Founder story: Linda Goodman
Human genomics in the light of evolution
Theo Dobzhansky said it best: Nothing in Biology Makes Sense Except in the Light of Evolution. It has taken me a long time to fully appreciate this statement, but thinking about biology through the lens of evolution — and about the relatedness and fluidity of all of biology — has guided my research since its humble beginnings, and also guides Fauna Bio’s mission today.
When I first thought of seriously studying biology, at the end of high school in Orange County, CA in 2003, the first draft of the human genome sequence had just been announced. As if I was hearing about Sputnik or the moon landing, I was sure that this was the beginning of an exciting new Golden Age of biology. It seemed that once we had the code of life, all of human disease would soon be decoded and the cures would come fully formed out of As, Ts, Cs, and Gs.
But in college, a few hours south at UC San Diego, I soon realized just how far away the science was from this promise. For a while, my interest in biology faded and other subjects held my attention - physics, math, and chemistry - which seemed more concrete, quantitative, and substantial. But my interest in biology was rekindled when I joined the lab of Hopi Hoekstra, Ph.D., and discovered the beautiful and complex mathematics of Population Genetics, which models how all life is shaped over time by the currents of evolution. Population Genetics tries to explain why our genomes look as they do, and why, despite evolutionary selection, humans still fall prey to disease.
With my quantitative background and belief in the power of evolution to explain human disease, I travelled first to England to pursue a Master of Philosophy in Computational Biology, and then back to Boston to begin a Ph.D. in Genetics at Harvard Medical School. It was here that I joined the lab of Steven McCarroll, Ph.D., determined to use evolution as a tool to understand and tackle human disease.
Figure from Boettger (Goodman) et al. 2016, showing the relationship between cholesterol levels in humans and different forms of the haptoglobin gene.
While we normally think of evolution happening in terms of single mutations — an A turns into a T here, or a C gets deleted there — the genomic deck of cards can often get mixed up in much more complex ways. Large regions of DNA can be deleted, moved, copied, and inverted. Paradoxically, even the most state-of-the-art DNA sequencing technology cannot easily detect these large tectonic shifts in our genome, and so they go mostly unnoticed, even today. Through much painstaking work on the structural evolution of a gene called haptoglobin, I uncovered that a deletion in this gene contributes to lower cholesterol levels in people and could play a role in heart disease (Boettger (Goodman) et al. 2016).
While this was a fascinating find, and a great way to end my graduate studies, there was one small wrinkle. This deletion has only a small effect on cholesterol levels, and would make for a pretty measly drug target. This put a wrench in my goal of studying evolution to help cure disease, but it is a common tale in human genomics – the vast majority of mutations associated with a disease only have very small effects. There’s a solid evolutionary reason for this: any mutation that plays a large role in disease is weeded out by good ol’ natural selection.
Adapted from Finucane et al., 2015.
It was clear that we needed more than just differences among humans to map disease back to the genome. Toward the end of my Ph.D., a new paper (Finucane et al. 2015) offered an exciting clue. If you line up the genomes of different humans and identify the regions which are rarely mutated, you find that these regions are more likely to be important, and mutations in them that you do see are more likely to cause disease. This new paper showed that if you take the genomes of many different mammals, not just different human genomes, and do the same, this effect is much stronger. These regions are actually even more important than those that code for proteins, which was the previous gold standard. In other words, by comparing the human genome to that of other mammals, you can learn new information about human disease, and potentially how to treat it.
Phylogeny of 200 Mammals Project animals. Credit: Jeremy Johnson (The Broad Institute)
The idea of using all of evolution – not just human differences – to inform disease biology, led me to my postdoctoral work at the Broad Institute with Drs. Kerstin Lindblad-Toh and Elinor Karlsson, who had just started a massive endeavor to sequence the genomes of over 200 new mammal species – the 200 Mammals Project. This single project would quintuple the number of available mammal genomes. We showed mathematically that if you were to line up all of those new genomes against ours, you could identify important genomic regions in Homo Sapiens down to the resolution of individual DNA letters.
At the close of my postdoctoral studies, I moved to the Bay Area to work with Carlos Bustamante, Ph.D. at Stanford. There I became friends with my future co-founders, Drs. Ashley Zehnder and Katie Grabek. As I continued my academic work, the ideas that would become central to Fauna Bio began to fall into place. I began seeing connections between mammalian evolution and human disease throughout my genomic data, and was floored by Katie’s hibernation research and its obvious implications for protecting humans from heart attacks and many other diseases. It was Carlos’ enthusiasm for translational research and the infectious climate of scientific entrepreneurship at Stanford that caused us to finally pull the trigger, and soon after, Fauna Bio was a reality.
At the start of my journey into genetics, I could not have dreamed of a more perfect calling. Today, as the Chief Technology Officer at Fauna Bio, I work every day towards cures for human diseases by scouring the genetic code of lemurs, squirrels, and bears. It turns out Dobzhansky was right: truly, this only makes sense in light of evolution.