When I was in school (it must have been in gymnasiet, roughly corresponding to secondary school or high school), I remember giving a presentation on a group project about the human genome project, and using the illiterate copyist analogy. After sequencing the human genome, we are able to blindly copy the text of life; we still need to learn to read it. At this point, I had no clue whatsoever that I would be working in genetics in the future. I certainly felt very clever coming up with that image. I must have read it somewhere.
If it is true that the illiterate scribe is a myth, and they must have had at least some ability to read, that makes the analogy more apt: even in 2003, researchers actually had a fairly good idea of how to read certain aspects of genetics. The genetic code is from 1961, for crying out loud (Yanofsky 2007)!
My classroom moment must have been around 2003, which is the year the ENCODE project started, aiming to do just that: create an encyclopedia (or really, a critical apparatus) of the human genome. It’s still going: a drove of papers from its third phase came out last year, and apparently it’s now in the fourth phase. ENCODE can’t be a project in the usual sense of a planned undertaking with a defined goal, but rather a research programme in the general direction of ”a comprehensive parts list of functional elements in the human genome” (ENCODE FAQ). Along with the phase 3 empirical papers, they published a fun perspective article (The ENCODE Project Consortium et al. 2020).
ENCODE commenced as an ambitious effort to comprehensively annotate the elements in the human genome, such as genes, control elements, and transcript isoforms, and was later expanded to annotate the genomes of several model organisms. Mapping assays identified biochemical activities and thus candidate regulatory elements.
The age means that ENCODE has lived through generations of genomic technologies. Phase 1 was doing functional genomics with microarrays, which now sounds about as quaint as doing it with blots. Nowadays, they have CRISPR-based editing assays and sequencing methods for chromosome 3D structure that just seem to keep adding Cs to their acronyms.
Last time I blogged about the ENCODE project was in 2013 (in Swedish), in connection with the opprobrium about junk DNA. If you care about junk DNA, check out Sean Eddy’s FAQ (Eddy 2012). If you still want to be angry about what percentage of the genome has function, what gene concepts are useful and the relationship between quantitative genetics and genomics, check out this Nature Video. It’s funny, because the video pre-empts some of the conclusions of the perspective article.
The video says: to do many of the potentially useful things we want to do with genomes (like sock cancer in the face, presumably), we need to look at individual differences (”between you, and you, and you”) and how they relate to traits. And an encyclopedia, great as it may be, is not going to capture that.
The perspective says:
It is now apparent that elements that govern transcription, chromatin organization, splicing, and other key aspects of genome control and function are densely encoded in the human genome; however, despite the discovery of many new elements, the annotation of elements that are highly selective for particular cell types or states is lagging behind. For example, very few examples of condition-specific activation or repression of transcriptional control elements are currently annotated in ENCODE. Similarly, information from human fetal tissue, reproductive organs and primary cell types is limited. In addition, although many open chromatin regions have been mapped, the transcription factors that bind to these sequences are largely unknown, and little attention has been devoted to the analysis of repetitive sequences. Finally, although transcript heterogeneity and isoforms have been described in many cell types, full-length transcripts that represent the isoform structure of spliced exons and edits have been described for only a small number of cell types.
That is, the future of genomics is in variation. We want to know about: organismic/developmental background (cell lines vs primary vs induced vs tissue), environmental variation (condition-dependence), genetic variation (gene editing assays that change local genetic variants, the genetic background of different cell line and human genomes), dynamics (time and induction). To put it in plain terms: We need to know how the genome regulation of different cells and individuals are different, and what that does to them. To put it in fancy terms: we are moving towards cellular phenomics, quantitative genomics, and an ever-expanding hypercube of data.
Eddy, S. R. (2012). The C-value paradox, junk DNA and ENCODE. Current biology, 22(21), R898-R899.
ENCODE Project Consortium, Snyder, M. P., Gingeras, T. R., Moore, J. E., Weng, Z., Gerstein, M. B., Ren, B., … & Myers, R. M. (2020). Perspectives on ENCODE. Nature, 583(7818), 693-698.
Yanofsky, C. (2007). Establishing the triplet nature of the genetic code. Cell, 128(5), 815-818.