Non-human genomes: why bother?

Why bother sequencing other species, when we already have an almost-complete human genome readily available?

By Dr Peter Bickerton

The benefits of the human genome project are clear for all to see. We have gained tremendous knowledge of the genetic basis of disease and can better predict whether we are susceptible to certain conditions — ushering us into a promising new era of personalised genomics for medicine and nutrition.

So why bother sequencing other species, when we already have an almost-complete human genome readily available?

By exploring the genomes of the unassuming fruit fly through to living fossils such as the coelacanth, as well as the diversity of cichlids and a plethora of mammals including naked mole rats, koalas and dogs, we can shed light not only on how we came to be — but how we can learn a whole lot more about ourselves.

It’s not only the human genome that has clear applications for improving our health. Similarly, a greater knowledge of the genomes of important crops and farmed animals, as well as the diseases and pests which affect them, can improve agricultural practises and human nutrition.

Why, then, do we sequence such a range of exotic and interesting species at EI?

It’s not just for fun.

Fruit flies are a common model organism for research. Credit: Shutterstock / Sebastian Janicki.

Diversity and evolution of genomes.

Just as we can’t possibly survive without our ecosystems, biodiversity and associated natural cycles, we can’t even begin to fully comprehend our own genetics without first gaining an understanding of evolution and the abundant diversity within the genomes of every species on earth.

If we were to take all the genomes ever sequenced and do a genome-wide analysis, we would see that most of the differences between organisms are found in non-coding elements — the bits in between the genes andother conserved, non-coding regions.

If a nucleotide is important, we should expect selection to remove deleterious mutations. Therefore, by comparing full genomes we can scan them for regions which are conserved across highly diverse species.

We can then zoom in on the conserved elements; DNA sequences that have stood the test of time, have wide functional and evolutionary relevance and can, therefore, be found throughout highly diverse species.

These species-wide DNA elements are incredibly enriched in variants associated with a suite of relevant traits — not only related to disease but to morphology and the way our bodies develop from a simple, highly conserved blueprint.

If we look at mammalian embryos after several weeks (or even months) — a human, cat and dolphin are almost indistinguishable. For a certain, albeit very brief, period in foetal development we have proto-gills and a tail.

By exploring non-human species, we can discover an incredible amount about how we came to be. Just as the study of Arabidopsis, a weed related to important crops such as broccoli and oilseed rape, can inform us about these commercial species (and others besides), the study of non-human genomes can help us to answer some of the most pressing issues relating to human health and wellbeing.

Human fetus, month one. Credit: Shutterstock/ Sebastian Kaulitzki

Limbs and things — a living fossil.

One such species, the coelacanth, is an exquisite example. This ancient fish was at one time thought to have gone extinct 70 million years ago, but was rediscovered in 1938 off the coast of South Africa.

This fish is an evolutionary link between fish and tetrapods (like ourselves, turtles, swans, guinea pigs etc.) and, in terms of family trees, lies between ray-finned fish and the lungfish. When it comes to discovering more about the evolution of tetrapods, what better organism to start with?

One reason the coelacanth is of great scientific interest is its appearance. It resembles fossils that date back to 300 million years ago, which has lent its branding as a “living fossil.” The coelacanth can inform us about many evolutionary processes, especially as it appears to be so lethargic in this regard compared to tetrapods.

You might think — why not sequence the lungfish? And this is a good question. However, the lungfish has an absolutely huge genome, five times bigger than our own (at least). The coelacanth has a genome of comparable length to our own, which makes finding the clues that little bit simpler.

Fascinatingly, cichlids can rapidly regrow their teeth — if they lose a tooth a new one perfectly drops into the vacated spot.

Study of the coelacanth has been particularly fruitful in telling us more about the transition from fins to limbs (and therefore to a life on land) — and highlights the nature of genetic conservation of important traits between species.

With the coelacanth, we can clearly see genetic sequences that are conserved in terms of limb development. Indeed, it’s possible to insert certain genes from a coelacanth into a mouse, which are able to initiate limb development.

These genes, absent in the ray-finned fish but expressed in coelacanths, frogs, chickens and humans alike, clearly point to the early origin of hands, feet and wings.

‘Gone fishing’ for answers in the search of diversity.

If we move back into the waters we are greeted by a huge variety of fishes, massively varying in colour, shape, size and body form. Each species has in some way utilised and ‘tinkered’ with these features to adapt to their environment.

The highlight example of this phenomenon lies with African cichlid fishes, with more than 2,000 known species found in various ecological niches, all evolving from a common ancestral species in the Nile River.

The study of cichlids can reveal the genomic toolkit that nature utilises to allow organisms to adapt to different environments. Such mechanisms are also likely at work in humans and other vertebrates, providing clues to functional and genetic diversity on a broad scale.

There are resurrection plants, and tumbleweeds that can dry out almost completely and blow around in a dormant state until the rain allows them to set root, flower, set seed, then die.

One such example is the adaptation of teeth and taste buds in cichlids that have allowed them to thrive in various conditions. Some cichlid species eat plankton, requiring few teeth as they quickly spot and swallow the plankton whole, whereas other species live on algae that need to be scraped from rock formations, requiring more teeth and more taste buds to distinguish different food forms.

Fascinatingly, cichlids can rapidly regrow their teeth — if they lose a tooth a new one perfectly drops into the vacated spot. The process is, in fact, similar to many mammals — understand these pathways and maybe we can identify ways to induce tooth regeneration in humans.

Given the wealth of fishes on earth, we still have a lot to process and digest from fish genomics, so what about the current state of fish as a food source? Well a well-known cichlid, namely Tilapia, is being utilised for it’s tractable farming and growing capabilities in aquaculture.

With the right measures and practices in place, farming of fish, including Tilapia, will have an important role to play in the global demand for fish.

Koalas, dogs, chlamydia and cancer.

Are you still thinking … but why?

There are so many reasons. Research into dogs has recently revealed some of the genetic elements involved in various cancers — cancers that are common in people, too. They can also inform us about diabetes, epilepsy and other conditions.

Why not find these in people? It’s hard. It’s simply much easier to find relevant genes in dogs — and quicker.

In the brief centuries that have witnessed the artificial selection of dog breeds, from dalmatians to King Charles Cavalier Spaniels, inbreeding has led to the fixation of many deleterious mutations. In these cases, the breeds are very well known.

For example, in Cavaliers, dogs suffer from mitral valve disease, leading to premature death in many cases. Labradors suffer from obesity, Huskies from autoimmune disorders, beagles from epilepsy and boxers from cancer. These diseases are all relevant to humans, and the study of dogs can help us to better understand them.

There are secrets dwelling within the genomes of other organisms that help shed light on the pathways to our own biology, and might even help us in fighting disease.

Did you know that giraffes can withstand severely high blood pressures? At 240/180, this is twice that of a normal person. At that pressure, we’d be suffering devastating organ failure.

Granted, giraffes have features, such as very thick blood vessels, to help them pump this high-pressure blood up their long neck. But still, for those who research high blood pressure in people, study of the coping mechanisms of giraffes is very interesting.

It’s simply much easier to find relevant genes in dogs — and quicker.

Then there are koalas. What might we learn from our marsupial cousins from down-under?

For a start, they don’t respond well to chlamydia — a disease that can kill koalas and can carry complications for people, including reactive arthritis in men and pelvic inflammatory disease in women. It can even lead to premature birth, miscarriages or stillborn babies.

Koalas also have a pouch. A dark, sweaty pouch laden with microbes such as bacteria and fungi. Like other marsupials, koalas give birth to a joey, which is relatively underdeveloped. How can these young, with a still-developing immune system, survive in these conditions? Are there novel peptides in koala milk or in the pouch that prevent disease? Can we use these to treat immunocompromised people?

What might we learn from our marsupial cousins from down-under? Credit: Shutterstock/ apple2499

The almighty naked mole rat.

Possibly the most impressive organism, in terms of sheer evolutionary bloody-mindedness, is the naked mole rat.

These far from beautiful but no less cute animals that live the majority of their life underground in strangely (for mammals) eusocial colonies, much akin to ants and wasps, are a wonder to biologists.

Firstly, they are long-lived — up to thirty years — and they just don’t develop cancer, to which they appear to be completely resistant. What lies within their genome and proteome that helps them do this?

They also don’t feel any pain. The naked mole rat lacks a certain neurotransmitter called substance P, which means that they can tolerate the scraping associated with being a naked mole rat in a dark tunnel without too much fuss.

The genome of this delightful species has been sequenced, and is already providing some insights into how they avoid the perils of ageing, such as cancer.

Seeds of knowledge.

It’s not just animals that are of interest. Through studying a variety of non-model plant species, far removed from those that we grow and eat, we can discover a vast amount that can help us to produce better crops.

Plants are possibly the most impressive of organisms, able to tolerate extreme conditions all while standing still in once place.

There are resurrection plants, and tumbleweeds that can dry out almost completely and blow around in a dormant state until the rain allows them to set root, flower, set seed, then die.

There are species that can survive the coldest and harshest environments, growing as tiny shrubs clinging as closely as possible to the ground, shielded against blustery polar winds.

In deserts, there are those that manage to accumulate and successfully store water, such as cacti andWelwitschia mirabilis, which thrive in conditions that cause most other life to perish.

In the salt marshes, there exist plants that can tolerate extremely high concentrations of salt, and indeed extremely low oxygen levels, without any mal-effect.

The mechanisms by which these plants can thrive in such diverse and extreme conditions are of great interest to us all. In a world in which the climate is rapidly changing, with temperatures and sea levels rising at a rate exceeding our conservative estimations, we are in a race against time when it comes to gearing our crops to weather the coming storm.

Welwitschia mirabilis, thrive in conditions that cause most other life to perish. Credit: Shutterstock/ Karel Gallas

So why bother?

We still have much to learn about ourselves. With the increased perils of cancer and dementia in an ageing population, as well as the emergence of new or recurrent diseases, there are many questions to answer in terms of improving the health of human populations.

There might be up to one trillion species on earth, within which lies a host of information that can help us unlock the secrets to our own biology.

It would be a shame not to harness the incredible diversity and natural variation that exists in the splendid and bountiful biodiversity on this planet, which can certainly, and demonstrably, help us to better survive.

By Dr Peter Bickerton
Public Engagement & Society Officer, Earlham Institute

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