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Wednesday, April 07, 2021

Bold predictions for human genomics by 2030

After spending several years working on a book about the human genome I've come to the realization that the field of genomics is not delivering on its promise to help us understand what's in your genome. In fact, genomics researchers have by and large impeded progress by coming up with false claims that need to be debunked.

My view is not widely shared by today's researchers who honestly believe they have made tremendous progress and will make even more as long as they get several billion dollars to continue funding their research. This view is nicely summarized in a Scientific American article from last fall that's really just a precis of an article that first appeared in Nature. The Nature article was written by employees of the National Human Genome Research Institute (NHGRI) at the National Institutes of Health in Bethesda, MD, USA (Green et al., 2020). Its purpose is to promote the work that NHGRI has done in the past and to summarize its strategic vision for the future. At the risk of oversimplifying, the strategic vision is "more of the same."

Green, E.D., Gunter, C., Biesecker, L.G., Di Francesco, V., Easter, C.L., Feingold, E.A., Felsenfeld, A.L., Kaufman, D.J., Ostrander, E.A. and Pavan, W.J. and 20 others (2020) Strategic vision for improving human health at The Forefront of Genomics. Nature 586:683-692. [doi: 10.1038/s41586-020-2817-4]

Starting with the launch of the Human Genome Project three decades ago, and continuing after its completion in 2003, genomics has progressively come to have a central and catalytic role in basic and translational research. In addition, studies increasingly demonstrate how genomic information can be effectively used in clinical care. In the future, the anticipated advances in technology development, biological insights, and clinical applications (among others) will lead to more widespread integration of genomics into almost all areas of biomedical research, the adoption of genomics into mainstream medical and public-health practices, and an increasing relevance of genomics for everyday life. On behalf of the research community, the National Human Genome Research Institute recently completed a multi-year process of strategic engagement to identify future research priorities and opportunities in human genomics, with an emphasis on health applications. Here we describe the highest-priority elements envisioned for the cutting-edge of human genomics going forward—that is, at ‘The Forefront of Genomics’.

What's interesting are the predictions that the NHGRI makes for 2030—predictions that were highlighted in the Scientific American article. I'm going to post those predictions without comment other than saying that I think they are mostly bovine manure. I'm interested in hearing your comments.

Bold predictions for human genomics by 2030

Some of the most impressive genomics achievements, when viewed in retrospect, could hardly have been imagined ten years earlier. Here are ten bold predictions for human genomics that might come true by 2030. Although most are unlikely to be fully attained, achieving one or more of these would require individuals to strive for something that currently seems out of reach. These predictions were crafted to be both inspirational and aspirational in nature, provoking discussions about what might be possible at The Forefront of Genomics in the coming decade.

  1. Generating and analysing a complete human genome sequence will be routine for any research laboratory, becoming as straightforward as carrying out a DNA purification.
  2. The biological function(s) of every human gene will be known; for non-coding elements in the human genome, such knowledge will be the rule rather than the exception.
  3. The general features of the epigenetic landscape and transcriptional output will be routinely incorporated into predictive models of the effect of genotype on phenotype.
  4. Research in human genomics will have moved beyond population descriptors based on historic social constructs such as race.
  5. Studies that involve analyses of genome sequences and associated phenotypic information for millions of human participants will be regularly featured at school science fairs.
  6. The regular use of genomic information will have transitioned from boutique to mainstream in all clinical settings, making genomic testing as routine as complete blood counts.
  7. The clinical relevance of all encountered genomic variants will be readily predictable, rendering the diagnostic designation ‘variant of uncertain significance (VUS)’ obsolete.
  8. An individual’s complete genome sequence along with informative annotations will, if desired, be securely and readily accessible on their smartphone.
  9. Individuals from ancestrally diverse backgrounds will benefit equitably from advances in human genomics.
  10. Breakthrough discoveries will lead to curative therapies involving genomic modifications for dozens of genetic diseases.

I predict that nine years from now (2030) we will still be dealing with scientists who think that most of our genome is functional; that most human protein-coding genes produce many different proteins by alternative splicing; that epigenetics is useful; that there are more noncoding genes than protein-coding genes; that the leading scientists in the 1960 and 70s were incredibly stupid to suggest junk DNA; that almost every transcription factor binding site is biologically relevant; that most transposon-related sequences have a mysterious (still unknown) function; that it's still a mystery why humans are so much more complex than chimps; and that genomics will eventually solve all problems by 2040.

Why in the world, you might ask, would we still be dealing with issues like that? Because of genomics.


  1. because of genomics

    Did you mean to say "because of genomicists"?

    1. Both are part of the problem. I've come to realize that Sydney Brenner was right to criticize the entire field of genomics for not being capable of delivering on their promises. The key word is "capable" - the field will never be able to say anything substantive about function. That requires hard work by biochemists using hypothesis-driven research.

  2. #2 "The biological function(s) of every human gene will be known; for non-coding elements in the human genome, such knowledge will be the rule rather than the exception." will go a lot easier if they just acknowledge that most of the nc elements are junk and have no function.

  3. Well of course epigenetics is useful. It's key to cell differentiation during development. Or were you referring to epigenetic inheritance between organismal generations? Sure, that's bollocks. But can you allow the definition to be hijacked in that way?

    1. The definition has already been hijacked in this way.

      But you are missing another problem. Whether or not epigenetic markers are heritable is one problem but the key issue is whether they play a role in gene expression. Are demethylation and histone modifications merely epiphenomena resulting from transcription factor binding or do they come first and determine whether transcription factors can bind? In other words, what's cause and what's effect?

      I favor the epiphenomenon hypothesis, also known as Ptashne's recruitment model, in which case it makes no logical sense to say that epigenetics plays a direct role in regulating gene expression.

    2. I meant epigenetics by the old, better definition, referring to non-genetic inheritance during development and, even older, the physical processes of development. Why allow the word to be taken by something bogus, leaving the real phenomena without a word to cover them?

    3. I will avoid the terminological debate but bring up one issue that is often missed or avoided when people invoke "epigenetics" as an explanation of long-term adaptation. Aside from the major issue of how long these modifications to the DNA persist, there is the question of whether they are adaptive. If your grandfather went through a famine and passed on epigenetic marks to you, do those tend to make you better adapted to famine? Or do they just make you more likely to get cancer or heart disease? People don't often raise this issue but it is important.

    4. @John Harshman

      There are lots of ways to define "epigenetics" so in order to have a rational discussion I need to understand your preferred definition.

      I suggest you read Mark Ptashne's article Epigenetics: Core misconcept and let me know whether you are in general agreement or whether you disagree.

      Then you can check out my own post at What the heck is epigenetics and see if you like any of the definitions there. The key questions are whether the inheritance of lac repressor molecules in dividing E. coli cells counts as epigenetics and whether the inheritance of restriction modification is a good example of non-genetic inheritance.