This Week's Finds In Genomics
Quick hits to start your week: Designing regulatory DNA, battle of the sexes, neuronal resiliency, and the conclusion to a philosophy of biology trilogy.
The newest book on my nightstand.
1. Designing realistic regulatory DNA
This spring at the Cold Spring Harbor Systems Biology meeting, I had the opportunity to chat with a team from Genentech about their work using language models to design regulatory DNA. I’m glad to see that their work is now out in Genome Research. One of the ongoing challenges in this field is to adapt language model architectures and training method to generate realistic DNA sequence. In this paper, the Genentech group introduced regLM to design synthetic regulatory DNA elements with custom cell type-specific activities.
2. Battle of the Sexes
Genetic variation is responsible for anywhere from 10%-40% of the variation in human height. However, this same genetic variation is not why human males are, on average, taller than females. The vast majority of genetic variants — all of the variants that are not on the Y chromosome — are present in both males and females. Despite being shared by both sexes, individual variants can have very different effects in males and females, leading to what is called sex-differential selection (SDS). This occurs when the fitness effect of a variant differs depending on whether it present in a male or a female. The phenomenon is well known, but its magnitude has been difficult to estimate in humans. A group out of the University of Texas at Austin has presented a new way to estimate SDS in humans. Their main punchline is that
An interesting life-history tradeoff emerges: Alleles that increase viability more strongly in females than males tend to increase fecundity more strongly in males than in females.
3. The Resiliency Project
The biggest risk factor for neurodegenerative disease isn’t genetics, but age. Up to half of those who live past 85 will develop some form of dementia. As Jeff Milbrandt, Director of Washington University’s McDonnell Genome Institute puts it, “Many of us aspire to live that long, but I don’t think we aspire to live that long with dementia.” Milbrandt recently discussed a major new project at the Genome Institute, called the Resiliency project. The hypothesis of the Resiliency project is that neurodegenerative disease is most often the cumulative consequence of damage caused by cellular stressors, from diet, toxins, mental stress, etc., which eventually results in the failure of neurons to maintain homeostasis. However, a remarkable feature of neuronal failure is its selectivity: some neuronal types are resistant to the same cellular stressors that cause other neuronal types in the same brain to fail.
In a recent talk, Milbrandt discusses his team’s efforts to understand this selective resistance using a massive ‘omics screen that tests combinations of stressors, genetic variants, and neuronal cell types.
4. Living on Earth
I recently picked up the latest book by the Australian philosopher of science Peter Godfrey-Smith, Living on Earth. It’s the concluding book in a trilogy that reflects deeply on the evolution of minds, metazoa, and, ultimately, all life on earth. I’ve long appreciated Godfrey-Smith’s clear writing and how he is able to straightforwardly pose complicated philosophical questions. (His introduction to Philosophy of Science, Theory and Reality, is IMHO the best book in the genre.)
I haven’t read the book yet, but there is a great review up at Undark, which calls it a “difficult but rewarding book”, which is exactly my kind of book.