The Science editors have issued their verdict: Of all scientific fields, the study of human genetic variation saw the most exciting developments in 2007. In this week's Breakthrough of the Year special issue (registration required), the staff of Science reviews how cheaper and faster sequencing and analysis techniques--and the avalanche of data those techniques generate--have shifted the emphasis from studying what makes us human to pinning down what makes each of us unique.

The opportunities and challenges the field brings seem as unlimited as human diversity itself. But how does one get to work on one of the hottest topics of the decade, and is it a blessing, or an additional pressure, for young scientists? Science Careers talked to three young scientists about their paths into this breakthrough field.

Crunching numbers to find genetic letters

Jonathan Marchini took a circuitous route to statistical genomics--a path that took him through both new continents and scientific fields. Marchini earned a degree in mathematics and statistics from Exeter University in England in 1994 with a career in academia in mind. But after graduation, he trained as a secondary school mathematics teacher and then went off to Tanzania for 3 years as a volunteer with the international development charity VSO. "Some people said that I would find it difficult" to pursue a career in academia after this, he says. But "I don't think it held me back at all."


Jonathan Marchini, age 34, lecturer in statistical genomics in the Department of Statistics at Oxford University.

Marchini went on to do a Ph.D. in the Department of Statistics at Oxford University, developing new statistical theories and computational methods for analysing brain imaging experiments. However, he found that challenging problems were drying up fast in the area. He decided to stay in the same department for a postdoc in genetics--a field in which the ongoing development of new sequencing and analysis techniques also meant there was a constant need for new statistical methods to handle the data. "It was a fast-moving field in 2002," Marchini says. "It is even faster-moving now."

Marchini initially worked on the International HapMap Project, which aims to map common one-letter variations between individuals to identify genes that, among other things, contribute to complex diseases. But while he was finding his way around his new field, Marchini was already working on designing new statistical tools that could be used in genome-wide association studies.

When the first data from the genome-wide association studies carried out by the nationwide Welcome Trust Case Control Consortium (WTCCC) started trickling in near the end of 2006, Marchini was ready to jump in. "Jonathan developed methods … that proved to be very important as a tool for some of the genetics that's under way at the moment," and made him a leader in the field, says Peter Donnelly, Marchini's former postdoc supervisor and one of the scientists behind the WTCCC project.

This was no mean feat. To work in genomics statistics, "You have to understand both the statistical methods and how to use them … and to understand the underlying genetics and the biology of DNA and the technique that is used to measure" the data, says Marchini. "The general challenge for people on the statistical development side is to stay close to the science," Donnelly says.

Deciphering the meaning of repeating


Heather Mefford, 36, research fellow in the Department of Genome Sciences at the University of Washington, Seattle.

Heather Mefford's route into medical genetics was far from straight either. Mefford initially earned a B.Sc. degree in chemical engineering from Washington University in St Louis, Missouri, in 1994. "But during my engineering studies, I realised I was more interested in … human biology and medicine," Mefford says. After spending a year in a research lab working at the crossroads of engineering, medicine, and genetics, she decided to do an M.D.-Ph.D. at the University of Washington, Seattle.

She studied human subtelomeres, genetic regions toward the ends of chromosomes that contain DNA blocks that vary in their copy number, location in the genome, and sequence among individuals. Based at the Division of Human Biology in the Fred Hutchinson Cancer Research Center, Mefford focused on a block containing olfactory receptor genes, studying the region's biological relevance and how it is passed on between different chromosomes during evolution. This research is "important because there are a lot of large duplicated sequences in the human genome … and for a long time these … have been thought to be junk DNA." But it now appears that differences in copy numbers may be a source of individuality--and diseases.

After graduating with a specialisation in clinical paediatrics in 2003, Mefford started a 3-year medical genetics fellowship in the university's Department of Genome Sciences. She's been working on identifying deleted and duplicated regions that lead to paediatric diseases and birth defects. "We are trying to define new syndromes and new diseases in human genetics," Mefford says. It's a unique approach because most geneticists still think about inherited traits that are transmitted vertically through pedigrees, Evan Eichler, Mefford's PI, writes in an e-mail to Science Careers. "What is novel here is we start with the genome and try to link human phenotypes to recurrent, de novo mutation event[s]," he writes.

Young scientists interested in the field should have some "creativity in terms of thinking outside of the box and the ability to hybridize computational and wet-bench approaches to solve biological problems," Eichler says. "That is a competitive field … but that can be exciting and it moves the field forward," Mefford says.

To add to the challenge, Mefford is juggling a dual career with a family of two young children. But she found that "it made me a much better paediatrician and makes you focus on what's really important … in life."

Bringing Neandertal DNA back to life


Johannes Krause, 27, Ph.D. student at the Department of Evolutionary Genetics in the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany.

After an early phase of discouragement, Johannes Krause was able to follow his long interest in genetics and even link it to another passion of his, paleoanthropology. Krause initially chose to study biochemistry at the University of Leipzig. But "I was almost about to quit" at the frustration of learning much more about basic chemistry than biology, he says. However, in the third year of his bachelor's degree, he took some specialised courses in genetics as an Erasmus student at the University College Cork in Ireland that revived his interest for the field.

Back in Leipzig, a summer internship on comparing gene expression between humans and chimpanzees at the Max Planck Institute for Evolutionary Anthropology sparked Krause's enthusiasm for good. He stayed on in the lab as a research assistant for 2 years before graduating in 2005. While there, Krause helped develop a biological method to read large pieces of ancient DNA, sequence the complete mitochondrial genome of the mammoth from fossil samples, and place it in the context of evolution. "Johannes has great technical skill and the judgment to distinguish a good project from a blind alley. Like few others he can see the interesting pattern that can hide in sometimes confusing data," Svante Pääbo, his principal investigator, writes in an e-mail to Science Careers.

Krause started a Ph.D. with Pääbo in 2005 on reconstructing the Neandertal genome--a challenging enterprise. First, samples are scarce, and "it's not always easy … to convince [paleoanthropologists and curators] to cut their bones to grind them to pieces," Krause says. He has to work with small, damaged bits of DNA, and be sure to avoid contamination with non-Neandertal DNA. A positive side to these practical difficulties is that few people do this kind of work, and results are more easily publishable, says Krause, whose CV already counts 11 papers in high-ranking journals.

With help from high-throughput sequencing company 454 Life Sciences, the team hopes to have the complete Neandertal sequence within a year. Besides learning a great deal more about our ancestors, the work should help pin down what's special about the human lineage by comparing the Neandertal genome to the human and chimpanzee sequences, both already available. It could also shed light on how our own species evolved, telling us "what genetic changes happened in the last 500,000 years," Krause says.

The field has challenges, however. "It's not so easy to stay in the field because there are a limited number of positions," Krause says. Once the Neandertal sequence is complete, he's contemplating choosing a postdoc that allows him to gain a broader view of genetics or some bioinformatics skills.

Myriad career options

Almost every corner of the field of human genetics seems full of excitement and opportunities. "The field of genetics will continue to grow for a long time because many techniques are being developed to sequence the genome in a fast way and [to] understand genes and pathways," Mefford says.

But the greatest shortage is in people who can work at the interface of genetics and applied mathematics. "I get many e-mails every week from academics and private … groups around the world [saying] 'we are looking for statisticians,'" Donnelly says.

"It's a fascinating field. It allows you to ask questions about human development, human evolution, about human diseases. … The opportunities really are endless in the type of questions you can ask," Mefford says.

Elisabeth Pain is contributing editor for South and West Europe.

Comments, suggestions? Please send your feedback to our editor.

Images. Top, Credit: Gerald Baber, Virginia Tech. Courtesy, National Science Foundation. Others: courtesy of the subjects.

DOI: 10.1126/science.caredit.a0700182

Elisabeth Pain is contributing editor for Europe.

10.1126/science.caredit.a0700182