The last molecular evolution exam: Question #2

The paper by Andrews et al. (2011) lists a number of common misconceptions held by their students. One of them is the idea that, “Evolution is a process that will never stop, even in the human species.” Why do they think this is a misconception? Do you agree?

Andrews, T.M., Kalinowski, S.T., and Leonard, M.J. (2011). “Are humans evolving?” A classroom discussion to change student misconceptions regarding natural selection. Evolution: Education and Outreach, 4:456-466. [doi: 10.1007/s12052-011-0343-4]

Question #1, Question #2, Question #3, Question #4, Question #5, Question #6

---

The last molecular evolution exam: Question #1

Eugene Koonin described his view of the proper null hypothesis for evolutionary questions. One of the examples he used concerns the evolution of recent gene duplications (Koonin, 2016 p.5). Describe how one possible fate of these genes relates to constructive neutral evolution. What are the other possible fates of these genes? Which one is most likely?

Koonin, E.V. (2016) Splendor and misery of adaptation, or the importance of neutral null for understanding evolution. BMC biology, 14:114 [doi: 10.1186/s12915-016-0338-2]

... in eukaryotes, duplicates of individual genes cannot be effectively eliminated by selection and thus often persist and diverge. The typical result is subfunctionalization, whereby the gene duplicates undergo differential mutational deterioration, losing subsets of ancestral functions. As a result, the evolving organisms become locked into maintaining the pair of paralogs. Subfunctionalization underlies a more general phenomenon, denoted constructive neutral evolution (CNE).

Question #1, Question #2, Question #3, Question #4, Question #5, Question #6

---

Somatic cell mutation rate in humans

A few years ago, Tomasetti and Vogelstein (2015) published a paper where they noted a correlation between rates of cancer and the number of cell divisions. They concluded that a lot of cancers could be attributed to bad luck. This conclusion didn't sit well with most people for two reasons. (1) There are many well-known environmental effects that increase cancer rates (e.g. smoking, radiation), and (2) there's a widespread belief that you can significantly reduce your chances of getting cancer by "healthy living" (whatever that is). The first objection is based on solid scientific evidence but the second one is not as scientific.

Some of the objections to the original Tomasetti and Vogelstein paper were based on the mathematical models they used to reach their conclusions. The authors have now followed up on their original study with more data. The paper appears in the March 24, 2017 issue of Science (Tomasetti and Vogelstein, 2017). If you're interested in the debate over "bad luck" you should read the accompanying review by Nowak and Waclaw (2017). They conclude that the math is sound and many cancer-causing mutations are, in fact, due to chance mutations in somatic cells. They point out something that should be obvious but bears repeating.

Sloppiness in translation initiation

There are two competing worldviews in the fields of biochemistry and molecular biology. The distinction was captured a few years ago by Laurence Hurst commenting on pervasive transcription when he said, "So there are two models; one, the world is messy and we're forever making transcripts we don't want. Or two, the genome is like the most exquisitely designed Swiss watch and we don't understand its working. We don't know the answer—which is what makes genomics so interesting." (Hopkins, 2009).

I refer to these two world views as the Swiss watch analogy and the Rube Goldberg analogy.

The distinction is important because, depending on your worldview, you will interpret things very differently. We see it in the debate over junk DNA where those in the Swiss watch category have trouble accepting that we could have a genome full of junk. Those in the Rube Goldberg category (I am one) tend to dismiss a lot of data as just noise or sloppiness.

Did Rosalind Franklin produce the first X-ray diffraction images of DNA?

There's an interesting video of ten famous women scientists at Interesting S_Word: [Top 10 Female Scientists of History]. The image of Rosalind Franklin caught my eye (see right).

Perhaps I'm nitpicking but fake news is all the rage these days so I think we'd better be extra careful to present real facts rather than alternative facts. In that spirit, I'll mention two things.

Why is life the way it is?

Nick Lane is very good at explaining complex biology and biochemistry. He is the winner of the Royal Society's Michael Faraday Prize for 2016. Here's his lecture. It's worth watching if you want to understand the latest informed (naturalistic) speculations on the origin of life.

---

Trying to educate a creationist (Otangelo Grasso)

Otangelo Grasso is a creationist who's convinced he can learn to understand biochemistry by reading what's on the internet and copy-pasting it into his website. He then takes that limited knowledge and concludes that evolution is impossible. He often poses "gotcha" questions based on his flawed understanding.

His behavior isn't very different from most other creationists who suffer from Dunning-Kruger Disease but he happens to be someone who I thought could be educated.

I was wrong.

Over the years I've tried to correct a number of errors he's made so we could have an intelligent discussion about evolution. You can't have such a discussion if one side ignores facts and refuses to learn. Here's an example of a previous attempt: Fun and games with Otangelo Grasso about photosynthesis. Here's a post from yesterday showing that I wasted my time: Otangelo Grasso on photosynthesi.

The evolution of the citric acid cycle

I just realized that I don't have a post devoted to the evolution of the citric acid cycle. This need to be remedied since I often talk about it. It's a good example of how an apparently irreducibly complex pathway can arise by evolution. It's also a good example to get students to think outside of the box. Undergraduate biochemistry courses usually concentrate on human physiology and too often students transfer that bias to all other species. They assume that what happens in humans is what happens in plants, fungi, protozoa, and bacteria.¹

Here's what the standard citric acid cycle looks like (Moran et al., 2011 p. 393).

What the heck is epigenetics?

"Epigenetics" is the (relatively) new buzzword. Old-fashioned genetics is boring so if you want to convince people (and grant agencies) that you're on the frontlines of research you have to say you're working on epigenetics. Even better, you can tell them that you are on the verge of overthrowing Darwinism and bringing back Jean-Baptiste Lamarck.

But you need to be careful if you adopt this strategy. Don't let anyone pin you down by defining "epigenetics." It's best to leave it as ambiguous as possible so you can adopt the Humpty-Dumpty strategy.¹ Sarah C.P. Williams made that mistake a few years ago and incurred the wrath of Mark Ptashne [Core Misconcept: Epigenetics].

The exit exam for biochemistry and molecular biology students

I'm a big fan of teaching fundamental concepts and principles and a big fan of teaching critical thinking. I think the most effective way of accomplishing these objectives is some form of student-centered learning. As I near the end of my teaching career, I wonder how we can tell if we succeed? It should be relatively easy to develop an exit exam for our biochemistry/molecular biology students to see if they grasp the basic concepts and can demonstrate an ability to think critically.

Here are some of the questions we could have on that exam. Each one requires a short answer with an explanation. The explanation doesn't have to be detailed or full of facts, just the basic idea. Students are graded on their ability to think critically about the answers. Many of the questions don't have a simple answer. Can you think of any other questions?

The proteome complexity myth

A reader pointed me to the ThermoFisher Scientific website. ThermoFisher Scientific is a major supply of scientific equipment and supplies. They created their life sciences wesite to help inform their customers and sell more products. The page I'm interested in is: Overview of Post-Translational Modifications (PTMs). It begins with,

Within the last few decades, scientists have discovered that the human proteome is vastly more complex than the human genome. While it is estimated that the human genome comprises between 20,000 and 25,000 genes (1), the total number of proteins in the human proteome is estimated at over 1 million (2). These estimations demonstrate that single genes encode multiple proteins. Genomic recombination, transcription initiation at alternative promoters, differential transcription termination, and alternative splicing of the transcript are mechanisms that generate different mRNA transcripts from a single gene (3).

The increase in complexity from the level of the genome to the proteome is further facilitated by protein post-translational modifications (PTMs). PTMs are chemical modifications that play a key role in functional proteomics, because they regulate activity, localization and interaction with other cellular molecules such as proteins, nucleic acids, lipids, and cofactors.

How many proteins in the human proteome?

Humans have about 25,000 genes. About 20,000 of these genes are protein-coding genes.¹ That means, of course, that humans make at least 20,000 proteins. Not all of them are different since the number of protein-coding genes includes many duplicated genes and gene families. We would like to know how many different proteins there are in the human proteome.

The latest issue of Science contains an insert with a chart of the human proteome produced by The Human Protein Atlas. Publication was timed to correspond with release of a new version of the Cell Atlas at the American Society of Cell Biology meeting in San Francisco. The Cell Atlas maps the location of about 12,000 proteins in various tissues and organs. Mapping is done primarily by looking at whether or not a gene is transcribed in a given tissue.

A total of 7367 genes (60%) are expressed in all tissues. These "housekeeping" genes correspond to the major metabolic pathways and the gene expression pathway (e.g. RNA polymerase subunits, ribosomal proteins, DNA replication proteins). Most of the remaining genes are tissue-specific or developmentally specific.

Splice variants of the human triose phosphate isomerase gene: is alternative splicing real?

Triose phosphate isomerase (TIM) is one of the enzymes in the gluconeogenesis pathway leading to the synthesis of glucose from simple precursors. It also plays a role in the degradation of glucose (glycolysis). The enzyme catalyzes the following reaction ....

Triose phosphate isomerase is found in almost all species. The structure and sequence of the enzyme is well-conserved. It is a classic β-barrel enzyme that usually forms a dimer. The overall structure of a single subunit is classic example of an αβ-barrel known as a TIM-barrel in reference to this enzyme.

To the best of my knowledge, no significant variants of this enzyme due to alternative promoters, alternative splicing, or proteolytic cleavage are known.¹ The enzyme has been actively studied in biochemistry laboratories for at least eighty years.

The most important thing about nature according to Bill Martin

My friend and colleague, Alex Palazzo, alerted me to an interview of Bill Martin published in the July 11, 2016 issue of Current Biology [Bill Martin]. I loved all his answers—Bill Martin is one of my scientific heroes—but his answer to the last question was particularly insightful. The question was, "What’s the single most important thing that you have come to realize about nature?"

His answer was ....

Life is an exergonic chemical reaction. It’s the energy releasing redox reaction at the core of metabolism that makes life run, and throughout all of life’s history it is one and the same reaction that has been running in uninterrupted continuity from life’s onset. Everything else is secondary, manifestations of what is possible when the energy is harnessed to make genes that pass the torch.

I'm a biochemist so you might think I'm a little bit biased but let me tell you why this answer is so important.

What is a "gene" and how do genes work according to Siddhartha Mukherjee?

It's difficult to explain fundamental concepts of biology to the average person. That's why I'm so interested in Siddhartha Mukherjee's book "The Gene: an intimate history." It's a #1 bestseller so he must be doing something right.

My working definition of a gene is based on a blog post from several years ago [What Is a Gene?].

A gene is a DNA sequence that is transcribed to produce a functional product.

This covers two types of genes: those that eventually produce proteins (polypeptides); and those that produce functional noncoding RNAs. This distinction is important when discussing what's in our genome.

Fun and games with Otangelo Grasso about photosynthesis

Otangelo Grasso just posted another one of his screeds. This time it's on photosynthesis. All of his "essays' conform to the same pattern. He looks for some complex set of biochemical reactions, usually in complex animals, then claims that it couldn't possibly have evolved because the whole thing is irreducibly complex according to his understanding of biochemistry and evolution.

It's a classic argument from ignorance.

In this case it's photosynthesis in flowering plants. He posted this figure from the Kegg database ....

Then he says,

In photosynthesis , 26 protein complexes and enzymes are required to go through the light and light independent reactions, a chemical process that transforms sunlight into chemical energy, to get glucose as end product , a metabolic intermediate for cell respiration. A good part of the protein complexes are uniquely used in photosynthesis. The pathway must go all the way through, and all steps are required, otherwise glucose is not produced. Also, in the oxygen evolving complex, which splits water into electrons, protons, and CO2, if the light-induced electron transfer reactions do not go all the five steps through, no oxygen, no protons and electrons are produced, no advanced life would be possible on earth. So, photosynthesis is a interdependent system, that could not have evolved, since all parts had to be in place right from the beginning. It contains many interdependent systems composed of parts that would be useless without the presence of all the other necessary parts. In these systems, nothing works until all the necessary components are present and working. So how could someone rationally say, the individual parts, proteins and enzymes, co-factors and assembly proteins not present in the final assemblage, all happened by a series of natural events that we can call ad hoc mistake "formed in one particular moment without ability to consider any application." , to then somehow interlink in a meaningful way, to form electron transport chains, proton gradients to " feed " ATP synthase nano motors to produce ATP , and so on ? Such independent structures would have not aided survival. Consider the light harvesting complex, and the electron transport chain, that did not exist at exactly the same moment--would they ever "get together" since they would neither have any correlation to each other nor help survival separately? Repair of PSII via turnover of the damaged protein subunits is a complex process involving highly regulated reversible phosphorylation of several PSII core subunits. If this mechanism would not work starting right from the beginning, various radicals and active oxygen species with harmful effects on photosystem II (PSII) would make it cease to function. So it seems that photosynthesis falsifies the theory of evolution, where all small steps need to provide a survival advantage.

I responded on Facebook, pointing out that the cytochrome bc complex and ATP synthase pre-date photosynthesis [Facebook: Photosynthesis]. I also pointed out that there are many living species that use only simpler versions of photsystem I or only photosystem II to carry out photosynthesis [e.g. A Simple Version of Photosynthesis]. Those nasty little facts don't seem to fit with his claim that, "In these systems, nothing works until all the necessary components are present and working."

I probably should have known better. Otangelo Grasso's standard response to such criticism is to avoid dealing directly with his false statements and shift the goalposts on to some other topic. He then posts all kinds of links to websites that seem to back up his claims even if they have nothing to do with the criticisms. You can see him at work on the Facebook thread.

It's pretty frustrating. I probably shouldn't respond to kooks, especially those who think they are experts in biochemistry.

---

How do you characterize these scientists?

We've been having a discussion on another thread about ID proponents. Are some of them acting in good faith or are they all lying and deceiving their followers?

I have similar problems about many scientists. I've been reading up on pervasive transcription and the potential number of genes for noncoding, functional, RNAs in the human genome. As far as I can tell, there are only a few hundred examples that have any supporting evidence. There are good scientific reasons to believe that most of the detected transcripts are junk RNA produced as the result of accidental, spurious, transcription.

There are about 20,000 protein-coding genes in the human genome. I think it's unlikely that there are more than a few thousand genes for functional RNAs for a total of less than 25,000 genes.

Here's one of the papers I found.

Guil, S. and Esteller, M. (2015) RNA–RNA interactions in gene regulation: the coding and noncoding players. Trends in Biochemical Sciences 40:248-256. [doi: 10.1016/j.tibs.2015.03.001]

Trends in Biochemical Sciences is a good journal and this is a review of the field by supposed experts. The authors are from the Department of Physiological Sciences II at the University of Barcelona School of Medicine in Barcelona, Catalonia, Spain. The senior author, Manel Esteller, has a Wikipedia entry [Manel Esteller].

Here's the first paragraph of the introduction.

There are more genes encoding regulatory RNAs than encoding proteins. This evidence, obtained in recent years from the sum of numerous post-genomic deep-sequencing studies, give a good clue of the gigantic step we have taken from the years of the central dogma: one gene gives rise to one RNA to produce one protein.

The first sentence is not true by any stretch of the imagination. The best that could be said is that there "may" be more genes for regulatory RNAs (> 20,000) but there's no strong consensus yet. Since the first sentence is an untruth, it follows that it is incorrect to say that the evidence supports such a claim.

It's also untrue to distort the real meaning of the Central Dogma of Molecular Biology, which never said that all genes have to encode proteins. The authors don't understand the history of their field in spite of the fact they are writing a review of that field.

Here's the problem. Are these scientists acting in good faith when they say such nonsense? Does acting in "good faith" require healthy criticism and critical thinking or is "honesty" the only criterion? The authors are clearly deluded about the controversy since they assume that it has been resolved in favor of their personal biases but they aren't lying. Can we distinguish between competent science and bad science based on such statements? Can we say that these scientists are incompetent or is that too harsh?

Furthermore, what ever happened to peer review? Isn't the system supposed to prevent such mistakes?

---

University of Toronto post-doc shares lab notes

The University of Toronto publicity department is making a big deal of Rachel Harding. She's a post-doc in the Structural Genomics Consortium (SGC). She works on Huntington's disease.

Here's the link to the press release and the first few paragraphs [Researcher is an Open Book: First to Share Lab Notes in Real Time].

Faculty of Medicine researcher Rachel Harding will be the first known biomedical researcher to welcome the world to review her lab notes in real time. The post-doctoral fellow with U of T’s Structural Genomics Consortium (SGC) is also explaining her findings to the general public through her blog. She hopes her open approach will accelerate research into Huntington’s disease.

“This should drive the process faster than working alone,” Harding says. “By sharing my notes, I hope that other scientists will critique my work, collaborate and share data in the early stages of research.” Her research at SGC is funded by CHDI Foundation, a non-profit drug-development organization exclusively dedicated to Huntington’s disease. Both organizations aim to accelerate research by making it open and collaborative.

Her approach is intended to leverage the experience of a community of scientists. Individual researchers often still work in relative isolation and then publish only their positive discoveries, usually years after the experiments were actually done. Thus, scientists often pursue similar ideas in parallel and miss many opportunities to learn from each other’s mistakes.

She has started by publishing raw data and play-by-play details of her first effort on the CERN open digital repository Zenodo. She also posts regular updates on her blog Lab Scribbles, where she includes an experimental summary written in lay terms.

It's been over 35 years since I first starting thinking and talking about electronic (computerized) lab notes¹ and it's been over twenty years since I first heard discussions about putting them online. I seriously doubt that Rachel Harding is the first biomedical researcher to put lab notes on the web. I'm also very skeptical about her keeping up the practice for very long.

Not only is it boring and tedious to write your lab notes in a word processing program but it's kinda embarrassing to post everything you do in the lab. At least it would have been for me. I made lots of mistakes and there are lots of R-rated words and phrases in my notes.

Let's keep an eye on this experiments to see how it goes. So far there are four items on the Zenodo website. The first is a Word document containing a few brief notes from Jan. 6, 7, 9, 11 and 25. There are brief notes posted on Feb. 6 and two on Feb. 11. I hope this isn't the extent of her lab notes.

The blog is Lab Scribbles. There are a few posts. It's interesting but I'm not sure anyone is going to read it even if you're interested in Huntington's.

Has anyone else experimented with open lab notes?

---

1. I still have a few floppy disks with those attempts from about 1981. Unfortunately, I don't have a machine that can read them.

Junk DNA doesn't exist according to "Conceptual Revolutions in Science"

The blog "Conceptual Revolutions in Science" only publishes "evidence-based, paradigm-shifting scientific news" according to their home page.

The man behind the website is Adam B. Dorfman (@DorfmanAdam). He has an MBA from my university and he currently works at a software company. Here's how he describes himself on the website.

A DNA quiz

Jerry Coyne discovered a Quiz on DNA. He calls is a so-so quiz on DNA. He says that one question is really, really, dumb. I disagree, I think there are several dumb questions.

I tried it and got a score of 19/19 in just under four minutes. This is misleading since you have to get every question right before continuing on to the next question. I had to anticipate what the authors wanted in order to proceed.

Try the quiz yourself before reading any further. There are spoilers below!