James and the Giant Corn Genetics: Studying the Source Code of Nature

While yesterday was draining, it had some really high points and I want to get these written down to remember on harder days.

On my way up the stairs to my office, one of my newest colleagues stopped me to ask a few questions and ended the conversation to tell me how much she likes the mentoring style she’s seen me exhibit with my students and we sympathized with each other on how hard it can be to thread the needle between leaving students without enough support, or just doing everything for them so they don’t have a chance to solve problems or figure out how to answer questions on their own.

Then an hour later I got an email from a former sandwich student (got his PhD at a chinese university, but got a fellowship to come do two years of his thesis research in my lab). He is just starting up his own lab in Sichuan.

Congratulation in advance for your promotion and I believe you will be an extraordinary scientist in the short future (such as the guy building the atom bomb, hahaha). … I finally realized the hardships of building a laboratory as you told us before. We are now training some undergraduate students in our lab but the process is very hard and I have to do every experiment in person to make these students do not “blow up” the lab.

Sent me a couple of photos of his students and lab and the fieldwork they’re doing that I was showing off to everyone I met with the rest of the day.

So yes. This is what a good day looks like as an assistant professor.

I’ve now been a part of the publication of three genomes, all grasses. One as a grad student (Brachypodium distachyon). One as a postdoc (Dichanthelium oligosanthes). And now one as a PI (Panicum miliaceum). Each species had different motivations: Brachypodium was intended to be a genetic model selected because it belonged to the same part of the grass family as wheat, barley, rye, and oats, but had a genome that was 1-2 orders of magnitude smaller. Dichanthelium was a comparative grade genome picked because stood between two groups of C4 grasses with sequenced genomes (maize and sorghum on one side, foxtail millet and pearl millet on the other) yet still used C3 photosynthesis, the ancestral state. Panicum miliaceum (proso millet or broomcorn millet) was sequenced because it’s an actual crop people grow in some of the driest cultivated land in the world (like inner Mongolia and western Nebraska), and having a reference genome sequence really does help with things like genomic selection, marker assisted selection, and QTL mapping. And each was sequenced using completely different technologies: Sanger sequencing (Brachypodium), Illumina short reads and mate pairs “next gen sequencing” (Dichanthelium), and PacBio long-reads combined with HiC “third gen sequencing” (proso millet). PacBio assemblies are SO MUCH BETTER than what we could manage with Illumina + mate pairs (I realize this is not news to most of you, but it’s one thing to hear it, it’s another to see it for yourself).

If I’ve learned one thing from these three experiences it is that it makes sense to work together with a whole team of people to put together a genome. The Dichanthelium genome project I was mostly working with a single other postdoc who also thought the potential for comparative genomics/biology of the species was cool, and in retrospect we bit off way more than we could chew, and were lucky to make it across the finish line to a paper. For both proso millet and brachypodium, I had the joy of working with big teams of people including folks whose whole job was genome assembly and annotation, and they were really REALLY good at it.

So what can I tell you about proso millet? It produces grain more efficiently per unit of water transpired than any other grain crop studied. It can produce grain in fewer days than any other crop I’ve worked with (some varieties are ready for harvest 50-60 days after planting!) It’s an allotetraploid, although so far we’ve only found a diploid lineage related to one of its subgenomes, not the other. One early approach we tried (see Ott et al below) was to use a technology designed to separate and phase the haplotypes of a diploid human to separate and phase the two subgenomes of an inbred tetraploid individual of proso millet. I’ve actually met farmers in both China and the USA who grow the crop, which is a really nice feeling. With one of my private sector hats on, I’ll get to use this genome to try to make higher yielding varieties of proso millet for those exact farmers. With my main public sector hat on, I’m excited to have a model for NAD-ME C4 photosynthesis that is easier to germinate, grow, and propagate than Panicum hallii or Panicum virgatum. There is nothing like working with wild grasses to make you appreciate the work all of our ancestors did to select against seed dormancy and photoperiod sensitivity while they were domesticating crops from wild species over dozens and hundreds of generations.

Zou C, Miki D, Li D, Tang Q, Xiao L, Rajput S, Deng P, Peng L, Huang R, Zhang M, Sun Y, Hu J, Fu X, Schnable PS, Li F, Zhang H, Feng B, Zhu X, Liu R, Schnable JC, Zhu JK, Zhang H. (2019) “The genome of broomcorn millet.” Nature Communications doi: 10.1038/s41467-019-08409-5

Ott A, Schnable JC, Yeh CT, Wu L, Liu C, Hu HC, Dolgard CL, Sarkar S, Schnable PS. (2018) “Linked read technology for assembling large complex and polyploid genomes.” BMC Genomics doi: 10.1186/s12864-018-5040-z

Editor’s note: this is a repost of an article which originally ran on James and the Giant Corn March 26th, 2017. I’m choosing to post this new, slightly amended version a little more than a year later to mark the publication of the paper describing Genotype Corrector. All told it took approximately 18 months from initial submission to final publication. However, to be fair a lot of that time was spent waiting for a single round of peer review at a different journal from the one in which the paper finally appeared.  

When doing anything even vaguely related to quantitative genetics I would chose more missing data over more genotyping errors any day of the week. There are lots of approaches to making missing data less of a pain. The most straightforward of these is called imputation. Imputation essentially means using the genetic markers where you do have information to guess what the most likely genotypes would be at the markers where you don’t have any direct information on what the genotype is. This is possible because of a phenomenon known as linkage disequilibrium or “LD.” Both imputation and LD deserve their own entire write ups and they are on the list of potential topics for when I have another slow Sunday afternoon. For now the  only thing you have to know about them is that, when information on a specific genetic marker is missing, it is often possible to guess with fairly high accuracy what that missing information SHOULD be. But when the information on a specific genetic marker is WRONG… well it’s usually a bit more of a mess (but I think the software solutions for this are getting better! Details at the end of the post.)

Figure 1: Genotype calls along chromosome 1 for six recombinant inbred lines (RILs).

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I’m now worked at four different scientific institutions in some capacity or another, and I’m always surprised how empty buildings are when I come in on Saturdays or Sundays. To be clear, I’m certainly not at work every weekend day myself, and I don’t expect the students or collaborators to work weekends.* I’m just realizing that, after 13 years of thinking “wow, people at University X really have a more relaxed approach to research than most places” maybe my idea of how many hours it is normal for a researcher to log in a week might be a tiny bit skewed.**

Although, to be fair, 9:15 AM on Easter Sunday might be the MOST representative time point. 😉

*I always say that my mentoring style is to focus on productivity, not hours worked in lab. I’m still working out what that means in practice. For an entertaining — as long as the person writing the e-mail isn’t your boss — glimpse of what the opposite sounds like, be sure to read this classical e-mail from 2002. 

**Growing up, I thought every family had dinner around 8 pm once everyone got home from the office, and that once you got a real job, “weekend” actually meant “sunday morning.”