medium to medium to large large

small INSTANT small GENIUS

WHAT IT’S MADE OF

THE HUNT FOR NESSIE

HOW IT CAN SOLVE CRIMES DNA HOW DO WE KNOW? How do we know?

THE STRUCTURE OF DNA BY KATHERINE NIGHTINGALE Before the discovery of the -carrying molecule DNA, we had no idea of the fundamental mechanics of life. How we described its iconic double helix form is one of the greatest scientific achievements

HE YEAR IS 1869 and a enormous diversity of life. As late as that characteristics are inherited in young researcher is toiling the 1940s, most scientists thought that discrete units. When his research away in a laboratory in an – large biological molecules was rediscovered in the early 1900s, old castle in Germany, on which come in all shapes and sizes a flurry of work determined that course to make a remarkable – were the only substances complex these units, or , must be in discovery. The lab studies enough to be the agents of heredity. . But what were they the composition of cells, Chromosomes, the coils of DNA made of – DNA or – and what and Friedrich Miescher is and protein that contain genes, had did they look like? analysing relatively simple first been spotted in cells in the early A German doctor named Albrecht T white blood cells, which 1840s. Later that century, researchers Kossel made some of the first steps he extracts from the pus in a local saw them double in number and then towards finding out. Working under clinic’s discarded bandages. Having halve again into separate ‘daughter’ Hoppe-Seyler in the late 1800s, he exhausted his efforts in classifying cells during cell division. In 1865, discovered DNA’s ‘bases’ (the chemical the cell’s proteins, Miescher turns his the Austrian monk Gregor Mendel opposite of acids) and named them attention to another substance that used pea plants to explore theories (T), (A), keeps appearing in his samples. He on genetic inheritance, proposing (C) and (G). This work was finds it odd – an acid that contains continued by , a phosphorus – and declares he has Lithuanian researcher driven to New discovered a completely new type of York in the early 1890s because of substance. Nuclein, or DNA as we now anti-Semitism in his adopted home call it, has been found. of St Petersburg. For three decades Like any good sceptical scientist, from the mid-1890s, Levene studied Miescher’s boss Felix Hoppe-Seyler the structure of DNA, identifying > IN A NUTSHELL is wary, and waits to repeat the its other components: a sugar called experiments before, two years later, and phosphate groups. allowing publication. But this delay He also discovered that DNA is It’s the key to all life on Earth: a would turn out to be negligible; it was made up of units that he called simple molecule known as DNA that many more decades before scientists . Each of these is made sits in every cell of your body. It saw the importance of DNA. Misecher up of a sugar, phosphate group and took several breakthroughs to realise its true form and understand went on to find DNA in a variety of base, and they are linked by bonds The double helix of DNA: the extent of its role in biology, cells, but even he couldn’t believe Gregor Mendel cross-bred different coloured peas in what between the phosphate groups ’s elegant solution that just one substance generated the were some of the earliest experiments into heredity of one and the sugar to file the blueprint of life triggering a scientific revolution. PHOTO: SCIENCE PHOTO LIBRARY, THINKSTOCK LIBRARY, SCIENCE PHOTO PHOTO: How do we know? How do we know?

of the next, forming a so-called to determining DNA’s structure. His more practically minded father was headed by , who backbone. But this was as far as , a physicist at built the first X-ray spectrometer – a began working at the University of his correct findings went. He thought the University of , and his son device for shooting a narrow beam of Leeds in 1928, having studied under CAST OF It took the efforts of these science greats that each DNA molecule contained William , a researcher X-rays at substances – and together William Henry Bragg at the Royal CHARACTERS to finally realise the structure of DNA only four nucleotides, one with each at the Cavendish Laboratory in they tested the theory on salt crystals. Institution. In 1937, Astbury was type of base, linked together in a ring Cambridge, laid the foundations for In these experiments, they placed a sent samples of calf DNA by Swedish he called a ‘tetranucleotide’. the field of X-ray photographic plate behind the crystal, researcher Torbjörn Caspersson. A William Astbury Levene’s tetranucleotides were too between 1912 and 1914. onto which the scattered X-rays few years previously, Caspersson had (1898-1961) was a simple to carry a genetic code, and so They were inspired by the work would produce a characteristic pattern. shown that DNA is a polymer – a long British molecular reinforced the idea that proteins must of Max von Laue, who discovered in William Lawrence Bragg came up chain of nucleotides – rather than the biologist and physicist be the hereditary agent. Revealing 1912 that X-rays bend when they pass with an equation, known as Bragg’s short lengths Levene had suggested. who spent much DNA’s hidden complexity was going through crystals, substances with highly Law, which allowed them to work Astbury’s PhD student, Florence of his working life to require a closer look. While Levene ordered structures. The younger backwards from the patterns to deduce Bell, took the first of hundreds of in Leeds. His work was unravelling the complexities of Bragg reasoned that because they have the crystal’s structure. The pair won a X-ray diffraction pictures of DNA that focused originally DNA in New York, across the Atlantic ordered patterns of atoms, the way the Nobel Prize in 1915. year. The fact that it produced a on the structure of a father-and-son team was establishing X-rays bend through crystals would One of the first groups to apply this pattern at all suggested that DNA had proteins in textiles but, a technique that would prove key reveal something about their structure. technique to biological molecules a ‘solvable’ structure. Astbury and Bell’s (1916-2004) was born along with his PhD pictures look like smears compared to near Northampton to student Florence Bell, the clear images that the owner of a shoe he took the first X-ray produced in the early 1950s, but they factory and became a photographs of DNA did reveal one crucial fact: the distance British biophysicist and in 1937. THE KEY It was a photo taken by biophysicist and crystallographer Rosalind Franklin that held the between the bases in the DNA molecule. molecular biologist. EXPERIMENT key to determining the make-up and structure of the DNA molecule In 1938, Astbury used the images to After co-discovering propose a structure for DNA in which the structure of the bases are stacked on top of each DNA, he went on to other, but the pictures weren’t detailed determine how DNA enough for him to get much further. codes for proteins, before venturing ROSALIND FRANKLIN’S KEY experiment – the into neuroscience. (1916-2004) was a results of which Watson glimpsed – was a CLUES IN BACTERIA British physicist and series of painstaking X-ray crystallography Meanwhile, back in the US, a medical molecular biologist experiments with DNA samples containing researcher named was who was born in New different amounts of water. The most busy refining a 1928 experiment by Zealand. As well as famous outcome of this is May 1952’s a British microbiologist called Fred his DNA research, he ‘’, which revealed key details Griffith. He had shown that it was worked in fields such as about the structure of DNA. possible to make harmless bacteria and radar and microscopy. The more a feature is repeated their progeny dangerous by mixing He remained at King’s within a structure, the more the them with virulent bacteria, suggesting College until his film will be bombarded with that something was being transferred retirement in 1981. X-rays diffracted in the same from the virulent to harmless bacteria. way, and the darker the Avery and his colleagues deliberately corresponding patch in the created conditions in which only DNA Rosalind Franklin image. The large dark patches – not protein – could be transferred. (1920-1958) was born at the top and bottom of the In this way, they determined that only in to a rich picture represent DNA’s bases, DNA could pass on traits. Though Jewish family. The and the X-shaped blobs indicate many would refuse to believe it, DNA X-ray crystallographer a helix. The arms of the cross had been strongly implicated as the and biophysicist represent the planes of carrier of inheritance, and science had provided much of the symmetry in a helix viewed from the tools to find out what it looked experimental evidence (1928- ) is an American the side; the ‘zig’ and the ‘zag’ of like. The stage was set for the race to for the structure of geneticist and molecular its turns. There are 10 spots on find the structure of DNA in the 1950s DNA before switching biologist born in each arm of the cross before you – only not everyone knew it was a race. her focus to at Chicago, who gained reach the large black patch at the top, DNA research was to benefit from Birkbeck College. She his PhD at just 22. After which corresponds with 10 bases the post-WWII mood in science, died of cancer at the co-discovering DNA’s stacked one on top of the other in each as many physicists who had been age of 38. structure in Cambridge turn of the helix. The fourth blob from employed in war work turned their in 1953, he worked at the centre is missing, which indicates attention to the more benign biological Harvard University and that one strand of DNA is slightly offset problems. Among them was Maurice then the Cold Spring against the other. Wilkins, who had worked on both Harbor Laboratory until Rosalind Franklin turned her attention radar and the Manhattan Project to he retired in 2007. to photo 51 in early 1953. Her notebooks build an atomic bomb. By the middle suggest that she had gleaned all its key The famous ‘Photo 51’, taken of 1950, Wilkins was assistant director information and may, in time, have reached via X-ray crystallography by of King’s College London’s the same conclusions as Watson and Crick. Rosalind Franklin, that reveals DNA’s double helix structure new biophysics unit. In a dank PHOTO: KINGS COLLEGE LONDON, NATIONAL PORTRAIT GALLERY, ALAMY X2, CORBIS, ALAMY COLD X2, SPRING HARBOR LABORATORY PORTRAIT GALLERY, NATIONAL LONDON, KINGS COLLEGE PHOTO: How do we know? How do we know?

basement underneath the Thames, Wilkins and PhD student NEED TO KNOW A series of experiments, which started in the 19th Century, were producing Get to grips with the structure of TIMELINE culminated in DNA’s structure being unravelled in 1953 much sharper X-ray pictures of DNA DNA with these key terms than Astbury had managed. Rosalind Franklin was invited to join the unit’s DNA research in Friedrich Miescher 1951, bringing with her important NUCLEOTIDE discovers DNA in his crystallography skills after making 1 The basic subunit of DNA. Each preparations of white her name in Paris with X-ray insights nucleotide is made up of a base (the ‘letters’ blood cells extracted of DNA: adenine, guanine, thymine or from the pus in surgical into the structures of coal, carbon bandages. He calls 1869 and graphite. But misunderstandings cytosine), a sugar and a phosphate group. it ‘nuclein’. with Wilkins over her role in the DNA The nucleotides form the two parallel research caused a rift that arguably complementary chains of DNA, with adenine cost them the scientific race. matched to thymine and guanine to cytosine. One of the biggest discoveries William Henry Bragg Franklin made in her time at King’s and son William Lawrence Bragg lay was to discover, along with Gosling, PHOSPHATE GROUP the foundations for that there are two forms of DNA: a 2 A phosphorous atom surrounded by the field of X-ray dehydrated, tightly packed ‘A’ form oxygen atoms. Phosphate groups, along with 1912-14 crystallography and a hydrated, longer ‘B’ form, which deoxyribose sugars, make up the ‘backbone’ when they realise produced different X-ray patterns. of the long DNA molecule. they can infer the Astbury’s blurry images must have structure of crystals from the patterns of been a combination of the two. scattered X-rays. The King’s group, and Franklin in X-RAY CRYSTALLOGRAPHY particular, believed that the structure 3 This is the study of the structure of 1920s would emerge from careful X-ray crystals by firing X-rays at them. The X-rays work. But at the Cavendish Laboratory bounce off the regular arrangements of Phoebus Levene discovers nucleotides – the in Cambridge, now headed by William atoms in crystals, and the patterns they combination of a sugar, base and phosphate Lawrence Bragg, a pair of researchers make are captured on film. An equation is group – and suggests they form short lengths then used to work out the crystal’s structure. of DNA called ‘tetranucleotides’. called James Watson and Francis James Watson (left) and Francis Crick (right) pose with their model of DNA that reveals its iconic double-helix Crick had other ideas. structure. They won the Nobel Prize for their discovery along with Maurice Wilkins

with Wilkins to focus on the A form, the Medical Research Council, which King’s data had played, and Franklin Florence Bell arrives in she put it aside. By January 1953, funded both groups. From this, Crick died in 1958, perhaps never having William Astbury’s lab THE RACE HEATS UP and takes the first Watson, an American researcher in Franklin had decided to leave King’s was able to deduce that the chains known. Watson, Crick and Wilkins X-ray images of his 20s who’d gained his PhD at an for Birkbeck College and began sharing in the DNA molecule look the same shared the Nobel Prize in 1962. With DNA (pictured). unusually young age, and Crick, older her work with Wilkins. Wilkins, who upside-down, and must therefore run no-doubt knowing understatement, Astbury makes with a reputation for a sharp mind, did had long believed that DNA was a in opposite directions. Watson and Crick wrote in their 1953 an attempt at famously little in terms of experiments helix, showed the image to Watson, The final piece of the puzzle was a paper: ‘It has not escaped our notice 1937 a structure the with DNA. Instead they chose to build who later wrote: “The instant I saw 1949 experiment by , that the specific pairing we have following year. physical models to work out how the picture, my mouth fell open and who had visited the Cavendish team in postulated immediately suggests a DNA’s known components could fit my pulse began to race.” Photo 51 1952. He determined that the number possible copying mechanism for the together. Much of their experimental immediately spelt out ‘helix’ to Watson, of As matched the number of Ts, and genetic material.’ Rosalind Franklin knowledge came from seminars and and he returned to Cambridge inspired. that the number of Cs matched the In the years since 1953, researchers takes ‘Photo 51’, a highly detailed image informal conversations with Wilkins, In February 1953, , Gs. Watson and Crick realised that As have learned how DNA copies itself of the ‘B’ or hydrated with whom they were on friendly terms. a giant of with must always bond to Ts, and Cs to Gs, and how its strings of As, Ts, Cs and Gs form of DNA. The 1952 At the end of 1951, Watson and Crick expertise in , producing a ladder-like helix with the provides a template for making photo is later seen invited the King’s team to see their proposed his own structure. But with paired bases forming the rungs and the proteins. More recently, analysis of the by Jim Watson latest model, which they believed to be only Astbury’s earlier data to go on, sugar-phosphate backbones the sides. human genome has allowed scientists (pictured) without the structure. Informed by Watson’s he got it wrong. Among other basic Model completed, the pair went for to glimpse the intricacies of how DNA her knowledge. memory of a talk by Franklin, it was mistakes, he suggested that DNA was lunch in a nearby pub called The Eagle orchestrates life.  made up of three DNA chains with the comprised of three chains. and declared that they had found the sugar-phosphate backbone on the Watson and Crick, concerned that meaning of life. When the King’s team Watson and Crick inside and the bases on the outside. Britain would lose the race, and seeing visited this time, they accepted the KATHERINE NIGHTINGALE is a science writer propose a model Franklin immediately knew it was a chance for themselves, returned to model immediately. “Rosy’s instant with a degree in molecular biology for the structure of the DNA molecule. wrong – DNA’s water content meant their model-building. They knew how acceptance of our model at first amazed They publish the the backbone had to be on the outside. far apart the bases were, that DNA’s me,” Watson wrote later. “Nonetheless… Find out more structure in the Embarrassed, Bragg banned the pair backbone was on the outside of the she accepted the fact that the structure Listen to ‘The Structure Of 1953 scientific journal from any more DNA work. molecule, that the overall structure was too pretty not to be true.” DNA’, an episode of Science Nature and suggest In May 1952, Franklin took Photo 51 was a helix, and that it was probably Crick and Watson’s structure was In Action that discusses the that the structure – a stunningly clear picture of the B made of two chains. They also saw published in the journal Nature in indicates DNA’s discovery of DNA and its impact on the function. form of DNA (see ‘The key experiment more of Franklin’s data, this time via a April 1953, along with two articles biological sciences. http://bbc.in/1977ZDx p92’). Abiding by an earlier agreement report to the biophysics committee of from King’s. None revealed the role that PHOTO: SCIENCE & SOCIETY X2, , CORBIS, SCIENCE PHOTO LIBRARY UNIVERSITY SCIENCE & SOCIETY X2, OF LEEDS, CORBIS, SCIENCE PHOTO PHOTO: BIOLOGY

THE

GENETIC

HUNT

FOR

NESSIE

For centuries, many have claimed that a creature lurks in Loch Ness. Now, by seeking out monster DNA from the loch’s waters, scientists are going to find out what’s down there GETTY GETTY WORDS: DR DARREN NAISH

8 BIOLOGY

he idea that new, large animal the enigma of Loch Ness once and for all. He species might be hiding in the and his team were set to use a technique not WHAT IS world’s wilder places has always previously used on the loch’s water. They were been one of the most romantic and going to hunt for environmental DNA, or eDNA eDNA? appealing of scientific concepts. (see box, right). T Even today, it remains possible that a few big mammals, fish or reptiles await ARE YOU THERE, NESSIE? DNA extracted from an an area can be extracted discovery in the forests of New Guinea or Most scientists do not think there is a monster organism can reveal from soil, groundwater, Southeast Asia, or in certain deep-sea basins. in the lake. This bold proclamation isn’t due to a great deal about its ice, freshwater and But can we take seriously the possibility, arrogant elitism or an inability or unwillingness relatedness to other seawater via so-called endorsed by a handful of die-hards and to examine the data that exists, but to the living things, both in environmental DNA BELOW: Tales of believers, that Loch Ness, Scotland’s largest a monster in fact that the evidence put forward to support the small-scale sense of or eDNA. and most famous lake, is home to a new species Loch Ness have Nessie’s reality has failed to be persuasive. how it compares with By collecting water of gigantic, dragon-like animal more than 10 been around for The photos and films are fakes, hoaxes, or other populations within from Loch Ness, scientist centuries. Prof metres long? Neil Gemmell is misinterpretations of known objects. Biological its species, and in the Prof Neil Gemmell and In May 2018, geneticist Prof Neil Gemmell of finding out what evidence that might support the creature’s broader sense of where his team hope that the University of Otago, New Zealand, embarked lurks in the existence – bones, carcasses, feeding signs it fits within the tree they have obtained on a project to collect and test genetic traces murky waters or droppings – is non-existent. And the large once and for all of life. eDNA from the loch of animals from the loch, and hoped to resolve number of eyewitness anecdotes provides But if it only takes a environment. They have nothing robust or consistent. Rather than tiny sample of organic also taken samples from monsters, there are instead assorted references tissue – a single skin or nearby lochs to analyse to all kinds of things seen on the loch, like gut cell, for example – their eDNA too. Back swimming deer, birds, seals, waves and wakes. for DNA to be extracted, in the laboratory, the “Can we take seriously the Few of these things are familiar to the average loch-side visitor. A psychological phenomenon then could DNA- samples will be analysed, possibility that Loch Ness known as ‘expectant attention’ is also important retrieval techniques be and any eDNA will be in influencing people’s experiences at Loch sophisticated enough for identified and extracted. Ness. It explains how people’s observations fit us to collect DNA that The samples are then is home to a new animal?” living things leave in profiled and compared their environments, via to those already in their shed cells, urine and genetic databanks. Many faeces? The answer is species already known yes. In a series of studies to be present in the that first appeared in loch will be identified print during the 1990s, in this way. The hope is ecologists and geneticists that species new to the worldwide have shown area, and perhaps even how the presence and new to science, will be an existing expectation, in this case, that they identity of organisms in discovered as well. will see a large, water-dwelling monster. Still, the idea of something mysterious in the lake has nonetheless captured the attention of scientists.Therefore, the water has been swept by vessels emitting sonar, and its depths have been explored by divers, submersibles and motion- detecting cameras. At least a few authors and scientists have gone on record to state their confident belief in the monster’s existence, the data that convinced them later proving inadequate or erroneous. In other words: science RIGHT: Most has searched for Nessie, and the results have eDNA found so come back negative. far belongs to living species In the 2016 book Hunting Monsters, I noted already known that the ability of scientists to search for to science. and analyse the genetic material that living However, some eDNA has been things leave in their environment – so-called found from environmental DNA, or eDNA – might provide extinct animals, the ultimate arbiter of like mammoths the presence or absence of a mystery creature in and giant sloths. This proves that the loch. Gemmell was inspired. “I was thinking eDNA can last how we might use eDNA to search for and for thousands of identify creatures that live in areas hard years in the right conditions GETTY X2 ILLUSTRATION BY RAJA LOCKEY BIOLOGY

“We could gain important southwest Pacific. This revealed the presence eDNA TO of six shark species that were not picked up at all via more conventional sampling techniques, information on valuable, THE RESCUE! like long-term observation and the use of baited locations set with automatic cameras. As well as helping us discover the truth about It’s doubtful that any of the scientists rare or sensitive species” Nessie, eDNA has many other useful applications… involved in these various eDNA projects ever considered how applicable this work might be to the search for lake monsters, but it’s with to investigate using traditional approaches, such as deep NEWT RESCUE SAVE THE WHALE this record of eDNA-based successes in mind oceans and subterranean water systems. Loch Ness seemed a Great crested newts are Scientists at Oregon that Gemmell announced his plans to collect perfect fit for that sort of project,” he says. “I’m not a Nessie protected by European State University want to and analyse eDNA from Loch Ness. An eDNA believer, but I’m open to the idea that I might be wrong. This law. When development use eDNA to investigate census of the loch could potentially reveal project is about understanding the biodiversity of Loch Ness, work that could affect beaked whales. This the presence of a large animal matching the with the added bonus being that we might find evidence freshwater bodies is elusive group of 23 ‘monster’ imagined by witnesses and Nessie- of something new that may explain the monster legend.” planned, some ecologists species – some of which hunters. But it would also provide a list of the According to Gemmell, the study could also have benefits for in the UK use eDNA have never been seen many additional species living there. Given the our understanding of the health of Loch Ness and its future techniques to check alive – are tough to success of eDNA in documenting the presence management. He’s currently awaiting the results of the survey. for the presence of the locate, which makes of animals, it is quite plausible that an eDNA amphibians before any eDNA a handy tool to study could document fish, molluscs or other SPECIES SEARCH building takes place. help us learn about these species not currently known to be living in the The study of eDNA has proved an invaluable tool to biologists mysterious animals. loch. Invasive species could be among them – ever since it was devised in the 1990s. It has been used to SHARK CONSERVATION organisms we urgently need to keep track of. examine the distribution of species no longer present in an Sharks are a priority FISH FARMING And we could also gain important information area, but whose genetic traces are still preserved in sediment. in ocean conservation. Every year, the on the whereabouts and movements of Nobody really expects to discover evidence It has also proved crucial in tracking the spread of invasive Yet as they have huge aquaculture industry economically valuable, rare or environmentally for a creature that might be regarded as similar species. Asian grass carp in the North American Great Lakes ranges, they can be loses huge numbers of sensitive species, like various members of the to the ‘Loch Ness Monster’ of popular lore. But and the New Zealand mud snail in the western USA, to use salmon family, or the European sturgeon. In much remains to be learnt about the biology difficult to monitor. By fish to disease. A team just two examples, have both had their progress monitored via short, the scientific pay-off for the study will and ecology of Loch Ness and its surrounding taking water samples at James Cook University eDNA. be substantial, whether a monster is discovered lochs and lakes. If eDNA and questions about from the Coral Sea and has used eDNA to detect eDNA studies have also been used in the search for species or not. “We figured at the outset that we would a monster help us to investigate this subject that are rarely seen by people and, in some cases, not seen at the Caribbean Sea, a bacteria and parasites likely describe the biodiversity of the loch. ABOVE: Sonar and learn more about the natural world and research team identified in the water of farms, reading of Loch all. A 2012 study of seawater from the Baltic confirmed the I anticipate finding evidence of all the fish Ness, taken by a how it functions, then this has proved a most presence of long-finned pilot whales in the area, a species not the distributions of at before any of the fish get species previously reported, plus perhaps some tour boat worthwhile endeavour. seen by people during the period covered by the study and least 21 species of shark, ill. This will help farmers others that we think may be present,” Gemmell captain, generally thought to be an extremely rare visitor there. More and proposed that eDNA to kill off any bugs says. “We also think we might find new forms of revealed a deeper section, Dr Darren Naish is a palaeontologist and science writer. He is remarkable is a 2018 study concerning eDNA collected from could help generate before they become bacteria and other life, particularly in samples which some the author of a number of books on cryptozoology, including the marine waters of the New Caledonian archipelago in the conservation strategies. a problem. from around methane seeps in the loch and the people think Hunting Monsters: Cryptozoology And The Reality Behind fridge-like depths 200m down.” could be a hiding

GETTY X5, SHUTTERSTOCK place for Nessie The Myths. He tweets from @TetZoo.

WHAT COULD NESSIE BE?

This eDNA study will be A PLESIOSAUR? A GIANT EEL? A STURGEON? SOME FLOATING VEGETATION? WEIRD SEISMIC ACTIVITY? the first to qualify if there A long-extinct group of aquatic reptiles Several monster experts have proposed Sturgeons are slow-moving, bottom- Biologist Dr Denys Tucker argued that Loch Ness is located within a geological – the plesiosaurs – have frequently been that Nessie might be an eel that has grown feeding fish that have a row of armour rotting masses of vegetation might fault known as the Great Glen, and is an unexpected creature mentioned in connection with Loch Ness, to a size about 10 times bigger than the plates along the spine, a pointed nose burst to the loch’s surface and then be certain sections of it are still seismically in Loch Ness. Here are the mostly because Nessie is often said to norm for its species, perhaps because and a sucker-like mouth. They can be propelled along at speed by the gases of active. Perhaps minor earth tremors suspects of what Nessie have a long neck, much like a plesiosaur. it has been living there for decades or up to seven metres long, and are known decomposition. Sightings of such events, are responsible for weird shapes in might be… But the fossil record gives no indication centuries. There are no good indications, to move in and out of lakes and rivers he argued, might explain monster reports. the water and releases of bubbles that that plesiosaurs have survived any more however, that eels really can keep growing according to the season. Sturgeons could However, scarcely any monster reports witnesses have interpreted as sightings recently than 66 million years ago. in this way. explain some Nessie reports. describe objects that match his idea. of monsters. COVERFORENSIC STORY SCIENCE

DNADNA DetectivesDetectives Law enforcement agencies have started investigating unsolved crimes by combining DNA databases and family trees. But should ‘genetic genealogy’ really be used to crack cold cases? WORDS: JV CHAMARY ILLUSTRATION: HOLCROFT JOHN 14 15 COVER STORY GENETIC VARIANTS The human genome is our complete set of 23 chromosomes. It’s made from DNA and is over three billion letters long. The differences between two individuals are most easily found at locations that commonly rom 1976 to 1986, the residents vary between us – genetic variants. Here are three different types that are used to compare people of California were terrorised by a masked man who raped at F least 48 women and murdered SINGLE NUCLEOTIDE POLYMORPHISMS MICROSATELLITES EPIGENETIC MARKS a dozen people. His carefully Nucleotides, the building blocks of DNA, include one of Approximately 3 per cent of the human genome is While they aren’t technically genetic variants, planned attacks suggested four chemical letters: A, C, G or T. The most common composed of microsatellites, also known as ‘short epigenetic marks do contribute to the differences military training, but after three decades, the East genetic variations in humans are ‘single nucleotide tandem repeats’ (STRs). Each microsatellite is a among people. Epigenetic marks are chemical Area Rapist – also known as the Golden State polymorphisms’, known as SNPs. These are positions in repeating unit made up of one to six DNA letters. modifications to DNA and its associated proteins Killer – seemed to have got away with his crimes. DNA where two people might carry the same letter, or The number of repeats varies among people. For that can influence whether genes are switched on or The case went cold. different letters. There are 10 million SNPs across the example, at any given location you might carry a off, and therefore affect the behaviour of our cells. Then on 25 April 2018, law enforcement genome and the vast majority don’t affect how your seven copies of the unit AATG, whereas someone Some marks are attached and removed during the officials announced that they had arrested Joseph body works. Personal genomics firms like 23andMe else might have a variant with eight copies. The course of development, others are the result of DeAngelo, a 72-year-old Navy veteran and former offer tests that read SNPs to generate a DNA profile, FBI’s Combined DNA Index System (CODIS) lifestyle choices such as smoking. Scientists can now cop. Investigators explained that semen samples which is compared against other profiles in their database has profiles created from 20 positions. read where marks highlight sentences on DNA, from crime scenes had been used to produce databases to indicate your family history, ethnic Such profiles are also used in forensics and meaning we could soon take tests that create the perpetrator’s DNA profile and search an background and risk of inherited diseases. paternity testing, comparing two individuals to epigenetic profiles, which could be used in forensics online database for potential relatives. The list of PERSON 1 see if they share the same number of repeats at to identify a smoker, for instance. Such personal matches was then used to build a family tree that each location. epigenomic reports might be able to reveal led to DeAngelo. information about your physical features. While catching killers using ‘genetic genealogy’ might sound like an obvious idea, it is by no A C A G C means straightforward. “Humans are really C T T G G A T C G SEVEN REPEATS EPIGENETIC MARK similar genetically: if I compared my genome to yours, we’d be 99.99 per cent identical,” says Prof Graham Coop, a population geneticist at the University of California, Davis. “But there are AATG positions in DNA which are variable between SNP MICROSATELLITES individuals.” GENE TESTING METHODS A Modern genetic tests read the letters of DNA at a C T T A G C T T C G EIGHT REPEATS selection of positions across the human genome G A A to generate a profile of genetic variants. These single-letter differences represent DNA regions that often vary among people, called ‘single nucleotide polymorphisms’ or SNPs (pronounced PERSON 2 ‘snips’). Personal genomics companies like 23andMe TOP ROW: Joseph and Ancestry offer ‘direct-to-consumer’ DNA tests DeAngelo, the Golden State Killer, during his that read about 700,000 SNPs. Those variants years as a police officer, GEDmatch, which compares SNPs shared by two forensic services to law enforcement agencies. After ETHICAL CONCERNS generate a profile that claim to reveal your family and (right) a 1976 police people to calculate their genetic similarity. The DeAngelo’s arrest, Parabon uploaded more than 100 While it may seem that catching bad guys can only history, ethnic background and susceptibility to sketch of the killer GEDmatch (GEnealogical Data match) website DNA profiles to GEDmatch, with its permission be a good thing, there are legal issues to consider, disease. ABOVE: DeAngelo was stores public profiles uploaded by its one million (investigators didn’t ask before uploading the Golden especially privacy concerns for people whose DNA Genealogists who want to study a family tree finally arrested in 2018. users. Unlike private databases run by DNA- State Killer’s profile). is stored in a database. What if your profile is in detail can upload DNA profiles to a site like His case is ongoing testing services like 23andMe, GEDmatch can Moore’s first case was a double murder in downloaded and leads to identity theft? Or genes be searched by anyone who registers for access, Washington State. The male killer’s DNA profile was associated with disease or ethnicity are used to which is how investigators found DeAngelo. uploaded on a Friday and by Saturday she had a list discriminate against you when trying to get a job? “Finding these genetic matches is easy,” says of matches for building a family tree that led to a Such scenarios could occur in future. “If police want a DNA Coop. “The actual work the investigators did is marriage that produced three daughters and one son. For Americans, the issue centres on whether you’re the hard part.” By Monday, she had a name for the police: William entitled to a reasonable ‘expectation of privacy’ under Catching the alleged Golden State Killer was a Talbott II. the Constitution. “One of the biggest sample, they need watershed moment in showing how combining Parabon now offers a genetic genealogy service to privacy protections is the Fourth Amendment, which databases and family trees can help crack cold any agency, not just existing customers. With enough protects individuals against unreasonable searches cases. “That really opened up the potential of human resources, it could help crack hundreds and seizures,” says Dr Natalie Ram of the University your consent or a what we would be able to accomplish,” says (maybe thousands) of cold cases. If DNA is available, of Baltimore School of Law. genetic genealogist CeCe Moore, who previously the approach could be applied to other infamous If police want a DNA sample, they need your focused on cases of unknown parentage, like criminals, such as the Zodiac Killer, who murdered at consent or a search warrant – at least in principle. In search warrant – at adoption. least five people in the late 1970s and taunted police practice, they can follow you until you discard DNA Moore now heads the new genetic genealogy with letters that might carry traces of saliva. in a public place – such as saliva on a coffee cup – unit for Parabon NanoLabs, a firm that provides then lawfully grab a ‘surreptitious sample’ (that’s least in principle” GETTY how police obtained DeAngelo’s DNA). It’s possible

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because you waive your rights to property when it’s Over-reach can happen through ‘function creep’ been thrown away, the ‘doctrine of abandonment’. – when the use of new technology (like DNA Even uploading your profile to a database might databases) is sneakily stretched beyond its original be considered ‘abandonment’ under US law: in purpose. This can cause an invasion of privacy, as the 1970s, the Supreme Court said the Fourth illustrated by the National DNA Database, which Amendment didn’t cover data voluntarily shared with initially added people who had been arrested but a third party. didn’t remove them after release. The case ended up What about here? For now, UK law only applies to in the European Court of Human Rights and led to DNA profiles for convicted criminals. “Our National the Protection of Freedoms Act. DNA Database is quite well-regulated in terms of who The danger is compounded by misplaced trust gets on it, who’s allowed to access it,” says Prof Carole in the forensic process, which is vulnerable to RIGHT: DNA McCartney of Northumbria University. “But there’s errors: investigators can cause contamination while testing is no rules about private companies – it will come down collecting DNA, or mix up samples while processing. helping to to their terms and conditions.” The European Union’s Despite what’s seen on TV police dramas, DNA is catch more criminals than recent General Data Protection Regulation (GDPR) rarely featured in trials, which is when experts ever, but the law gives citizens greater control over how their explain its reliability. “DNA evidence is seen to be wider information is handled, but McCartney thinks it’s so powerful, it’s very difficult to defend yourself if ramifications need to be accepted that the police can use genetic data. British you’ve got your DNA matched,” says McCartney. considered police could search GEDmatch profiles to track down suspects with American relatives. HOW IT WORKS Identifying the perpetrator of a crime using DNA databases and family trees

1. COLLECTING SAMPLES 2. TESTING DNA 3. SEARCHING DATABASES 4. BUILDING TREES 5. FINDING SUSPECTS

PERP Crime scene investigators collect DNA molecules are cut into The DNA profile of genotypes for one The chances of matching many first or second cousins in a Police, FBI and other law enforcement agencies use biological material such as blood, fragments and added to a person, the criminal, is compared against database the size of GEDmatch, which contains one million conventional investigative methods before arresting a semen, hair or skin. The DNA ‘genotyping chip’. Genotyping the profiles from other people in DNA profiles, is extremely low (unless your family’s keen suspect. For the Golden State Killer, investigators only had molecule decays over time and chips are covered in an array of GEDmatch’s public database. Each on ancestry). But there’s a high probability that you’ll find a list of third cousins (sharing great-great-grandparents has a 521-year half-life under 700,000 microscopic wells, each genotype is a single DNA letter or ‘single tens or even hundreds of third and fourth cousins, as there and under 1 per cent genetic similarity) so they had to use ideal conditions (-5ºC), but containing a probe that will nucleotide polymorphism’ (SNP) at one of are enough profiles and their DNA is still similar enough to an extensive process of elimination (the offender was degrades quickly when exposed match a genetic variant, which 700,000 positions that vary in the human be identified through genetic similarity. about 5’9” and 75kg, for example) to narrow it down to to heat, light, water and air. may or may not be present in the population. The pattern and number of Joseph DeAngelo. Whether DNA stays viable also DNA sample. If a fragment SNPs shared by any two people is used to Genetic genealogists build a family tree by applying depends on how well it’s stored. matches, it can be labelled calculate their genetic similarity. traditional techniques to database information, such as the Identifying a suspect requires putting all the pieces of a The oldest DNA recorded was with one of several fluorescent names of two people and their DNA similarity. This includes puzzle together. In Moore’s first genetic genealogy case, found in Greenland ice, and was dyes that enables a computer A database search is unlikely to return finding records like census data, newspaper obituaries and GEDmatch had a list of possible relatives that included two estimated to be between to read each associated matches with high similarity. As a person birth and marriage certificates, and interviewing living distinct matches, each with a 3 per cent similarity to the 450,000 and 800,000 years old. DNA letter. inherits half their DNA from each parent, relatives. Nowadays it also involves figuring out killer’s DNA. This suggested they they’re 50 per cent similar to their mother relationships via Facebook and other social networks. were second cousins from USER When someone orders a £100 Genomics companies use and father, 25 per cent to a grandparent. different branches of DNA testing kit from direct-to- different genotyping chips, For each generation since cousins last Once links between cousins are confirmed, a genetic the family tree, consumer genomics companies depending what that company shared a common ancestor, similarity is genealogist works backwards to find where enabling Moore to like 23andMe, Ancestry or believes are the most reduced by a quarter. So first cousins the separate branches of a tree are identify William MyHeritage, they spit into a informative genetic variants. share roughly 12.5 per cent of their DNA, connected at their long-dead Talbott II by collection tube or take cells from Most companies allow users to second cousins 3.125 per cent, etc. ancestors. Recent twigs of the triangulation. a cheek swab, then post the download a text file showing family tree – living relatives – sample to the company. After their genetic variants Genetic similarity can show if two people are then added by building four to eight weeks, they log into or ‘genotypes’, are related, but not the relationship forwards, what expert CeCe their account for a which are also between them. You share half your DNA Moore calls ‘reverse report on their uploaded to with each parent, as do any siblings, so a genealogy’, which can genetic GEDmatch, a 50 per cent match could be mum or dad, sometimes succeed in variants. searchable sister or brother. Going back to fifth ‘triangulation’ – when two genealogy cousins (sharing great-great-great-great- distant branches intermarry. website. grandparents) the overlap is just 0.05 per cent – so you’re effectively unrelated.

GENETIC GENEALOGY GETTY X4, FIMM

18 19 COVER STORY GENETICS

ABOVE: Michael If you’re a law-abiding citizen with nothing to GEDmatch has since revised its terms to explicitly Usry Sr with a picture of his hide, you may still be asking yourself the state that profiles could help identify a perpetrator of then 19-year-old question: where’s the harm in using my DNA to a violent crime. son. Usry Jr was help catch a killer? The answer depends on your Informed consent also means being conscious of vilified online as a murderer due personal ethics and how you weigh the benefits the impact ‘familial searching’ could have on others. to partial DNA for victims against potential costs to other people. “I like to think about it in terms of your cousin evidence, but One key issue is informed consent. “I’m really getting arrested,” explains Berkman. “Some would was later found innocent not confident that people understand or are even say ‘The fact that my DNA indirectly helped to lead aware that their genetic genealogy can be used for him to justice, it’s fine’, but you can imagine other criminal or forensic purposes,” says Dr Benjamin people who would feel guilt or conflict about having Berkman, a bioethicist at the US National caused a relative to go to jail.” Institutes of Health. Until recently, he adds, information about such disclosures was ‘buried in FALSE POSITIVES the small print’. When someone is under suspicion for a crime, their Berkman says the problem stems from name can get leaked to the press – and in contrast expectations. People signed up to GEDmatch to the criminal justice system, in the media you’re ICHARD III (1452-1485) is to study their family history, not aid law often guilty until proven innocent. That’s what about to be reburied in enforcement. And although the site’s original happened to US film-maker Michael Usry Jr, who Leicester, the city where his terms of service did warn users that DNA profiles was investigated in 2014 for a 1996 murder, based skeleton was discovered could be used to help identify related to victims on a partial match to his father’s DNA following a under a car park in 2012. or criminals, some members didn’t realise that familial search of a database (the FBI even secured a RDNA tests the following year made him

until DeAngelo’s arrest hit the headlines, then warrant for cheek swabs). Even if you’re later cleared, the most ancient specific individual to be PHOTO: GETTY felt so misled that they deleted their accounts. as Usry was, being branded a killer could still haunt identified by genetic analysis. A follow-up you for the rest of your life. study, published last year in the journal “At the end of the day it’s your genome,” Berkman Nature Communications, revealed a case concludes. “And if you want to learn more about of regal infidelity. It seems a ‘false ILLUSTRATION: CHRISSTOCKERDESIGN.CO.UK “In contrast to the your ancestry or your genealogy or your health, paternity’ occurred sometime between I don’t know that other people get to tell you what the 14th and 19th centuries. Does this you can and can’t do with your DNA.” mean, as some have claimed, that the criminal justice system, But for genetic genealogist CeCe Moore, the ethical Windsor monarchy is illegitimate? balance tips toward the victims of crime and their DNA analysis of Richard III’s Richard III was killed at the Battle of families. “These families have often been waiting Bosworth in 1485, the last of the in the media you’re for decades for justice and some sort of closure,” skeleton has cast doubt on his Plantagenet kings and the last English she says. “And we are finally able to provide that monarch to die in battle. His remains The latest computer SHUTTERSTOCK through this new technology and techniques.” title. Zoe Cormier examines the were buried unceremoniously at the modelling techniques often guilty until were used to create this genetic evidence and finds a Greyfriars medieval church. They reconstruction of what were then forgotten, and when the JV Chamary is a writer with a PhD in molecular evolution and Richard III would have monarchy muddied by infidelity monastery was closed by Henry VIII looked like proven innocent” genetics. He covers science and technology for Forbes.com

20 SUMMER 2014 / FOCUS / 21 XXXXXXXGENETICS GENETICS

in the Dissolution, his final resting place was paved over. But in 2012, the Richard III Society joined forces with a team from the University of Leicester to dig into the car park that stands there today, in DNA DETECTIVES PATRILINEAL MATRILINEAL the hope of finding his remains. How your genetic material has been Great-grandfather Great-grandmother Great-grandmother Great-grandfather The skeleton they unearthed was passed down to you – and how it can promising: it had a curved spine due to be used to trace your family history scoliosis, and radiocarbon dating indicated the person died in the late 15th Century. Most excitingly, they found that the skeleton 1 1 was male, and bore the scars that historical 1 Only great-grandmothers pass on records say the king suffered, including a eggs with mitochondrial DNA, and only great-grandfathers pass on sperm fractured skull from an axe wound. Grandfather Partner with Y-chromosomes. Grandfather’s Grandmother’s Grandmother Partner “It was like a ‘missing persons’ case. sister brother Richard was last seen here, with a twisted spine, and died of battle wounds. But to 2 Grandmothers and grandfathers really prove his identity we needed both inherit mitochondrial DNA from their respective parents, but only genetic evidence,” says Dr Turi King of 2 2 the University of Leicester, who proved the grandfathers inherit Y-chromosomes. her case by grinding up teeth from the In the next generation, the pattern repeats: only grandmothers pass on skeletal remains in order to extract DNA. Father Mother But there was one problem: Richard did mitochondrial DNA and only grandfathers not leave any descendants behind. Enter pass on Y-chromosomes. genealogist Prof Kevin Schürer, who painstakingly traced the family trees of The pattern repeats: everyone DNA was extracted from Richard’s 3 inherits mitochondrial DNA, but the monarch and all his relatives, going skeleton by grinding up his teeth 3 3 back four generations to Edward III only uncles and fathers inherit Y-chromosomes.

“Both daughters In sons and daughters, both Son Daughter mtDNA 4 inherit the mitochondrial DNA, and Egg and sons receive both are part of the matrilineal line, but only sons inherit the Y- DNA Sperm mitochondrial DNA and are part of the patrilineal line. from their mothers, 4 Y-chromosome but only daughters will pass it on” and Richard III – so the infidelity could Indeed, the genetic analysis indicates the have occurred in any of 19 generations. cuckolding could have occurred on either The archaeological dig in a Leicester car park that unearthed Newspapers seized on this to suggest side of Edward III’s descending lineage, Richard III’s skeleton in September 2012 that the entire Tudor dynasty, and and is statistically most likely in any of the (1312-1377), and then down to anyone therefore Queen Elizabeth II, may not 15 generations between John of Gaunt and living today related to the 14th Century ‘batteries’ of cells. While both eggs and have a claim to the throne. However, the the Duke of Beaufort. king. “But of course, many people are sperm contain mitochondria, those found only case of unfaithfulness that would Multiple scientific surveys have indicated related to Richard III in some distant way in the sperm are broken down shortly make this true would have had to involve that between one in 50 and one in 100 – only people related to him in a specific after fertilisation. This means there are no John of Gaunt (1340-1399), son of Edward people are not the children of the men way were useful to us,” he explains. paternal mitochondria present as an III and the last common ancestor of the believed to be their fathers, so it’s not The key was tracking down the direct embryo develops (see ‘DNA detectives’). current royal family and the descendants surprising that there was some case of false descendants of Anne of York (1439-1476), Both daughters and sons receive of the Duke of Beaufort. paternity in the regal lines. A case in point: Richard’s sister. Eventually the team found mitochondrial DNA from their mothers, London cabinet maker Michael Ibsen (left) meets a model Tudor historian Alison Weir says there King and Schürer’s analysis also showed

ILLUSTRATION: ACUTE GRAPHICS ACUTE ILLUSTRATION: one: Michael Ibsen, a London cabinet but only daughters will pass it on. of his distant ancestor, King Richard III have long been rumours that John of that one of the five male descendants of the maker. A comparison of the matrilineal Gaunt was a changeling. Gossip in the late Duke of Beaufort did not have the same DNA of Richard III and Ibsen proved an The skeleton’s Y-chromosome DNA 1300s suggested that his mother, Philippa Y-chromosome as the other four, revealing exact match. What’s more, Ibsen and WHO’S THE DADDY? did not match any of the five male of Hainault (1314-1369), had accidentally that there must have been another genetic Richard III shared one of the rarest types of Next, King and Schürer examined the descendants of Henry Somerset, the 5th killed her firstborn son in infancy by break somewhere along the line. mitochondrial DNA, known as ‘haplotype patrilineal DNA. This is the DNA in the Duke of Beaufort (1744-1803). King and crushing him in her sleep, and – to hide “When I started going into this, I knew J1C2C’, which is carried by just 1-2 per cent Y-chromosome, which is passed down Schürer say that there must have been a her shame from her husband Edward III that infidelity was something we may of the population. Subsequent analysis of from fathers to sons only. Human DNA case of “false paternity” at some point – replaced him with another baby. “But find,” says King. “It’s very common.”  another living descendant of Anne of York comes in packages called chromosomes, after the reign of Edward III, the last this was propaganda spread when John also showed a match, though not as exact. and each of us has 46 of them in each of common ancestor of the Duke of Beaufort was in his 30s by his political enemies – Matrilineal DNA is inherited from our cells – 23 from each parent. One of and Richard III. But 15 generations there is nothing to substantiate this,” says mothers and is found in the mitochondria Injuries to the skeleton found in Leicester were consistent these pairs can come in either XX (female) separated Edward III and the Duke of Weir. “People love conspiracy theories, but ZOE CORMIER is a science journalist and PHOTO: UNIVERSITY OF LEICESTER X2, CORBIS X2 X2, UNIVERSITY OF LEICESTER PHOTO: of cells. The mitochondria are the with contemporary accounts of Richard’s death in battle or XY (male) combinations. Beaufort, and four separated Edward III we really shouldn’t pay much attention.” author with a background in biology