Mendelspod Podcast

In recent months on Mendelspod, we’ve explored how new sequencing and proteomics technologies are revealing biology in regions of the genome (and proteome) that have long escaped our attention. From repeat expansion disorders to new approaches in cancer diagnostics, the dark genome is increasingly becoming clinically relevant.
Today we’re revisiting a conversation from earlier in the year that asks an even bigger question. What if much of this unexplored genomic territory is not simply functional, but a reservoir of evolutionary possibility?
Last March, we talked with Sudhakaran Prabakaran, computational biologist at Northeastern University, founder of NonExomics, and author of Eclipsed Horizons: Unveiling the Dark Genome.
Drawing on his lab’s work cataloging more than 250,000 non-canonical proteins, Prabakaran argued that regions outside traditional gene definitions may be continually generating new proteins with implications for adaptation, evolution, and disease.
From rapidly diversifying cichlid fishes to human accelerated regions (HARs) of the human genome linked to schizophrenia, Sudhakaran makes the case that protein birth and death is continuous, cheap, and exploratory. In his framing, the “dark genome” functions less like debris and more like a flexible evolutionary sandbox. His company, NonExomics, is also exploring how these previously overlooked proteins might become biomarkers for cancer and other diseases.
As our recent interviews have demonstrated, we’re entering a new era of genomic discovery. Prabakaran challenges us to think about just how much biology remains to be found.


This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit www.mendelspod.com/subscribe

Repeat expansions are places where the genome has remained stubbornly dark. Long-read sequencing is beginning to illuminate them, and now that new visibility is moving into clinical testing.
Today we’re joined by Simon Sadedin, Head of Clinical Bioinformatics at Victorian Clinical Genetics Services in Australia, and Alex Lindell, Senior Director of Product Marketing at Oxford Nanopore.
Until now, testing for repeat expansions has largely meant building a separate assay for each disorder. A patient might be tested for Fragile X, get a negative result, and then move on to another test, sometimes waiting months at each step. Some repeat expansions have been difficult to test for at all. Simon’s group is trying to replace that serial approach with a single assay covering roughly 60 repeat expansion loci, which is now being submitted for clinical accreditation.
The promise goes beyond simply finding an expansion. Long reads can reveal its length, sequence, methylation and mosaicism, while adaptive sampling makes it possible to target these difficult regions in software rather than building a new wet lab assay for each one.
Some say we are at a new threshold in genomics, where parts of the genome that have remained dark are finally becoming accessible to both discovery and clinical medicine.


This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit www.mendelspod.com/subscribe

Sometimes the best evidence that a new medical technology is working is simply that doctors start depending on it. For years, the promise of molecular medicine has been that better genomic information would lead to better patient care. At Roswell Park Comprehensive Cancer Center, Vice Chair of Molecular Pathology, Sean Glenn, offers a compelling example of that promise becoming routine clinical practice.
Hematologic cancers can require information from many different kinds of genomic alterations and traditionally from multiple tests and laboratories. Glenn and his team developed a comprehensive pan-hematological assay that brings much of that information together, using both DNA and RNA to detect alterations across myeloid and lymphoid cancers. The panel targets nearly 400 genes on the DNA side and about 125 on the RNA side, while automation has helped Roswell Park achieve an average turnaround time of roughly two and a half days for the 50 to 60 tests it runs each week.
And the oncologists are depending on it. Since introducing the panel, Glenn says Roswell Park has seen “a transformation and a resurgence of clinical care” in its leukemia and lymphoma clinics. His favorite measure of success is wonderfully practical. The oncologists are no longer calling the lab every few days asking where their results are. The information simply arrives in the patient’s record, in time to help make treatment decisions.


This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit www.mendelspod.com/subscribe

Plant biology too is benefiting from single cell resolution.
Unlike animals, plants cannot move away from environmental stress. They have evolved tremendous biological complexity to stay rooted in one place. Their genomes are complex too, with repeated genome duplications producing families of related genes that can take on different functions. And within a single leaf are many specialized cell types, from photosynthetic and epidermal cells to vasculature and rare trichomes, each with its own patterns of gene expression.
It’s early days for plant science. The field is only beginning to assemble the large, high quality single cell atlases needed to understand that complexity and eventually make better predictions and enable a new world of plant engineering.
Robin Buell and Anita Giabardo join us from the University of Georgia to discuss one of those new atlases. Their BioPoplar project aims to engineer fast growing poplar trees to produce new biomaterials, bioproducts and biofuels. Using Illumina’s PIPseq, Anita and colleagues created an atlas of more than 159,000 cells across the developing poplar shoot.
That resolution matters. The researchers were able to find rare trichome cells, the tiny hairs on leaves whose specialized metabolism makes them attractive little factories for engineered products. They then identified a promoter that can specifically direct gene expression to those cells.
Robin has watched plant genomics progress from Northern blots to bulk RNA sequencing and now to single cell. She predicts that within ten years single cell could become the standard. The ability to see biology cell by cell is not only changing what scientists can discover about plants. It will mostly likely change what they can build.


This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit www.mendelspod.com/subscribe

What new insights can we learn about cancer when researchers are able to look at the genome and the methylome together?
Recently, Illumina launched its 5-base for Cancer Research Grant Contest to explore that question. Today, the three winners join us on Mendelspod with three very different problems in cancer research.
Richard Tothill of the University of Melbourne is studying cancers of unknown primary and in collaboration with Hartwig Medical Foundation is combining DNA methylation and mutation profiling to reveal the primary origins of these aggressive cancers. Jacob Blum of Johns Hopkins is working with tiny amounts of circulating tumor DNA, combining genetic variants with methylation signals in hopes of improving detection of minimal residual disease and developing a model that other researchers could use. And Alfonso Bellacosa of Fox Chase Cancer Center is investigating what methylation can reveal about the mechanisms behind response and resistance to cancer immunotherapy.
The projects are early stage, but together they give us a snapshot of how cancer researchers are using a new tool that brings epigenetics and genetics into the same experiment and analysis. Joining the discussion is Danielle Goldberg from Illumina, who talks about what the company saw across nearly 200 grant applications and the growing interest in combining genomic and methylation data in cancer research.


This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit www.mendelspod.com/subscribe