Pig’s ’ere – and far from a bore

First love

When I was a lad I quite often worked on my Uncle’s farm in Cumberland and it was there that I first fell in love. It was reciprocated too, in a sort of way – I think largely contingent on presenting myself regularly bearing armfuls of potato peelings and summoning the courage to lean over the wall and do a bit of ear tickling. To this day pigs remain a love of my life and, given my enthusiasm for the wonders of DNA sequencing, readers will be unsurprised that the convergence of the two is irresistible.

Sequencing Sus scrofa

The genome sequence of a female domestic pig (with the less than alluring name of T. J. Tabasco), together with those of some of her relatives, have just been published. Before we get on to why you less love-struck unfortunates should give a grunt, we should make clear that no animals were harmed in unveiling this sequence. Rather, a small piece of an ear or a few teaspoons of blood were enough to grow cells from which DNA was distributed to the research groups involved.

1.11807_Pig1_cutout

Almost like a pig

So what did the members of the Swine Genome Sequencing Consortium gives us as the result of their labours? Well some things you would have guessed anyway: pigs have about as much DNA in their cells as we do (about 3,000 million base pairs). Of course they do: they’d have to be pretty similar for folk to go round falling in love with them. And within that sequence they have more genes encoding smell receptors than any other animal (over 1300) – which obviously helps if you have to rootle around for a bite to eat and not become reliant on admirers bringing gifts, though you can sense a downside to being so olfactorily endowed.

Them and us

But what about the differences? Well, close though I feel to them, pigs and humans last had a common ancestor about 90 million years ago and a domesticated pig first trotted out of South East Asia about 4 million years ago. Separate strains of the domestic pig then evolved in western Europe and East Asia that diverged from the various strains of wild boar – though the separation is somewhat murky due to pigs being prone to roam – a habit that led to what is delicately called ‘genetic mixing.’ So Hampshires and Large Whites turn out to be more closely related to European wild boars than they are to Chinese pigs such as the Meishan.

Model humans

One of the things that happened as pigs went their separate evolutionary way is that their DNA became unusually prone to being broken. Although damaged DNA is usually repaired two consequences tend to arise. Sometimes a gene just gets lost and this has happened with quite a few that we originally shared with pigs that enable us to taste things like salt: by losing that sensitivity pigs have acquired the ability to eat things we can’t. The other result is that pigs are quite good at shuffling bits of DNA to make novel genes (and hence proteins) – something called alternative splicing. But perhaps the most important outcome is that pig DNA has acquired about 100 changes (mutations) that in humans are linked to increased risk of things like Alzheimer’s disease and diabetes.

Pigs have a long and noble history as good models for human disease and we use their heart valves in replacement surgery (how’s that for reciprocated love?). Having a peek at their DNA has revealed that they also offer a natural model to find out what happens in some of our worst afflictions.

Pigs: giving us their hearts, sorting out our frailties – and making more roast dinners than you can shake a stick at. Everyone should love ‘em!

Reference

Groenen, M.A.M. et al., (2012). Analyses of pig genomes provide insight into porcine demography and evolution. Nature 491, 393-398.

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Family Tree of Breast Cancer

Minding my language

There may be the odd soul out there who has now read Betrayed by Nature and spotted that, just once in while, there’s some very unscientific language. The select band of blog followers (I think of them as The Few) will have noted the same thing (in ‘Touching base with our rellos’, for example). The odd ‘astonishing’ slips out. An occasional ‘incredible’ creeps in – we’ve even been ‘stunned’. “What on earth is he on about?” you might wonder. Scientists aren’t supposed to talk like that. For them it’s measured tones, words weighed with care and, of course, they do sitting on spiky fences with such aplomb you might conclude they’re a bit on the kinky side.

It’s a fair cop

It’s all true. But here’s my defence. Of late, when you might think I’ve been a shade ott, it’s almost always because I’ve been talking about sequencing DNA. Here the events of the last few years have been truly breathtaking. In all respects, I would maintain, they rank among the most awe-inspiring in the history of science. There are two reasons for this belief so let me share them with you, prompted by yet another absolutely remarkable piece of work on cancer that has just been published.

Two astonishing things

First is the technology. Today’s machines can carry out 100s of millions of separate sequencing reactions at the same time (just say that slowly). In the jargon it’s ‘massively parallel sequencing’. How they work matters not here but the ingenuity and engineering that make it possible to find the order of bases in DNA at such speeds is simply mind-boggling.

Second is the outcome. The speed of these gadgets means that the entire DNA sequence of an individual can be obtained in a day or so and that tumours are now being sequenced on an industrial scale. That’s being done to obtain a picture of the sets of mutations that define sub-sets of the major cancers.

The Family Tree of One Individual Breast Tumour

You can’t have too much of a good thing

But these advances mean you can do something else: sequence the same tumour again and again – hundreds of times. Why would you want to do that? The answer is that tumours are a real mixture – a gemisch of groups of cells (called ‘clones’), each descended from a single common ancestor so that the cells in a clone are genetically identical. So, if you really want to know what you’ve got, you need to be able to detect individual clones and the only way to do that is to sequence over and over again until you can get reliable data for the rarer DNA codes that come from smaller clones. That’s just been done for one individual breast tumour and the result is an evolutionary tree showing how the cancer had developed from the fertilized egg to the point it was diagnosed.

The major clones that made up the tumour when it was diagnosed (B, C and D) all descended from a predecessor (A), the most-recent common ancestor. Tens of thousands of mutations went into making A. Thousands more accumulated to form B, C and D. The arrows extending from B, C and D represent the emergence of further clones in what is a continuing, dynamic process. Their record is written in their genomes – a book of progress reports.

One more pretty remarkable thing

In the UK and the USA about 12% of women will be diagnosed with breast cancer. In 2008 world-wide 458,503 women died from the disease and we still have no treatment that is specific in targetting only the tumour cells. It is, therefore, really staggering that improvements in surgery, radiotherapy and drugs in the last 60 years has seen the 5-year survival rate go from 40% to over 90% for white American women and to about 80% in the UK.

Despite this progress, the ideal for every cancer would be to use the family tree to identify the key driving mutations from the tens of thousands in the major clones and then use cocktails of specific drugs to zonk them. At the moment we are a long way from having such an armoury but the current rate of progress in defining tumours at the molecular level, driven by the fabulous technology of sequencing, means that at long last we can proceed on a rational basis, rather than by the time-honoured method of trial and error.

Reference

Nik-Zainal et al., The Life History of 21 Breast Cancers, Cell (2012), doi:10.1016/j.cell.2012.04.023

http://libsta28.lib.cam.ac.uk:2057/science/article/pii/S0092867412005272