Larry Moran: What’s in your genome?

Courtesy of Prof. Laurence Moran

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Kat: Danuta and her team at Nucleome certainly have their work cut out trying to pinpoint the important genetic variations in the dark genome that affect gene activity and are linked to disease. That’s because an awful lot of DNA in the human genome really doesn’t seem to do anything much at all.

As we’ve mentioned several times already in this episode, less than 2% of the human genome is actually made of protein-coding sequences - what we would call genes. And while there are undoubtedly important control switches and structural elements in the other 98% of the ‘dark genome’, that still leaves a lot of non-coding DNA unaccounted for. So - is it just junk? And if not, then what is it doing? And how much is actually doing anything?

This question came to a head in 2012 with the publication of data from ENCODE - a massive research project studying many characteristics of the human genome at a molecular level. The team concluded that 80% of the human genome was functional in some way, based on the detection of transcription - the copying of DNA into a molecular messenger called RNA - and particular proteins. The study made headlines around the world, but not everyone was convinced. One of them is Larry Moran, professor emeritus in the Department of Biochemistry at the University of Toronto, who for many years has argued that the vast majority of the human genome really is just junk after all.. 

He’s now laid out his thinking and the evidence supporting it in a book entitled What’s in Your Genome? Why 90% of your genome is junk - described by a certain science writer and genetics podcaster as a “thought-provoking and pugnacious book that will make you wonder afresh at the molecular intricacies of life.” 

So, when I got the chance to sit down for a chat with him, I had to start by asking him the obvious question: what is in our genome?

Larry: We've pretty much nailed down the amount of coding regions. It's about 1%. So about 1% of the human genome codes for proteins. Then everyone makes the mistake of assuming, "Oh, only 1% is genes!" Well, that's just not true. The average protein coding gene consists mostly of introns. The average protein coding gene is 40 kb long.

Larry: 38 to 40% of the genome is made up of protein-coding genes, okay, which consists of a small amount of coding region and a large amount of introns. 

Larry: So right away, people don't even ask themselves, what is a gene? You know, a gene is not just the little bits of coding region in this great big long stretch that's transcribed. The only reasonable definition of a gene is a DNA sequence that's transcribed to produce some kind of functional RNA and then may be processed, right? 

Larry: So first of all, 40% of our genome is protein-coding genes. How many people know that? Very few, right? 

Larry: Now, most of it is introns. So, what are the introns? What are they doing? Are they real? Are they junk? Well, you can make a darn good case that it's mostly junk. It's full of little bits and hunks of transposons and even a few pseudogenes. The sequences aren't conserved. The lengths aren't conserved. I mean, it looks like junk by all reasonable criteria, right?

Larry: So right away, we've established that 40% of the genome is protein-coding genes, it's mostly introns, and the introns are junk. Then you've got all the intragenic stuff, which is transposons and bits of repetitive DNA. You know, we knew back in the late 1960s that half the human genome was repetitive DNA. And so, where did this myth arise that those scientists were incredibly stupid? They thought, "Oh my god, there's only 2% protein-coding regions in the genome, all the rest must be junk!" 

Larry: We knew about regulatory sequences, I mean, you know, there's these guys, Jacob and Monod got a Nobel Prize, you know... And that's so annoying!

Kat: How would you actually then define junk DNA? Is it just purely stuff that we can't ascribe a function to, or stuff that could be gotten rid of and wouldn't make a difference? 

Larry: Yeah, so it's difficult to come up with a precise definition of anything in biology, right? 

Kat: There's always exceptions, always.

Larry: There's always exceptions! Okay, but by and large junk DNA is DNA that can be deleted from the sequence without having any effect on the survivability of the species or the individual. So it's totally dispensable DNA. You could get rid of it and there's no effect.

Kat: I think we get into an interesting argument when we move from, OK, well we can define junk in some ways.

Kat: I think the more interesting thing to do is to try and define what "functional" means. I think that really is the nub of it because there are definitely some people who go, "Well, just because something isn't conserved, it might have the same function." And, you know, we see that across evolution, that things can have different evolutionary origins but they're serving the same function.

Kat: So how do we, when it comes to DNA, actually define a function? 

Larry: So if you've identified a DNA sequence that, say, encodes one of the enzymes of the glycolytic pathway. It's been well characterised, you mutagenise it, it doesn't work anymore, I mean, there are clear cases where we know a heck of a lot about whether something is functional or not.

Larry: So the ambiguous cases are where we don't know what the product is or exactly what it does. So then you have to ask, do we have any good reason to believe that this stretch of DNA actually serves a function? Well, you can mutate it or delete it, and see whether it has any effect or not. But you know, you can't do those experiments with 90% of the genome, so the quick criteria is: is it conserved?

Larry: And there are very few examples of sequences with well defined, well understood functions that aren't conserved. So until someone comes up with multiple examples of that, let's just go with that criterion. 

Kat: So if I was to actually pin you down on it and say, okay, you know, in your opinion, what proportion of the human genome do you think really is junk?

Kat: If we were designing a minimum viable genome for a human, you're like, "Right, we can strike out this much." How much do you think that would be? 

Larry: The subtitle of my book is "90% of your genome is junk." 

Larry: You know, you have to step back and look at the big picture. Is there any logical reason why we should assume that 90% of the non-conserved human genome actually has some mysterious function that we don't know about?

Larry: No, there isn't. In fact, we have lots and lots of evidence, and circumstantial evidence, and direct evidence, that it just doesn't have a function. So it doesn't. And that's perfectly consistent with my worldview. of what biochemistry and genomes and molecular biology looks like. But if it conflicts with your worldview, you know, if you've been raised by Richard Dawkins to think that everything that’s there, everything that's present there is to drive an organism to the top of some adaptive peak, then all the data that's coming in conflicts with that worldview.

Larry: And so then you develop really bizarre rationalisations to try and make them consistent rather than just say, "Oh, maybe my view is wrong!" 

Kat: It's curious that, Dawkins obviously being very famously an atheist, it's almost a quasi-religious viewpoint. It's like, "Well, it must be in there for a reason. Everything happens for a reason..." Which is sort of, you know, "God wills it." 

Larry: Yeah. So at one point I was working on another book, the working title was "Evolution by Accident '' - in which I kind of lumped adaptationists like the Dawkins view in with intelligent design. They're both advocating design for the wrong reasons as far as I'm concerned.

Larry: Yes, it's true that, you know, wings are for flying and stomachs are for digesting. Of course there are adaptations. But not everything is an adaptation. There are just random changes that happen in your genome and a larger genome could be simply junk. Again, my bugaboo is not so much that I think I'm right and everybody else is wrong - although I do - but that the alternative point of view, the one I'm expressing, doesn't even make it into the literature.

Larry: Everyone just assumes that - oh my god, we haven't found a function for this, but there must be one somewhere! 

Kat: But actually, all the function we need is probably in that 10%. 

Larry: That's what the evidence shows as far as I'm concerned. So I think 10% is functional, but we only know the function of half of that.

Larry: So 10% is conserved, we can identify functions for about 4% of the genome. So that leaves still a lot of new things to be discovered, right? 

Kat: Is there like one thing you would really want a student or researcher in, working in genetics today to really understand about the human genome? 

Larry: One thing, wow.

Larry: I would like all students working in this field - so, molecular biology in general - to understand more about evolution, to understand that not everything is an adaptation. Natural selection isn't anywhere near as powerful as they think it is, and some things just don't work perfectly. And so, there's no reason to develop adaptationist thinking about everything.

Larry: Have an open mind! Recognise that, you know, maybe this little tiny effect you see on some signal transduction pathway may be irrelevant. At least consider that possibility, okay? This little transcript may not be important, it may not do anything. Don't just assume that because it's there it does something. Understand that there's another possibility.

Thanks to Prof. Larry Moran