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Adam Siepel: Conquering Comparative Genomics

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Title: Professor, Biological Statistics & Computational Biology, Cornell University

Education: PhD, University of California, Santa Cruz, 2005

Recommended by: Eric Green, David Haussler

Adam Siepel is developing algorithms to identify novel functional elements in mammalian genomes, with a focus on the human genome. He is zeroing in on new protein-coding genes, RNA genes, and regulatory elements. Through simul-taneous modeling and analysis, he aims to reveal how evolution and function interact to affect genomic sequences.

Siepel has always been fascinated by the intersection of mathematical methods and models of living systems, but says he's had a rather circuitous route to his present position. 

Upon graduating from Cornell with a dual major in agriculture and bioengineering, Siepel began work in the Los Alamos National Laboratory doing HIV sequence analysis. After working as a software engineer in the late '90s, he decided to get back to science and pursue his PhD with David Haussler at Santa Cruz. His timing couldn't have been more perfect.

“The comparative analysis of the human and mouse genome was going on and Santa Cruz was heavily involved in that. … It really was a great area for me because it involved a lot of creative algorithms work and it also involved a lot of evolutionary analysis,” says Siepel. “It was an area that's time had come.”

While working in Haussler's lab, Siepel designed a program called Exoniphy, which predicts evolutionarily conserved protein-coding exons from multiple aligned genomics sequences. The program discerns between coding and noncoding sequences using the phylogenetic hidden Markov model and other techniques. Siepel and his collaborators identified thousands of potentially novel human exons after running the program on alignments of the human, mouse, and rat genomes.

Siepel is also known for leading development of PhastCons, another hidden Markov model-based program. Using PhastCons, Siepel and his team have conducted one of the most extensive studies to date of conserved elements in vertebrate, insect, nematode, and yeast genomes. They found that as organism complexity increases, larger fractions of conserved bases fall outside of coding regions, potentially reflecting the increasing importance of regulatory functions.

“We're working on really basic scientific questions which I think ultimately affect all of biology, although the impact is not always immediate,” he says. “So one of the things I'm working on is filling out the catalogue of human genes. There's still a lot of human genes that aren't yet known, and that just has a lot of obvious consequences for biology and medicine.”

Looking ahead

Siepel would like to see evolutionary biology, comparative genomics, and population genetics join forces in the near future. Population genetics has a lot of potential for detecting selection and understanding changes that take place over shorter time scales within populations, says Siepel. “I think there's a general feeling that those two areas need to come together,” he says. He would also like to see more of a systems biology approach take hold in his field. “We're still just trying to identify the sequences in the genome that are important for one reason or another and trying to annotate them,” he says. “But it's clear that we need to move a lot farther in terms of understanding how they interact and actually result in living organisms.”

Publications of note

In 2005, Siepel and his colleagues published a paper entitled “Evolutionary conserved elements in vertebrate, insect, worm, and yeast genomes.” This Genome Research paper introduced PhastCons as a method for identifying evolutionarily conserved sequences, now widely used in the comparative genomics community.

And the Nobel goes to…

Siepel says if he were to win the Nobel Prize, he hopes it would be for “fundamental contributions to the functional annotation of the human genome.”

— MD

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