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HGP is 10: What animals can tell us

Jonathan Wood

In the second of a series of articles marking the 10th anniversary of the Human Genome Project [HPG], OxSciBlog talks to Professor Chris Ponting of the MRC Functional Genomics Unit at Oxford University.

Chris explains what we can learn about ourselves by comparing our DNA with the genomes of other animal species.

OxSciBlog: What genome efforts have you been involved with?
Chris Ponting: It all started when I was phoned up and asked whether I’d like to help coordinate a set of analyses for the Human Genome Project. Of course, I jumped at the chance but still feel it ironic that, as someone who gave up biology at school at 16 to focus on a training in physics, I was offered this chance. Since then I’ve worked with many people and groups from around the world on the genomes of the mouse, rat, dog, marsupial, duck-billed platypus, chicken, zebra finch, fruit fly and lizard.

OSB: What can all this genetic information from different species tell us?
CP: Having DNA from different species is crucial to understanding the human genome. Each additional genome is an evolutionary yardstick against which human DNA can be compared.

For example, when you ‘walk’ down each chromosome you see DNA letters that are the same in us and in mice – they have stayed unaltered over tens of millions of years because of their biological importance. This is because spontaneous changes (mutations) in important, conserved DNA tend not to be carried over into subsequent generations as they cause illness or even death.

By separating DNA that has remained relatively unaltered across animal evolution from DNA that has changed rapidly, we efficiently separate ‘functional’ DNA from ‘junk’ DNA. One of the biggest surprises has been the amount of ‘junk’ DNA. Only about 10% of the human genome appears to ‘do’ something, the rest appears not to be important at all.

OSB: What does your own research focus on?
CP: Genomics is rapidly permeating into many areas of biology and medicine, and we have tried our hand at many things over the past few years. My group is trying to understand which genetic changes cause disorders such as autism, intellectual disability or Parkinson’s disease, whilst thinking about how zebra finches learn how to sing or how the platypus senses its prey under water.

It has been particularly enjoyable discovering that there are no more genes making protein in the human genome than they are in a microscopic nematode worm. Science is good like that: its perspective is often humbling.

We can learn a lot just from the gene sequences, seeing how they’ve been conserved or have changed across the millennia and across the tree of life. But most of what we do is to solve puzzles: putting together pieces of information drawn from diverse areas such as evolution, genetics, natural history and clinical medicine. Synthesising this information is often very rewarding and tells us something new.

OSB: What can we look forward to in the future?
CP: As sequencing becomes cheaper, some are advocating sequencing the DNA from all animals. Certainly, most of the species that are important to biology and medicine are being, or have been, sequenced. I look forward to seeing soon the DNA sequence of many animals, from ants to zebras.

Nowadays, we’re looking past the DNA that encodes protein to the hundreds of millions of DNA letters that appear to be doing something, but certainly don’t make protein. It is this ‘genomic dark matter’ that we need to illuminate if we are to better understand the differences between ourselves, or even between us and other animals.

OSB: Might this research hold benefits for human health?
CP: Sequencing DNA is becoming cheaper and cheaper. The first human genome, sequenced ten years ago, cost a staggering $3 billion. Soon one genome will cost $1000. With these plummeting costs come the realisation that individuals’ genomes can be sequenced to try and understand the DNA changes that cause rare or common diseases.

Some might be fearful of what their own genomes could tell them: might they, and perhaps their children, carry some genetic change that predisposes them to disease? In the vast majority of cases, the outcomes aren’t likely to be as simple or as clear cut as that.

I think there are two things to be said here. First, everyone’s genomes carry many changes (‘genetic blemishes’) that give marginal changes to disease susceptibility. In this sense, everyone’s genomes are far from ‘perfect’. Second, despite being able to read someone’s genomes, we are a long way from understanding them so, as scientists and clinicians, we are usually far from assigning single DNA changes to diseases.

OSB: You suggest that these approaches could lead to fewer animals being used in research. How?
CP: All our work is done in the computer and, as time has gone on, we’ve become more sophisticated at spotting genes that do equivalent things in different species. As a result, we have separated genes which are less informative from others which, if studied in model organisms such as fruit flies and mice, immediately provide insights into human biology. Also, evolutionary approaches can now make good guesses of what a gene’s functions are, all of which reduces the number of uninformative experiments. Computational studies are certainly doing their bit to reduce the use of animals in science.