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THE BIOCENTER OF THE UNIVERSITY OF WÜRZBURG

The Largest Genome of All Animals Decoded

08/14/2024

An international research team has sequenced the largest genomes of all animals – those of lungfish. The data will help to find out how the ancestors of land vertebrates managed to conquer the mainland.

No other animal in the world has a genome as large as the South American lungfish (Lepidosiren paradoxa).
No other animal in the world has a genome as large as the South American lungfish (Lepidosiren paradoxa). (Image: Katherine Seghers / Louisiana State University)

Let's travel back through time to the late Devonian period, around 380 to 360 million years in the past. In a shallow shore area, something is happening that will change life on our planet forever: A lobe-finned fish, whose descendants include the lungfish, is using its powerful fins, arranged in pairs at the body sides, to pull itself out of the shallow water onto land and move across the muddy shore floor. It is in no hurry to return to the water. Its respiratory organs allow it to stay in the air without any problems, as this fish already has lungs like today's land vertebrates.

This or something similar could have been the first time a vertebrate went ashore – and thus one of the most important events in evolution. After all, later land vertebrates – the so-called tetrapods – can be traced back to a fish. In addition to amphibians, reptiles and birds, tetrapods also include mammals, including humans.

But one mystery remains: How did it come about that the Devonian carnivore was so well prepared for the conquest of the mainland?

A Look at the Living Relatives

To find a solution to this mystery, the genetic material of the closest living relatives of the ancient tetrapod has now been deciphered and analysed to draw conclusions about its genetic make-up as well as the characteristics anchored within. Only three lines of lungfish still exist today; they are the closest living relatives of our common Devonian ancestor, though evolution seems to have forgotten them; of these ancient "living fossils" there is only one species left in Australia, four species in Africa and one species in South America, and yet they still look like their ancestors did 100 million years ago.

Because the genetic material, DNA, of all living organisms is made up of the four nucleobases A, T, G, and C, the lungfish genome sequence contains traceable genetic information. Thus, knowledge of the complete genome sequences of the "living fossils" is essential for such an analysis. It was known that the genomes of lungfish are huge, but how massive they are and what can be learnt from them was not clear until now.

As the genomes of lungfish are among the largest in the animal kingdom, sequencing them was technically and bioinformatically challenging and extremely complex. An international research team led by Würzburg biochemist Manfred Schartl and Constance biologist Axel Meyer has now succeeded for the first time in completely sequencing the genome of the South American lungfish (Lepidosiren paradoxa) and the African lungfish (Protopterus annectens). The largest genome sequence until now was that of the Australian lungfish (Neoceratodus forsteri) that was previously sequenced by the same team (Meyer et al. Nature 2021). The results of the current work have now been published in the journal Nature.

Very, Very Large – But Why?

The genetic material of the South American lungfish in particular breaks all records in terms of size: "With over 90 gigabases (i.e. 90 billion bases), the DNA of the South American species is the largest of all animal genomes and more than twice as large as the genome of the Australian lungfish. Eighteen of the 19 chromosomes of the South American lungfish alone are each larger than the entire human genome with its almost three billion bases," says Schartl.

So-called autonomous transposons are responsible for the fact that the lungfish genome has grown to this enormous size over time. Transposons are DNA segments that produce many copies of themselves, change their position in the genome and can multiply, at least theoretically indefinitely – which in turn makes the genome grow.

Although this also happens in other organisms, the researchers’ analyses have shown that the expansion rate of the genome of the South American lungfish is by far the fastest known: every ten million years its genome grew by the size of an entire human genome.

"And it continues to grow," reports Schartl. "We have found evidence that those transposons are still active." The group at Julius-Maximilians-Universität Würzburg led by bioinformatician Susanne Kneitz, co-author of the study, discovered the mechanism for this gigantic genome growth. In contrast to animals with a regular genome size, lungfish have an extremely low content of piRNAs. This type of ribonucleic acid is an important part of a molecular mechanism that normally limits the spread of transposons.

Surprisingly Stable Despite Everything

Because transposons multiply and jump around in the genome, they can greatly alter and destabilise the genetic material of an organism. This is not always detrimental and can even be an important driving force of evolution as sometimes these "jumping genes" also lead to evolutionary innovations by changing gene functions.

It is therefore more surprising that the current study found no correlation between the enormous transposon excess and genome instability – the genome of the lungfish is unexpectedly stable, and the gene arrangement is surprisingly conservative. This fact allowed the researchers to reconstruct the appearance of the chromosome set (karyotype) of the ancestral tetrapod from the sequences of those lungfish species that still exist today. In addition, the comparison of the various lungfish genomes enabled them to draw conclusions about the genetic basis of differences between the living species of today.

The Australian lungfish, for example, still has the limb-like pectoral and pelvic fins that once allowed its relatives to move on land. In today's other lungfish representatives from Africa and South America, these fins, which are similar in bone structure to our arms and legs, have developed over the last 100 million years or so into thread-like fins, which are useless for locomotion. "In our study, we were also able to use CRISPR-Cas transgenic experiments with mice to reveal that this simplification of the fins is due to a change in the so-called Shh signalling pathway," says Axel Meyer.

As scientists now have the complete genome sequences of all current lungfish species at their disposal thanks to the new study, genetic comparative studies such as this one will provide further insights into the lobe-finned ancestors of land vertebrates in the future – and thus help to solve the puzzle of the conquest of land by tetrapods.


Facts

- Original publication: Manfred Schartl, Joost M. Woltering, Iker Irisarri et al... A. Meyer (2024) The genomes of all lungfish inform on genome expansion and tetrapod evolution. Nature; doi: https://doi.org/10.1038/s41586-024-07830-1

- Contact: Professor Manfred Schartl, University of Würzburg; T +49 931 31-84149, e-mail: phch1@biozentrum.uni-wuerzburg.de and Professor Axel Meyer, University of Konstanz; T + 49 7531 88-4163, 88-3069; e-mail: axel.meyer@uni-konstanz.de

- Funding: German Research Foundation (DFG) and Next Generation Sequencing Competence Network (NGS-CN)

By Gunnar Bartsch

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