PROFILE

Profile of David M. Hillis

hilippe Padieu was called a mod- down through the maternal line. However, ern-day Casanova. Women said both types of analyses had their short- Pthey were drawn to him for his comings: chloroplast DNA analysis was sweet personality and charm. restricted to plants, and mtDNA evolves However, Padieu harbored a secret. In so quickly that it was best suited for 2009, he was found guilty of aggravated reconstructing relatively recent di- assault for purposefully infecting six vergence events. So Hillis looked to nu- women with HIV and sentenced to 45 clear ribosomal DNA, as well as nuclear- years in prison. Credit for Padieu’s guilty encoded proteins, to reconstruct the verdict goes partly to David Hillis, an evolutionary history of amphibians. The evolutionary biologist at the University results revealed enormous hidden di- of Texas at Austin. versity among morphologically similar Hillis, elected to the National Academy amphibians (2, 3). Rather than throwing of Sciences in 2008, has devoted his re- out centuries of morphological work, search career to phylogeny, the study of however, Hillis worked to integrate mo- evolutionary relationships. His work tack- lecular and morphological studies of les some of the greatest questions of evo- phylogeny (4). lutionary : How do species arise? Soon Hillis turned his attention to how How do genes diversify and acquire new individual genes evolve and diversify. For functions? How do pathogens evolve, and instance, when Hillis and his colleagues how can that information be used to un- studied the evolution of the ZFY gene, derstand diseases? And ultimately, can we then thought to trigger male development reconstruct the complete Tree of Life and in mammals, they found that the gene was use that information to help make pre- unrelated to sex determination in reptiles dictions about biology? (5). “It was one of the first indications Before the Padieu case, Hillis and col- that the ZFY gene was not actually the sex leagues had used phylogeny to determine determination gene, as it was initially the degree of relatedness among HIV David M. Hillis. thought to be,” Hillis says. Soon after, the carriers. However, in the Padieu case, actual sex-determining gene of mammals, prosecutors needed to show that the HIV SRY, was discovered. traveled from Padieu to his victims, rather no distractions like television or anything Hillis’ work in frogs and reptiles made than the other way around. HIV was like that. The primary way I had to en- clear that phylogenies could reveal how known to infect each host with billions of tertain myself was to run around the life on Earth evolved. Rather than look at virions. However, when the virus travels jungles of Africa and catch lizards and single species, Hillis now devotes much of from a source to recipient, a genetic bot- snakes and butterflies,” Hillis says. his time to modeling evolution on com- tleneck occurs and typically only one of That scientific curiosity stayed with puters and coming up with ways to detect those virions makes the jump into the new Hillis as the family fled the Congolese civil evolutionary patterns in enormous data- host. Because the virus evolves rapidly, war. The family later lived in Calcutta, sets. Although his early interest in science Hillis’ team was able to show that six of , and then Baltimore, MD, where may have come from his father, Hillis the samples were derived from the sev- both Hillis’ parents took up faculty posi- gives credit for his more recent work to enth. In court, that seventh sample was tions at The . his mother, a biostatistician. revealed as belonging to Padieu (1). By high school, Hillis had grown intrigued by reptiles and amphibians. “I became Watching Evolution Amphibian Evolution fascinated with reptiles in Africa, where Hillis’ shift toward statistical and com- Much of Hillis’ early exposure to science I’d caught and kept lizards and learned putational approaches to evolution began came through his father, an Air Force that many adults were scared of snakes,” when he accepted a faculty position at the physician and epidemiologist. Hillis was he recalls. “A little kid with a snake feels University of Texas at Austin, where he born in Copenhagen, , but his powerful, I think, as many adults have now works. There, he met his colleague family later relocated to San Antonio, learned an unnatural fear of them.” As an Jim Bull, initially a skeptic of phyloge- TX. There, in the early 1960s, Hillis’ fa- undergraduate, Hillis realized that am- netic analysis. “He didn’t think there were ther treated a veterinarian who had con- phibians were also ideal organisms for any convincing studies of the accuracy of tracted hepatitis from one of the chim- studying how species diverge and evolve. phylogenetic methods,” Hillis says. Bull panzees used in the US space program. He graduated in 1980 with a degree in had reason to doubt. By that point in the That case and other ones like it over- biology from Baylor University in Waco, late 1980s, phylogenetic analysis was turned the belief that chimps were im- TX, and entered a graduate biology pro- growing in popularity, but its accuracy mune to the disease, suggesting instead gram at the in remained in question. Because much that chimps could be carriers. Un- Lawrence to study amphibian evolution. evolution occurs over lengthy time scales, derstanding hepatitis’ mode of trans- At that time, phylogenies were largely it usually cannot be observed directly. mission consumed the elder Hillis’ constructed based on the morphology of Morphological change can be examined subsequent work, and the family re- organisms, by using such characteristics as in the fossil record, but molecular located to the Congo so he could study shape and size. However, Hillis realized chimpanzees in the wild. En route to that much more information on evolu- Africa, though, the Hillis’ belongings tionary relationships was encoded in ge- This is a Profile of a recently elected member of the Na- were stolen, a strangely serendipitous nomes. Researchers were just beginning to tional Academy of Sciences to accompany the member’s experience. “We had no toys. There were analyze chloroplast and DNA, passed Inaugural Article on page 21242 in issue 50 of volume107.

www.pnas.org/cgi/doi/10.1073/pnas.1107823108 PNAS Early Edition | 1of3 Downloaded by guest on September 28, 2021 changes—increasingly the basis for phy- phylogenies as well as the bacteriophages tranceway of the biology building at logenetic studies—are not preserved they had studied in the laboratory (9, 10). University of Texas’ Austin campus. Next in fossils. In the mid-1990s, biologists began to the location of humans, the tree has Hillis was convinced he could get Bull tackling phylogenies with hundreds of a “you are here” sign. “At the beginning to come around. So they made a deal. species. Many people were skeptical that of the semester, there are always a lot of “The stakes were high,” Hillis jokes. “We such large phylogenies—which Hillis says mystified students looking at it saying bet a quarter.” For a convincing case, contain more potential solutions than ‘I don’t understand... is this a map of Hillis and Bull needed to find a species the number of fundamental atomic par- campus?’” Hillis says. that evolved fast enough to be observable ticles in the universe—could be recon- in real time—one that could grow, re- structed accurately. One of the larger Evolution Matters produce, and accumulate mutations in trees at the time was produced by Pam The theoretical groundwork laid, Hillis minutes rather than millennia. The two and Doug Soltis, evolutionary biologists became interested in applying phyloge- researchers settled on T7 bacteriophage, who now work at the University of Flor- netic methods to answer questions about a virus that doubles its population in less ida in Gainesville. The duo had recon- the molecular processes underlying evo- than 15 minutes. They started with a sin- structed the evolutionary relationships lution. Hillis first ventured into the study gle ancestral stock and let it reproduce among 228 species of flowering plants by of HIV transmission following a high- for hundreds of generations, separating comparing their ribosomal RNA genes profile case in the early 1990s in which an out colonies at predetermined intervals. (11). However, some researchers were HIV-positive dentist in Florida was ac- To encourage rapid evolution, the prog- unconvinced by the Soltises’ findings, ar- cused of transmitting the virus to several eny were exposed to a chemical that guing that efforts to recreate the evolu- patients. After evaluating blood samples promotes mutations during viral tionary histories of just a handful of from infected individuals, the Centers for replication (6). species required the analysis of many Disease Control determined that the HIV Hillis, who was blinded to the experi- more genes—and that the same principle strains in the doctor and his patients were mental setup to avoid biasing the results, should hold true for larger data sets, like related. Hillis was asked to review the mapped the genomes of the evolved ex- the flowering plants. results of this new methodology. The perimental viruses and used five phylo- To resolve the dispute, Hillis simulated methods the Centers for Disease Control genetic methods to reconstruct the the evolution of the ribosomal RNA genes used were sound, Hillis says, but the phage’s evolutionary history. When the on a computer. Expecting to find that case never went to trial because the dentist blinded labels were decoded, Bull agreed the Soltises needed more data, Hillis was died in the interim. that the estimated trees provided an ac- surprised to discover that denser sampling It took another high-profile case for the curate picture of the actual evolutionary of species generated more realistic phy- phylogenetic analysis of HIV to make history. Moreover, the ancestral genomes logenetic trees. “Analyzing more genes its way into US courtrooms. In the late at each branching point in the phylogeny was helpful, but analyzing more species 1990s, a physician stood accused of in- had been reconstructed with greater than was critical for phylogenetic accuracy,” tentionally injecting his ex-girlfriend with 98% accuracy. The pair soon devised Hillis says. “It was great news for the an HIV-infected blood sample from an ways to test the validity of the phyloge- Soltises and for the field as a whole” (12). unwitting patient. The prosecution thus netic methods under more difficult con- Densely sampled trees provided more needed to show that the HIV samples ditions, such as subjecting divergent accurate reconstructions of evolutionary between the patient and ex-girlfriend were lineages to vastly different rates of evo- history and allowed researchers to develop related (19). lution or similar selective conditions more detailed and accurate models of The science behind showing the re- (7, 8). Even then, the phylogenetic DNA evolution (13, 14). As a result, Hillis latedness of HIV strains is straight out of methods could account for the evolu- says, “many researchers are now tackling the phylogeny textbook, Hillis says. As tionary changes. problems with thousands of species.” noted, when HIV passes from source to That meant that phylogenetic methods Leading the charge is the National Sci- recipient, typically only one virion makes could help researchers piece together ence Foundation and its ambitious Tree the jump. That virion then diversifies evolutionary history, including the de- of Life program, which aims to generate rapidly inside its new host. To determine tailed reconstruction of ancient gene a phylogenetic tree connecting all life relatedness between samples, researchers sequences. “A lot of people have ex- forms on Earth (15–17). take many samples of the virus from the tended that work to look at the gene se- Estimates, however, suggest that the victim and defendant and reconstruct the quences of extinct organisms extending Earth contains approximately 9 million phylogeny of the virus as it mutates and back to the common ancestor of life,” species, making it difficult to view the evolves into different strains. The re- Hillis says. complete Tree of Life in 2D space, Hillis sultant trees either support or rule out Looking back to the dawn of life, al- says. So Hillis and his colleagues devel- hypotheses about the virus’s transmission though, presents other challenges. Unlike oped new techniques to visualize complex from person to person. the experimental viral trees, the evolu- phylogenetic information (18). Among In the case of the physician’s girlfriend, tionary relationships in most phylogenetic other solutions, they designed a circular her HIV sequences supported the hy- trees cannot be observed directly. So how tree with 3,000 clickable points, each pothesis that she contracted HIV from can biologists assess the accuracy of an- representing a different taxonomic group. the physician’s patient. The final step was cient phylogenies? In a series of pio- Clicking a point opens up another 3,000 for the courts to determine whether to neering papers, Hillis and his colleagues points, for a total of 9 million points—or permit these HIV phylogenies as evi- showed how statistical resampling ap- species. “That way, the whole tree of life dence in the courtroom. Hillis was called proaches and Monte Carlo simulations, can be represented in two layers,” in as an expert witness to explain phylo- which predict the probabilities of certain Hillis says. genetic analysis to the court. The judge outcomes based on prespecified models, An early version of that circular tree of agreed to admit the phylogenetic evi- can be used to assess confidence in a given life has now entered pop culture: some dence—together with all the other evi- phylogenetic tree. The researchers tested of Hillis’ graduate students have tattooed dence about means, motive, and the reliability of these statistical ap- the design on their backs and a giant Tree opportunity—and the jury found the proaches on experiments with simulated of Life mural currently graces the en- physician guilty of attempted murder.

2of3 | www.pnas.org/cgi/doi/10.1073/pnas.1107823108 Gupta Downloaded by guest on September 28, 2021 Hillis’ Inaugural Article (1) pushes fo- educator very seriously.” He penned his According to historic accounts, Christo- rensic applications of phylogeny a step first textbook, a how-to manual for re- pher Columbus brought cattle from further by showing how phylogenies can constructing phylogenies, in 1990 (20–23). Europe to the Caribbean in the late 1400s. also provide information on the direction More recently, Hillis has become an From there, the cattle were taken to of transmission. Because of the genetic outspoken critic of efforts to weaken the Mexico and the American Southwest, bottleneck that occurs at the point of teaching of evolution in schools, a partic- where they escaped and formed feral transmission, a recipient’s tree is expected ularly heated debate in Hillis’ home state herds. Over the centuries, the cattle to be nested within the source’s tree, of Texas. Part of informing students evolved longer horns, which served as Hillis says. In the case of Phillipe Padieu, about the importance of evolution, Hillis defense against predators. With the cattle and a very similar case from Washington says, is making biology more accessible genome now complete, Hillis and his state, information about the direction of and relevant to students. “The contents of students are comparing breeds of do- transmission was integral to the estab- college textbooks generally are accurate,” mestic cattle from region to region to lishment of the men’s guilt. he says, “but I find it depressing how reconstruct their population histories. However, if the science behind phylo- boring most of them are.” As with his other work, Hillis’ research genetic analysis of HIV is straightforward, In the past few years, Hillis has auth- into the cattle has shifted from mere sci- the ethics are not. Practiced incorrectly, ored two introductory biology textbooks, entific curiosity to a search for practical phylogenetic analysis could become a way Life: The Science of Biology, and Principles applications. Texas Longhorns have many of criminalizing those with HIV, Hillis of Life, to address that shortcoming (24– genes that confer disease resistance, fe- cautions. Fear of criminal liability could 26). Thanks to that work and his efforts to cundity, longevity, and ease of birthing, also prevent people from getting tested, advise the Texas State Board of Educa- all of which are important in creating which could be especially problematic in tion on the science curriculum, Hillis won hardy breeds of grass-fed, free-range AIDS-ridden countries. Rather, Hillis the Stand Up For Science award in 2009 cattle, he says. says, before applying phylogenetic analysis (from the Texas Freedom Network) and Evolution, says Hillis, helps answer both to transmission questions, it is funda- the Friend of Darwin award in 2010 sweeping questions (what is the origin of mental to first have evidence of criminal (from the National Center for Science life?) and ordinary ones (how does one intent, as well as a clear a priori hypothesis Education). create better cows?). Hillis’ motivation for to test. Hillis applies and enjoys evolution on studying evolution is simple: “I like a personal level as well. The proud owner thinking about the common ancestors Science Education of the aptly named Double Helix Ranch in that I share with the cotton fibers in my Hillis’ latest endeavor may turn out to be Texas, Hillis has been studying his pop- shirt,” he says. the most complicated. As with his re- ulation of Texas Longhorn cattle to un- search, Hillis says he takes his “role as an derstand their evolutionary roots. Sujata Gupta, Freelance Science Writer

1. Scaduto DI, et al. (2010) Source identification in two 11. Soltis DE, et al. (1997) Angiosperm phylogeny inferred 20. Hillis DM, Moritz C (1990) Molecular (Si- criminal cases using phylogenetic analysis of HIV-1 DNA from 18S ribosomal DNA sequences. Ann Mo Bot Gard nauer, Sunderland, MA). sequences. Proc Natl Acad Sci USA 107:21242–21247. 84:1–49. 21. Hillis DM, Mable BK, Larson A, Davis SK, Zimmer EA 2. Hillis DM, Frost JS, Wright DA (1983) Phylogeny and 12. Hillis DM (1996) Inferring complex phylogenies. Na- (1996) Hillis DM, Mable BK, Moritz CNucleic acids IV: biogeography of the Rana pipiens complex: A bio- ture 383:130–131. Sequencing and cloning. Molecular Systematics, eds. chemical evaluation. Syst Zool 32:132–143. 13. Zwickl DJ, Hillis DM (2002) Increased taxon sampling Hillis DM, Mable BK, Moritz C (Sinauer, Sunderland, 3. Hillis DM, Davis SK (1986) Evolution of ribosomal DNA: greatly reduces phylogenetic error. Syst Biol 51: MA), 2nd Ed, pp 321–381. Fifty million years of recorded history in the frog ge- 588–598. 22. Swofford DL, Olsen GJ, Waddell PJ, Hillis DM (1996) nus Rana. Evolution 40:1275–1288. 14. Heath TA, Zwickl DJ, Kim J, Hillis DM (2008) Taxon Phylogenetic inference. Molecular Systematics, eds. 4. Hillis DM (1987) Molecular versus morphological ap- sampling affects inferences of macroevolutionary Hillis DM, Mable BK, Moritz C (Sinauer, Sunderland, proaches to systematics. Annu Rev Ecol Syst 18:23–42. processes from phylogenetic trees. Syst Biol 57: Massachusetts), 2nd Ed, pp 407–514. 5. Bull JJ, Hillis DM, O’Steen S (1988) Mammalian ZFY 160–166. 23. Hillis DM, Mable BK, Moritz C (1996) Applications of sequences exist in reptiles regardless of sex-deter- 15. National Science Foundation (2011) Assembling the molecular systematics and the future of the field. mining mechanism. Science 242:567–569. Tree of Life (ATOL) ATOL update: 3/14/11. Available at Molecular Systematics, eds. Hillis DM, Mable BK, 6. Hillis DM, Bull JJ, White ME, Badgett MR, Molineux IJ http://www.nsf.gov/funding/pgm_summ.jsp?pims_id= Moritz C (Sinauer, Sunderland, MA), 2nd Ed, pp (1992) Experimental phylogenetics: generation of 5129&org=EF. Accessed April 27, 2011. 515–543. a known phylogeny. Science 255:589–592. 16. Halanych KM, et al. (1995) Evidence from 18S ribo- 24. Hillis DM, Sadava D, Heller HC, Price MV (2010) Prin- 7. Bull JJ, et al. (1997) Exceptional convergent evolution somal DNA that the lophophorates are protostome ciples of Life. Sinauer Associates and W. H (Sinauer, in a virus. Genetics 147:1497–1507. animals. Science 267:1641–1643. Sunderland, MA). 8. Cunningham CW, Zhu H, Hillis DM (1998) Best-fit 17. Hillis DM (2005) Health applications of the Tree of Life. 25. Sadava D, Heller HC, Orians GH, Purves WK, Hillis DM maximum likelihood models for phylogenetic in- Evolutionary Science and Society: Educating a New (2006) Life: The Science of Biology (Sinauer, Sunderland, ference: Empirical tests with known phylogenies. Generation, eds. Cracraft J, Bybee R (Biological Scien- MA), 8th Ed. Evolution 52:978–987. ces Curriculum Study, Colorado Springs, CO), pp 26. Sadava D, Hillis DM, Heller HC, Berenbaum M (2009) 9. Hillis DM, Bull JJ (1993) An empirical test of boot- 139–144. Life: The Science of Biology (Sinauer, Sunderland, MA), strapping as a method for assessing confidence in 18. Hillis DM, Heath TA, St John K (2005) Analysis and vi- 9th Ed. phylogenetic analysis. Syst Biol 42:182–192. sualization of tree space. Syst Biol 54:471–482. 10. Hillis DM, Huelsenbeck JP, Cunningham CW (1994) 19. Metzker ML, et al. (2002) Molecular evidence of HIV-1 Application and accuracy of molecular phylogenies. transmission in a criminal case. Proc Natl Acad Sci USA Science 264:671–677. 99:14292–14297.

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