Transcription activity in repeat regions of the human genome

A detailed examination of the new complete human genome reveals that 54% of it consists of various repetitive elements. Some of them are transcribed and some aren't.

This is my fourth post on the complete telomere-to-telomere sequence of the human genome in cell line CHM13 (T2T-CHM13). There were six papers in the April 1st edition of Science. My posts on all six papers are listed at the bottom of this post.

The fourth paper extends the ENCODE-type analysis of the T2T-CHM13 sequence by focusing on repeats.

Hoyt, S.J., Storer, J.M., Hartley, G.A., Grady, P.G., Gershman, A., de Lima, L.G., Limouse, C., Halabian, R., Wojenski, L., Rodriguez, M. et al. (2021) From telomere to telomere: the transcriptional and epigenetic state of human repeat elements. Science 376:57. [doi: 10.1126/science.abk3112]

Mobile elements and repetitive genomic regions are sources of lineage-specific genomic innovation and uniquely fingerprint individual genomes. Comprehensive analyses of such repeat elements, including those found in more complex regions of the genome, require a complete, linear genome assembly. We present a de novo repeat discovery and annotation of the T2T-CHM13 human reference genome. We identified previously unknown satellite arrays, expanded the catalog of variants and families for repeats and mobile elements, characterized classes of complex composite repeats, and located retroelement transduction events. We detected nascent transcription and delineated CpG methylation profiles to define the structure of transcriptionally active retroelements in humans, including those in centromeres. These data expand our insight into the diversity, distribution, and evolution of repetitive regions that have shaped the human genome.

The most useful part of this paper is the complete analysis of all repetitive elements in the T2T-CHM13 genome. This gives us, for the first time, a complete picture of a human genome. The exact values of the various components aren't important because there's considerable variation with the human population but the big picture is informative.

These are the percentages of the human genome occupied by the different classes of repetitive DNA.

• SINEs 12.8%
• Retrotransposon 0.15%
• LINEs 20.7%
• LTRs 8.8%
• DNA transposons 3.6%
• simple repeats 8%

The total comes to 54%. There are other estimates that are higher because of a more lenient cutoff value for sequence similarity but this gives you a pretty good idea of what the genome looks like. Most of the transposon-related sequence consists of fragments of once active transposons so the fraction of the genome consisting of true selfish DNA capable of transposing is a small fraction of this 54%.

We have every reason to believe that most of this DNA is junk DNA based on several lines of evidence developed over the past 50 years but most of the authors of this paper are reluctant to reach that conclusion so the fact that these repetitive sequences might be junk isn't mentioned in the paper. Instead, the authors concentrate on mapping CpG methylation sites and transcribed regions. They refer to this as "functional annotation" but they don't provide a definition of function.

We provide a high-confidence functional annotation of repeats across the human genome.

As you might expect, the repeat elements that retain vestiges of promoters are often transcribed and this includes adjacent genomic sequences that are found near these promoter (e.g. near LTRs). The long stretches of short tandem repeats (e.g. satellite DNA) do not contain any sequences that resemble promoters so these regions are not transcribed. (The authors seem to be a bit surprised by this result.) Further work is needed to decide how much of this DNA is truly functional and which parts contribute to human uniqueness. Naturally, that will require much more ENCODE-type work and T2T sequencing of other primates.

Finally, our work demonstrates the need to increase efforts toward achieving T2T-level assemblies for nonhuman primates to fully understand the complexity and impact of repeat-derived genomic innovations that define primate lineages, including humans. Although we find repeat variants that appear enriched or specific to the human lineage, in the absence of T2T-level assemblies from other primate species, we cannot truly attribute these elements to specific human phenotypes. Thus, the extent of variation described herein highlights the need to expand the effort to create human and nonhuman primate pan-genome references to support exploration of repeats that define the true extent of human variation.

This will cost millions of dollars. I suspect the grant applications have already been sent.

• What do we do with two different human genome reference sequences?
• Karen Miga and the telomere-to-telomere consortium
• A complete human genome sequence (2022)
• Epigenetic markers in the last 8% of the human genome sequence
• Segmental duplications in the human genome
• Transcription activity in repeat regions of the human genome
• Genetic variation and the complete human genome sequence

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