Gene Genie #40

 
The 40th edition of Gene Genie has been posted at Human Genetics Disorders [Gene Genie Edition 40].

NSGC Conference exibit and MBA thesis poster presentation videos from the October 24-28 2008 AEC Conference by Chavonne Jones

The beautiful logo was created by Ricardo at My Biotech Life.

The purpose of this carnival is to highlight the genetics of one particular species, Homo sapiens.

Here are all the previous editions .....

1. Scienceroll
2. Sciencesque
3. Genetics and Health
4. Sandwalk
5. Neurophilosophy
6. Scienceroll
7. Gene Sherpa
8. Eye on DNA
9. DNA Direct Talk
10. Genomicron
11. Med Journal Watch
12. My Biotech Life
13. The Genetic Genealogist
14. MicrobiologyBytes
15. Cancer Genetics
16. Neurophilosophy
17. The Gene Sherpa
18. Eye on DNA
19. Scienceroll
20. Bitesize Bio
21. BabyLab
22. Sandwalk
23. Scienceroll
24. biomarker-driven mental health 2.0
25. The Gene Sherpa
26. Sciencebase
27. DNA Direct Talk
28. Greg Laden’s Blog
29. My Biotech Life
30. Gene Expression
31. Adaptive Complexity
32. Highlight Health
33. Neurophilosophy
34. ScienceRoll
35. Microbiology Bytes
36. Human Genetic Disordrs
37. The Genetic Genealogist
38. ScienceRoll
39. Genetics & Health
40. Human Genetics Disorders

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My Desk

 
Eva re-starts another meme.

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I Hate Ironing

 
But these guys seem to like it. What am I missing?

I've been following this sport for several years and I still don't get how they do it. Maybe I need a new iron?

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[Hat Tip: Canadian Cynic, of course.

They're Coming to Your Town!

 
The American Family Association sells Christmas crosses that remind you of something evil [Hide it under a bushel? NO!]. But the website has lots more stuff as pointed out by one reader who commented on my earlier posting.

You really need to see They're Coming to Your Town DVD.

Residents of the small Arkansas town of Eureka Springs noticed the homosexual community was growing. But they felt no threat. They went about their business as usual. Then, one day, they woke up to discover that their beloved Eureka Springs, a community which was known far and wide as a center for Christian entertainment--had changed. The City Council had been taken over by a small group of homosexual activists.

The Eureka Springs they knew is gone. It is now a national hub for homosexuals. Eureka Springs is becoming the San Francisco of Arkansas. The story of how this happened is told in the new AFA DVD “They’re Coming To Your Town.”

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Arwen

 
This is Arwen. Ms. Sandwalk tells me there's a connection between her and Monday's Molecule #97. I didn't know that.¹ Did you?

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1. This is really just an excuse to post the photo.

Monday's Molecule #97

 
Today we're taking a bit of a break from boring old biochemical molecules and fruit flies to look at some specific individuals of the species Homo sapiens. Your task for today is to identify these men. I need all of their names and the name that collectively identifies them.

The answer is indirectly related to this week's Nobel Laureate. See if you can make the connection.

The first one to correctly identify the individuals and name the Nobel Laureate(s), wins a free lunch at the Faculty Club. Previous winners are ineligible for one month from the time they first collected the prize. There are only three ineligible candidates for this week's reward: Bill Chaney of the University of Nebraska, Dima Klenchin of the University of Wisconsin and Dale Hoyt from Athens, Georgia. Dale has agreed to donate the free lunch to a deserving undergraduate so the first undergraduate to win and collect a free lunch can also invite a friend.

THEME:

Nobel Laureates
Send your guess to Sandwalk (sandwalk (at) bioinfo.med.utoronto.ca) and I'll pick the first email message that correctly identifies the "molecule" and names the Nobel Laureate(s). Note that I'm not going to repeat Nobel Laureate(s) so you might want to check the list of previous Sandwalk postings by clicking on the link in the theme box.

Correct responses will be posted tomorrow. I reserve the right to select multiple winners if several people get it right.

Comments will be blocked for 24 hours. Comments are now open.

The band is Aerosmith and this should remind you of the book "Arrowsmith" by Sinclair Lewis who won the Nobel Prize for Literature in 1930. Arrowsmith is a book about scientists.

Three people knew who the band was—one of them was Ms. Sandwalk! Only one person saw the connection between Aerosmith and a Nobel Laureate but that person (Dima) is ineligible. I decided to award the free lunch to Ms. Sandwalk, making her ineligible for any more lunches for one month!!!

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Hide it under a bushel? NO!

 

This is the latest in Christmas decorations from the American Family Association.

Let Your "Light" Shine For Christ This Christmas Season!

Looking for an effective way to express your Christian faith this Christmas season to honor our Lord Jesus? Now you can.... with the "Original Christmas Cross" yard decoration.

Light up your front yard, porch, patio, driveway, business, organization or church this holiday season with a stunning Christmas cross.

Can't you just picture these five and-a-half foot crosses in the middle of front yards all across America?

What in the world are they thinking?

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[Hat Tip: LuLu at Canadian Cynic]

Be Afraid

 
There have been some changes on Uncommon Descent. Bill Dembski won't be posting as often (Boo!) and the chief web person will be Barry Arrington [What’s New At UD].

Here's a warning from the new chief IDiot.

We live in exciting times. The Darwinist/materialist hegemony over our culture has definitely peaked, and we are privileged to watch the initial tremors that are shaking the Darwinist house of cards. These are only the beginning of woes for St. Charles’ disciples, and I look forward to one day watching the entire rotten edifice come crashing down. I am persuaded that just as when the Soviet Union went seemingly overnight from “menacing colossus astride the globe” to “non-existent,” the final crash of the House of Darwin will happen with astonishing suddenness. You can be sure that we at UD will be there not only reporting on events, but also lending our intellectual pry bars to the effort.

Hmmm ... "intellectual pry bars" ... that's an image that's going to be hard to shake.

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Why do we blog and other important questions

 
OK, so I'm not a Nature Network blogger, but I thought I'd answer the questions anyway.

1. What is your blog about?
   It's about science, religion, universities, politics, and almost everything else I'm interested in. Mostly science and science education.


2. What will you never write about?
   Aha! A trick question! You almost got me!


3. Have you ever considered leaving science?
   No.


4. What would you do instead?
   I dunno, what do other people do? (Eva has a much funnier reply to this question)


5. What do you think will science blogging be like in 5 years?
   Pretty much the same as it is now. Which is pretty much the same as it's been for the past five years. Which isn't a lot different than the newsgroups were for the previous 20 years before that.


6. What is the most extraordinary thing that happened to you because of blogging?
   I've made dozens of new friends. (For me, that's extraordinary.)


7. Did you write a blog post or comment you later regretted?
   Yes.


8. When did you first learn about science blogging?
   I don't recall exactly. It was probably sometime around 2002 when I first learned that people were actually reading them.


9. What do your colleagues at work say about your blogging?
   Most of them don't understand the blogging culture. They think it's bizarre. They think I'm bizarre—but they thought that even before I started Sandwalk

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Be the First in Your School

 
Be the first in your school, or church, to have one of these T-shirts—or others like it. (It also comes in red and black.) Go to Evo-Ts.

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Making Sense in Biology

When I teach students how to read the scientific literature, I caution them not to believe everything they read. Science is, by it's very nature, tentative and exploratory. Much of what is published doesn't get confirmed and is quietly ignored. Many of the ideas and speculations that are published never amount to anything. Some experiments are flawed. Many skim over hidden assumptions so that the conclusions aren't valid.

How do you tell the difference between the wheat and the chaff? Well, for one thing, you ask yourself whether the results "make sense" in light of what you already know. Are there any basic principles of biology that conflict with the conclusions? You always have to be on the lookout for papers that just don't fit in with your current model of how things work.

There are two potential problems with this approach. First, your model may not be correct. Maybe you don't know enough to make a judgment. Second, it prevents you from recognizing truly novel results that may change your idea of what makes sense.

The first problem is curable. The second is more serious. Science is basically conservative in its acceptance of new ideas. This may seem like a bad thing but, in fact, it's the only way to do good science. You simply can't afford to believe in several paradigm shifts every day before breakfast because most of them will turn out to be wrong. Today, when scientists want to convince their colleagues of something new that may not "make sense", they are obliged to present solid evidence that will convince the skeptics. It's an uphill fight. And it should be.

One of my colleagues has been following the discussion about alternative splicing and he directed my attention to a paper he just published in Nature Genetics. He pointed out that far from being an overestimate of alternative splicing, the EST data actually underestimates the extent of alternative splicing.

The paper by Pan et al. (2008) makes two extraordinary claims.

1. Their data indicates that about 95% of all multiexon human genes undergo alternative splicing.
2. They estimate that there are, on average, seven (7) alternative splicing events per multiexon human gene.

Neither of these claims make sense. It's not reasonable to assume that most conserved housekeeping genes produce variants by alternative splicing yet that's exactly what would have to happen if 95% of all genes undergo alternative splicing. It means that most most genes for things like metabolic enzymes, RNA polymerase, ribosomal proteins and transport proteins will have variants due to alternative splicing. This doesn't make sense from an understanding of biochemistry and it doesn't make sense in light of evolution.

That's good reason to be skeptical.

But surely the data must be convincing? Surely the proponents of these extraordinary claims have extraordinary data to back their cease?

Frankly, I don't know. I can't evaluate the Pan et al. (2008) paper because I have no idea how they actually do their experiments and whether those experiments are reliable. Part of the problem is that the authors don't tell me enough and part of it is that this is unfamiliar technology (to me).

All I know is that it doesn't make sense. I've asked the author to give me some specific examples of alternative splicing predictions for common genes, like those in the citric acid cycle. By looking at specific, rather than global, data it might be possible to see whether the results make sense.

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Pan, Q., Shai, O., Lee, L.J., Frey, B.J. and Blencowe, B.J. (2008) Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nature Genetics, published online Nov. 2, 2008. [DOI:10.1038/ng.259]

Students and a Sense of Entitlement

 
A recent study by Greenberger et al. (2008) looked at student's sense of entitlement in order to see where it comes from. Here's the abstract ...

Abstract Anecdotal evidence suggests an increase in entitled attitudes and behaviors of youth in school and college settings. Using a newly developed scale to assess ‘‘academic entitlement’’ (AE), a construct that includesexpectations of high grades for modest effort and demanding attitudes towards teachers, this research is the first to investigate the phenomenon systematically. In two separate samples of ethnically diverse college students comprised largely of East and Southeast Asian American, followed by Caucasians, Latinos, and other groups (total N = 839, age range 18–25 years), we examined the personality, parenting, and motivational correlates of AE. AE was most strongly related to exploitive attitudes towards others and moderately related to an overall sense of entitlement and to narcissism. Students who reported more academically entitled attitudes perceived their parents as exerting achievement pressure marked by social comparison with other youth and materially rewarding good grades, scored higher than their peers in achievement anxiety and extrinsic motivation, and engaged in more academic dishonesty. AE was not significantly associated with GPA.

I don't put a lot of credence in these studies but I thought it was interesting that the problem was at least being investigated. The survey results, below, are interesting.

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[Hat Tip: Musings of the Mad Biologist]

Greenberger, E., Lessard, J., Chen, C. and Farruggia, S.P. (2008) Self-Entitled College Students: Contributions of Personality, Parenting, and Motivational Factors. Journal of Youth and Adolescence 37:1193-1204 [Springerlink]

Tangled Bank #118

 
The latest issue of Tangled Bank has been published on Submitted to a Candid World [Tangled Bank #118: Yes We Did Edition].

It’s my pleasure to bring you this edition of Tangled Bank, a biweekly collection of posts on important issues of biology and science. How I managed to secure the first post-election Tangled Bank for this little politics blog is beyond me: far be it for me to complain, but it really makes you wonder about PZ Myers’ processes for vetting new hosts… I’ll try my best not to play Sarah Palin to his John McCain.

Common readers of this site will know from experience that I, like all the co-writers of this blog, pushed hard for Obama’s election, and new visitors will guess as much from the site’s browser icon (surprise!). Now that the man’s elected, though, there’s a lot of work to be done - especially because, over the past eight years, scientific integrity somehow became a Democrats-only issue. America’s science community has a lot of ground to recover and, until Obama decides to restore the office to its pre-Bush grandeur, we, the concerned netroots, are the closest thing he has to White House science advisers. Thus, I present to you President-Elect Barack Obama’s first science briefing -

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Send an email message to host@tangledbank.net if you want to submit an article to Tangled Bank. Be sure to include the words "Tangled Bank" in the subject line. Remember that this carnival only accepts one submission per week from each blogger.

Nobel Laureate: Edward Lewis

 

The Nobel Prize in Physiology or Medicine 1995.

"for their discoveries concerning the genetic control of early embryonic development"

Edward B. Lewis (1918 - 2004) won the Noble Prize for his studies on the genetics of Drosophila melanogaster, especially the homeotic mutants in the bithorax complex. These are the mutations that cause transformation of the 3nd thoracic segment into the 2nd, giving rise to a fly with four wings instead of two.

The significance of this work can't be underestimated. It led to our modern understanding of development and evolution. Thanks to Lewis, we now know that small changes in the regulation of gene expression can have large effects on phenotype. It means that the number of mutations required to make the difference between mice and humans, for example, may be far less that what people imagined 50 years ago.

Edward Lewis shared the prize with Christiane Nüsslein-Volhard and Eric Wieschaus. Here's what the press release said about Lewis.

THEME:
Nobel Laureates

The fly with the extra pair of wings

Already at the beginning of this century geneticists had noted occasional malformations in Drosophila. In one type of mutation the organ that controls balance (the halteres), was transformed into an extra pair of wings (Fig. 2). In this type of bizarre disturbance of the body plan, cells in one region behave as though they were located in another. The Greek word homeosis was used to describe this type of malformations and the mutations were referred to as homeotic mutations.
Figure 2.

Fig. 2. Comparison of a normal and a four-winged fruit fly. The third thoractic segment has developed as a duplicate of the second due to a defectic homeotic gene. In the normal fly only the second segment develops wings.

The fly with the extra pair of wings interested Edward B. Lewis at the California Institute of Technology in Los Angeles. He had, since the beginning of the forties, been trying to analyze the genetic basis for homeotic transformations. Lewis found that the extra pair of wings was due to a duplication of an entire body segment. The mutated genes responsible for this phenomenon were found to be members of a gene family ( bithorax-complex) that controls segmentation along the anterior-posterior body axis (Fig. 3). Genes at the beginning of the complex controlled anterior body segments while genes further down the genetic map controlled more posterior body segments (the colinearity principle). Furthermore, he found that the regions controlled by the individual genes overlapped, and that several genes interacted in a complex manner to specify the development of individual body segments. The fly with the four wings was due to inactivity of the first gene of the bithorax complex in a segment that normally would have produced the halteres, the balancing organ of the fly (Fig 3). This caused other homeotic genes to respecify this particular segment into one that forms wings.

Edward Lewis worked on these problems for decades and was far ahead of his time. In 1978 he summarized his results in a review article and formulated theories about how homeotic genes interact, how the gene order corresponded to the segment order along the body axis, and how the individual genes were expressed. His pioneering work on homeotic genes induced other scientists to examine families of analogous genes in higher organisms. In mammalians, the gene clusters first found in Drosophila have been duplicated into four complexes known as the HOX genes. Human genes in these complexes are sufficiently similar to their Drosophila analogues they can restore some of the normal functions of mutant Drosophila genes.

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[The book is a tribute to Edward Lewis, edited by my colleague Howard D. Lipshitz.]

[Image Credit: California Institute of Technology]

Two Examples of "Alternative Splicing"

THEME:
Transcription
Last week I bumped into a colleague who teaches in our third year molecular biology course. I was lamenting about the sad state of science these days and we got to talking about alternative splicing. I repeated my complaint that much of the predicted alternative splice variants are artifacts. It makes no sense that conserved genes would be producing alternative protein variants that are species specific. I am convinced that the EST databases are full of artifacts and that most predicted splice variants do not exist.

My colleague was shocked. He is firmly convinced that most human genes express a number of different protein products that are produced as the result of alternatively spliced mRNA precursors. I asked him if he had ever looked at his favorite genes to see if the predicted variants make any sense. The ones that I've looked at certainly don't. (Join in the fun: see the challenge below.)

My colleague is very knowledgeable about the genes for the major subunits of eukaryotic RNA polymerase since it was his lab that cloned the first one. I suggested that he look at the predicted alternative splice variants of the two human genes and let me know if he is still convinced that these variants make biological sense. I'm not sure he will do it so let's take a look ourselves.

Eukaryotic RNA polymerase is a complex protein machine consisting of ten different subunits. Two of the subunits, Rpb1 and Rbp2, are more commonly known as A and B. In the human genome they are encoded by the genes POLR2A and POLR2B respectively [RNA Polymerase Genes in the Human Genome].

If you click on the Entrez Gene URLs you will end up at a page that summarizes what is known about the gene. Down the right-hand side of the page there are links to several other webpages, including a link to AceView, a database of alternative splice variants. Before following this link to the POLR1A variants, let's note that on the annotated Entrez Gene website there are no alternative splice variants listed. Apparently someone has decided that the predicted variants are probably artifacts.

Go to the AceView page for AceView POLR2A. The first thing you see is a short explanation.

RefSeq annotates one representative transcript (NM included in AceView variant.a), but Homo sapiens cDNA sequences in GenBank, filtered against clone rearrangements, coaligned on the genome and clustered in a minimal non-redundant way by the manually supervised AceView program, support at least 11 spliced variants.

AceView summary
Note that this locus is complex: it appears to produce several proteins with no sequence overlap.
Expression: According to AceView, this gene is expressed at very high level, 4.8 times the average gene in this release. The sequence of this gene is defined by 537 GenBank accessions from 518 cDNA clones, some from breast (seen 40 times), marrow (29), head neck (19), brain (18), eye (18), leukopheresis (18), lung tumor (18) and 132 other tissues. We annotate structural defects or features in 13 cDNA clones.
Alternative mRNA variants and regulation: The gene contains 29 different introns (28 gt-ag, 1 gc-ag). Transcription produces 13 different mRNAs, 11 alternatively spliced variants and 2 unspliced forms. There are 7 probable alternative promotors and 5 non overlapping alternative last exons (see the diagram). The mRNAs appear to differ by truncation of the 5' end, truncation of the 3' end, overlapping exons with different boundaries, alternative splicing or retention of 4 introns. 337 bp of this gene are antisense to spliced gene pluvu, raising the possibility of regulated alternate expression.
Protein coding potential: 10 spliced and the unspliced mRNAs putatively encode good proteins, altogether 11 different isoforms (3 complete, 4 COOH complete, 4 partial), some containing domains RNA polymerase Rpb1, domain 1, RNA polymerase, alpha subunit, RNA polymerase Rpb1, domain 3, RNA polymerase Rpb1, domain 4, RNA polymerase Rpb1, domain 5, RNA polymerase Rpb1, domain 6, RNA polymerase Rpb1, domain 7, Eukaryotic RNA polymerase II heptapeptide repeat [Pfam]. The remaining 2 mRNA variants (1 spliced, 1 unspliced) appear not to encode good proteins.

Here's the figure showing the various predicted alternatively spliced transcripts and the various different proteins.


It's really difficult to imagine that any of these are biologically relevant. How could a small bit of the large RNA polymerase subunit ever be part of the RNA polymerase protein complex? It's not a surprise that the Entrez Gene annotators have ignored these predictions.

If, as I believe, most of the small ESTs on which these predictions are based are artifacts, then the overall pattern makes sense. What you see are examples of splicing errors where an intron has not been correctly removed. These extremely rare splicing errors are copied into cDNA during construction of EST libraries and specifically selected by screening out all the correctly spliced mRNAs. (That's how you make most EST libraries.)

Here's what AceView says about the gene for the other large subbunit [AceView: POLR2B].

RefSeq annotates one representative transcript (NM included in AceView variant.a), but Homo sapiens cDNA sequences in GenBank, filtered against clone rearrangements, coaligned on the genome and clustered in a minimal non-redundant way by the manually supervised AceView program, support at least 9 spliced variants.

One again, AceView notes that the annotated human genome has ignored the predicted alternative plice variants but maintains that there are at least nine of them.

Here's the figure, decide for yourself whether this is credible.


There are several well-known examples of human genes producing different protein variants due to alternative splicing. The ones I can think of off the top of my head are the genes for class I antigens, α-tropomyosin, and calcitonin. I'm sure there are half a dozen others.

Here's the challenge. See if you can find a human gene for a well-studied protein where the structure of the protein is known and there are multiple protein variants derived by alternative splicing. I bet that readers of Sandwalk can't find very many where the predicted variants many any sense and are likely to be biologically significant.

What does this mean? Whenever you look at your favorite well-studied gene you see that the predictions of alternative splicing are silly. So why should we believe the genome wide analyses? Is it just a coincidence that the more we learn about a given gene the most we become willing to reject the ESTs as artifacts? Or is it possible that alternative splicing is mostly confined to those genes that have not been well studied?

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