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Monday, September 22, 2014

Are lncRNAs really mRNAs in waiting?

Biology News Net has become a joke. It's rare to see a paper that it hasn't mangled or a press release that it hasn't fallen for, hook line and sinker. I read it for amusement.

A recent report began with ... [Parts of genome without a known function may play a key role in the birth of new proteins]
Researchers in Biomedical Informatics at IMIM (Hospital del Mar Medical Research Institute) and at the Universitat Politècnica de Catalunya (UPC) have recently published a study in eLife showing that RNA called non-coding (lncRNA) plays an important role in the evolution of new proteins, some of which could have important cell functions yet to be discovered.
That sounds intriguing. Maybe I should read the paper even though it's in eLife.

It took a little more work than I expected, but eventually I found the paper (Ruiz-Orera et al., 2014). Here's the abstract.
Deep transcriptome sequencing has revealed the existence of many transcripts that lack long or conserved open reading frames (ORFs) and which have been termed long non-coding RNAs (lncRNAs). The vast majority of lncRNAs are lineage-specific and do not yet have a known function. In this study, we test the hypothesis that they may act as a repository for the synthesis of new peptides. We find that a large fraction of the lncRNAs expressed in cells from six different species is associated with ribosomes. The patterns of ribosome protection are consistent with the translation of short peptides. lncRNAs show similar coding potential and sequence constraints than evolutionary young protein coding sequences, indicating that they play an important role in de novo protein evolution.
The study suggests that a lot of "noncoding" RNAs are being translated. The products appear to be short polypeptides of less than 100 residues.

New protein encoding genes do arise from time to time although the number of proven examples is very small. Let's assume, for the sake of argument, that a new gene arises about once every million years in a given lineage. That would mean about five new genes in humans since they split from chimpanzees and that seems about right for an upper limit.

Now, if you make a lot of junk RNAs by randomly transcribing junk DNA, then some of them will undoubtedly make short polypeptides. There's a chance that random mutations will create a peptide that takes on a functional role of some kind. There's an even smaller chance that this function will confer a selective advantage on the individual carrying the mutation. That's one way new genes are born.

Is this a reason for carrying a huge amount of junk DNA in your genome and making thousands of lncRNAs? Is the potential to make a new gene one million years in the future sufficient explanation for the preservation of junk DNA? The answer is "no."

You don't have junk DNA because it might proven useful in the future. You have it because you can't get rid of it. You don't transcribe your junk DNA because it might be useful, you transcribe it because the general properties of RNA polymerase and transcription factors don't allow for perfect discrimination between real genes and junk DNA. Junk transcripts aren't translated because they contain potential coding regions, they are sometimes translated because they must, by chance, contain some open reading frames.

Sloppiness might, by accident, lead to new genes but that's not why things are sloppy. If having junk DNA were a clear advantage for future evolution then the genomes of all extant lineages should have lots of junk DNA and should make lots of lncRNAs.

Ruiz-Orera, J., Messeguer, X., Subirana, J.A., and Alba, M.M. (2014) Long non-coding RNAs as a source of new peptides. eLife 2014;3:e03523 [doi: 10.7554/eLife.03523]

What are lncRNAs?

Many genes encode proteins and many other genes specify functional RNAs that do not encode proteins. The "RNA genes" include the classic genes for ribosomal RNAs and tRNAs as well as genes for very well-studied RNAs that carry out catalytic roles in the cell. There are a myriad of small RNAs required for things like splicing and regulation. All species, both prokaryotes and eukaryotes, contain genes for a wide variety or functional RNAs.

Eukaryotes seem to have an abundance of genes for small RNAs that perform a number of specific roles in regulation etc. They also have a lot of DNA regions complementary to long noncoding RNAs or lncRNAs (also lincRNA). The definition of long noncoding RNAs seems arbitrary and ambiguous [see Long Noncoding RNA]. Some of them might even encode proteins!

As a general rule, these RNAs are longer than 200 bp and some scientists put the cutoff at 1000 bp. Simple eukaryotes, such as yeast, don't have a lot of lncRNAs but eukaryotes with large complex genomes that are full of junk DNA seem to have a lot of different lncRNAs. The DNA regions1 that specify these lncRNAs ar not conserved. This strongly suggest that many of the lncRNAs are spurious nonfunctional transcripts even though some of them have well-characteized functions [see On the function of lincRNAs].

As usual, we have a definition problem. Are "lncRNAs" just a generic class of long noncoding RNAs that include thousands of nonfunctional molecules that are nothing more than junk RNA? Or, does the term "lncRNA" refer only to the subset that has a function? If it's the latter, then we should probably be referring to "putative" lncRNAs most of the time since the vast majority have not been shown to have a function. (There are about 10,000 of these RNAs in humans.)

I don't see how you can avoid the elephant in the room whenever you talk about lncRNAs. The most important question in NOT whether some of them have a function—that was demonstrated 30 years ago. The important question is whether the majority, or even a substantial minority, have a function.

That's why I was eager to read a short review by Rinn and Guttman in a recent issue of Science (Rinn and Guttman, 2014). They describe two lncRNAs that probably play a role in organizing chromatin within the nucleus (Xist and Neat1, both fram mammals). That's cool.

Then they say,
Collectively, these studies suggest that lncRNAs may shape nuclear organization by using the spatial proximity of their transcription locus as a means to target preexisting local neighborhoods. lncRNAs can in turn modify and reshape the organization of these local neighborhoods to establish new nuclear domains by interacting with various protein complexes, including chromatin regulators. Once established, a lncRNA can act to maintain these nuclear domains through active transcription and recruitment of interacting proteins to these domains. While the mechanism for how lncRNAs establish these domains is not fully understood, it is becoming increasingly clear that lncRNAs are important at all levels of nuclear organization—exploiting, driving, and maintaining nuclear compartmentalization.
It sure sounds like they are describing a particular function (nuclear organization) to the majority of lncRNAs. But what if 90% of all 10,000 lncRNAs have no function and what if only 100 of the remaining functional lncRNAs are involved in nuclear organization? That means there are 900 functional lncRNAs that play a different role in the cell?

If that were true, you would write that last paragraph very differently. If you recognize the elephant, you might say something like this ....
Very few lncRNAs have been shown to have a function and there's a very good chance that most of them are spurious transcripts that have no function. However, a small percentage do seem to have a function. In this review we have identified some long noncoding RNAs that appear to be involved in nuclear organization. We propose to call these RNAs "noRNAs" for "nuclear organizer RNAs" on the grounds that once a function has been identified we should stop referring to them as lncRNAs.
But that doesn't sound nearly as exciting as the subtitle of the article, "Long noncoding RNAs may function as organizing factors that shape the cell nucleus" or the quotation that's prominently displayed in a box in the center of the page, "... it is becoming increasingly clear that IncRNAs are important in all levels of nuclear organization—exploiting, driving, and maintaining nuclear compartmentalization." When did science become so dedicated to hype over substance? I must have missed the memo.

1. I use "DNA regions" instead of "genes" because the definition of a gene requires that the gene product be functional. You can't call them genes unless you have demonstrated that the RNA has a function.

Rinn, J. and Guttman, M. (2014) RNA and dynamic nuclear organization. Science 345"1240-1241 [doi: 10.1126/science.1252966]

Monday, September 15, 2014

Looking for Frankenfood

The students in my third year lab course are about to test various food products to see if they contain any DNA from genetically modified organisms. They'll be using a variety of PCR primers to detect the Cauliflower mosaic virus 35S promoter and the nopaline synthase terminator sequence from the Ti plasmid of Agrobacterium tumefaciens [see Roundup Ready® Transgenic Plants ].

Every student has to bring in their own food sample to test but I'll be providing a number of "controls" that I picked up in the cafeteria and at the grocery store. Which ones are Frankenfood?

We're using some additional sets of primers as controls. One set detects a chloroplast gene (rbcL). We have two sets of primers for corn-specific genes (invertase and zein) and one set for a soybean specific gene (lectin). An important part of the exercise is figuring out what controls to use and what DNA samples to analyze. Each group of two students can do 24 PCR reactions. It's going to be a challenge for them to figure out which reactions are the most important.

(They were told that corn and soy products are most likely to test positive in the GMO assay.)

Friday, September 12, 2014

The logic of lawyers

Barry Arrington is a lawyer from Colorado [Encyclopedia of American Loons]. Here's an example of the logic of lawyers posted on Uncommon Descent [Not Merely False].
The following statements are so obvious as to be considered truisms.

1. The primordial datum: I am subjectively self-aware.

2. It is not possible even in principle to account for mental facts, such as the primordial datum, on the basis of physical facts. They are different sorts of things; therefore one cannot account for the other. Trying to account for subjective self-awareness by suggesting it is an epiphenomenon of the electro-chemical process of the brain is like saying the color blue can be reduced to its constituent banana peels.

3. It follows that a reductionist materialism is not merely false but obviously false.

4. Just as obviously, it does not follow that committed materialists will admit that reductionist materialism is false, for they have reasons to put their faith in their metaphysical commitments that have nothing to do with the evidence and logic of the matter.
I would not want him to defend me if I were innocent. On the other hand, he might be a good choice if I were guilty because I could easily fool him into thinking that I was innocent.

Thursday, September 11, 2014

The mystery of Maud Menten

Maud Menten is best known for the Michaelis-Menten equation and her work on enzyme kinetics. She was born in Port Lambton, Ontario and she is a graduate of the University of Toronto.

The "mystery" concerns her degrees and the year she graduated. The video below was prepared when she was inducted into the Canadian Medical Hall of Fame in 1998 [Maud Menten]. If you watch the first few minutes you'll hear that in 1911 Maud Menten was one of the first Canadian women to receive a medical degree. You find similar statements all over the web, although sometimes it says she graduated in 1913—as in the text on the Canadian Hall of Fame website.

Wednesday, September 10, 2014

The perils of genetic testing

Most people don't understand the consequences of genetic testing. You may think that you can handle all of the data and information but think again.

This is the story of someone who got their DNA tested by a commercial company and he persuaded his parents to participate as well. What could possibly go wrong? The title of the article tells the story: With genetic testing, I gave my parents the gift of divorce.

Turns out he has a half-brother! His father never mentioned that he had a son with another woman.
At first, I was thinking this is the coolest genetics story, my own personal genetics story. I wasn't particularly upset about it initially, until the rest of the family found out. Their reaction was different. Years of repressed memories and emotions uncorked and resulted in tumultuous times that have torn my nuclear family apart. My parents divorced. No one is talking to my dad. We're not anywhere close to being healed yet and I don't know how long it will take to put the pieces back together.
It's not always true that having information is better than not having information. If you beleive that then you are very naive.

The Non-Conference Is Coming

Website Countdown Clock

Do IDiots understand evolutionary theory?

Do Intelligent Design Creationists (IDiots) understand evolution? ... of course not.

It's been really frustrating over the past 25 years trying to explain modern evolutionary theory to IDiots. They continue to refer to "Darwinism" and "neo-Darwinism" but it's obvious that they don't have a clue what they mean by those terms. This become especially obvious when they discover, once again, that real evolutionary biologists don't accept the IDiots' version of evolutionary theory.

Check out the latest post by Casey Luskin on Evolution News & Views. It would be so easy for him to explain to his readers what the textbooks say on evolutionary theory and how it differs from what the IDiots are promoting in their own books and on their websites [Are Biologists Rejecting Neo-Darwinian Evolution?]. He doesn't do this, of course, and that's only partly because it suits his purpose to be dissembling. It's mostly because he really doesn't understand what he's talking about. We know this because dozens of people have tried to explain it to him over the years and he still doesn't get it.

In fairness, Casey Luskin is responding to an article on The BioLogos Forum by philosopher Robert C. Bishop [Two Rhetorical Strategies (Reviewing “Darwin’s Doubt”: Robert Bishop, Part 2)]. It's pretty clear that Bishop doesn't understand modern evolutionary theory either. Unfortunately, there are many scientists who share these misconceptions but that's not an excuse for Luskin and his fellow travelers since they are supposed to understand what they spend so much time attacking.

The atheist barmaid's error

I'm usually a big fan of Jesus and Mo but today's cartoon is a bit disappointing. It is "resurrected" from 2009 [nerve2] and it is prompted by an excellent article on militant atheists written by Nick Cohen [The phantom menace of militant atheism]. Even Jerry Coyne likes it [A wonderful attack on the "militant fundamentalist atheism" trope].

The issue here is whether an atheist needs to study all religions in order to be an atheist. The barmaid seems to concede that point since she advances arguments that require knowledge of specific religions. Both of her examples require the provisional acceptance of gods because they refer to particular properties of those gods (i.e. whether they can have sons and prophets).

A Christian, for example, would happily engage the barmaid in a debate about the the divinity of Jesus as long as they begin with the assumption that gods exist. In order to engage seriously in that debate, the barmaid would have to read a ton of Christian apologetic literature. In other words, she would have to understand "sophisticated" religion. She would not be defending atheism even if she won the debate since there are billions of religious people who don't believe in the divinity of Jesus.

But atheists, by definition, don't believe in gods. The only arguments that are relevant are whether gods exist. Those arguments are not specific to any particular religion and they certainly aren't going to be found in the Bible or the Qur'an. I do not accept the premise that gods exist so I'm not the least bit interested in studying the religious beliefs of anyone who begins with the "fact" that gods exist. I'm about as interested in debating whether any of the gods had children as I am in debating how many angels can dance on the head of a pin.1

The atheist barmaid made a mistake. She should have said "Let's see - I understand that all religions begin with the idea that gods exist. What evidence do you have that this is true?"

Or, for that matter, the problem of evil. If there are no gods then there's no problem. Debating the "problem" of evil or whether Jesus is the son of gods is just like debating the cut of the Emperor's new clothes [On the Existence of God and the Courtier's Reply].

Wednesday, September 03, 2014

Club Day at the University of Toronto

Today's the day that clubs strut their stuff and try to get new students to sign up. It's an important part of campus life and an important part of a university education even though the majority of students don't participate.

There's a club for just about everyone, even biochemists!

All of that will disappear when universities shut down and undergraduate education is confined to MOOCs and glorified Skype conferences. You can't join a rowing club if you're a thousand kilometers from the clubhouse.

I suppose there are lot of business types out there who don't care about this sort of thing as long as you pay your money, get a degree, and go on to a decent job where you can pay back your student loan.

Harrison Ford vs Ian McKellen

It's hilarious even when you know it's photoshopped.

Are universities doomed?

This month's issue of The Atlantic has another one of those boring articles on the imminent death of universities (colleges) [The Future of College?].

This time it's a new "university" called MINERVA that's going to kill off all the old-school schools. Minerva is a for-profit university where all the learning takes place in electronic seminars of up to 19 students. Sort of like a Skype conference call only it uses copyrighted software. Students will pay only $28,000 (US) per year for this experience.

There have been articles about the death of universities published every year for as long as I can remember. Almost all of them think that a "university" is just a place where you go to get an undergraduate education. That's because almost all of the potential murderers only experienced university as an undergraduate.

Tuesday, September 02, 2014

What are they playing?

Apparently the Queen's Guards surprised everyone by playing a new song during the changing of the guard at Buckingham Palace on July 15, 2014.

Name that song!

Do you know it?

Here's a hint ... the actual theme is better but it's the thought that counts.

The top ten cities in the world

The Economist has surveyed cities from all over the world to find the ones that are the most livable (i.e. best places to live). Here's a summary of the criteria described in the report [A Summary of the Liveability Ranking and Overview]
The concept of liveability is simple: it assesses which locations around the world provide the best or the worst living conditions. Assessing liveability has a broad range of uses, from benchmarking perceptions of development levels to assigning hardship allowance as part of expatriate relocation packages. The Economist Intelligence Unit’s liveability rating quantifies the challenges that might be presented to an individual’s lifestyle in any given location, and allows for direct comparison between locations.
Bjørn Østman alerted me to the list by posting a link to this article: The World's Most Livable Cities All Have One Big Thing in Common. What do the top ten cities all have in common?—none of them are in the USA.

Here's the list ....

1. Melbourne, Australia
2. Vienna, Austria
3. Vancouver, Canada
4. Toronto, Canada
5 (tie). Adelaide, Australia
5 (tie). Calgary, Canada
7. Sydney, Australia
8. Helsinki, Finland
9. Perth, Australia
10. Auckland, New Zealand

There's obviously more to "livability" than meets the eye. Some of these places are a lot less interesting than Paris, London, or New York.

I think the ranking also depends very much on how much money you have. I'd need to be offered a hell of a lot more money if I were to consider a move to Calgary, Helsinki, or Perth.1

1. I've never been to Perth but it doesn't seem like a place I'd like to live.

IDiots exploring evolution

Modern evolutionary theory is far more advanced than the simple version that's attacked by Intelligent Design Creationists. Neutral Theory, population genetics, and the importance of random genetic drift are just a few of the additions that were incorporated in the 1960s. (That's almost 50 years ago.)

Most IDiots are half-a-century behind in their knowledge of science. They think that random mutations and natural selection are the only way that evolution can occur.1 That's why they refer to evolution as "Darwinism."

Many of them have heard vague rumors of change, proving that from time to time they do, indeed, take their fingers out of their ears. They've discovered that modern scientists have moved well beyond natural selection as an explanation for every bit of evolution. This makes the IDiots very happy since, to them, it means that evolution is wrong. And if evolution is wrong then gods must exist.

They've even developed a course to explain why Neutral Theory and random genetic drift support the idea that gods must be making bacterial flagella and protein-protein contacts. It looks like a very interesting course ...

1. A few of them might know differently but they will never admit it in public.