sequence confirmed that knowledge. Subsequent work on the human genome over the past 20 years has provided additional evidence of junk DNA so that we can now be confident that something like 90% of our genome is junk DNA. Here's a list of data and arguments that support that claim.

The 20th anniversary of the human genome sequence: 4. Functional DNA in our genome

We know a lot more about the human genome than we did when the draft sequences were published 20 years ago. One of the most important discoveries is the recognition and extent of true functional sequences in the genome. Genes are one example of such functional sequence but only a minor component (about 1.4%). Most of the functional regions of the genome are not genes.

Here's a list of functional DNA in our genome other than the functional part of genes.

• Centromeres: There are 24 different centromeres and the average size is four million base pairs. Most of this is repetitive DNA and it adds up to about 3% of the genome. The total amount of centromeric DNA ranges from 2%-10% in different individuals. It's unlikely that all of the centromeric DNA is essential; about 1% seems to be a good estimate.
• Telomeres: Telomeres are repetivie DNA sequences at the ends of chromosomes. They are required for the proper replication of DNA and they take up about 0.1% of the genome sequence.
• Origins of replication: DNA replication begins at origins of replication. The size of each origin has not been established with certainlty but it's safe to assume that 100 bp is a good estimate. There are about 100,000 origin sequences but it's unlikely that all of them are functional or necessary. It's reasonable to assume that only 30,000 - 50,000 are real origins and that means 0.3% of the genome is devoted to origins of replication.
• Regulatory sequences: The transcription of every gene is controlled by sequences that lie outside of the genes, usually at the 5′ end. The total amount of regulatory sequence is controversial but it seems reasonable to assume about 200 bp per gene for a total of five million bp or less than 0.2% of the genome (0.16%). The most extreme claim is about 2,400 bp per gene or 1.8% of the genome.
• Scaffold attachment regions (SARs): Human chromatin is organized into about 100,000 large loops. The base of each loop consists of particular proteins bound to specific sequences called anchor loop sequences. The nomenclature is confusing; the original term (SAR) isn't as popular today as it was 35 years ago but that doesn't change the fact that about 0.3% of the genome is required to organize chromatin.
• Transposons: Most of the transposon-related sequencs in our genome are just fragments of defective transposons but there are a few active ones. They account for only a tiny fraction of the genome.
• Viruses: Functional virus DNA sequences account for less than 0.1% of the genome.

If you add up all the functional DNA from this list, you get to somewhere between 2% and 3% of the genome.

---

Image credit: Wikipedia.

The 20th anniversary of the human genome sequence: 3. How many genes?

This week marks the 20th anniversary of the publication of the first drafts of the human genome sequence. Science choose to celebrate the achievement with a series of articles that had little to say about the scientific discoveries arising out of the sequencing project; one of the articles praised the opennesss of sequence data without mentioning that the journal had violated its own policy on openness by publishing the Celera sequence [The 20th anniversary of the human genome sequence: 1. Access to the data and the complicity of Science].

I've decided to post a few articles about the human genome beginning with one on finishing the sequence. In this post I'll summarize the latest data on the number of genes in the human genome.

The 20th anniversary of the human genome sequence: 2. Finishing the sequence

It's been 20 years since the first drafts of the human genome sequence were published. These first drafts from the International Human Genome Project (IHGP) and Celera were far from complete. The IHGP sequence covered about 82% of the genome and it contained about 250,000 gaps and millions of sequencing errors.

Celera never published an updated sequences but IHPG published a "finished" sequence in October 2004. It covered about 92% of the genome and had "only" 300 gaps. The error rate of the finished sequence was down to 10^-5.

International Human Genome Sequencing Consortium (2004) Finishing the euchromatic sequence of the human genome. Nature 431:931-945. doi: 10.1038/nature03001

We've known for many decades that the correct size of the human genome is close to 3,200,000 kb or 3.2 Gb. There's isn't a more precise number because different individuals have different amounts of DNA. The best average estimate was 3,286 Gb based on the sequence of 22 autosomes, one X chromosome, and one Y chromosome (Morton 1991). The amount of actual nucleotide sequence in the latest version of the reference genome (GRCh38.p13) is 3,110,748,599 bp and the estimated total size is 3,272,116,950 bp based on estimating the size of the remaining gaps. This means that 95% of the genome has been sequenced. [see How much of the human genome has been sequenced? for a discussion of what's missing.]

Recent advances in sequencing technology have produced sequence data covering the repetitive regions in the gaps and the first complete sequence of a human chromosome (X) was published in 2019 [First complete sequence of a human chromosome]. It's now possible to complete the human genome reference sequence by sequencing at least one individual but I'm not sure that the effort and the expense are worth it.

---

Image credit the figure is from Miga et al. (2019)

Miga, K.H., Koren, S., Rhie, A., Vollger, M.R., Gershman, A., Bzikadze, A., Brooks, S., Howe, E., Porubsky, D., Logsdon, G.A. et al. (2019) Telomere-to-telomere assembly of a complete human X chromosome. Nature 585:79-84. [doi: 10.1038/s41586-020-2547-7]

Morton, N.E. (1991) Parameters of the human genome. Proceedings of the National Academy of Sciences 88:7474-7476. [doi: 10.1073/pnas.88.17.7474]

The 20th anniversary of the human genome sequence: 1. Access to the data and the complicity of Science

The first drafts of the human genome sequence were published 20 years ago. The paper from the International Human Genome Project (IHGP) was published in Nature on Febuary 15, 2001 and the paper from Celera was published in Science on February 16, 2001.

The original agreement was to publish both papers in Science but IHGP refused to publish their sequence in that journal when it choose to violate its own policy by allowing Celera to restrict access to its data. I highly recommend James Shreeve's book The Genome War for the history behind these publications. It paints an accurate, but not pretty, picture of science and politics.

Lander, E., Linton, L., Birren, B., Nusbaum, C., Zody, M., Baldwin, J., Devon, K., Dewar, K., Doyle, M., FitzHugh, W., Funke, R., Gage, D., Harris, K., Heaford, A., Howland, J., Kann, L., Lehoczky, J., LeVine, R., McEwan, P., McKernan, K., Meldrim, J., Mesirov, J., Miranda, C., Morris, W., Naylor, J., Raymond, C., Rosetti, M., Santos, R., Sheridan, A. and Sougnez, C. (2001) Initial sequencing and analysis of the human genome. Nature 409:860-921. doi: 10.1038/35057062

Venter, J., Adams, M., Myers, E., Li, P., Mural, R., Sutton, G., Smith, H., Yandell, M., Evans, C., Holt, R., Gocayne, J., Amanatides, P., Ballew, R., Huson, D., Wortman, J., Zhang, Q., Kodira, C., Zheng, X., Chen, L., Skupski, M., Subramanian, G., Thomas, P., Zhang, J., Gabor Miklos, G., Nelson, C., Broder, S., Clark, A., Nadeau, J., McKusick, V. and Zinder, N. (2001) The sequence of the human genome. Science 291:1304 - 1351. doi: 10.1126/science.1058040