Fellows Feature: Yang Li

yangYang was born in Xian and grew up in Brussels and Montreal. He studied mathematics and computer science at McGill University. Motivated by a strong desire to work on social issues of great importance, Yang started to learn biology and, after a summer internship in George Church’s lab, moved to Liverpool to pursue his newly developed interest in the genetics of aging. Before joining Jonathan Pritchard’s lab at Stanford, he earned a DPhil in evolutionary genomics at the University of Oxford, where he worked with Chris Ponting and Richard Copley. In his free time, Yang climbs, cooks, and travels. 

This content has been transcribed from an interview that took place on Stanford campus Tuesday, October 20, 2015 with CEHG’s Director of Programs, Cody Montana Sam and Communications Manager, Katie M. Kanagawa.

Can you tell us about your research and how it is going?

The major question I’d like to answer is how does genetic variation affect complex traits. This is the question that essentially all human geneticists are asking. Presumably, there are many ways genetic variation can affect complex traits: one is by directly changing the sequence of a protein, so you can have one amino acid that’s changed because you have a mutation in your genome. This mutation may affect protein structure and can lead to differences in phenotypes and diseases. But, from recent GWAS (genome-wide association studies) on complex traits, it has been found that the vast majority of the genetic variants that are associated with diseases are non-coding, that is to say they do not appear to affect coding sequence. Instead, many believe that these non-coding variants affect gene expression levels, perhaps in a specific cell type or in a particular developmental stage.

I’ve been interested in this and the work of Jonathan [Pritchard] and Yoav [Gilad] that explores how genetic variation affects gene expression levels as well as other cellular phenotypes. Jonathan’s, Yoav’s and others’ ten years of work in this area has mostly focused on one cell line, the lymphoblastoid cell lines (LCLs), but now people are trying to do this in multiple different tissues and cell lines. We’re still working on LCLs because we have this wealth of data measuring every stage of gene regulation: DNA, RNA, and protein. We are trying to understand how genetic variation affects the entire gene regulatory cascade and, ultimately, disease.

Genetic variation can affect gene expression, but it can also affect alternative splicing and contribute to complex traits by affecting both protein sequence and expression level. I became interested in alternative splicing a few years ago and so I joined Jonathan’s lab last year to work on this. I’m happy to say that I am now writing up a story on genetic variation, gene regulation – including splicing – and complex traits that will be submitted soon.

How did you become interested in splicing?

I moved to Oxford in order to get a better training in comparative genomics. While there, I worked on several genome sequencing projects. I compared the genomes of different species, and the thing that really struck me was how hard it is to predict genes and their alternative spliced isoforms. I started to become interested in splicing and its implications when I realized that it’s not just the genes that matter, it’s the isoforms (i.e. the transcript the gene produces). When I was studying alternative splicing in the brains of many species I looked at, there was a higher complexity (there were more splicing events and it looked more conserved and regulated across different species). Because the brain is very complex and has many different cell types, it’s quite possible that, to function, it requires a splicing network that is tightly regulated and additional protein isoforms.

To me, it was not just regulation of total gene expression that mattered, but also accurate regulation of splicing.

What initially brought you to this line of inquiry? What was your background and how did you find your way to this research?

At McGill, I did my major in pure math and computer science. It was very theoretical and it was clear to me that I wanted something more concrete with application to the real world. So I started to learn more about biology in general and popular science. I was also interested in philosophy and I started to think about aging because I saw an article by Aubrey de Grey. I don’t particularly like his science, but he’s one person who promotes solving or curing aging, looking at aging as a disease that needs to be cured. That got me really interested because I didn’t think of aging as something malleable.

I started to think about different species and their differences in longevity. So why do mice live, for instance, 2-4 years, rats can live 4 years, dogs can live over 20 years, cats 30 years, and humans can live to over a hundred now?

When you think about it, there is no real reason why we have to age.

To explore this topic, I did a Summer internship at Harvard, in George Church’s lab, and worked on comparing the transcriptomes of the mouse and the naked mole-rat, which is a rodent that can live over 30 years and that doesn’t get cancer. We could have discovered something great about cancer and longevity. We didn’t in the end, but that really is the point when I started to think about a career in biology.

Do you have service interests you would like to pursue, outside of research?

There are these problems that are perhaps less interesting in terms of basic research or academia but that are useful in terms of clinical medicine: for instance, you can try to identify the cause for some rare diseases. You can do something very simple: sequence the patient’s DNA and RNA and try to find out what’s going wrong. Sometimes there is something obvious going wrong, because the phenotype’s very severe. If I had time outside of research, I would try to do these kinds of things. I think that has a very big impact, at least on the families of the affected patients. Maybe in the future, it will be more common to spend 10% of your time on these problems, as a service.

Who do you look to for support?

My parents were always really supportive about whatever I wanted to do. Their main advice was to focus and to not give up. What really pushed me, however, was my close-knit group of friends in college. I still keep in touch with them and they are already very successful. Most of them stayed in math. I think it’s meeting these people who are extremely motivated and interested in their work that carved my scientific path. That’s one reason I moved out of math, because they had this passion for what they did and that was not an interest that I shared. But I found this strong interest in biology and genomics, so that is what kept me going. I always think if I don’t like something, I should really find something I like.




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