The sequence of the human genome was announced on June 26, 2000 although the actual sequence wasn't published until a year later. There were two sequences. One was the product of the International Human Genome Project led by Francis Collins who said,
"It is humbling for me and awe-inspiring to realize that we have caught the first glimpse of our own instruction book, previously known only to God."
The sequence was a composite of a number of individuals.
The second sequence was from Celera Genomics, led by Craig Venter. It was mostly his genome, making him the second being to know his own instruction book ... right after God.
It took another seven years to finish and publish the complete sequence of all of Craig Venter's chromosomes. The paper was published in PLoS Biology (Levy et al., 2007) and highlighted in a Nature News article: All about Craig: the first 'full' genome sequence.
What's unique about this genome sequence—other than the fact that it's God's Craig Venter's—is that all 46 chromosomes were sequenced. In other words, enough data was generated to put together separate sequences of each pair of chromosomes. That produces some interesting data.
There were 4.1 million differences between homologous chromosomes (22 autosomes). 78% of these events were single nucleotide polymorphisms (SNPs). The rest were indels (insertions and deletions) and these accounted for 0.9 million nucleotides. Thus, indels made up 74% of the total number of variant nucleotide sequence.
In addition, there were 62 copy number variants (duplication) accounting for an additional 10Mb of variation between haploid sets of chromosomes. The total number of nucleotide differences is 13.9Mb when you add up all the indels, SNPs, and duplications. The two haploid genomes differ by about 0.5% by this calculation (total amount sequenced was 2,895Mb).
When the two copies of all annotated genes were compared, it turned out that 44% were heterozygous—the two copies were not identical.
Craig Venter's genome sequence differs from the composite human reference genome at 4,118,889 positions. Most of these were already known as variants in the human population but 31% were new variants (in 2007).
Venter has written about his genome sequence in A Life Decoded. He has variants in his APOE gene sequence that are associated with Alzheimer's and cardiovascular diseases. He has variants in his SORL1 that also make him at risk for Alzheimer's according to 2007 data. Just about everyone who gets their genomes sequenced will find variants that put them at greater risk for some genetic disease.
Massimo Pigliucci is an atheist who thinks that science and religion are compatible because they rule in different domains. He takes a very narrow view of "science"— one that excludes the work of historians and philosophers who are presumably using some other way of knowing. (He doesn't tell us what that is.)
I prefer the broad view of science as a way of knowing that relies on evidence, rational thinking, and healthy skepticism. This broad view of science is not universal—but it's not uncommon. In fact, Alan Sokel has defended this view of Massimo Pigiucci's own blog: [What is science and why should we care? — Part III]. According to this view, any attempt to gain knowledge should employ the scientific worldview. Historian and philosophers should follow this path if they hope to be successful. Pigliucci should know that there are different definitions and any discussion of the compatibility of science and religion must take these differences into account.
We know quite a lot about the origin of new genes (Carvunis et al., 2012; Kaessman, 2010; Long et al., 2003; Long et al., 2013; Näsvall et al., 2012); Neme and Tautz, 2013; Schlötterer, 2015; Tautz and Domazet-Lošo (2011); Wu et al., 2011). Most of them are derived from gene duplication events and subsequent divergence. A smaller number are formed de novo from sequences that were not part of a gene in the ancestral species.
In spite of what you might have read in the popular literature, there are not a large number of newly formed genes in most species. Genes that appear to be unique to a single species are called "orphan" genes. When a genome is first sequenced there will always be a large number of potential orphan genes because the gene prediction software tilts toward false positives in order to minimize false negatives. Further investigation and annotation reduces the number of potential genes.
Thanks for reading the commentary on my university’s communication page, hastily written for brevity and digestibility by me and our science communication officer, Lawrence Goodman. I was originally hoping the piece could focus on my latest research, but it turned into this sort of general Q&A chat. The commentary was written rather quickly and meant for a general audience perusing Brandeis research, so it is obviously not a peer-reviewed scientific publication.
I am well aware of both your reputations as fiery critics and experts of evolutionary biology, and you have somewhat of a following on the internet. Some of your earlier blog posts have been entertaining and even on point regarding how big projects like ENCODE have over-hyped the functional proportions of our genomes. So, it does NOT surprise me one bit that I would become your latest vitriolic target in your posts here, and here.
Could I learn more from you two about evolutionary biology theory? Indeed, I could. Can we revise our Q&A commentary to be more scientifically accurate while still being digestible to a general audience? Perhaps, if we have the time and I survive my tenure review, we may do so and take your input into consideration. Why respond and risk another snarky post from you guys? I could care less about your trivial blog critiques when I’ve received plenty of grants and paper rejections that cut much deeper into my existence as a young academic struggling to survive when the academic track has never been more challenging (<10% grant success rates at NIH, NSF, CIHR, etc).
I’m responding to ask that both of you reflect on the message your posts are sending to students and postdocs. As a young scientist, having a chat with my university PR rep, I have to now think twice about two senior tenured professors slamming my scientific credibility on your internet soapbox without a single direct email to me. How passive-aggressive!
Your message is saying that Academic science even less inviting to young scientists as it is, with faculty positions and grants falling way short of demand, and the tough sacrifices every young scientist is already making for the craft that we love. If we condone this type of sniping behavior, why would any young scientist want to learn and discuss with the older scientists of your generation?
A direct email from you to me expressing your scientific concerns of our commentary would have been a better way to go. I am willing to stand corrected. Your blog posts, however, are disappointing and appear petty to me. Let’s all set a better example here for our trainees.
If you wish to post this response verbatim on your blogs, go ahead, since I had thought of posting this response on your blog’s comments section. But to follow my own advice, I’ll try a direct email to you first. And if I don’t hear back from you, I may then ask my friend Bjorn to help me post this on his blog.
This time it's Assistant Professor of Biology Nelson Lau. He studies Piwi proteins and PiRNAs.
Lau was interviewed by Lawrence Goodman, a science communication officer at Brandeis University: DNA dumpster diving. The subject is junk DNA and you will be astonished at how ignorant Nelson Lau is about a subject that's supposed to be important in his work.
How does this happen? Aren't scientists supposed to be up-to-date on the scientific literature before they pass themselves off as experts? How can an Assistant Professor make such blatantly false and misleading statements about his own area of research expertise? Has he never encountered graduate students, post-docs, or mentors who would have corrected his misconceptions?
Here's the introduction to the interview,
Since the 1960s, it's largely been assumed that most of the DNA in the human genome was junk. It didn't encode proteins -- the main activity of our genes-- so it was assumed to serve no purpose. But Assistant Professor of Biology Nelson Lau is among a new generation of scientists questioning that hypothesis. His findings suggest we've been wrong about junk DNA and it may be time for a reappraisal. If we want to understand how our bodies work, we need to start picking through our genetic garbage.
BrandeisNow sat down with Lau to ask him about his research.
There's nothing wrong with being a "new generation" who questions the wisdom of their elders. That's what all scientists are supposed to do.
But there are certain standards that apply. The most important standard is that when you are challenging other experts you'd better be an expert yourself.
First off, what is junk DNA?
About two percent of our genome carries out functions we know about, things like building our bones or keeping the heart beating. What the rest of our DNA does is still a mystery. Twenty years ago, for want of a better term, some scientists decided to call it junk DNA.
Dan has already addressed this response but let me throw in my own two cents.
There was never, ever, a time when knowledgeable scientists said that all 98% of the DNA that wasn't part of a gene was junk. Not today, not twenty years ago (1996), and not 45 years ago.
There has never been at time since the 1960s when all non-gene DNA was a mystery. It certainly isn't a mystery today. If you don't know this then you better do some reading ... quickly. Google could be your friend, Prof. Lau, it will save you from further embarrassment. Search on "junk DNA" and read everything ... not just the entries that you agree with.
I added a bunch of links at the bottom of this post to help you out.
Is it really junk?
There’s two camps in the scientific community, one that believes it doesn’t do anything and another that believes it’s there for a purpose.
And you’re in the second camp?
Yes. It's true that sometimes organisms carry around excess DNA, but usually it is there for a purpose. Perhaps junk DNA has been coopted for a deeper purpose that we have yet to fully unravel.
It is possible that the extra DNA in our genome has an unknown deeper purpose but right now we have more than enough information to be confident that it's junk. You have to refute or discredit all the work that's been done in the past 40 years in order to be in the second camp.
Maybe when junk DNA moves to the right place in our DNA, this could cause better or faster evolution. Maybe when junk genes interacts with the non-junk ones, it causes a mutation to occur so humans can better adapt to changes in the environment.
Most of the undergraduates who took my course could easily refute that argument. I'm guessing that undergraduates in biology at Brandeis aren't as smart. Or maybe they're just too complacent to challenge a professor?
We've got a serious problem here folks. There are scientists being hired at respectable universities who aren't keeping up with the scientific literature in their own field. How does this happen? Are there newly hired biology professors who don't understand evolution?
Niu, D. K., and Jiang, L. (2012) Can ENCODE tell us how much junk DNA we carry in our genome?. Biochemical and biophysical research communications 430:1340-1343. [doi: 10.1016/j.bbrc.2012.12.074]
Doolittle, W.F. (2013) Is junk DNA bunk? A critique of ENCODE. Proc. Natl. Acad. Sci. (USA) published online March 11, 2013. [PubMed] [doi: 10.1073/pnas.1221376110]
Graur, D., Zheng, Y., Price, N., Azevedo, R. B., Zufall, R. A., and Elhaik, E. (2013) On the immortality of television sets: "function" in the human genome according to the evolution-free gospel of ENCODE. Genome Biology and Evolution published online: February 20, 2013 [doi: 10.1093/gbe/evt028
Eddy, S.R. (2013) The ENCODE project: missteps overshadowing a success. Current Biology, 23:R259-R261. [10.1016/j.cub.2013.03.023]
Hurst, L.D. (2013) Open questions: A logic (or lack thereof) of genome organization. BMC biology, 11:58. [doi:10.1186/1741-7007-11-58]
Kellis, M., Wold, B., Snyder, M.P., Bernstein, B.E., Kundaje, A., Marinov, G.K., Ward, L.D., Birney, E., Crawford, G. E., and Dekker, J. (2014) Defining functional DNA elements in the human genome. Proc. Natl. Acad. Sci. (USA) 111:6131-6138. [doi: 10.1073/pnas.1318948111]
Morange, M. (2014) Genome as a Multipurpose Structure Built by Evolution. Perspectives in biology and medicine, 57:162-171. [doi: 10.1353/pbm.2014.000]
I'm taking Ms. Sandwalk and hope to show her Down House. She loves old English houses.
She'll also be really excited to see Darwin's tomb in Westminster Abbey and tour the Natural History Museum. We'll make it a fun-filled week of science and evolution! Why don't you join us?
He brings up two points that are worth discussing.
What is a model organism?
There are two common definitions. Birney leans toward defining a model organism as one that models human biochemistry and physiology. This is a common definition. It emphasizes the meaning of "model" as "model of something."
Watch two medical educators from my Faculty of Medicine at the University of Toronto. They are being interviewed by Steve Paiken of The Agenda. They rightly deplore the traditional lecture style of learning that's common in my university but their solution is more online learning.
The real problem with medical education is that much of the first two years is based on the "memorize and regurgitate" model that we know is ineffective. The best way to change the system is to use evidence-based methods that emphasize student-based learning. The idea is to teach medical students how to access information and how to interpret it rather than have them memorize facts. When teaching biochemistry, for example, it's pointless to ask medical students to take an exam based on structures and pathways that they will forget the day after the exam.
These two physicians are in charge of reforming medical education. They want to please the students by creating a new way of teaching that emphasizes the way "millennials" want to learn. (Short online courses, no lectures.) You'll watch the entire show without hearing any references to the pedagogical literature and what's known to work. Is there any evidence that undergraduate medical students are experts on medical education? (Hint: ... no.)
If this is the wave of the future, I fear that future doctors are not going to be any more informed that the current crop. They will still not be capable of critical thinking.
The way we teach needs to change, but not this way.
We've known for a long time that the most common mistake is assuming that there's only one solution to a problem. They see an end result, like a bacterial flagellum, or resistance to malaria, or the binding of two proteins, and assume that a few very specific mutations had to occur in a specific sequence in order to produce that result.
judmarc calls this the "lottery fallacy" and I think it's a good term [see lottery fallacy],
This is of course what I like to call the "lottery fallacy." It's used by virtually every ID proponent to produce erroneously inflated probabilities against evolution.
Lottery fallacy: The odds against any *particular individual* winning the PowerBall lottery are ~175 million to 1. But there were three winners just last night. That's because *someone* winning the PowerBall is not an especially rare occurrence. It happens every few weeks throughout the year.
In exactly the same way, Axe, Gauger, Behe, and the rest of the ID folks always base their math on the chances that a *particular* neutral or beneficial mutation will occur, and just as with the lottery, the chances of a *particular* outcome are utterly minuscule. The occurrence of *some* neutral or beneficial mutation, however, is, as with the lottery, so relatively common as to be completely unremarkable.
To summarize: ID proponents misuse probability math to make the common appear impossible.
As it turns out, someone on Evolution News & Views (sic) just posted an excellent example of this fallacy [Intelligent Design on Target]. Here's what he/she/it says,
In his second major treatise on design theory, No Free Lunch: Why Specified Complexity Cannot Be Purchased without Intelligence, William Dembski discusses searches and targets. One of his main points is that the ability to reach a target in a vast space of possibilities is an indicator of design. A sufficiently complex target that satisfies an independent specification, he argues, creates a pattern that, when observed, satisfies the Design Filter. There are rigorous mathematical and logical proofs of this concept in the book, but at one point, he uses an illustration even a child can understand.
Consider the case of an archer. Suppose an archer stands fifty meters from a large wall with a bow and arrow in hand. The wall, let us say, is sufficiently large that the archer cannot help but hit it. Now suppose each time the archer shoots an arrow at the wall, the archer paints a target around the arrow so that the arrow sits squarely in the bull's-eye. What can be concluded from this scenario? Absolutely nothing about the archer's ability as an archer. Yes, a pattern is being matched; but it is a pattern fixed only after the arrow has been shot. The pattern is thus purely ad hoc. [No Free Lunch, pp. 9-10, emphasis added.]
Most people have experience with target shooting of some kind, whether with bows and arrows, guns (including squirt guns), snowballs, darts, or most sports like baseball, soccer, basketball, hockey, and football. Children laugh when they picture an archer who "couldn't even hit the broadside of a barn" and rushes up to the arrow and paints a bull's-eye around it. Grown-ups might compare that to a biologist looking at an irreducibly complex biological system and simply stating, "It evolved." In each of these cases, Dembski would say that since the pattern was not independently specified, therefore it is ad hoc.
Do you see the fallacy? Just because we observe a complex adaptation or structure does NOT mean that it was specified or pre-ordained. There are certainly many different structures that could have evolved—most of them we never see because they didn't happen. And when a particular result is observed it doesn't mean that there was only one pathway (target) to producing that structure.
To continue the analogy—at the risk of abusing it—there may be hundreds of targets in the woods and most of them have very large bullseyes. Imagine you're out for a walk in the woods and you see that almost every tree has a big target with a large bullseye. You find an arrow stuck at the edge of one of the bullseyes and lots of arrows stuck in the trees, the ground, and parts of most of the targets outside of the central bullseyes. Would you write a book about how good the archer must have been?
I've been trying to figure out why Intelligent Design Creationists are so excited about epigenetics. They seem to think it's going to overthrow everything we know about evolution (= "Darwinism"). That means, in their minds, that "naturalism" and "materialism" aren't sufficient to explain biology.
I'll just quote the relevant part and let you try and figure out whether Denyse represents mainstream Intelligent Design Creationism. 'Cause if she does, the movement is in far worse shape than even I imagined.
I remember one adoptive mother, taunted by a rebellious teenager who wanted to find her “real” mother, taking the girl by the shoulders and saying, “Look, I raised you from when you were seven days old; I supported you, sat with you in emergency rooms and juvenile court, laughed and cried with you, … and got you into a good school in the end. I don’t know who or where your birth mother is. But I do know this: I am the only ‘real mother’ you have ever had or ever will have. Look at me. Get used to it. It doesn’t GET better than this.”
I hope the kid smartened up. Meanwhile what if she discovers, when she has children, that their genome reflects in part traits she acquired growing up in the adoptive home? Maybe that would allay some of the sense of alienation.
Might epigenetics could provide some basis for understanding? Time will tell.
See also: Epigenetic change: Lamarck, wake up, you’re wanted in the conference room!
Vincent Torley read a post by Jerry Coyne where Jerry wondered if Intelligent Design Creationism was in trouble because the Discovery Institute has lost Bill Dembski and Casey Luskin [Is the Discovery Institute falling apart?].
Torley disagrees, obviously, but he focuses on a couple of the scientific statements in Jerry Coyne's post and comes up with Two quick questions for Professor Coyne.
I hope Professor Coyne won't mind if I answer.
Before answering, let's take note of the fact that Vincent Torley has been convinced by the evidence that most of our genome is junk. I wonder how that will go over in the ID community?
If Behe & Snoke are correct then modern evolutionary theory cannot explain the formation of new functions that require multiple mutations.
Cassey Luskin is aware of the fact that this result has not been widely accepted. He mentions one specific criticism:
In 2008, Behe and Snoke's would-be critics tried to refute them in the journal Genetics, but found that to obtain only two specific mutations via Darwinian evolution "for humans with a much smaller effective population size, this type of change would take > 100 million years." The critics admitted this was "very unlikely to occur on a reasonable timescale."
He's referring to a paper by Durrett and Schmidt (2008). Those authors examined the situation where one transcription factor binding site was disrupted by mutation and another one nearby is created by mutation. The event requires two prespecified coordinated mutations.
Casey Luskin is worried about university students. Apparently, they aren't getting enough correct information about intelligent design. Luskin uses the example of a student named Michael Heckle at Iowa State University. Mr. Heckel said; "So far, there has been no research done by intelligent design advocates that has led to any sort of scientific discovery."
The Canadian Institutes of Health Research (CIHR) is the main source of research funding for Canadian health researchers, including those doing basic research like most of the researchers in my biochemistry department.
A few years ago, CIHR decided to revamp the process of applying for and obtaining research grants. They did this without taking into consideration the wishes of most applicants. (They did "consult," but consulting isn't the same as listening.)
The result has been a disaster. Most researchers are confused and discouraged by the new process and there's great fear that the results of the next competitions will be harmful to basic research and harmful to new investigators.
But even before the new rules came into play the funding of basic, curiosity-motivated, science was taking a major hit. Many mid-career basic researchers at the University of Toronto have lost their grants or are struggling to make do with a lot less money. This is partly due to a lack of money in the system but it's been exacerbated by a deliberate shift in priorities under the previous Conservative government of former Prime Minister Stephen Harper.
The first one is "What Is Evolution Anyway?" You won't surprised to learn that Joe Hanson conflates "evolution" with "natural selection" and fails to mention the most important features of evolution [see What Is Evolution]. You WILL be surprised to learn that Jerry Coyne has the same objections I do! [Twelve Days of Evolution: #1: What’s evolution?]
We need to do a much better job of educating the general public about the meaning of evolution but first we need to educate the teachers. It's okay to be smart but it's not okay to just pretend to be smart.
Another article about evolution and the attainment of perfection has appeared. This one was published by Nathaniel Scharping on the Discover website [Could Evolution Ever Yield a ‘Perfect’ Organism?].
The article focuses on a recent paper from Richard Lenski's group at Michigan State University (Lenski et al., 2015). Lenski's group asked a different question. They wanted to know whether there was a limit to the increase in fitness in their evolving E. coli populations in the Long-Term Evolution Experiment (LTEE). It's a different question than whether evolution can select for a "perfect" organism because Lenski and his collaborators understand modern evolutionary theory. They know that mutations causing small fitness increases are beyond the reach of natural selection in their evolving populations and they know that deleterious mutations can be fixed by random genetic drift.
They know that real evolving populations can never reach the summit of an adaptive peak or, if they do, they can never stay there.
Intelligent Design Creationism is a movement based on bad science. Every single one of their positive, science-like, claims about ID have been refuted, or discredited, or shown to be completely unnecessary in the face of robust evolutionary explanations. Some of them have the distinction of being unnecessary AND refuted AND discredited (e.g irreducible complexity).
In addition to a small number of claims in support of ID, the proponents of Intelligent Design Creationism also advance dozens and dozens of arguments against evolution. In fact, this is by far the main activity of most adherents to the movement. Some of their arguments focus on legitimate scientific controversies. They are legitimate criticisms of some aspects of evolution but, even then, ID proponents often misrepresent and/or misunderstand the science behind the controversy (e.g. junk DNA).
However, the vast majority of their attacks on evolution are just as bad as their attempts to build a positive case for intelligent design. A disturbingly large number of such attacks exhibit a profound ignorance of science and how it works. In particular—surprisingly—they are ignorant of evolution. The movement is full of kooks. It will never become a credible source of information unless it purges itself by getting rid of the kooks.
You should read the article. It's a remarkable example of apologetics and why lawyers shouldn't try and explain science. While it's true that Judge Jones said lots of things we could quibble about, the big-picture take-home lesson from the trial is correct. No ID explanation stood up to the scrutiny of science. They were all shown to be either irrelevant or wrong.
That's why none of them should be presented in science class except as examples of bad science and faulty scientific reasoning.2
1. Luskin won't even admit that Young Earth Creationism is absurd.
2. In my opinion, they SHOULD be discussed in class since it's important to teach critical thinking and that requires that you directly confront common misconceptions.
There are about 20,000 protein-coding genes in the human genome. Protein products for about 18,000 of these genes have been detected in at least one human tissue (Kim et al, 2015; Wilhelm et al., 2015) [see How many proteins do humans make?].
About 10,000 of these proteins are present in all cells (Wilhelm et al., 2015) and somewhere between 1500 and 2000 are derived from genes that are essential in the average human cell (Blomen et al., 2015; Wang et al, 2015; Hart et al., 2015) [see How many human protein-coding genes are essential for cell survival?].
Let's assume there are about 10,000 protein-coding genes that are expressed in a typical human cell. Does this mean that there are only 10,000 different proteins in those cells? The answer is "no" but the differences are often subtle. The activities of some proteins, for example, are regulated by covalent modification so a typical cell will contain different versions of the protein: some are modified and some are not (e.g. phosphorylated and non-phosphorylated). These would be genuine versions of different proteins although you probably wouldn't want to make a fuss about it.
In some cases, there are various intermediates produced during protein synthesis. For example, some proteins destined for the mitochondria have an N-terminal tag that's cleaved when the proteins reach their destination. There are two different versions of the protein but, again, this isn't really a big deal. We should really only count the steady-state, terminal, stage of processing and modification.
Similarly, there are proteins that are glycosylated in various ways and cells will always contain intermediates including non-glycosylated versions that have just entered the ER. These don't count as different versions of the protein.
Some genes are alternatively spliced to give proteins that have different internal amino acid sequences. These are genuinely different proteins produced from the same gene.
If you add up all the genuinely different versions of proteins produced from 10,000 protein-coding genes, how many proteins are present in a typical human cell?
Here's a standard answer given in a recent news article in Nature (Savage, 2015)
The human body contains roughly 20,000 genes that are capable of producing proteins. Each gene can produce multiple forms of a protein, and these in turn can be decorated with several post-translational modifications: they can have phosphate or methyl groups attached, or be joined to lipids or carbohydrates, all of which affect their function. “The number of potential molecules you can make from one gene is huge,” says Bernhard Küster, who studies proteomics at the Technical University of Munich in Germany. “It's very hard to estimate, but I wouldn't be surprised to have in one cell type 100,000 or more different proteins.”
I suspect that Küster is one of those scientists who think that almost all human protein-coding genes are alternatively spliced to yield several different proteins in each cell. He has to imagine that there are, on average, ten different versions of a protein produced from each gene that's expressed in a typical cell.
That means ten different versions of each of the subunits of pyruvate dehydrogenase and RNA polymerase. It means ten different versions of triose phosphate isomerase and each of the ribosomal proteins. There should be ten different versions of actin and ten different versions of cytochrome c.
This seems very unlikely to me.
Discuss.
(There may be a few genes that have thousands of different variants, although I'm skeptical. In that case there may be 100,000 different proteins in a human cell but surely this is misleading even if it's accurate?)
Blomen, V.A., Májek, P., Jae, L.T., Bigenzahn, J.W., Nieuwenhuis, J., Staring, J., Sacco, R., van Diemen, F.R., Olk, N., and Stukalov, A. (2015) Gene essentiality and synthetic lethality in haploid human cells. Science, 350:1092-1096. [doi: 10.1126/science.aac7557 ]
Hart, T., Chandrashekhar, M., Aregger, M., Steinhart, Z., Brown, K.R., MacLeod, G., Mis, M., Zimmermann, M., Fradet-Turcotte, A., and Sun, S. (2015) High-Resolution CRISPR Screens Reveal Fitness Genes and Genotype-Specific Cancer Liabilities. Cell 163:1515-1526. [doi: 10.1016/j.cell.2015.11.015]
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I agree with Casey Luskin. During the trial, Behe was asked to define scientific theory and of course he adopted the broad view of science. He said, "Under my definition, a scientific theory is a proposed explanation which focuses or points to physical, observable data and logical inferences."
Here's the exchange that took place during the trial [Dover: Day 11].
Q In any event, in your expert report, and in your testimony over the last two days, you used a looser definition of "theory," correct? A I think I used a broader definition, which is more reflective of how the word is actually used in the scientific community. Q But the way you define scientific theory, you said it's just based on your own experience; it's not a dictionary definition, it's not one issued by a scientific organization. A It is based on my experience of how the word is used in the scientific community. Q And as you said, your definition is a lot broader than the NAS definition? A That's right, intentionally broader to encompass the way that the word is used in the scientific community. Q Sweeps in a lot more propositions. A It recognizes that the word is used a lot more broadly than the National Academy of Sciences defined it. Q In fact, your definition of scientific theory is synonymous with hypothesis, correct? A Partly -- it can be synonymous with hypothesis, it can also include the National Academy's definition. But in fact, the scientific community uses the word "theory" in many times as synonymous with the word "hypothesis," other times it uses the word as a synonym for the definition reached by the National Academy, and at other times it uses it in other ways. Q But the way you are using it is synonymous with the definition of hypothesis? A No, I would disagree. It can be used to cover hypotheses, but it can also include ideas that are in fact well substantiated and so on. So while it does include ideas that are synonymous or in fact are hypotheses, it also includes stronger senses of that term. Q And using your definition, intelligent design is a scientific theory, correct? A Yes. Q Under that same definition astrology is a scientific theory under your definition, correct? A Under my definition, a scientific theory is a proposed explanation which focuses or points to physical, observable data and logical inferences. There are many things throughout the history of science which we now think to be incorrect which nonetheless would fit that -- which would fit that definition. Yes, astrology is in fact one, and so is the ether theory of the propagation of light, and many other -- many other theories as well. Q The ether theory of light has been discarded, correct? A That is correct. Q But you are clear, under your definition, the definition that sweeps in intelligent design, astrology is also a scientific theory, correct? A Yes, that's correct. And let me explain under my definition of the word "theory," it is -- a sense of the word "theory" does not include the theory being true, it means a proposition based on physical evidence to explain some facts by logical inferences. There have been many theories throughout the history of science which looked good at the time which further progress has shown to be incorrect. Nonetheless, we can't go back and say that because they were incorrect they were not theories. So many many things that we now realized to be incorrect, incorrect theories, are nonetheless theories. Q Has there ever been a time when astrology has been accepted as a correct or valid scientific theory, Professor Behe? A Well, I am not a historian of science. And certainly nobody -- well, not nobody, but certainly the educated community has not accepted astrology as a science for a long long time. But if you go back, you know, Middle Ages and before that, when people were struggling to describe the natural world, some people might indeed think that it is not a priori -- a priori ruled out that what we -- that motions in the earth could affect things on the earth, or motions in the sky could affect things on the earth.
I mostly agree with Behe.1 Astrology was an attempt to explain human behaviors by relating them to the position of the Earth on the day you were born. There is no connection. So today we think of astrology as bad science. It's not true that the stars determine your behavior and whenever we make this claim to an astologist we make sure to point out that the evidence is against it.
What we don't do is tell astrologers that they are entitled to believe whatever they want because astrology is not science and therefore we can't make a scientific statement about whether it's correct or not.
Intelligent Design Creationism is bad science. So is most of evolutionary psychology and some of genomics. So is the attempt to find god in a football helmet [The God Helmet: Your Brain on Religion].
It's disingenuous to make fun of Behe's testimony without understanding that the real issue is epistemology and the demarcation problem. Behe's view of science is perfectly legitimate but it didn't jibe with what the plaintiffs were trying to establish during the trial. They wanted to prove that ID isn't science and the best way to do that was to show that something can't be science unless it's true. In other words, science isn't a "way of knowing," it's the end result.
What does this mean? It means that every discredited attempt to explain something using science as a way of knowing becomes "not science" with hindsight. All those people who tried to show that genes were proteins were wrong so it means that what they were doing is not science. It means that of the two sides arguing about junk DNA, one of them will be wrong so, at some time in the future, their current activities will be seen as "not science."
Isn't that bizarre?
1. He should have been defining "science" not "scientific theory." That's the fault of his lawyers who failed to make this point during his direct testimony.
Of course the ID movement didn't die after Kitzmiller v. Dover. From the outside (i.e. not in the USA) it seems to be as strong as ever. State legislatures all over America are still trying to suppress the teaching of evolution and promote creationist perspectives. The movement has captured the attention of many (most?) prominent politicians and much of the American public still believes that scientists are wrong about evolution.
I just re-read a 1997 paper by Francis Ayala and Walter Fitch (Ayala and Fitch, 1997). The opening two paragraphs describe the Modern Synthesis of Evolution in a very interesting way. The emphasis is on the history and the contributions of Theodosius Dobzhansky (1900-1975) but it makes another point that I'd like to mention.
Theodosius Dobzhansky (1900–1975) was a key author of the Synthetic Theory of Evolution, also known as the Modern Synthesis of Evolutionary Theory, which embodies a complex array of biological knowledge centered around Darwin’s theory of evolution by natural selection couched in genetic terms. The epithet ‘‘synthetic’’ primarily alludes to the artful combination of Darwin’s natural selection with Mendelian genetics, but also to the incorporation of relevant knowledge from biological disciplines. In the 1920s and 1930s several theorists had developed mathematical accounts of natural selection as a genetic process. Dobzhansky’s Genetics and the Origin of Species, published in 1937 (1), refashioned their formulations in language that biologists could understand, dressed the equations with natural history and experimental population genetics, and extended the synthesis to speciation and other cardinal problems omitted by the mathematicians.
The current Synthetic Theory has grown around that original synthesis. It is not just one single hypothesis (or theory) with its corroborating evidence, but a multidisciplinary body of knowledge bearing on biological evolution, an amalgam of well-established theories and working hypotheses, together with the observations and experiments that support accepted hypotheses (and falsify rejected ones), which jointly seek to explain the evolutionary process and its outcomes. These hypotheses, observations, and experiments often originate in disciplines such as genetics, embryology, zoology, botany, paleontology, and molecular biology. Currently, the ‘‘synthetic’’ epithet is often omitted and the compilation of relevant knowledge is simply known as the Theory of Evolution. This is still expanding, just like one of those ‘‘holding’’ business corporations that have grown around an original enterprise, but continue incorporating new profitable enterprises and discarding unprofitable ones.
The important point here is that evolutionary theory is a complex synthesis of sub-theories, hypotheses, and observations. While it may be convenient to refer to this synthetic version as the "Theory of Evolution," it's also very misleading.
I strongly recommend that we abandon that term and use "evolutionary theory" instead. Furthermore, we should be careful about using the term "Modern Synthesis" unless we are specifically referring to the version of evolutionary theory that was popular in the 1950s.
It's true that Ayala and Fitch would like to retain the term "Synthetic Theory" to refer to the expanded version of the Modern Synthesis. They want to emphasize that there have been important extensions to the original Modern Synthesis but these are merely add-ons. Darwin's basic idea of evolution by natural selection remains at the core of their version of the "Theory of Evolution."
That seems like a very pluralistic view but I'd like to note several things about this paper.
The word "drift" appears only once and it's in the form "neutral drift." There's no mention of random genetic drift as a mechanism of evolution that's been incorporated into the synthetic version of evolutionary theory.
The word "neutral" appears five times but "Neutral Theory" is not mentioned. The authors do concede that "the neutral-selection controversy rages on."
There are 50 references but not a single paper by Mootoo Kimura is mentioned. They do, however, discuss molecular clocks and discuss whether amino acid substitutions are really of "no adaptive consequence."
There's a fairly well-known paper by Gould and Lewontin that might be relevant in a discussion about the synthetic version modern evolutionary theory. They neglected to mention it.
Ayala, F.J., and Fitch, W.M. (1997) Genetics and the origin of species: an introduction. Proc. Natl. Acad. Sci. (USA) 94:7691-7697. [PDF]
Gould, S.J., and Lewontin, R.C. (1979) The spandrels of San Marco and the Panglossian paradigm: a critique of the adaptationist programme. Proc. Roy. Soc. (London) Series B. Biological Sciences 205:581-598. [doi: 10.1098/rspb.1979.0086]
The human genome contains about 20,000 protein-coding genes and about 5,000 genes that specify functional RNAs. We would like to know how many of those genes are essential for the survival of an individual and for long-term survival of the species.
It would be almost as interesting to know how many are required for just survival of a particular cell. This set is the group of so-called "housekeeping genes." They are necessary for basic metabolic activity and basic cell structure. Some of these genes are the genes for ribosomal RNA, tRNAs, the RNAs involved in splicing, and many other types of RNA. Some of them are the protein-coding genes for RNA polymerase subunits, ribosomal proteins, enzymes of lipid metabolism, and many other enzymes.
The ability to knock out human genes using CRISPR technology has opened to door to testing for essential genes in tissue culture cells. The idea is to disrupt every gene and screen to see if it's required for cell viability in culture.
Three papers using this approach have appeared recently:
Blomen, V.A., Májek, P., Jae, L.T., Bigenzahn, J.W., Nieuwenhuis, J., Staring, J., Sacco, R., van Diemen, F.R., Olk, N., and Stukalov, A. (2015) Gene essentiality and synthetic lethality in haploid human cells. Science, 350:1092-1096. [doi: 10.1126/science.aac7557 ]
Wang, T., Birsoy, K., Hughes, N.W., Krupczak, K.M., Post, Y., Wei, J.J., Lander, E. S., and Sabatini, D.M. (2015) Identification and characterization of essential genes in the human genome. Science, 350:1096-1101. [doi: 10.1126/science.aac7041]
Hart, T., Chandrashekhar, M., Aregger, M., Steinhart, Z., Brown, K.R., MacLeod, G., Mis, M., Zimmermann, M., Fradet-Turcotte, A., and Sun, S. (2015) High-Resolution CRISPR Screens Reveal Fitness Genes and Genotype-Specific Cancer Liabilities. Cell 163:1515-1526. [doi: 10.1016/j.cell.2015.11.015]
Each group identified between 1500 and 2000 protein-coding genes that are essential in their chosen cell lines.
One of the annoying things about all three papers is that they use the words "gene" and "protein-coding gene" as synonyms. The only genes they screened were protein-coding genes but the authors act as though that covers ALL genes. I hope they don't really believe that. I hope it's just sloppy thinking when they say that their 1800 essential "genes" represent 9.2% of all genes in the genome (Wang et al. 2015). What they meant is that they represent 9.2% of protein-coding genes.
By looking only at genes that are essential for cell survival, they are ignoring all those genes that are specifically required in other cell types. For example, they will not identify any of the genes for olfactory receptors or any of the genes for keratin or collagen. They won't detect any of the genes required for spermatogenesis or embryonic development.
What they should detect is all of the genes required in core metabolism.
The numbers seen too low to me so I looked for some specific examples.
The HSP70 gene family encodes the major heat shock protein of molecular weight 70,000. The protein functions as a chaperone to help fold other proteins. They are among the most highly conserved genes in all of biology and they are essential. The three genes for the normal cellular proteins are HSPA5 (Bip, the ER protein); HSPA8 (the cytoplasmic version); and HSPA9 (mitochondrial version). All three are essential in the Blomen et al. paper. Only HSPA5 and HSPA9 are essential in Hunt et al. (This is an error.) (I can't figure out how to identify essential genes in the Wang et al. paper.)
There are two inducible genes, HSPA1A and HSPA1B. These are the genes activated by heat shock and other forms of stress and they churn out a lot of HSP70 chaperone in order to save the cells. There are not essential genes in the Blomen et al. paper and they weren't tested in the Hunt et al. paper. This is an example of the kind of gene that will be missed in the screen because the cells were not stressed during the screening.
I really don't like these genomics papers because all they do is summarize the results in broad terms. I want to know about specific genes so I can see if the results conform to expectations.
I looked first at the genes encoding the enzymes for gluconeogenesis and glycolysis. The results are from the Blomen et al. paper. In the figure below, the genes names in RED are essential and the ones in blue are not.
As you can see, at least one of the genes for the six core enzymes is essential. But none of the other genes is essential. This is a surprise since I expect both pathways (gluconeogenesis and glycolysis) to be active and essential in those cells. Perhaps the cells can survive for a few days without making these enzymes. It means they can't take up glucose because one of the hexokinase enzymes should be essential.
These result suggest that the Blomen et al. study is overlooking some important essential genes.
Now let's look at the citric acid cycle. All of the enzymes should be essential.
That's very strange. It's hard to imagine that cells in culture can survive without any of the genes for the subunits of the pyruvate dehydrogenase complex or the subunits of the succinyl C0A synthetase complex. Or malate dehydrogenase, for that matter.
Something is wrong here. The study must be missing some important essential genes. I wish the authors had looked at some specific sets of genes and told us the results for well-known genes. That would allow us to evaluate the results. Perhaps this sort of thing isn't done when you are in "genomics" mode?
The "core fitness" protein-coding genes that were identified are more highly conserved than the other genes and they tend to be more highly expressed. They also show lower levels of variation within the human population. This is consistent with basic housekeeping features.
Each group identified several hundred unannotated genes in their core sample. These are genes with no known function (yet).
The results of the three studies do not overlap precisely but most of the essential genes were common to all three analyses.
All living organisms have developed highly accurate DNA replication complexes and sophisticated mechanisms for repairing DNA damage. The combination results in DNA replication errors that are about 1 per 10 billion base pairs (10-10 per bp). DNA damage due to other factors is effectively repaired with an error rate of 1 in 100 per base pair (10-2 per bp).
Mutations can be beneficial, deleterious, or neutral. In organisms with large genomes there are many more neutral mutations than the other two classes but in organisms with smaller genomes a higher percentage of mutations are either beneficial or deleterious. In all cases, there are more deleterious mutations than beneficial ones.
If deleterious mutations are harmful to the individual then natural selection should favor a low mutation rate in order to minimize that effect. This is especially true in large multicellular organisms where somatic cell mutations cause cancer and other problems. It seems logical that the optimal mutation rate should be zero in order to maximize the survival of the individual and its offspring.
Nothing in biology makes sense except in the light of population genetics.
Michael Lynch But even though the number of beneficial mutations is low compared to those that are deleterious, this is the stuff of adaptive evolution. In the long run the population will become more fit if beneficial mutations occur and become fixed by natural selection. Eliminating mutations might provide a short-term advantage but eventually the population will go extinct if it can't adapt to new environments. (Neutral and deleterious mutations can also contribute to adaptation over the long term.)
The simplest explanation for this apparent paradox is that there's a trade-off between selection to minimize deleterious mutations and selection for long-term evolutionary advantage. The problem with that explanation is that it is very difficult to show how you can select for the future benefit of mutations to the species (population). It seems as though you have to invoke two bogeymen; group selection and teleology.
Maybe there's a better explanation?
Jerry Coyne recently thought about this problem and posted his analysis under the provocative title: The irony of natural selection. He concludes that there's some constraint that limits the ability of natural selection to achieve a zero mutation rate.
The most probable explanation is that evolution does not produce perfect adaptations. In the case of mutations, though natural selection favors individuals most able to repair any changes in DNA (although a small percentage of these might be adaptive), this level of perfection cannot be achieved because of constraints: the cost of achieving perfection, the fact that all errors are impossible to detect or remove, or that some cells (i.e., sperm or eggs) may not even have DNA-repair mechanisms because of genetic or physiological constraints.
I used to think that this was the best explanation. I taught my students that the accuracy of DNA replication, for example, comes at the cost of speed. The more accurate the polymerization process, the slower it takes. This makes a lot of sense and there's experimental support for the claim. Slowing down the time it takes to replicate the genome will affect the time it takes for cell divisions and that could be harmful ... or so the argument goes.
Unfortunately, I ran into Michael Lynch at an evolution meeting and he quickly destroyed that argument. There's no evidence that the speed of DNA replication is limiting the rate of cell divisions and, besides, there are easy ways for selection to get around such a limitation if it ever occurred. (This is a photo of Michael Lynch looking at me right after setting me straight. He's wondering how I could have been so stupid.)
When you think about it, there doesn't seem to be any biochemical or physiological constraints that could prevent the mutation rate from getting to zero ... or at least a lot closer than it is now.
Michael Lynch has a better answer and he explains it in a paper titled: "The Lower Bound to the Evolution of Mutation Rates" (Lynch, 2011).
As the mutation rate is driven to lower and lower levels by selection, a point must eventually be reached where the advantage of any further increase in replication fidelity is smaller than the power of random genetic drift (Lynch 2008, 2010). The goal here is to evaluate the extent to which such an intrinsic barrier can provide an adequate explanation for the patterns of mutation rates known to have evolved in natural populations.
The main "constraint" is the limited power of natural selection in the presence of random genetic drift. This will depend to some extent of the size of the population.
This idea is called the "drift-barrier hypothesis. It is described in Sung et al. (2012):
... the drift-barrier hypothesis predicts that the level of refinement of molecular attributes, including DNA replication fidelity and repair, that can be accomplished by natural selection will be negatively correlated with the effective population size (Ne) of a species. Under this hypothesis, as natural selection pushes a trait toward perfection, further improvements are expected to have diminishing fitness advantages. Once the point is reached beyond which the effects of subsequent beneficial mutations are unlikely to be large enough to overcome the power of random genetic drift, adaptive progress is expected to come to a standstill. Because selection is generally expected to favor lower mutation rates as a result of the associated load of deleterious mutations, and because the power of drift is inversely proportional to Ne, lower mutation rates are expected in species with larger Ne.
The Lynch lab has produced lots of evidence in support of the hypothesis although there may be some confounding factors in some populations.
The bottom line is that the real irony of natural selection is that it's just not powerful enough to reduce the error rate of replication and repair below the values we currently see.
In a sense, it's the "error rate" of fixation by natural selection in the face of random genetic drift that allows evolution to occur.
The more we learn about biology the more we learn that it's messy and sloppy at every level. Evolution is not a watchmaker and it's not even a blind watchmaker. It's a tinkerer1 and the "watch" barely keeps time.
1. Jacob, F. (1977) Evolution and tinkering. Science (New York, NY), 196:1161. [PDF]
Lynch, M. (2011) The lower bound to the evolution of mutation rates. Genome Biology and Evolution, 3:1107. [doi: 10.1093/gbe/evr066]
Sung, W., Ackerman, M.S., Miller, S.F., Doak, T.G., and Lynch, M. (2012) Drift-barrier hypothesis and mutation-rate evolution. Proc. Natl. Acad. Sci. (USA) 109:18488-18492. [doi: 10.1073/pnas.1216223109]
Sometime back in the pre-Cambrian (before blogs) there was a newsgroup called talk.origins—it still exists. In 1993 I wrote a little essay that tried to convince creationists1 of the difference between facts of evolution and evolutionary theory [Evolution is a Fact and a Theory]. I relied heavily on Stephen Jay Gould's essay on "Evolution as Fact and Theory" originally published in Discover magazine in 1981 and re-printed in Hen's Teeth and Horse's Toes.
Today Google celebrates the birthday of Lucy Maud Montgomery (November 30, 1874 – April 24, 1942). She is the author of Anne of Green Gables and other books.
Lucy Maud Montgomery was born in Prince Edward Island (Canada) and after getting her teaching certificate from Prince of Wales College in Charlottetown (P.E.I.) she attended Dalhousie University in Halifax (Nova Scotia, Canada) before taking up a teaching position in P.E.I. That's when she wrote Anne of Green Gables (1908).
In 1911 she married a Presbyterian minister, Ewen Macdonald, and moved to Uxbridge, Ontario (northeast of Toronto). In 1926, she and her husband moved to Norval, Ontario, a small village due north of where I live in Mississauga, Ontario. We've passed her house many times. She lived there until 1935 when she moved to Swansea, Ontario, now a part of western Toronto between the Humber River and High Park. She died there in 1942 and was buried in P.E.I.
Lucy Maud Montgomery is a distant cousin of mine. I descend from the Coles. The genealogy is confusing but at some point in time a Mr. Cole and his wife Mary (maiden name unknown) came to North America, probably New York. Their son, Benjamin Cole, is my great4-grandfather. Mr. Cole died sometime around 1765 and Mary married George Penman. The history is confusing, they may have lived in New England and moved to P.E.I. just before or after the American Revolution. They self-identify as United Empire Loyalists.
Mary is my great5 grandmother and she had several children with George Penman. Two of them were Nancy (b. 1768) and Elizabeth ("Betsy") (b. 1769). Nancy married Donald Montgomery of the "New Moon" farm in Malpeque, P.E.I. (Emily of New Moon). Her sister married David Murray.
Donald Montgomery, the son of Nancy & Donald, married his first cousin Ann Murray, daughter of Elizabeth & David. Their son, Hugh John Montgomery, was Lucy Maud Montgomery's father.
Thus, Lucy Maud Montgomery's great grandmother is my great-great-great-great-great grandmother.
I recently had occasion to re-read a paper by Motoo Kimura from 1968. (Kimura, 1968). I noticed, for the first time, that he estimates a mutation rate based on his understanding of the error rate of DNA replication. He also makes a comment about creationists.
Remember, this was in 1968 and we didn't know as much then as we do now. Kimura took note of the fact that evolutionary trees based on comparing amino acid sequences gave rates of amino acid substitutions that seemed far too high. His conclusion is in the abstract.
Last week we went to the Canadian Warplane Heritage Museum in Hamilton, Ontario (Canada) with our grandson Luca [see The Latest Excursion]. Here I am with Luca standing beside a Hawker Hurricane from World War II.
My father, F/L Laurence Victor "Vic" Kirsch,1 was a fighter pilot in World War II and he flew Hurricanes and, later, rocket-firing Hawker Typhoons with the RAF 164 Squadron known as the Argentine British Squadron because of the volunteers from Argentina. (My father was seconded from the RCAF (Canada)).
Here's a picture of him (below) in the cockpit of one of his planes.
I have his log books. The first page (right) shows him flying Hurricanes ("Hurry") in sorties over France in December 1943. This was just when the squadron was preparing to switch to Typhoons and become specialists in ground support in preparation for D-Day.
The next entries (below) are facing pages from June, 1944. Note the entry for June 6, 1944. On the left is "DER TAG" in red and on the right is "LONG AWAITED 2nd FRONT IS HERE." The entry for June 5th reads, "Deas and self flew to Cherbourg and reported the weather. Flew over the invasion fleet, impressive sight. Hundreds of naval craft and A/C cover. Wouldn't have missed this sight for the world. Dark when we landed and silly old Deas practised landing on his belly."
The entry for June 6th (D-Day) reads, "Followed SQDN across channel. Saw hundreds of ships. Jumped by 90's."
On June 14th (one week after D-Day) the squadron lands at their new base in Crépon, France.
1. He died in a plane crash when I was four months old. My mother remarried and I was adopted by my stepfather, K.R. Moran.
