Completing the puzzle of life on Earth

In 1998, a millimetre-long nematode worm, Caenorhabditis elegans, was the first animal to have its whole genome sequenced. This achievement laid the groundwork for the first human genome five years later. Now an effort is underway to revolutionise biology itself – by sequencing not just one or two species, but all of them

Why sequence all life on earth?

The Sanger Institute was founded to complete the genome of C. elegans and Homo sapiens. Now it is at the forefront of a new endeavour, forging a path where none exists. Together with ten partners, the Institute has embarked on a vast new voyage of discovery: the Darwin Tree of Life project, which aims to sequence the genomes of around 70,000 animal, plant, fungi and protist species in Britain and Ireland. These genomes will in turn contribute to the Earth BioGenome Project (EBP), the global effort to sequence the genomes of all species on our planet.

For Mark Blaxter, Head of the Tree of Life Programme at Sanger, this is his dream job. “When the Human Genome Project was completed, I wrote an article that said, ‘Great, the human genome is done… now we can do the rest of life.’ Ever since I’ve been a scientist, I’ve wanted to observe life at the genomic level. Much of our understanding of life is based on a handful of organisms – sequencing all life will enable us to properly understand evolution and will be the foundation of biology for the next century.”

Darwin Tree of Life is similar to the Human Genome Project in that the precise applications and discoveries it will enable are not yet fully known – it is a moonshot endeavour that requires technological and experimental advances along the way if it is even to be completed. And in a world facing the twin existential threats of biodiversity loss and global heating, it is perhaps natural to ask what sequencing the genomes of all the planet’s species will do to address these problems.

Though this genetic machinery is common to all life, the sheer range of forms and abilities it can create is astounding. We need only to look at the natural world to see this, whether that is the cancer-proof, age-defying biology of a naked mole-rat, the reactive camouflage of a cuttlefish or the regenerative abilities of plants. All of these abilities are the result of genes and the proteins they create.

There are also large regions of DNA that do not code for proteins, which account for around 99 per cent of the genome in humans. Some of these regions are involved in gene regulation, but most of this 'dark matter' of the genome is likely neutral, invisible to the forces of evolution. About half of our genome is made up of remnant mobile DNA elements that generate additional copies of themselves but individually do little harm.

But more recently, research has begun to explore the possibility that dark matter DNA can be recruited to new functions, such as the ‘antifreeze’ gene that prevents the blood and tissues of Arctic cod from freezing in conditions that would kill other fish, which researchers now think evolved independently from a dark region of the genome, rather than from an existing gene.

It is this untapped promise that is at the heart of Darwin Tree of Life and the reason why reference genomes – complete from end to end of every chromosome – are so crucial. These complete genomes hold the key not only to what makes a species what it is, but how it got there and what it could become in future.

Fuelling economies of the future

It is envisaged that whole new economies will be founded on genomic data. Among them are new biomaterials, pharmaceuticals, fuels and crops, and some of these are closer to reality than you might think.

Plastic is a huge problem from an environmental and health perspective. An island of plastic waste in the Pacific Ocean covers an area three times the size of France. Because plastic breaks down into smaller pieces rather than biodegrading, microplastic particles have polluted every ecosystem on earth, including the placentas of unborn babies, with the long-term effects unknown.

Ironically, the other problem with plastic is that we will run out of the raw ingredients required to make it in the coming years as the world phases out oil.

“Researchers are already figuring out how to replace oil-derived plastics with materials created from or inspired by spider silk,” said Mark. “What gives a particular silk its remarkable strength, or elasticity? The answer is in the spider’s genome and if we can understand that biology, we can recreate it using engineered bacteria in bioreactors, fed by renewable resources. This is a great example of how genomes can become the raw material of whole new bio-economies.”

Another example from the University of Edinburgh shows how genomics is being used to tackle greenhouse gas emissions at source. By analysing the genotype of individuals, the programme is selectively breeding ‘green cows’ that require less feed and produce less methane.

The genome engine

Kerstin’s role today is to oversee Sanger’s novel species sequencing. “Our operation here is very much like an engine. The fuel is the samples that Darwin Tree of Life partners supply. The power output is genomic data. There are lots of moving parts that need to be looked after to keep things running smoothly. But we also have to improve the engine so that we can accelerate towards our goal.”

The first step in the process is to get hold of biological tissue from the target species. Samples are contributed by the ten project partners or one of the many organisations across Britain and Ireland that are helping to collect particular species. All of this activity is coordinated by Nancy Holroyd’s Sample Management team.

When samples arrive at Sanger, they’re checked into a sample management system so that they can be tracked through the DNA pipeline, then stored in -70 degree freezers until needed.

The issue of genomes within genomes, where the DNA of parasites or bacteria living within the target species become mixed up with its DNA during extraction, is an example of a problem currently tackled by Jo Wood’s curation team.

“Curation is kind of like spell-checking the assemblies built by Shane’s team. We’ll identify errors, such as duplications of a gene or contamination from non-target DNA, then remap the assembly to chromosome level. When the genome leaves us, it is to all intents and purposes whole again.”

Jo is another scientist whose career began working on the Human Genome Project. Back then, genome curation was done manually. Unlike many aspects of leading-edge genomics, it is still done manually today.

To give a sense of this scale, analysing the data for a genome with around one billion base pairs of DNA, such as the smoky wainscot moth, requires around one thousand CPU hours and one terabyte of disk space. Manual curation by one of Jo’s team will then take anywhere from two hours to two days, depending on the complexity of the genome.

None of this bioinformatics work would be possible without the vast strides that have been made in computer science in recent years. A lot of work goes on to support the core teams and manage so much raw data, from writing software to developing algorithms to maintaining databases. Much of this work is done by Andrew Varley and Matthieu Muffato, who lead teams that have built bespoke data tracking systems and efficient analysis pipelines to support the whole genome sequencing process, from finding the specimen in the wild to submitting the completed genome to public databases.

Their teams have written more than 250,000 lines of code so far, now deployed on dozens of servers and continuously processing data and metadata. “The challenge,” Andrew says, “is to deal with the inherent complexity of biology. As much as programmers would like to use logic and method to code their way out of problems, they continuously need to adapt to what comes through the genome engine.”

If there is anything that is able to focus attention on the climate and biodiversity crises that we are living through, it should be the thought of the world that we leave to the generations to come.

It is entirely possible that today’s children could be working with Darwin Tree of Life data in 15 years’ time, whether as biologists helping to untangle the evolutionary web that underpins all life on earth, as conservationists helping to preserve this life or as engineers working with new biomaterials. They could be pharmacologists working to unlock the medicinal potential of newly discovered molecules, or racing to overcome drug-resistance in dangerous pathogens.

If they are to have a chance to do so, however, there’s no getting away from the fact that humanity will need to make significant progress on reducing greenhouse gas emissions and preserving biodiversity in the next ten years.

There are signs that the world is finally getting to grips with these crises. Genomic data will have a role to play in transitioning to net zero, whether that is helping to reduce emissions from food production or replace polluting materials with greener ones.

One thing that is certain – there is a wealth of life and biology waiting to be discovered, as genomics pushes us once again into the unknown.