Notes on "Comparative genomics of mortal and immortal..." by Pascual-Torner et al.

Comparative genomics of mortal and immortal cnidarians unveils novel keys behind rejuvenation

Maria Pascual-Torner et al., 2021, PNAS

Summary

This article wants to uncover the molecular basis of the life cycle reversal in the hydrozoan T. dohrnii by comparing the genome of the negligibly senescent T. dohrnii with the hydrozoan species Turritopsis rubra, which has a lifespan of weeks.

The authors determined that the T. dohrnii genome is 390 Mb with ~17,468 genes, while the T. rubra is 210 Mb with only ~9,324 genes. Furthermore, rejuvenation may be linked to duplications of genes involved in replication and repair, such as POLD1, POLA2, RFC3, TOP3B, XRCC5, GEN1, RAD51C, MSH2, GAR1. The gene duplication findings are summarized in the image below.

Furthermore, the authors found that the silencing of PRC2 targets and activation of pluripotency targets are two mechanisms in cell reprogramming with the germ-line factors OSKM and are also involved in T. dohrnii life cycle reversal.

Remaining Questions

• What biological clocks do hydrozoans have? Do the bodies of hydrozoans know how old they are? Is rejuvenation achieved by turning this clock back?

• Dos more copies of the longevity genes translate into more expression of these genes, and how is the interaction of the duplicates coordinated?

Issues with article

• It is unclear why T. rubra was chosen, and the authors even note that the senescent T. nutricula would have been a better choice as it is much closer to T. dohrnii evolutionarily.

Jellyfish Background

Hydrozoans start their life as larvae on the sea floor. The larvae grow into colonies of polyps, which then bud many bell-shaped medusa in a matter of days. Medusas are commonly known as jellyfish. The medusas grow for a few weeks, sexually mature, and then release germ cells of their own. The germ cells meet, form a fertilized egg, a new larvae is produced, and the cycle continues. Remarkably, some cnidarian species can revert from medusas back to polyps. Even more remarkably, the cnidarian Turritopsis dohrnii, which grows to be 2-5 mm, has been documented to repeatedly revert from medusa to polyp continuously, even after it has reproduced. It has become a model negligibly senescent organism. Turritopsis rubra, on the other hand, has never been documented to rejuvenate after reproduction.

Nice image from the article illustrating the hydrozoan lifecycle

Polycomb repressive complex 2 background

The Polycomb repressive complex 2 (PRC2) is an essential chromatin regulatory complex involved in repressing the transcription of various developmental genes. This complex of proteins consists of H3K27 methyltransferases.

Note on transposons and junk DNA

In this study, repetitive elements were found to represent around half of the genome in both T. dohrnii and T. rubra, which is similar to other cnidarians. In my opinion, this is evidence against the transposon theory of aging. Half of the genome of each T. dohrnii that has been sequenced has been transposons. Still, this hydrozoan does not age!

It seems the authors had trouble classifying which sequences were functional genes. The authors have a very restrictive definition of amplifications. Amplications are usually defined as any genes with two or more copies in the genome. Here, "gene amplifications were only reported when two or more independent protein sequences overlapped the same sequence of the corresponding human orthologs", whatever that means?

Gene amplification number:

Considering their difference in genome size and number of genes, we would expect to find more amplified genes in T. dohrnii than in T. rubra. However, we found that the percentage of observed in T. dohrnii from our manually annotated list was 3.77 times higher than the one we obtained from a representative gene set of the whole genome in this species.

Addressing the fallacies in the first paragraph:

There is an unwritten rule that the first sentence of every academic is a complete triviality. This article, however, references many debunked theories of aging in its opening paragraph, which is reproduced below.

"Natural selection declines with age and particularly affects genes that are important in prereproductive phenotypes, regardless of their postreproductive effects. Thus, variants that are damaging only late in life are not readily eliminated from the gene pool (1). Consequently, aging has evolved over time through modulation of traits related to the hallmarks of health (2) or to the determinants of aging, such as cellular senescence or genomic instability, which impair pluripotency and regeneration potentials (3). Several cnidarian species have challenged some of these traits and stand out for their singular developmental plasticity and even ontogeny reversals, while still sharing genomic structural features and pivotal genes with bilaterians (4–6)."

Firstly, the authors are assuming aging is inevitable in their opening sentence when they refer to natural selection. Aging is the increased probability of death with the passage of time. There is no reason that organisms must age. To say "natural selection declines with chronological age" is to assume that organisms become less fertile and/or less likely to survive with the passage of time. However, again, there is no reason that the body cannot grow stronger and healthier with each passing year. In fact, if the human body did become healthier and more fertile with each passing year, there most certainly would be an evolutionary incentive to select for longevity. Secondly, genes are turned on and off all the time. Hence, there is no reason to think that genes that are "important in prereproductive phenotypes" become "damaging only late in life". Evolution should have eliminated those genes, just as it eliminated the expression of all the developmental genes after embryonic development.