Long-live the Revolutions!!

There’s a general view that most folk don’t know much about science and, because almost day by day, science plays a more prominent role in our lives, that’s considered to be a Bad Thing. Us scientists are therefore always being told to get off our backsides and spread the word – and I try to do my bit in Betrayed by Nature, in Secret of Life (a new book shortly to be published) and in these follow-up blogs.

We may be making some progress – and, I have to admit, television has probably done more than me – though I am available (t.v. & movie head honchos please note). As one piece of evidence you could cite the way ‘DNA’ has become part of the universal lexicon, albeit often nonsensically. As evidence I call Sony Corp. Chief Executive Kazuo Hirai, as reported in The Wall Street Journal: “I’ve said this from day one. Some things at Sony are literally written into our DNA …”

Well, of course, that’s gibberish Kazuo old bean – but we know what you mean. Or do we? Most probably couldn’t tell you what the acronym stands for – but that doesn’t matter if they can explain that it’s the stuff (a ‘molecule’ would be better still!) that carries the information of inheritance and, as such, is responsible for all life. Go to the top of the class those who add that the code is in the form of chemicals called bases and there are just four of them (A, C, G & T). Something that simple doesn’t seem enough for all life but the secret is lies in the vast lengths of DNA involved. The human genome, for example, is made up of three billion letters.

A little bit of what is now history …

In the mid-1980s a number of scientists from around the world began to talk about the possibility of working out the sequence of letters that make up human DNA and thus identifying and mapping all the genes encoded by the human genome. From this emerged The Human Genome Project, a massive international collaboration, conceived in 1984 and completed in 2003. I quite often refer to this achievement as the ‘Greatest Revolution’ – meaning the biggest technical advance in the history of biology.

As that fantastic enterprise steadily advanced to its triumphant conclusion, it was accompanied by a series of mini-revolutions in technology that sky-rocketed the speed of sequencing and slashed the cost – the combined effect being an increase the efficiency of the whole process of more than 100 million-fold.

Brings us to the present …

These quite astonishing developments have continued since 2003 such that by 2009 it was possible to sequence 12 individuals in one study. By August 2016 groups from all over the world, coming together under the banner of The Exome Aggregation Consortium (ExAC), have raised the stakes 5,000-fold by sequencing no fewer than 60,706 individuals.

The name of the outfit tells you that there’s what you might think of as a very small swizz here: they didn’t sequence all the DNA, just the regions that code for proteins (exomes) – only about 1% of the three billion letters. But what highlights the power of current methods is not only the huge number of individuals sequenced but the depth of coverage – that is, the number of times each base (letter) in each individual exome was sequenced. In effect, it’s doing the same experiment so many times that errors are eliminated. Thus even genetic variants in just one person can be picked out.


Sequence variants between individuals. For most proteins the stretches of genomic DNA that encode their sequence  are split into regions called exons. All the expressed genes in a genome make up the exomeBy repeated sequencing The Exome Aggregation Consortium have shown that genetic variants in even one person can be reliably identified. Variants from the normal sequence found in four people are shown in red, bold letters.

It turns out that there are about 7.5 million variants and they pop up remarkably often – at one in every eight sites (bases). About half only occur once (which illustrates why DNA fingerprinting, aka DNA profiling, is so sensitive). As Jay Shendure put it, this gives us a “glimpse of the bottom of the well of genetic variation in humans.”

One of the major results of this study is that, by filtering out common variants from those associated with specific diseases, it will help to pin down the causes of Mendelian diseases (i.e. genetic disorders caused by change or alteration in a single gene, e.g., cystic fibrosis, haemophilia, sickle-cell anaemia, phenylketonuria). It’s clear that, over the next ten years, tens of millions of human genomes will be sequenced which will reveal the underlying causes of the thousands of genetic disorders.

The prize … and the puzzle

The technology is breathtaking, the amount of information being accumulated beyond comprehension. Needless to say, private enterprise has leapt on the bandwagon and you can now get your genome sequenced by, for example, 23andMe who offer “a personalised DNA service providing information and tools for individuals to learn about and explore their DNA. Find out if you are at risk for passing on an inherited condition, who you’re related to etc.” All for a mere $199!!

But you could say that the endpoint – the reason for grappling with DNA in the first place – is easy to see: eventually we will be able to define the molecular drivers of all genetic diseases and from that will follow ever improving methods of treatment and prevention.

Nevertheless, in that wonderful world I suspect we will still find ourselves brought up short by the underlying question: how one earth does DNA manage to carry the information necessary for all life?

For those who like to ponder such things, in the next piece we’ll try to help by looking at DNA from a different angle.


Ng, SB. et al. (2009). Nature 461, 272-276.

Lek, M. et al. (2016). Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285–291.


A Taxing Inheritance

The centenary of the beginning of the First World War prompted me, as perhaps many others, to reflect on how successive generations have done since then in terms of what they’ve bequeathed to their offspring. I didn’t need to think for too long though, to find myself muttering ‘Thank heavens for science’—because most of the rest is a pretty dismal chronicle. I know, not all technological advances in the past one hundred years have been a cause of unrestrained joy but many of them transformed life in the most wonderful ways. Would that we could point to such success in other fields.

Our best defence may be to aver: “Man cannot control the current of events. He can only float with them and steer”, a saying attributed to Otto von Bismarck. If the ‘Iron Chancellor’ actually did utter those words it seems to me he was being coy beyond belief. He is, after all, generally credited with unifying Germany, seeing off the last French monarch (Napoleon III) and establishing the peaceful domination of Europe by the German Empire that lasted until long after his death—and setting up the first welfare state along the way. “The main thing is to make history, not to write it” sounds much more like Bismarck in full and frank mode.

Nature and Nurture

One form of history that we do write but indeed we cannot control comes in the form of the genetic material that we pass to the next generation. We’re all familiar with some of this legacy because we literally see it in physical resemblances and other attributes between parents and children (“He’s got his Mum’s eyes”) or shared by siblings (“Jack and Jill are wonderful musicians”). They’re shared because large chunks of the genetic code (i.e. DNA) are identical between the individuals concerned. But if conserved DNA makes for similarities, what of the differences—the fact that our parents and brothers look different to all the seven thousand million other people on the planet? Our unique features come from variations in the genetic code—odd changes in the units (bases) of DNA scattered through our genome. Called SNPs (pronounced ‘snips’ for single nucleotide polymorphisms), they’re what make the differences between us. In other words, a SNP is a difference in a single nucleotide—A, T, C or G—within a stretch of DNA sequence that is otherwise identical between two individuals. For example, you have AAGCCTA whereas I have AAGCTTA. These genetic variations that make individuals different are the basis of DNA fingerprinting.

There’s about three million SNPs scattered throughout the human genome (so, on average, you’d come across one in every 1,000 bases if you scanned your DNA from beginning to end) and they’re what makes each of us unique. Within ethnic groups common patterns of such variants confer characteristics (dark skin/light skin, tall/short, etc) and, with that in mind, you might guess that there will also be variants that make such groups more (or less) susceptible to diseases.

Of course, there’s an endless debate about the border between our genetic inheritance and how the world we experience makes us what we are—how much of Jack and Jill’s precocious talent is because Mum and Dad made them practice twelve hours a day from age five? Fortunately we can ignore nurture here and stick to genes because we’re trying to pin down the good and the bad of our genetic legacy.

What’s all this got to do with cancer?

A good bit is that we’re distinct from everyone else but still share family features. However, our genetic baggage may also contain some unwanted freebies—the most potent of which can give a helping hand to a variety of diseases, including cancers. Cancers are caused by damage to DNA—a build-up of changes, i.e. mutations, that affect the activity of proteins critically involved in controlling cell growth. For most cancers (90%) these mutations accumulate over the lifetime of the individual—they’re called “somatic mutations”—so you can’t blame anyone but yourself and Lady Luck. But about 10% get a kind of head start when someone is born with a key mutation. That is, the mutated gene came from either egg or sperm (so it’s a germline mutation). This effect gives rise to cancers that “run in families”: a critical mutation is passed from generation to generation so that children who inherit it have a greatly increased risk of developing cancer. Two of the most common cancers that can come in hereditary form are those of the breast and bowel.


A mutational steeplechase leads to cancer. Of the tens of thousands of mutations that accumulate over time in a cancer cell, a small number of distinct “drivers” make the cancer develop (four are shown as Xs). Almost all mutations arise after birth, but about one in every ten cancers start because a person is unfortunate enough to be born with a mutation: they are already one jump ahead and are much more likely to get cancer than those born with a normal set of genes. The rate at which mutations arise is increased by exposure to carcinogens, e.g., in tobacco smoke.

Breast cancer is about twice as common in first-degree relatives of women with the disease as it is in the general population (you’re a first degree relative if you’re someone’s parent, offspring, or sibling). About 5% of all female breast cancers (men get the disease too but very rarely—about 1% of all breast cancers) arise from inherited mutations. In the 1990s two genes were identified that can carry such mutations. These are BRCA1 and BRCA2 and their abnormal versions can increase the lifetime risk of the disease to over 50%, compared with an average of about 10%. Since then heritable mutations in some other genes have also been shown to increase the risk.

Angelina Jolie

Angelina Jolie

A star turn

Breast cancer genetics came under the spotlight with the much-publicised saga of Angelina Jolie, the American film actress. Jolie’s mother and maternal grandmother had died of ovarian cancer and her maternal aunt from breast cancer—a family history that persuaded Jolie to opt for genetic testing that indeed revealed she was carrying a mutation in BRCA1 (BRCA1 and BRCA2 mutations account for about 10% of breast cancers and 15% of ovarian cancers). For Jolie the associated lifetime risk of breast cancer was estimated as 87%, prompting her to have a preventative double mastectomy, thereby reducing her risk to less than 5%. The months after she revealed her story saw the “Angelina effect”, a doubling in the number of women being referred for genetic testing for breast cancer mutations.

What’s all this got to do with SNPs?

The story so far is of the one in ten cancers that get kicked off by a powerful, inherited mutation that changes the action of the affected protein—the BRCAs being the best-known examples. However, the BRCAs and other known mutated genes account for only about 25% of familial breast cancers, meaning that for three quarters of cases the genetic cause remains unknown. And yet we know there is an inherited (genetic) cause simply because of the generational thread. Which brings us back to those other, more subtle tweaks to DNA that we mentioned—SNPs—alterations that don’t directly affect proteins, so they’re often called variants to distinguish them from mutations.

It seems very likely that the missing culprits are indeed SNPs—lots of them. These DNA variants each make a contribution so small that on its own would have no detectable effect on the chances that the carrier will get cancer. Their impact comes from a cumulative effect. They’re like pieces of straw, individually easily bent or broken but put a dozen of them together and you have a rope. Thus combinations of individually insignificant SNPs can raise the risk of cancer by, say, 10%—not a massive increase but not negligible either. Twins who are genetically identical have similar risks of developing breast cancer, consistent with the idea that many variants, each having a very small effect, can combine to give a substantial increase in risk. Very slowly, by sequencing lots of genomes, these rare variants are being identified. Given that clusters of appropriate variants confer risk, people with the “other” variant have, in effect, a degree of protection against cancer.

And in our more distant relatives?

All this comes from the huge effort that has gone into finding genetic variants linked to one of the most common cancers but, unsurprisingly, almost all the attention has focused on European women. Not before time, someone has got round to looking for breast cancer variants in East Asians who, after all, make up over one fifth of all the people in the world. Cai Qiuyin and his colleagues at the Vanderbilt University School of Medicine compared the genomes of over 20,000 cancer cases from China, Japan and South Korea with a similar number of disease-free controls. After much selecting and comparing of sequences, three particular DNA variants consistently associated with significant cancer risk. The variants were much less common in European women, suggesting that as the DNA keyboard has been strummed by evolution, distinct patterns associated with breast cancer have emerged in diverse populations.

Just two problems then. First it’s a huge task to assemble the lists of runners (and as the Asian results show, they will differ between ethnic groups). But the real challenge is yet to come. Almost all of these variants (99.9%) don’t change the sequence of proteins (i.e. how the proteins work). What they do is exert subtle effects on, for example, how much RNA or protein is made from a DNA gene at any time. At the moment we have little understanding of how this works, yet alone ideas on how to intervene to change the outcome.

Although identifying the BRCA genes that help to drive breast and ovarian cancers was a giant breakthrough, we still have no effective therapy for countering their malign influences. The intervening twenty-five years of effort have brought us to a new era of revealing the more subtle effects of variants. But the price we pay for unveiling the complete picture is perceiving just how tough is the therapeutic challenge.


Qiuyin Cai, et al. (2014). Genome-wide association analysis in East Asians identifies breast cancer susceptibility loci at 1q32.1, 5q14.3 and 15q26.1. Nature Genetics 46, 886–890. doi:10.1038/ng.3041.

Policing DNA

In A Sinister Side to Sequencing we noted that, wondrous though the advances in sequencing DNA have been, every silver lining …, so to speak. This was in the context of our now being able to determine whether babies will be born with genetic defects, raising the prospect that parents may opt not to have afflicted children. Because we feel that the avoidance of politics has such beneficial effects on the tone of these pieces, we did not mention another problem raised by the ready availability and sophistication of current DNA analysis methods, namely use of the data by police forces, specifically by the procedure usually called DNA fingerprinting. But, needs must …

First of all, what’s DNA fingerprinting?

DNA profiling (or fingerprinting) methods, pioneered by Sir Alec Jeffreys at the University of Leicester, have undergone substantial refinement since they were first used as a police forensic test in 1986 to identify the rapist and killer of two teenagers. Regardless of detail, the essential point is that that the genetic code of individuals is compared using DNA that can be extracted from most tissues or body fluids (e.g., blood, semen, cheek cells, etc.). From the samples to be compared short lengths of DNA are generated and separated by size in a gel, stained so that the DNA fragments show up as bands. Each of us has a unique pattern. In the picture the pattern from suspect 2 is identical to that of DNA taken from the crime scene – so he dunnit!

DNA patterns




Short lengths of DNA samples obtained from a crime scene and from the tissues of three suspects separated in a gel and stained to show as black bands





Why is it in the news?

The Supreme Court of the United States has just ruled that the police should be permitted to take DNA samples from an arrested individual, as Maryland officers had done from a character who’d been waving a shotgun only to find that he’d committed an unsolved rape case in 2003 from which they were still holding a DNA sample. An excellent result, you might think. Perhaps, but the ruling has nevertheless got the liberals up in arms, as represented by Antonin Scalia, an Associate Justice of the Supreme Court. Put briefly, his point is that DNA sampling is following the path of fingerprinting, things will go headlong downhill and before long we’ll have to submit to it if we want to get on a plane or play for a school sports team. This would clearly be an unacceptable invasion and so, inevitably, The Fourth Amendment to the United States Constitution is invoked – for outsiders that’s the thing purporting to protect citizens from ‘unreasonable’ actions by the powers that be, whatever that means to any administration that happens to be in charge.

No one sane is arguing that the police should not be permitted to use DNA in the pursuit of villains. The problem is how to keep the lid on Pandora’s box. So, without for a moment implying that the good denizens of the US of A might be a touch parochial, let’s take the drastic step of casting a glance beyond the limits of sea to shining sea.

In the rest of the world?

What better place to start than with the mother of modern democracy and what was the land of the free before the US of A was invented? Shock horror: it emerges that little old England has more DNA samples per head of population in the hands of its police than any other country for which information is available! How can this have come about? Well, the Police and Criminal Evidence Act of 1984 permitted the police to take fingerprints and body samples without consent from people charged with, or convicted of, a recordable offence (these include begging, being drunk and disorderly and taking part in an illegal demonstration – ‘illegal’ having been interpreted somewhat flexibly in recent times). However, those powers were extended in 2004 to permit samples being taken from anyone arrested on suspicion of any recordable offence. You will recall that this was during the Premiership of Mr. Blair, a chap with little interest in civil liberties and none at all in parliamentary democracy.

Back in 1949, when a parliamentary democracy seemed an immovable feature of British life, the United Kingdom (UK) became a founder member of something called The Council of Europe – designed to promote cooperation over matters relating to the law and human rights. Bear in mind that this is quite distinct from the European Union (EU) – the organization that lives in decadent style in Brussels to which the mother of parliaments has for some time ceded control of its affairs. EU members include Poland, Hungary and Estonia and it’s largely run by the Germans and the French. Funny how things turn out. Shock horror number 2 is that the UK is the only Council of Europe member that allows retention of biological samples from people who have been acquitted of charges or against whom criminal charges have been dropped. The Council of Europe has a sort of sub-body called The European Court of Human Rights before which was recently brought a UK case about whether the retention of DNA and fingerprints from innocent people is consistent with human rights law. In short, they don’t think it is and it’s worth quoting a key phrase in their conclusions: “… retention … constitutes a disproportionate interference with the applicants’ right to respect for private life and cannot be regarded as necessary in a democratic society.

So, what’s happened?

Well, for once let us rejoice in being interfered with by those pesky Europeans because, as of May 2012, the UK now has a Protection of Freedoms Act covering the operation of the UK Police National DNA Database. A critical feature is that DNA and fingerprint records of over a million innocent individuals will be deleted and the DNA samples destroyed. It should be added that seemingly Maryland law also requires destruction of DNA samples taken in cases that do not lead to conviction.

What will be done?

The problem with protecting freedoms is that laws are OK but someone needs to do the protecting. No one who has reviewed the activities of the British police that have come to public attention over the last twenty years would have any confidence either in their morality or their competence, never mind their inclination to police themselves. The fact that, according to GeneWatch UK, companies have been permitted to use the police DNA Database for research purposes without, of course, individual consent would confirm your doubts.

Re-crossing the Atlantic it would also seem sensible to ensure first that reasonable legal safeguards are in place across all states to control police activity  but after that to keep Mr. Scalia’s concerns in mind and remain vigilant in ensuring that those provisions are adhered to.

Finally, all that having been said and with due regard to the seriousness of this matter, one might observe that countries prone to promoting themselves as models of human rights that nevertheless pass laws permitting indefinite detention of citizens without trial and are not averse to the use of torture have somewhat weightier matters to resolve than what the fuzz do with a few cheek swabs.





National Defense Authorization Act, 2012.