Nobel Prize for DNA repair

Tomas Lindahl, Paul Modrich, and Aziz Sancar shared the 2015 Nobel Prize in Chemistry for "for mechanistic studies of DNA repair" [Nobel Prize, Chemistry 2015].

Here's some of the press release.

In the early 1970s, scientists believed that DNA was an extremely stable molecule, but Tomas Lindahl demonstrated that DNA decays at a rate that ought to have made the development of life on Earth impossible. This insight led him to discover a molecular machinery, base excision repair, which constantly counteracts the collapse of our DNA.

Aziz Sancar has mapped nucleotide excision repair, the mechanism that cells use to repair UV damage to DNA. People born with defects in this repair system will develop skin cancer if they are exposed to sunlight. The cell also utilises nucleotide excision repair to correct defects caused by mutagenic substances, among other things.

Paul Modrich has demonstrated how the cell corrects errors that occur when DNA is replicated during cell division. This mechanism, mismatch repair, reduces the error frequency during DNA replication by about a thousandfold. Congenital defects in mismatch repair are known, for example, to cause a hereditary variant of colon cancer.

What about Phil Hanawalt?

Meanwhile, in other news: Discovery and Characterization of DNA Excision Repair Pathways: the Work of Philip Courtland Hanawalt ...

In 1963, Hanawalt and his first graduate student, David Pettijohn, observed an unusual density distribution of newly synthesized DNA during labeling with 5-bromouracil in UV-irradiated E. coli. These studies, along with the discovery of CPD excision by the Setlow and Paul Howard-Flanders groups, represented the co-discovery of nucleotide excision repair.

And Wikipedia [Philip Hanawalt] says,

Philip C. Hanawalt (born in Akron, Ohio in 1931) is an American biologist who discovered the process of repair replication of damaged DNA in 1963. He is also considered the co-discoverer of the ubiquitous process of DNA excision repair along with his mentor, Richard Setlow, and Paul Howard-Flanders. He holds the Dr. Morris Herzstein Professorship in the Department of Biology at Stanford University,[1] with a joint appointment in the Dermatology Department in Stanford University School of Medicine.

Here's what Hanawalt himself says about discovering DNA excision repair [The Awakening of DNA Repair at Yale] ...

Upon joining the faculty at Stanford University in late 1961 as Research Biophysicist and Lecturer, I returned to the problem of what UV did to DNA replication, now that we knew the principal photoproducts. I wanted to understand the behavior of replication forks upon encountering pyrimidine dimers, and I was hoping to catch a blocked replication fork at a dimer. Using density labeling with 5-bromouracil and radioactive labeling of newly-synthesized DNA, we were able to observe partially replicated DNA fragments in E. coli [13]. However, in samples from UV irradiated bacterial cultures, the density patterns of nascent DNA indicated that much of the observed synthesis was in very short stretches, too short to appreciably shift the density of the DNA fragments containing them [14]. I communicated these results to Setlow by phone and learned that he had just discovered that pyrimidine dimers in wild type cells, but not in Ruth Hill’s UV sensitive mutant, were released from the DNA into an acid soluble fraction. We speculated in discussion that my student, David Pettijohn, and I were detecting a patching step by which a process of repair replication might use the complementary DNA strand as template to fill the single-strand gaps remaining after the pyrimidine dimers had been removed. At about the same time, Paul Howard-Flanders in the Department of Therapeutic Radiology at Yale had isolated a number of UV-sensitive mutants from E. coli K12 strains, and he was able to show that these mutants were also deficient in removing pyrimidine dimers from their DNA. The seminal discovery of dimer excision was published by the Setlow and Howard-Flanders groups, as the first indication of an excision repair pathway [15,16]. Of course, the excision per se is not a repair event but only the first step, since it generates another lesion, the gap in one strand of the DNA. We carried out more controls, to then claim that we had discovered a non-conservative mode of repair replication, constituting the presumed patching step in the postulated excision-repair pathway [17]. I later showed that DNA containing the repair patches could undergo semiconservative replication with no remaining blockage [18].

Richard Boyce and Howard-Flanders at Yale also documented excision of lesions induced by mitomycin C in E. coli K12 strains, indicating some versatility of excision repair [19]. In a collaboration with Robert Haynes, I found a similar pattern of repair replication after nitrogen mustard exposure to that following UV, and we concluded that “it is not the precise nature of the base damage that is recognized, but rather some associated secondary structural alteration …” We speculated that “[s]uch a mechanism might even be able to detect accidental mispairing of bases after normal replication,” thus predicting the existence of a mismatch repair pathway [20]. Mismatch repair was reported by Wagner and Meselson a decade later [21] and yet another excision repair mode, termed base excision repair, was discovered by Tomas Lindahl [22].

One of Hanawalt's students was Jonathan Eisen [Tree of Life]. I'll be interested in hearing what he has to say about this Nobel Prize. It seems unfair to me.

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Ten years after Dover - an excellent decade for Intelligent Design Creationism?

This month marks the tenth anniversary of the Kitzmiller v. Dover case in Pennsylvania [Tammy Kitzmiller, et al. v. Dover Area School District, et al.]. The legal victory will be celebrated by NCSE and Panda's Thumb and by many other supporters of science and evolution. If American law is your thing, then please join in the celebration of a legal victory.

It's much more interesting to evaluate whether the legal victory in Pennsylvania had any significant effect on the general public. Did it cause people to change their minds and abandon Intelligent Design Creationism to embrace science? Has America moved closer to the time when real science can be taught in the schools without interference from religion? Have politicians stopped trying to water down evolution in the public schools because of Judge Jones' decision in Kitzmiller v Dover? Have politicians stopped opposing evolution and has the public stopped voting for those who do?

Get a Job! - Department of Biochemistry, University of Toronto

This is my department [Department of Biochemistry]. Apply now!

Don't be fooled by the ad. Cutting edge biochemists can also apply.

Applications are invited for two Tenure-Stream Positions

The Department of Biochemistry at the University of Toronto invites applications for two tenure-stream appointments, at the rank of Assistant Professor. The appointments will commence on 1 July, 2016.

We seek candidates undertaking cutting edge research in cell, systems, molecular, or chemical biology. Technical knowledge including but not limited to metabolomics, synthetic biology, and structural biology (particularly, cryo-electron microscopy) that will complement our existing strengths would also be an asset.

Candidates must have a Ph.D. or equivalent in Biochemistry, Biophysics, Molecular Biology, Genetics, or a related discipline and have postdoctoral experience with an established record of excellence in research as demonstrated through a strong track record in publication. The successful candidates will be expected to mount an original and independently-funded research program at the highest international level and to publish articles in internationally recognized journals. The successful candidates must also demonstrate teaching excellence at the undergraduate and graduate levels through letters of reference. Salary will be commensurate with qualifications and experience.

The Department is one of the premier academic life sciences departments in North America, with 67 full-time faculty members and more than 200 graduate students and postdoctoral fellows.

All qualified candidates are invited to apply online by clicking on the link below. All application materials should be submitted online and include: 1) a detailed curriculum vitae; 2) a 3-5 page statement detailing research interests and objectives as well as potential teaching interests. We recommend combining documents into one or two files in PDF/MS Word format. Applicants should also arrange for three letters of reference commenting specifically on the applicant’s experience in teaching and research, to be sent directly to the department at chair.biochemistry@utoronto.ca by November 16, 2015.

Review of applications will begin on November 16, 2015, and applications will be accepted until the position is filled. Submission guidelines can be found at: http://uoft.me/how-to-apply. If you have questions about this position, please contact us at chair.biochemistry@utoronto.ca. For more information about the Department of Biochemistry, please visit http://biochemistry.utoronto.ca/.

The University of Toronto offers the opportunity to teach, conduct research and live in one of the most diverse cities in the world. The University is strongly committed to diversity within its community and especially welcomes applications from visible minority group members, women, Aboriginal persons, persons with disabilities, members of sexual minority groups, and others who may contribute to further diversification of ideas.

All qualified candidates are encouraged to apply; however, Canadians and permanent residents of Canada will be given priority.

For further details and to apply online please visit https://utoronto.taleo.net/careersection/10050/jobdetail.ftl?job=1501211

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Genetic variation in human populations

The Human Genome Project produced a high quality reference genome that serves as a standard to measure genetic variation. Every new human genome that's sequenced can be compared with the reference genome to detect differences due to mutation. It's possible to build large databases of genetic variation by sequencing genomes from different populations. Genetic variation can be used to infer evolutionary history and to test theories of population genetics. Detailed maps of genetic variation can also be used to infer selection (genetic sweeps) and distinguish it from random genetic drift.

In addition to this basic science, the analysis of multiple human genomes can be used to map genetic disease loci through association of various haplotypes with disease. The technique is called genome wide association studies (GWAS). The same technology can be used to map other phenotypes to identify the genes responsible.

The 1000 Genomes Project Consortium has just published their latest efforts in a recent issue of Nature (Oct. 1, 2015) (The 1000 Genomes Project Consortium, 2015; Studmant et al., 2015). They looked at the genomes of 2,504 individuals from 26 different populations in Africa, East Asia, South Asia, Europe, and the Americas.

The idea is to identify variants that are segregating in humans. Single nucleotide polymorphisms (SNPS) are difficult to identify because the error rate of sequencing is significant. When comparing a new genome sequence to the reference genome you don't know whether a single base change is due to sequencing error or a genuine variant unless you have a high quality sequence. Most of the 2,504 genome sequences are not of sufficiently high quality to be certain that the false positive rate is low but by sequencing multiple genomes it becomes feasible to identify variants that are shared by more that one individual within a population.

Recall that every human genome has about 100 new mutations so that even brothers and sisters will differ at 200 sites. The 1000 Genomes Consortium looks at the frequency of alleles in a population to determine whether the genetic variation is significant. They use a preliminary cutoff of 0.5%, which means that a variant (mutation) has to be present in 5 out of 1000 genomes in order to count as a variant that's segregating within the population. They estimate that 95% of SNPs meeting this threshold are true variants. For small insertions and deletions the accuracy is about 80%.

For variants at lower frequency, additional sequencing to a depth of >30X coverage was done and the putative variant was compared against other databases of genetic variation. The predicted accuracy of variants at 0.1% frequency is about 75%.

Given those limitations, the results of the studies are very informative. Looking at single base pair changes and small indels (insertions and deletions), the typical human genome (yours and mine) differs from the standard reference genome at about 4.5 million sites. That's about 0.14% of our genomes. Humans and chimpanzees differ by about 1.4% or ten times more.

SNPs and small indels account for 99.9% of variants. The others are "structural variants" consisting of; large deletions, copy number variants, Alu insertions, LINE L1 insertions, other transposon insertions, mitochondrial DNA insertions (NUMTS), and inversions. The typical human genome has about 2,300 of these structural variants of which about 1000 are large deletions.

Most of these variants are in junk DNA regions but the typical human genome carries about 10-12,000 variants that affect the sequence of a protein. Many of these will be neutral and some of the ones that have a detrimental effects will be heterozygous and recessive. The average person has 24-30 variants that are associated with genetic disease. (These are known detrimental alleles. If you get your genome sequenced, you will learn that you carry about 30 harmful alleles that you can pass on to your children.)

The Consortium reports that the the typical genome has variants at about 500,000 sites mapping to untranslated regions of mRNA (UTRs), insulators, enhancers, and transcription factor binding sites. I assume they are using the ENCODE data here so we need to take it with a large grain of salt. Most of these sites are not biologically relevant.

As expected, common variants are distributed in populations all over the world. These are the result of mutations that arose several hundred thousand years ago and reached significant frequencies before the present-day populations separated. However, 86% of all variants are restricted to a single continental group. These are the result of mutations that occurred after the present-day populations split.

The African populations contain more genetic variation than the Asian and European populations. Again, this is is expected since the European and Asian groups split from within the African group after Africans had been evolving on that continent for thousands of years. The differences are not great—Africans differ at about 4.3 million SNPs while the typical Europeans and Asian differ at only 3.5 million SNPs.

Only a small number of loci show evidence of selective sweeps, or recent selection (adaptation). It indicates that most of the differences between local ethnic groups are not associated with adaptation. The exceptions are SLC24A5 (skin pigmentation), HERC2 (eye color), LCT (lactose tolerance), and FADS (fat metabolism).

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Sudmant, P.H., Rausch, T., Gardner, E.J., Handsaker, R.E., Abyzov, A., Huddleston, J., Zhang, Y., Ye, K., Jun, G., Hsi-Yang Fritz, M., Konkel, M.K., Malhotra, A., Stutz, A.M., Shi, X., Paolo Casale, F., Chen, J., Hormozdiari, F., Dayama, G., Chen, K., Malig, M., Chaisson, M.J. P., Walter, K., Meiers, S., Kashin, S., Garrison, E., Auton, A., Lam, H.Y.K., Jasmine Mu, X., Alkan, C., Antaki, D., Bae, T., Cerveira, E., Chines, P., Chong, Z., Clarke, L., Dal, E., Ding, L., Emery, S., Fan, X., Gujral, M., Kahveci, F., Kidd, J.M., Kong, Y., Lameijer, E.-W., McCarthy, S., Flicek, P., Gibbs, R.A., Marth, G., Mason, C.E., Menelaou, A., Muzny, D.M., Nelson, B.J., Noor, A., Parrish, N.F., Pendleton, M., Quitadamo, A., Raeder, B., Schadt, E.E., Romanovitch, M., Schlattl, A., Sebra, R., Shabalin, A.A., Untergasser, A., Walker, J.A., Wang, M., Yu, F., Zhang, C., Zhang, J., Zheng-Bradley, X., Zhou, W., Zichner, T., Sebat, J., Batzer, M.A., McCarroll, S.A., The Genomes Project, C., Mills, R.E., Gerstein, M.B., Bashir, A., Stegle, O., Devine, S.E., Lee, C., Eichler, E.E., and Korbel, J.O. (2015) An integrated map of structural variation in 2,504 human genomes. Nature, 526(7571), 75-81. [doi: 10.1038/nature15394]

The Genomes Project Consortium (2015) A global reference for human genetic variation. Nature, 526(7571), 68-74. [doi: 10.1038/nature15393]

How many RNA molecules per cell are needed for function?

One of the issues in the junk DNA wars is the importance of all those RNAs that are detected in sensitive assays. About 90% of the human genome is complementary to RNAs that are made at some time in some tissue or other. Does this pervasive transcription mean that most of the genome is functional or are most of these transcripts just background noise due to accidental transcription?

Jerry Coyne retires

We knew this was coming but it's still a noteworthy event [I retire today].

I like what Jerry Coyne says about his career, so far, but one particular section caught my eye.

Several years ago, I began to realize that my job as a scientist and academic was not as challenging as it had been for the previous 35 years. I had mastered the requisites of such a job: doing research, writing papers, mentoring and teaching students, getting grants, and so on. The one challenge left was discovering new things about evolution, which was the really exciting thing about science. I’ve always said that there is nothing comparable to being the first person to see something that nobody’s seen before. Artists must derive some of the same satisfaction when creating new fictional worlds, or finding new ways to see the existing world, but it is only those who do science—and I mean “science” in the broad sense—who are privileged to find and verify new truths about our cosmos.

But finding truly new things—things that surprise and delight other scientists—is very rare, for science, like Steve Gould’s fossil record, is largely tedium punctuated by sudden change. And so, as I began to look for more sustaining challenges; I slowly ratcheted down my research, deciding that I’d retire after my one remaining student graduated. That decision was made two years ago, but the mechanics of retirement—and, in truth, my own ambivalence—have led to a slight delay. Today, though, is the day.

For me, the pace of discovery in the lab was far too slow. Yes, it's true that you can be the very first person ever to see something that nobody has ever seen before but those "somethings" are often trivial. I learned that there was a heck of a lot that I didn't know but other people did. Furthermore, I needed to know all that stuff before I could really interpret my own lab results.

It was far more efficient, and far more exciting, for me to learn facts and information from others than to try and discover something truly important in my own lab.

That's why I decided to concentrate on writing, especially biochemistry textbooks. It was my opportunity to learn about everything and my opportunity to teach others about what was important and what was not important. It was my opportunity to think about biochemistry and evolution. That was much more satisfying, intellectually, than the tedium of everyday lab work. I was cocky enough to believe that I, personally, could contribute more to science through theory (and teaching) than through working at the bench.

As it turned out, I found far more ways of "seeing the existing world," as Jerry puts it, though reading, thinking, and teaching than I ever did by cloning a gene and studying its expression. So far, none of those ways are terribly original but they're at least new to me. And many of them are new to all the people around me who I keep pestering whenever I come across something interesting.

Nowadays, the tedium of stasis in everyday science isn't the only problem facing young scientists. There's also the tedium of grant writing and the tedium (and stress) of not getting a grant to keep your lab running. Perhaps they should get out of that rat race. We need more thinking in science and not more ChIP assays or RNA-Seq experiments.

I'd like to create an Institute for Advanced Study based on the Princeton model but with an emphasis on biology. I think we need to celebrate and honor thinking biologists and not just "doers" who run megalabs churning out more ENCODE results, or the genome sequence of a new species, or the 1001st human genome sequence.

I can think of a dozen scientists who I would hire right away if I had the money. Can you imagine how exciting it would be to put them all in one place where they can interact and be creative?

Maybe I should apply for a Templeton grant?

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Stealin' All My Dreams

Canada is in the middle of a Federal election campaign. The vote is on October 19th.

Currently the Conservative Party under Stephen Harper has a majority in Parliament but the polls show a three-way race between the Conservatives, the Liberals under Justin Trudeau, and the New Democratic Party (NDP) under Thomas Mulcair.

About two-thirds of Canadians are intending to vote for anybody except the current Prime Minister (Stephen Harper). If you want to know why, listen to Blue Rodeo singing Stealin' All My Dreams.



Vote for the party in your riding that's most likely to beat the Conservatives.

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How can she go wrong?—let us count the ways ...

There's a very good reason why the creationist website Evolution News & Views (sic) doesn't allow comments but that won't stop us from making comments on Sandwalk. Check out Ann Gauger's latest offering at: Waiting for Mutations: Why Darwinism Won't Work.

There are a few errors in that post. How many? Let us count the ways.¹

Theme
Mutation
-definition
-mutation types
-mutation rates
-phylogeny
-controversies
What's interesting about that post is that we've been over the data many times in an attempt to explain mutation to the creationists. Last year I tried to explain why humans and chimpanzees have accumulated about 22 million point mutations since the time they evolved from a common ancestor about 6 million years ago. I thought it would be helpful if they understood why these numbers are perfectly reasonable according to population genetics.

What happened was that the vast majority of commenters on Uncommon Descent called me names and told me I was wrong. A few creationists, Sal Cordova, Vincent Torley, and Branko Kozulic took up the challenge and, for a short while I thought they understood.

Lessons not learned from 50 years ago

A few months ago Nature published an article on how to create a science-literate population. There's a letter in the Sept. 17th (2015) issue that addresses this point by reminding readers of another article published 50 years ago (1965).

The title of that older article was "New thinking in undergraduate education." Here's what it said ....

Students are in danger of "spending too much of their time memorizing facts, and [have] insufficient time at [their] disposal to master the principles underlying [their] subject and to develop [their] powers of thought." .... the most important purpose of a university education is to teach [students] to think for [themselves] ... it may on occasion demand a re-examination of the whole approach to a subject in undergraduate courses."

I remember that the biology department where I was an undergraduate (Carleton University in Ottawa) organized a weekend conference to discuss revising undergraduate education in 1967. I spoke about the need to focus on ideas and concepts and get away from boring lectures about facts.

plus ça change, plus c'est la même chose
UPDATE: A reader asked for the references. The letter in the Sept. 17th issue is from Barry S. Winkler [doi: 10.1038/525321f]. The original article from 1965 is in the issue of Feb. 27, 1965 [doi: 10.1038/205835a0]. The 2015 article referred to in the recent letter to Nature is Bradforth et al. (2015).

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Bradforth, S.F., Miller, E.R., Dichtel, W.R., Leibovich, A.K., Feig, A.L., Martin, J.D., Bjorkman, K.S., Schultz, Z.D., and Smith, T.L. (2015) University learning: Improve undergraduate science education. Nature 523:282-284 [PDF]

For the King gets greenlit and furry companions

My son's new game, For The King, is doing well on Kickstarter. So far they have over 1600 backers and over $78,000 [Kickstarter: For The King]. They met their launch goal within 24 hours and now they're adding stretch goals when additional support comes in.

I'm excited that they've reached $75,000 because that activates the "Furry Companions" addition to the game. You'll be familiar with the concept if you remember Hack and NetHack [see Pet - WikiHack]. You now get a pet in For The King. But be careful! Sometimes your pet can turn on you and you don't want that to happen if you have a pet dragon or a pet cockatrice.

In other news, the team has created musicians ...

As we near the inevitable Furry Companions stretch goal, we have our sites now on The Sound of Music stretch goal. The Sound of Music will add musicians and musical instruments to the game along with some potentially awesome mechanics. Primarily a support class, musicians make everyone around them better through their inspiring songs and ballads.

We'll be experimenting with some unique mechanics for this class like having them guarantee a successful slot for other party members if they successfully play an inspiring ballad. However if they miss a few notes it may have the opposite effect, so you'll have to use this ability wisely. They can potentially use the reverse of this ability against their enemies, forcing them to fail a slot. In this manner they can neutralize enemy special attacks and critical strikes if they're on key.

Different instruments will allow for different abilities so the option will also be there for them to play ballads of destruction doing AOE type damage to groups of enemies. Think Fire Lutes! We're really excited about this class and can't wait to share our ideas and progress on it with you.

I'm relieved at this description 'cause I was worried that the musicians would play the kind of music that my son used to listen to when he was growing up!

Give them more money if you want The Sound of Music. (I suspect that this stretch goal is aimed at Ms. Sandwalk and my daughter and granddaughter.)

The most exciting news is that For The King has been Greenlit. I suspect that most Sandwalk readers don't have any idea what this means. It means that the game has been accepted by the Steam community so it will be published on Steam—a fantastic gaming platform: Steam Greenlights For The King. They got voted in within 5 days!

I'm beginning to think that this game will be a success and my son and daughter-in-law won't have to move into our basement. Thanks to all Sandwalk readers who supported my son.

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Emile Zuckerkandl and the 50th anniversary of the birth of molecular evolution

Emile Zuckerkandl (1922-2013) and Linus Pauling (1901-1994) published a paper on the evolution of proteins back in 1964. The original paper was published first in a Russian translation. The English version appeared in 1965 and that paper marks the beginning of the field of molecular evolution (Zuckerkandl and Pauling, 1965a).

Dan Graur has a nice post: Happy Birthday Molecular Evolution! You’re 50 Years Old. I stole the photo from Dan's post. It shows Linus Pauling (left) and Emile Zuckerkandl (right) in Japan in 1986.

Most of you have heard of Linus Pauling—he won two Nobel Prizes—but you've probably not heard of Emile Zuckerkandl. That's a shame because he made significant contributions to the field of molecular evolution. Those early papers (Zuckerkandl and Pauling, 1965a; Zuckerkandl and Pauling, 1965b; Zuckerkandl and Pauling, 1965c) were remarkably insightful.

One of my graduate students, Sharon Shtang, was so impressed with the "Evolving Genes and Proteins" paper that she quoted from it at the beginning of her Ph.D. thesis. The authors were commenting on the, then novel, use of amino acid sequences in proteins to demonstrate evolution. They were worried that some people would think this was overkill since evolution was a well-established fact. They said ... [On Beating Dead Horses]

Some beating of dead horses may be ethical, where here and there they display unexpected twitches that look like life.

This is an obvious reference to creationism.

Café Scientifique in Mississauga

Some of you might recall that I gave a presentation last June on "Replaying the Tape of Life" at a Café Scientifique in Mississauga )(Ontario, Canada) [Café Scientifique]. It was a lot of fun and there were many interesting people.

The new season begins tomorrow with a meeting at 7 pm at The Franklin House, 263 Queen St S., in Streetsville, Mississauga (Ontario Canada) [see Meetup]. Come and join us for a discussion about science outreach ...

Come hear Randy Attwood, Executive Director of the Royal Astronomical Society of Canada, interviewed for a Star Spot podcast by host Justin Trottier.

In his interviews at the Star Spot, Mr. Trottier aims to go beyond the science under discussion to explore the implications of specific discoveries, why we explore, and how to engage the public in scientific pursuits. Where applicable The Star Spot dives into the intersection of science, philosophy and life's big questions.

Randy is Executive Director of the Royal Astronomical Society of Canada and founder of the RASC Mississauga Centre. He is co-organizer of the Mississauga Star Gazers meetup group and of the monthly Observe the Moon and planets through large telescopes event at Riverwood Conservancy. He is a frequent guest on CTV called upon to explain astronomy and space exploration news.

An Engineering Science graduate of the University of Toronto, Justin is best is a frequent guest on radio and TV programs discussing church-state separation, skeptical inquiry and fundamental freedoms. While known to many of us as the founder of Center for Inquiry Canada (CFIC) as well as of the Freethought Association of Canada, the range of his interests is very broad. He is a founder of the U of T Astronomy and Space Exploration Society and a former board member of the Canadian Space Society.

Don't be shy about joining us. There are plenty of newcomers at each meeting. All you have to do is walk upstairs at the restaurant and order your beer (and food if you're hungry)!

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Does genome size affect fitness in seed beetles?

Many of us think that the C-Value Paradox isn't really a paradox any more. We think that the variations in genome size among different species can be explained because expansion and contraction of genome size is mostly neutral with respect to evolution and thus the differing sizes of genomes in different species is explained by random genetic drift. Only a small percentage of most eukaryotic genomes is actually functional and the rest is junk. In the case of the human genome, about 90% is junk DNA.

Some scientists aren't happy with this explanation of the C-Value Paradox so they have come up with other explanations to account for the differences in genome sizes. A recent paper by Arnqvist et al. (2015) suggests that genome size affects reproductive fitness in seed beetles.

The introduction to their paper is a nice summary of the controversy ...

What does this big number mean?

There's a big number (63,000) in the windows of a biology laboratory somewhere in the world. There's also a picture of Darwin so it probably has something to do with evolution.

What could it possibly mean? Can you guess before clicking on the answer at 63,000 Strong?

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For The King: Kickstarter meets its launch goal in 24 hours!!!!

Recall that my son, Gord, and his friends Colby Young, David Lam, and Sean Hoyle [The Dev Team] formed IronOak Games to create "For The King." They need money to pay for development. I promoted their Kickstarter campaign at: Kickstarter - For The King.

I'm delighted to announce that they have met their threshold goal of $40,000. That means that all the donations will go through and the project has launched! (You need to achieve a minimum goal or none of the Kickstarter donations count.)

Gord posted a little happy dance video to celebrate.

They are now at $52,000 with over 700 backers. Because they reached the minimum goal, they have activated "stretch goals" where they can add extra features to the game. Here's what the Dev Team said in a email message to the supporters.

What a few days it’s been! First of all.....we did it! Thank you to so many people for backing us, sharing the project and showing interest! It’s really amazing, we’ve been humbled and just couldn’t be happier. An extra special thanks to our friends, family and colleagues who supported us as soon as the campaign was live, you people are awesome!

We worked immense hours as the launch date got closer and closer, fine tuning and polishing everything we could think of. It was a great feeling to hit the green Publish button, but I’m not going to lie, we were terrified. It feels really good to have people appreciate something we believe so firmly in.

The next order of business is that we already hit a mini stretch goal, The Dead Shall Rise! As a big thank you, all of our Kickstarter backers will be able to play as the adorable undead and carry on with their adventure even though death clearly came knocking a long time ago. To clarify, the undead skins are just aesthetic alternatives for our 6 core playable characters which grant no gameplay advantage whatsoever.

Looking ahead we are beginning to creep up on the Frost Realm stretch goal! I am so excited because we were forced to make some cuts from the our core set of realms and we made the hard decision of removing it. This was done not because we didn’t want it in the game but because it needs the extra attention to be everything it should be!
The Frost Realm will be a whole new biome with its own crippling weather and secluded boroughs to discover. New scourges, yetis, ice dungeons and other frozen abominations terrorizing the foolish who seek adventure. This will be a truly savage addition to Fahrul’s colorful kingdom.

I should mention that the speed at which this all unfolded blindsided us, sorry for any delays! Stretch Goal reveal will be coming shortly!

For The King!

I bought a university and a professor-sage character who gives players advice on how to win the game. Ms. Sandwalk bought a village fair with a princess who lets you win valuable prizes in the midway games. Now we have to design our characters. You will encounter them in the game!

The Frost Realm is cool¹ but I'm looking forward to the next stretch goal at $70,000. I'm not supposed to tell you what it is but here's a hint ... it's one of the most important features in Hack!

Keep donating to make the game even better.

Here's a video that I hadn't seen before. It features my son (and a few other dudes)! I'm so proud of him. He couldn't have done any of this without a business degree from McGill!

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1. Pun intended.