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Finding Function in Dark Matter

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  • Title: Senior Staff Scientist, Lawrence Berkeley National Laboratory; Head, Genetic Analysis and Genomic Technologies Programs, Joint Genome Institute
  • Education: PhD, Stanford University, 1998
  • Recommended by: Eddy Rubin

Len Pennacchio takes genetic variation seriously. As head of the programs for genetic analysis and genomic technologies at the US Department of Energy's Joint Genome Institute and a senior staff scientist at Lawrence Berkeley National Laboratory, Pennacchio focuses on genetic variation, especially of the regulatory parts of the genome. Specifically, he looks at how noncoding regions called enhancers promote gene expression during development, and how this "dark matter" of the genome might play a role in disease risk.

He uses a combination of sequencing and comparative analysis to pinpoint possible enhancers, and then goes one step further into functional analysis. "We're very interested in testing sequences in animals," Pennacchio says, "so we make our predictions and then immediately go in and test the sequences to see if they can turn on gene expression in mice."

Using a beta-galactosidase reporter gene, he's determined the activity of nearly 1,000 potential enhancers in humans. While most of the elements were selected based on their conservation with other vertebrates, conservation alone doesn't say what the gene is doing. "You can look at that sequence and try and predict until you're blue in the face, but you'll never most likely have any real clue as to what it's doing" until functional analysis is performed. In the end, animal readout lets him see when and where a given gene is expressed. His lab primarily focuses on the developing brain and nervous system.

Linking genetic variation to disease is a looming goal, and he hopes to throw next-gen sequencing at the problem. Pennacchio, who got his PhD with Rick Myers and did a postdoc in Eddy Rubin's lab, still devotes most of his own research time to health-related issues. "We're very interested in sequencing individual genomes and trying to understand what are sequence variants and how do they contribute to human disease," he says. "We also set up a pipeline so that we can brute-force sequence genes in thousands of people [to] better understand the relationship of human variation to disease phenotypes."

Looking ahead

Pennacchio sees the biggest challenge for his field to be a technological one. While JGI has next-gen sequencers up and running — "and they're exponentially more powerful than the old capillary sequencers," he says — it's still too expensive and labor-intensive to get individual human genome sequences.

And even with all that sequencing data, the true power resides in functional testing. "I think now it's time to try and figure out, does noncoding DNA play a large role in disease and what makes each of us who we are, or is it involved in protein encoding parts of the genome?" he says. In the next five years, Pennacchio predicts that research will move toward functional analysis of noncoding DNA to better understand the role of regulatory elements in human disease.

Publications of note

In 2006 Pennacchio was first author on a Nature paper that characterized the in vivo enhancer activity of a large group of noncoding elements in the human genome that were conserved across humans and pufferfish or ultra-conserved across humans, mouse, and rat. Using his transgenic mouse assay, he found that 45 percent, or 75 of the 167 conserved segments, were enhancers of gene expression during embryonic development, and that the majority of the 75 enhancers directed expression to various regions of the developing nervous system.

And the Nobel goes to …

Pennacchio says he'd like to win the Nobel for "trying to drive functional insights into the noncoding portion of the genome."

The Scan

Unique Germline Variants Found Among Black Prostate Cancer Patients

Through an exome sequencing study appearing in JCO Precision Oncology, researchers have found unique pathogenic or likely pathogenic variants within a cohort of Black prostate cancer patients.

Analysis of Endogenous Parvoviral Elements Found Within Animal Genomes

Researchers at PLOS Biology have examined the coevolution of endogenous parvoviral elements and animal genomes to gain insight into using the viruses as gene therapy vectors.

Saliva Testing Can Reveal Mosaic CNVs Important in Intellectual Disability

An Australian team has compared the yield of chromosomal microarray testing of both blood and saliva samples for syndromic intellectual disability in the European Journal of Human Genetics.

Octopus Brain Complexity Linked to MicroRNA Expansions

Investigators saw microRNA gene expansions coinciding with complex brains when they analyzed certain cephalopod transcriptomes, as they report in Science Advances.