What percentage of the human genome hasn't been sequenced yet? I have read different estimates, e.g.:

If there isn't a consensus on the percentage of the human genome that hasn't been sequenced yet, why is it difficult to estimate?

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    $\begingroup$ Why do you care if it is 5% or 6%? What are you going to do with the number, which in any case will probably have changed in 12 months time. That isn't an interesting scientific question, which is why you are unlikely to find a "consensus" — people aren't discussing it. What is interesting is nearer to your last question. Why it is difficult to estimate is subsidiary to the question why the remaining gaps are difficult to fill. I suggest you search for info on that (perhaps even here on SE Biology) and come back with a modified question if necessary. $\endgroup$ – David Jul 5 '19 at 12:23
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    $\begingroup$ @David's comment may be a bit harsh, but I think the recommendation to focus on the last sub-question as the actually interesting bit is good. Although you say there is not consensus, "4-9%" and "8%" are estimates in complete agreement with each other because 8% is in the range 4-9%. The second article you link specifically explains why this is different from the "99%" or "complete" number in your first link (99% is relative to the amount that "can" be sequenced with the technique used). $\endgroup$ – Bryan Krause Jul 5 '19 at 16:18
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    $\begingroup$ @BryanKrause I don't think that's correct: The 99% estimate and the other estimates essentially refer to the same. They are simply vastly different and contradictory estimates. In particular, the amount that “can” be sequenced and assembled has been sequenced and assembled to exactly 100%. $\endgroup$ – Konrad Rudolph Jul 6 '19 at 8:49
  • $\begingroup$ @KonradRudolph Further evidence that the interesting question is the one David suggests rather than the title. $\endgroup$ – Bryan Krause Jul 6 '19 at 9:04
  • $\begingroup$ This is likely related to long repeating sequences of DNA which are unlikely to be sequenced with current sequencing techniques. Essentially we cannot determine the number of repeats and thus we have to estimate how much of the DNA that remain unsequenced. $\endgroup$ – Jeppe Nielsen Jul 8 '19 at 1:02

I answered a related question here that may be helpful.

Some initial notes:

  • Your first bullet point ("99%") is to my reading talking about not the total genome size but the data that they actually assembled- e.g. for 99% of nucleotides, we are 99.99% that the nucleotide at that position is not some other nucleotide, but there may be other positions not included in the denominator that are simply not in the assembly in the first place. In other words, the existence of the position in the assembly and our confidence of the accuracy of a nucleotide call for such a position are two different (though related) phenomena.
  • Also, you are comparing a 2003 estimate to a 2017 estimate. We learned a lot in those 14 years.

To answer the last and most specific question about why this number is hard to know, there are a variety of reasons why:

  1. There is no single number that is the "actual" true sequenced percentage of the human genome. In this I strongly disagree with commenter Konrad Rudolph (technological change is now giving us telomere-to-telomere assemblies of human chromosomes! The question is not how much it's possible to sequence and assemble but more whether it's the worth the time and expense to do so.). No two genomes are exactly alike, and that means not only that the nucleotides are different but that the positions are different. So even if we sequence 100% of your genome, that may only include 99% of my genome. These variable regions are, as suggested in the comments, largely repetitive regions but also just big chunks that are missing; to learn more about this google "structural variation" (here is an older review on the topic).

  2. As mentioned already, technological advances have changed how we view the linear sequence of the genome. Earlier estimates were limited by available technology of the time; now that we have 3rd-generation sequencing tech like nanopore and pacbio, we are learning more about the extent of our ignorance. In that sense, it is unsurprising that the denominator has changed/increased.

  3. As commenter Jeppe Nielsen states, all of these are statistical estimates based on available data. As available data increase and the statistical models that we use to estimate change, thus do the estimated outcomes change.

  4. Related to (1): Different populations have different chunks of genome that are unique. The initial sequencing project selected a small number of humans, who were not representative of all human diversity. Efforts to fully characterize the human pangenome are ongoing.

  5. Sometimes contaminants sneak into genome assemblies, which have to be removed. So for every sequence in the human genome assembly, especially if it's fragmentary or recently added, there's a nonzero chance that it's not actually part of any human genome.

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