Profile of Alec J. Jeffreys s one of the great contributors to modern genetics, Sir was born with curiosity in his genes as the son and Agrandson of prolific inventors. Jeffreys displayed an insatiable quest for knowl- edge, and his father fostered his son’s budding scientific interests with gifts of a microscope and chemistry set, the latter of which produced one of Jeffreys’ most memorable scientific ventures. ‘‘Those were back in the happy days of chemis- try,’’ Jeffreys points out, ‘‘where you could go down to your local pharmacist and get virtually everything you wanted.’’ The end result of that chemistry experiment was the detonation of his aunt’s apple tree and a set of scars that Jeffreys still bears to- day. ‘‘You learn science very fast that way,’’ he says, ‘‘but it was quite fun.’’ Jeffreys’ scientific curiosity only in- creased after the apple tree incident, and years later it would lead to one of the Alec J. Jeffreys most widely used applications in genetics: DNA fingerprinting. Among other uses, the DNA fingerprinting technique has freys go there, so Jeffreys entered the turn led to another groundbreaking find- helped solve numerous criminal investi- university in 1968. He was at first intent ing about the composition of eukaryotic gations, settle countless paternity dis- on pursuing a degree in DNA: introns (3). ‘‘I was 27 at the time, putes, and spark a resurgence of interest but soon decided to alter his course. so still a real rookie, with the ability to in the forensic sciences. That achieve- ‘‘This was no criticism of the way it was detect single-copy DNA by Southern blot ment alone is worthy of merit, contrib- taught,’’ he says of biochemistry at Ox- hybridization and a nice paper on introns uting to Jeffreys’ receiving three high ford, ‘‘but rather a reflection of the fac- under my belt, which is, yeah, not a bad distinctions in 2005: the Albert Lasker ulty’s research, which leaned heavily to start,’’ he says. Clinical Research Award, induction into physical biochemistry.’’ Jeffreys had be- the National Inventors Hall of Fame, come more interested in genetics and DNA’s First Fingerprint and election to the National Academy molecular evolution, so after he received After these heady research achievements, of Sciences as a Foreign Associate. his B.A. in biochemistry in 1972, he Jeffreys was faced with the question of Aside from the invention of DNA fin- remained at to complete his ‘‘What next?’’ In 1977, he returned to gerprinting, Jeffreys has made many other D. Phil. in genetics in 1975. England to accept a Lecturer position pioneering contributions to the field of Jeffreys then received an European in the Department of Genetics at the human genetics. These accomplishments Molecular Organization (EMBO) University of Leicester (Leicester, include the discovery of eukaryotic in- research fellowship to work with Piet ), where he remains trons, further understanding of the evolu- Borst at the University of Amsterdam in today as a professor, but scientifically tion of gene families, and insight into the The Netherlands. His project was in- the decision of what to do next was secrets of genetic recombination. Some of tended to study yeast transfer RNA genes, problematic. The logical course seemed these secrets are documented in Jeffreys’ but then he met up with another re- to be to study introns, but Jeffreys ex- Inaugural Article in this issue of PNAS searcher, Richard Flavell. Says Jeffreys, pected that a lot of major laboratories (1), which looks at the mechanisms of ‘‘[Flavell] said, ‘We’ve got this crazy would move into this field. ‘‘And it was ectopic recombination, in which locally project attempting to isolate and purify obvious to me that, being essentially by similar DNA sequences are exchanged. mammalian genes, specifically the rabbit myself—I had just a part-time technician This recombination process can generate ␤ -globin gene. Would you be interested?’ working for me—with no funding, and variation in gene copy number and lead to I mean, at the time, nobody had ever de- really having to start from scratch, that inherited pathological disorders. tected or cloned or analyzed a single-copy to carry on with the intron work would mammalian gene. So I said, ‘Yeah, bet not be competitive,’’ he says. Instead, Oxford to Introns your bottom dollar, I’m in.’’’ Jeffreys sought to combine his recently Born in 1950 in Oxford, England, Jef- Jeffreys and Flavell hoped to biochemi- acquired molecular biology experience freys grew up in the shadow of the Uni- cally purify a vast amount of rabbit DNA with his interests in human genetics. versity of Oxford, but he did not have via mRNA hybridization enrichment, but ‘‘The first question we asked was, ‘If any connections to the storied institu- their plan ultimately did not work. In the you can see DNA restriction fragments, tion. ‘‘We were very much on the other process, however, Jeffreys, with the aid of side of the tracks,’’ he says of his family. the then-new technology of Southern blot-

Thus, Jeffreys never gave much thought ting analysis, developed a way to probe This is a Profile of a recently elected member of the National to attending Oxford University, but his and detect the globin gene. The probes Academy of Sciences to accompany the member’s Inaugural high school headmaster, an Oxford led to the creation of the first physical Article on page 8921. alumnus, seemed determined that Jef- map of a mammalian gene (2), which in © 2006 by The National Academy of Sciences of the USA

8918–8920 ͉ PNAS ͉ June 13, 2006 ͉ vol. 103 ͉ no. 24 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0603953103 Downloaded by guest on September 26, 2021 PROFILE

can you see variation between people in identification. My life completely changed DNA fingerprinting. This was science, those fragments?’’’ says Jeffreys, who ulti- at that point,’’ he says. helping this poor family who got them- mately was able to, in the form of the selves in a bureaucratic tangle,’’ says Jef- second-ever description of restriction frag- The Boy from Ghana freys. He dreads to think of what would ment length polymorphisms (RFLPs) (4). After the discovery of the first DNA fin- have happened had he found the opposite ‘‘We were beaten to the post by Y. W. gerprint, Jeffreys rushed out of the x-ray result, but as it was, this heartwarming Kan, bless him, he well deserved it,’’ says developing room and proclaimed to his story made national headlines and helped Jeffreys. Although RFLPs would help ad- group, ‘‘I think we’re onto something re- open the floodgates for DNA fingerprint- vance several areas of genetics research, ally exciting here.’’ Within a half-hour, he ing technology. Jeffreys was a bit frustrated with them. and his laboratory had written down a ‘‘They were hard work to detect at the slew of potential applications, including Forensic Crimefighting time, and they weren’t very genetically forensics, paternity or twin testing, and In 1986, as Jeffreys and his small labora- informative. We felt that there must exist conservation biology. ‘‘We were then tory handled all the DNA test requests for bits of DNA that are far more variable faced with two challenges, really. The first issues regarding immigration, paternity, than standard RFLPs,’’ he says. was to improve the technology from that and the like, Jeffreys faced challenges for Three years and an assortment of un- blurry mess to something that would actu- making DNA fingerprinting appropriate successful approaches later, Jeffreys found ally be reliable enough for real casework. for use in forensics. Together with Peter a clue in a completely different project The second was whether anybody would Gill at the United Kingdom’s Home Of- looking at the organization and evolution pay a blind bit of notice,’’ he says. A few fice Service, he quickly of globin genes, particularly the often- months of tinkering solved the first chal- established that DNA could survive in overlooked myoglobin. The trail began lenge to Jeffreys’ satisfaction, and an op- forensic samples, clearing one potential with a lump of seal meat donated by the portunity to meet the second arrived soon hurdle. Another obstacle was that DNA British Antarctic Survey (, after. fingerprint blots were fairly complex and United Kingdom). ‘‘Seals express myo- needed to be simplified. The solution for globin at very high levels in their muscle,’’ this problem came from Jeffreys’ work in explains Jeffreys, ‘‘and that made the mes- The first DNA cloning individual minisatellites from senger RNA, and hence the gene, much the fingerprints (10). ‘‘Once you get the easier to isolate.’’ Successful isolation of fingerprint was ‘‘a cloned minisatellite, you can make the the seal myoglobin gene paved the way thing locus-specific,’’ he explains. These cloned probes could detect highly variable for the isolation of the human myoglobin horrible, smudgy, alleles of different lengths and produce gene, and within that gene Jeffreys found easy-to-read two-band patterns, one for a short stretch of DNA with tandem blurry mess.’’ each copy of the allele. By sampling multi- repeats: a minisatellite (5, 6). ple loci on each sample, a ‘‘DNA profile’’ ‘‘At first, it was a little bit of ‘so what?’’’ could be built. recalls Jeffreys of the finding. ‘‘This wasn’t In April 1985, Jeffreys received a letter In 1986, Jeffreys was contacted by local even variable.’’ But a few examples of from Sheona York, a London lawyer. police regarding a murder case where two York had read about DNA fingerprinting variable minisatellites had emerged in re- schoolgirls had been raped and murdered in the newspaper and wondered whether cent literature, and they seemed to share 3 years apart in an apparent copycat kill- this technique could help sort out a tricky some sequence similarity. To better define ing. The police had a suspect in custody, immigration dispute involving a family this similarity, Jeffreys hybridized the but although he confessed to the second myoglobin minisatellite to a human from Ghana. The youngest boy had gone murder, he denied the first. Jeffreys was genomic library and pulled up numerous back to Ghana and returned with a asked to use DNA profiling to tie the sus- cross-reacting clones, all sharing a 10- to United Kingdom passport that appeared pect to both cases. The results were com- 15-bp core sequence (7). ‘‘That told us tampered. Immigration authorities sus- pletely unexpected: both semen samples that if you want to isolate minisatellites in pected that the boy was a noncitizen sub- belonged to the same man but were not large numbers, you use this motif. So we stitute, perhaps a cousin, trying to sneak from the suspect (10). Jeffreys initially thought, ‘OK, we’ll just try a simple ex- into the country. Although the standard thought something was flawed with the periment of taking a Southern blot of var- genetic tests at the time could prove a DNA profile, because the police were ious individuals and hybridizing it with a familial relationship, they could not deter- sure they had their culprit, but repeated probe of these repeat motifs,’’’ he says. mine specifically which relationship. Com- tests confirmed the discrepancy, and the His laboratory even had an available blot plicating matters, the mother was not ex- suspect was eventually set free. ‘‘And lying around, which included DNA from actly sure who the father of the boy was, that’s something a lot of people forget,’’ his technician, Jenny Foxon, and her and none of her sisters were available for Jeffreys says. ‘‘They tend to see DNA as parents. testing. a powerful tool for the prosecution, but ‘‘And on the morning, 5 past 9, of Says Jeffreys, ‘‘I first thought, ‘Well, don’t realize it’s just as powerful for the Monday, the 10th of September 1984, we forget it! This is a jigsaw puzzle with too defense.’’ got our first truly awful DNA fingerprint many pieces missing!’’’ He decided to give Says Jeffreys, ‘‘Then the police did purely by chance,’’ Jeffreys says. Yet as it a try, however, and managed to recon- something that I thought was fantastically soon as he took a look at what he remem- struct the DNA fingerprint of the missing brave. Rather than disbelieve DNA, they bers being ‘‘a horrible, smudgy, blurry father by using DNA from three other totally believed it and launched what mess,’’ he could tell what was going on: children. He then showed that every ge- proved to be the world’s first DNA-based he could spot the family group present in netic character of the disputed boy manhunt, asking for blood samples from that blot and distinguish all three mem- matched the mother or father (9). As a men from the entire local community.’’ In bers by what appeared to be a simple result, the immigration tribunal dropped a Hollywood-like twist though, the perpe- pattern of inheritance (8). ‘‘We suddenly the case and allowed the boy back into trator devised an elaborate deception realized that we’d essentially stumbled the United Kingdom as a full citizen. ‘‘So wherein he forged his passport and had a upon a DNA-based method for biological that was a fabulous story to the start of friend stand in for him as a proxy. Fortu-

Zagorski PNAS ͉ June 13, 2006 ͉ vol. 103 ͉ no. 24 ͉ 8919 Downloaded by guest on September 26, 2021 nately, the friend confessed to the ruse With STR typing, Jeffreys and his progeny, creating a hotspot paradox (15). while at a pub one night, which allowed group felt that the fundamental science ‘‘In other words, any mutation that down- for the apprehension of the real murderer, of DNA fingerprinting had largely been regulates a hotspot will be favored by the who was positively profiled via DNA test- solved. ‘‘So, it was time to let go of the recombination process and should then ing. ‘‘So that was the birth of forensic baby’s hand and walk off in another direc- wipe that hotspot out,’’ he says. More re- DNA in real casework,’’ says Jeffreys, tion,’’ he says, ‘‘although the baby has cently, Jeffreys has demonstrated that ‘‘and this was DNA potentially saving the flourished quite well.’’ He has been hotspots could come or go without any life of future victims, which was quite so- pleased with the media attention that change whatsoever in the local DNA, such that two individuals could differ in bering stuff.’’ DNA fingerprinting has received, viewing it as a good platform to enthuse people the presence or absence of a particular hotspot but have the exact same DNA Launching about genetics. In fact, one of his fondest sequences for kilobases around that experiences was participating in a televi- By the end of the 1980s, the word had area (16). spread about DNA fingerprinting, and sion program in 1990 where DNA finger- In his PNAS Inaugural Article (1), Jef- DNA profiling had established itself as an printing showed that two sisters were in freys and graduate student Kwan-Wood international gold standard for genetic fact identical twins, a show viewed by G. Lam examined another mysterious testing. Jeffreys realized, however, that nearly 18 million people. ‘‘Now, I’m a uni- crossover event, ectopic recombination. limitations existed with the technique. ‘‘It versity teacher, so my typical class will be Ectopic recombination occurs between was slow, not very sensitive, and the tech- about 20 people. To reach out and hit segments of locally repeated DNA, such nology had to move on,’’ he says. That 18 million in one go is phenomenal,’’ he as in gene family clusters, and can result technology would soon arrive in the form says. If Jeffreys has any gripes about his in gene duplications or deletions. Return- of PCR, which had been invented in 1983 ‘‘baby,’’ it’s only that some of the publicity ing to the globin genes he had studied has distorted its value, placing too much early in his career, Jeffreys used the and advanced to a user-friendly form. ␣ Also, the identification of microsatellites, emphasis on the criminal context and not -globin gene family as a model to investi- gate the rules governing ectopic recombi- which are Ϸ100 bp long compared with enough on the many other applications, such as for familial or immigration testing. nation events. Jeffreys and Lam found several thousand base pairs for a typical that genetic exchanges involving ␣-globin minisatellite, provided variable loci that Recombination and Globin’s Return gene regions are surprisingly common, can could be easily amplified and more resis- In recent years, Jeffreys has returned to occur in both sperm and blood, and can tant to degradation. ‘‘It was absolutely basic questions about minisatellites and occur between short regions of sequence obvious to me that this was going to be ␣ human genetic diversity. ‘‘Why were identity. Chromosomes with -globin gene the way forward,’’ says Jeffreys. these bits of DNA so astonishingly vari- deletions are prevalent in Asian and Afri- Jeffreys soon tested the power of mic- able between people?’’ he asks. Jeffreys can populations and are likely maintained via malaria selection for ␣-globin-deleted rosatellite, or single tandem repeat (STR), has found that DNA recombination chromosomes (17, 18). Indeed, Jeffreys typing. In 1990, he was contacted by a plays a crucial role as the driving force prosecutor in Frankfurt, Germany, who and Lam found that, despite high levels of behind minisatellite mutation. ‘‘These instability, exchanged chromosomes are was seeking assistance in proving that bits of DNA were hooking into the mei- some recovered skeletal remains belonged rare in geographic regions without ma- otic recombination process and basically laria, suggesting strong selective pressure. to Josef Mengele, the infamous Nazi Ger- getting themselves in a mess,’’ he says. man physician and officer. Together with Of course, these recombination events Looking at recombination events more still pose many unanswered questions, and Erika Hagelberg, an Oxford colleague closely, Jeffreys has found that recombi- like the detectives of the popular televi- with expertise in DNA extraction—‘‘she nation preferentially occurs at tightly sion show ‘‘CSI: Crime Scene Investiga- can get DNA out of a stone, just about,’’ controlled sequence elements, or hot- tion,’’ Jeffreys is eager to tackle them and says Jeffreys—he developed spots (12). ‘‘And the picture that’s be surprised by the answers. For him, sci- profiles from the samples. Compar- emerging is that these hotspots are ence has always been an exploration of ing the DNA profiles with those of likely quite dynamic features of the hu- the unknown, and the best experiments Mengele’s widow and son confirmed the man genome,’’ he says, noting a study are those where one has no idea what is authenticity of the skeletal remains (11) that found that despite nearly identical going to happen. ‘‘If someone had told and helped close the book on a 40-year- genomes, humans and chimpanzees have me in 1980, ‘Alec, go away and figure out old war-crimes investigation. Surprisingly, radically different haplotype structures a way of identifying people with DNA,’ despite such noteworthy success with STR (13, 14). I would have sat there looking very stupid typing, several more years passed before These dynamic hotspots are also puz- and got nowhere at all,’’ he says. ‘‘So, if this technique became the new standard zling, because Jeffreys observed that some I could tell you what I would be doing for forensic science. Jeffreys believes this single nucleotide polymorphisms (SNPs) 5 years from now, I’d be very depressed, lag ‘‘was a testimony to just how good the inside hotspots could down-regulate activ- because that means I sort of know the answers.’’ old-fashioned Southern blot hybridization ity but then engage in a bizarre process approach was.’’ whereby they are overtransmitted into Nick Zagorski, Science Writer

1. Lam, K.-W. G. & Jeffreys, A. J. (2006) Proc. Natl. Acad. 8. Jeffreys, A. J., Wilson, V. & Thein, S. L. (1985) Nature 316, Science 308, 107–111. Sci. USA 103, 8921–8927. 76–79. 14. Ptak, S. E., Hinds, D. A., Koehler, K., Nickel, B., Patil, N., 2. Jeffreys, A. J. & Flavell, R. A. (1977) Cell 12, 429–439. 9. Jeffreys, A. J., Brookfield, J. F. Y. & Semeonoff, R. (1985) Ballinger, D. G., Przeworski, M., Frazer, K. A. & Paabo, 3. Jeffreys, A. J. & Flavell, R. A. (1977) Cell 12, 1097– Nature 317, 818–819. S. (2005) Nat. Genet. 37, 429–434. 1108. 10. Wong, Z., Wilson, V., Patel, I., Povey, S. & Jeffreys, A. J. 15. Berg, I., Neumann, R., Cederberg, H., Rannug, U. & 4. Jeffreys, A. J. (1979) Cell 18, 1–10. (1987) Ann. Hum. Genet. 51, 269–288. Jeffreys, A. J. (2003) Am. J. Hum. Genet. 72, 1436–1447. 5. Blanchetot, A., Wilson V., Wood, D. & Jeffreys, A. J. 11. Jeffreys, A. J., Allen, M., Hagelberg, E. & Sonnberg, A. 16. Neumann, R. & Jeffreys, A. J. (2006) Hum. Mol. Genet. 15, (1983) Nature 301, 732–734. (1992) Forensic Sci. Int. 56, 65–76. 1401–1411. 6. Jeffreys, A. J., Wilson, V., Blanchetot, A., Weller, P., 12. Jeffreys, A. J., Murray, J. & Naumann, R. (1998) Mol. Cell 17. Flint, J., Hill, A. V. S., Bowden, D. K., Oppenheimer, S. J., Spurr, N., Goodfellow, P. & Geurts van Kessel, A. H. M. 2, 267–273. Sill, P. R., Serjeantson, S. W., Bana-Koiri, J., Bhatia, K., (1984) Nucleic Acids Res. 12, 3235–3243. 13. Winckler, W., Myers, S. R., Richter, D. J., Onofrio, R. C., Alpers, M. P., Boyce, A. J., et al. (1986) Nature 321, 7. Jeffreys, A. J., Wilson, V. & Thein, S. L. (1985) Nature 314, McDonald, G. J., Bontrop, R. E., McVean, G. A., Gabriel, 744–750. 67–74. S. B., Reich, D., Donnelly, P. & Altshuler, D. (2005) 18. Hill, A. V. S. (1992) Baillieres Clin. Haematol. 5, 209–238.

8920 ͉ www.pnas.org͞cgi͞doi͞10.1073͞pnas.0603953103 Zagorski Downloaded by guest on September 26, 2021