Student Perceptions of "The Spandrels of San Marco"

 
Hopeful Monster asked his senior biology majors to read "The Spandrels of San Marco and the Panglossian Paradigm: A Critique of the Adaptationist Programme." [Student perceptions of San Marco].

I think he was disappointed.

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How Women Got Their Menopause

The December 13 issue of New Scientist has an article about the evolution of menopause in humans [Are daughters-in-law to blame for the menopause? ]. The author is Alison Motluk, the Toronto corresponent for New Scientist.

She begins with ..

IT FLIES in the face of natural selection, yet in humans it seems fixed and universal: at around age 50, not far past the midpoint of life, normal healthy women lose their capacity to bear children. Following a decade of gentle winding down, the whole reproductive system screeches to a halt. It is as though, after a few years of wearing bifocals, all women suddenly went blind.

Menopause is a mystery. It leaves women with 20, 30, perhaps even 50 years of life - squandered time in evolutionary terms, because no further genes can be passed on. Yet the selection pressure for menopause must have been strong: there are no known pockets of women around the world who do not go through it. All the evidence suggests menopause has been around a long time, and that the age at which it hits has changed little. Increased longevity seems not to have budged our closing hours. Nor, apparently, has lifestyle; it hits hunter-gatherers at pretty much the same age as hip New Yorkers.

The search for an adaptive explanation for menopause has been going on for over fifty years.

The most common just-so story is called the "Grandmother Hypothesis." It imagines a time in the distant past when humans females were fertile until the day they died, which for 75% of women who survived childhood was before the age of 30 according to a recent study. A mutation arose in one individual and the effect was to induce menopause, or sterility, at about age 50. This new mutation proved to be so beneficial that it spread throughout the species. Today every woman undergoes the pain and frustration of menopause.

Why was it so beneficial? Because post-menopausal women whose partners were still alive could invest their time in looking after their grandchildren instead of having more children of their own.

To its credit, the New Scientist article reviews the latest work on the Grandmother Hypothesis and concludes, correctly, that the effect on ancient hunter-gather societies could not possibly have been significant enough to be adaptive.

The same reasoning applies to the "Mother Hypothesis," which claims that by going through menopause a mother will avoid the risks of future childbirths enabling her to concentrate on raising her existing children. Both of these hypotheses assume that "just saying no" was not a reasonable strategy in ancient societies and that's why menopause was necessary.

So what's the alternative if you are committed to an adaptive just-so story? You are going to be shocked ... menopause evolved to benefit daughters-in-law!!! (Our daughter-in-law will be so pleased.)

I'm not even going to dignify such a stupid idea by pointing out the obvious flaws.

In case you haven't clued in by now, the bottom line is that all these hypotheses are flawed from the get-go because they all make the unnecessary assumption that the pain and suffering of menopause are adaptive. What if they aren't? What if menopause is neutral with respect to evolution or even maladaptive? What's the point of making up irrational just-so stories when there's no evidence to suggest that menopause has any positive effect of fitness?

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Get a Job

 

Assistant Professor, Tenure Stream
Dept. of Cell & Systems Biology
University of Toronto

The Department of Cell & Systems Biology at the University of Toronto invites applications for a tenure track faculty position to be appointed at the Assistant Professor level in the field of Systems Biology to begin July 1, 2009.

We particularly encourage applications from candidates who have demonstrated excellence in addressing fundamental questions in biology using high-throughput approaches or gene/protein network analyses with bioinformatic, genomic, proteomic, or imaging tools. Our vision is to advance systems biology-based research, with a specific interests in developing expertise in systems neurobiology, but we welcome applicants from all others areas of systems biology which complement existing strengths in the department (www.csb.utoronto.ca).

Candidates should have at least two years of research experience beyond their doctoral degree. In addition to pursuing a vigorous, internationally-recognized research program, the successful candidate will contribute to undergraduate and graduate teaching in the molecular life sciences. The successful candidate would also be expected to network with researchers university-wide to take advantage of the extensive resources in systems biology at the University of Toronto and its affiliated institutions. A generous start-up package will be provided. Salary will be commensurate with qualifications and experience.

We encourage qualified applicants to submit their applications online at: www.jobs.utoronto.ca/faculty.htm. Applicants should submit their curriculum vitae, copies of significant publications, and statements of research and teaching interests. Applicants should also arrange for three confidential letters of recommendation to be sent directly to: Professor Daphne Goring, Chair, Department of Cell & Systems Biology, University of Toronto, 25 Harbord Street, Toronto, Ontario M5S 3G5, Canada; or by email to search@csb.utoronto.ca by January 31, 2009.

The University of Toronto offers the opportunity to teach, conduct research and live in one of the most diverse cities in the world, and is responsive to the needs of dual career couples. The University of Toronto 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 the further diversification of ideas.

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

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Poinsettias Are Poisonous

 
Friday's Urban Legend: False

From 6 Medical Myths Debunked For Christmas.

Dr. Vreeman and Dr. Carroll found that the largest study of poinsettia "toxicity" to date involved an analysis of 849,575 plant exposures reported to the American Association of Poison Control Centers. None of the 22,793 poinsettia cases revealed significant poisoning. No one died from poinsettia exposures or ingestions, and more than 96 percent did not even require treatment in a health care facility. Another study, looking at poinsettia ingestion by rats, could not find a toxic amount of poinsettia, even at doses which would be the human equivalent of consuming 500-600 poinsettia leaves or a pound and a half of the plant's sap. Dr. Vreeman cautions, though, that you should always call a poison control center if someone eats a plant not intended for consumption.

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Suicides Increase Over the Holidays

 
Friday's Urban Legend: False

From 6 Medical Myths Debunked For Christmas.

The holidays can bring out the worst in people, and the stresses of family get-togethers, loneliness, and the cold, dark winter months are commonly thought to increase the number of suicides at Yule time. But studies conducted around the globe show that, while the holidays may be a difficult time for some, there is no scientific evidence to suggest a holiday peak in suicides, according to Dr. Vreeman and Dr. Carroll. Furthermore, suicides are actually more common during warm and sunny times of the year.

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Sugar Makes Kids Hyperactive

 
Friday's Urban Legend: False

From 6 Medical Myths Debunked For Christmas.

This is without a doubt false, report Dr. Vreeman and Dr. Carroll, who are both pediatricians at Riley Hospital for Children. They write that "in at least 12 double-blinded, randomized, controlled trials, scientists have examined how children react to diets containing different levels of sugar. None of these studies, not even studies looking specifically at children with attention deficit-hyperactivity disorder, could detect any differences in behavior between the children who had sugar and those who did not." This includes sugar from candy, chocolate and natural sources. Even in studies of children who were considered "sensitive" to sugar, children did not behave differently after eating sugar-full or sugar-free diets.

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Let's Count the Ways a Creationist Can Go Wrong

 
The latest posting on Uncommon Descent tries to undermine the concept of a natural origin of life [Life From Chiral Crystals . . . Really?]. Maybe one of these days they'll actually put up some evidence to support Intelligent Design Creationism instead of always attacking science.¹

Patrick is worried about the chirality problem, which can be pretty well explained by just applying a bit of common sense [Amino Acids and the Racemization "Problem"]. Unfortunately, it's not just the IDiots who are confused about the chirality problem. Many chemists and biologist also seem to have weird ideas about the requirement for 20 L-amino acids when life began.

Patrick quotes Timothy Standish who says,

Much as the Miller-Urey experiment demonstrated that it is possible to produce insignificant yields of a very few biologically important monomers in a laboratory device, Noorduin et al. demonstrated that chemists are capable of producing enantiomerically pure crystals under laboratory conditions. This laboratory technique fails to show a mechanism by which enatiomerically pure solutions of all 20 amino acids used in protein construction may have existed before the advent of life, not to mention the other chiral molecules found in living things. As a consequence, the chirality problem for chemical evolution remains unresolved by this technique.

How many things are wrong with this paragraph?

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1. Not holding my breath.

Speciation in Monkeyflowers

 
Within a species there may be distinctive subspecies that have different allele frequencies. The differences are maintained because there is restricted gene (allele) flow between them. The two subspecies may look very different or they may be very similar in appearance.

Genetic exchange between the subspecies is often prevented because the subspecies are geographically separated. This is the first step on the path to allopatric speciation. But genetic exchange can also be restricted by other mechanisms, for example the timing of reproduction, that occurs even if the subspecies inhabit the same environment. This could lead to sympatric speciation.

In either case, the two subspecies will become distinct species—as defined by the biological species concept—when it becomes impossible to form hybrids due to genetic incompatibility. The study of actual speciation events is a hot topic in evolution these days. One of the goals is to identify the genes responsible for preventing the formation of fertile hybrids. The other goal is to identify the mechanism by which the alleles of these genes become fixed in the subspecies. Is it by natural selection or random genetic drift? (Shuker et al. 2005)

One of the best studied examples of speciation in action is due to the work of H.D. Bradshaw and Douglas Schemske at the University of Washington in Seattle, Washington (USA) (Schemske is now at Michigan State University). They studied two species of monkeyflowers that grow near streams and rivers in the mountains and valleys of western North America.

Mimulus lewisii (top) is found primarily at higher elevations (1600 m to 3000 m) while Mimulus cardinalis (right) grows at lower elevations (sea level to 2000 m). Their ranges overlap at moderate elevations in the mountains of California but hybrids are exceedingly rare.

The species differ in a number of characteristics including leaf shape and stem height but the most obvious differences are in the flowers. Mimulus lewsii has pink flowers that are quite open. They attract bumblebees and in the wild 100% of pollinations within this subspecies are by bees. Mimulus cardinalis has red flowers with a more narrow shape. These flowers attract hummingbirds who are responsible for 98% of pollination events in M. cardinalis.

When crossed in a greenhouse, the two species produce fertile hybrids so technically they are not really species but subspecies.

Ramsey et al. (2003) have studied the barriers to gene flow in the wild. Much of it is due to ecogeographic isolation, which is a fancy way of saying that the species don't often come in contact. They grow at different elevations and each species has become adapted to that elevation so that M. lewisii, for example, does not survive well at low elevations and M. cardinalis can't take the cold and the shorter growing season at high elevations.

The fact that the two species have different pollinators is a major factor in preventing gene flow between them. Hummingbirds hardly ever visit M. lewisii and in the overlapping zones there were very few recorded instances of bees visiting flowers from both species. Thus, the opportunities for cross-pollination were effectively zero. What this means is that, "even in sympatry these species are isolated to a large degree by pollinators" (Ramsey et al. 2003).

There are other factors contributing to genetic isolation. The hybrid plants are somewhat less fit and cross-pollination results in fewer seeds than pollination within a (sub)species. The sum of all these factors means that, in the wild, the total reproductive isolation between the two species is 0.9974 to 0.9998. In other words, they don't mix! (But recall that they can readily form fertile hybrids when crossed in the greenhouse.)

In this example, a major component of the restricted gene flow is due to physical separation of the species and that separation is the result of adaptation to different environments. In that sense, the path to speciation is driven, in part, by natural selection. The species are not genetically incompatible so we're not dealing with mutations that prevent hybridization as would be the case if they were true biological species.

Attention has focused on flower color and shape since that determines whether an individual is pollinated by bumblebees or hummingbirds. It's another step toward preventing gene flow between the species. Is it due primarily to selection or drift?

Schemske and Bradshaw (1999) identified a locus, called yellow upper (YUP), that plays a large role in determining flower color in the two species. The locus affects carotenoid distribution in the petals. In M. cardinalis carotenoids are found throughout the petals and the flowers are red. Bees are not attracted to red flowers. The YUP allele in M. lewisii results in less carotenoid and the flowers are pink. These flowers attract bees.

A subsequent study by Bradshaw and Schemske (2003) established that the YUP alleles are directly responsible for much of the pollinator discrimination observed in monkeyflowers. In the second study the authors created near-isogenic lines (NIL) that differed only at the YUP locus.

The normal M. lewisii flower is pink and the petals are in an open shape (a). The normal M. cardinalis flower is red and the shape of the flower is quite different (c). The dominant YUP allele from M. lewisii prevents carotenoid deposition and when it is bred into M. cardialis the flowers are pink (d). The recessive yup allele from M. cardinalis causes more carotenoid to be deposited making the flowers orange in an M. lewisii background (b).

The plants were tested in a natural environment where the ranges of the two species overlapped and both bees and humingbirds were common. Bees preferred the pink flowers whether they were in an M. lewisii background or an M. cardialis background. Conversely, hummingbirds preferred the orange and red flowers in both backgrounds. Thus, the two species have adapted to different pollinators and a large part of this adaptation is due to flower color.

Here's where it gets tricky. Is the switch from bee pollination to hummingbird pollination driven by natural selection? In other words, when the mutation causing red flowers first arose did it confer a fitness advantage on the individuals that came to be pollinated by hummingbirds?

Here's how Bradshaw and Schemske (2003) address this question,

As ‘mutations’ at the YUP locus decrease visitation by the current pollinator guild, and simultaneously increase visitation by a new pollinator guild, are there plausible ecological circumstances in which the mutant might be favoured by natural selection? The combined rate of bumblebee and hummingbird visitation to the yellow-orange-flowered ‘mutants’ of M. lewisii is just 26% of that to the wild-type pink flowers, and the combined rate for dark-pinkflowered ‘mutants’ of M. cardinalis is 95% of the wild type. This implies that a change in the relative abundance of bumblebees and hummingbirds, compared with the pollinator assemblage present during our field experiments, would be required for the mutant to be favoured by natural selection in the common ancestor of M. lewisii and M. cardinalis. The change in relative abundance of pollinators necessary to produce equal visitation to both flower colour phenotypes can be estimated from our data. A ninefold decrease in the relative abundance of bumblebees would produce equal combined visitation rates in the wild-type pink-flowered and ‘mutant’ yellow-orange-flowered M. lewisii NILs. At the equilibrium point, 99% of visitors to wild-type M. lewisii flowers would be bumblebees, whereas 87% of visitors to ‘mutants’ would be hummingbirds. In the M. cardinalis NILs, a twofold increase in the relative abundance of bumblebees would produce equal visitation rates to pink and red flowers. At the equilibrium point, hummingbirds would be virtually the only visitor to the wild-type red M. cardinalis flowers, and remain the major visitor (89% of visits) even to the dark-pink ‘mutants.’

In order for the red flower allele to be fixed by natural selection there would have to be a significant decline in the bee population at the time the mutation arose. Presumably, this decline would have only occurred in a small part of the range leading to a subpopulation with red flowers while the main, wild-type, population (pink flowers) continued to be visited by bees.

The authors don't mention the other possibility; namely, that the red flower allele (yup) spread in a subpopulation by random genetic drift. In this scenario, there is no selective advantage to individual plants if they are pollinated by humingbirds. Clearly the evolution of pollinator discrimination by flower color will lead to restricted gene flow between the two species but it is not clear whether this epiphenomenon is due to selection for hummingbird pollination or random genetic drift.

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[Photo Credits: Mimulus lewisii or Purple monkey-flower (top) is from flickr. Mimulus cardinalis or Cardinal monkeyflower (second from top) is from the Arizona-Sonore Desert Museum.


Bradshaw, H.D. Jr. and Schemske, D.W. (1999) Allele substitution at a flower colour locus produces a pollinator shift in monkeyflowers. Nature 426:176-178. [doi:10.1038/nature02106] [PDF]

Ramsey, J., Bradshaw, H.D. Jr., Schemske, D.W. (2003) Components of Reproductive Isolation between the Monkeyflowers Mimulus lewisii and M. cardinali (Phrymaceae). Evolution 57:1520-1534. [PDF]

Schemske, D.W. and Bradshaw, H.D. Jr. (2003) Pollinator preference and the evolution of floral traits in monkeyflowers (Mimulus). Proc. Natl. Acad. Sci. (USA) 96:11910-11915. PDF]

Shuker, D.M., Underwood, K., King, T.M., and Butlin, R.K. (2005) Patterns of male sterility in a grasshopper hybrid zone imply accumulation of hybrid incompatibilities without selection. Proc. Biol. Sci. 272:2491-2497. [DOI: 10.1098/rspb.2005.3242]

Is Bill O’Reilly Really this Stupid?

 
Don't answer that. It's a rhetorical question.

Honestly, I just don't understand how someone who's a prominent television personality can be so totally ignorant of the very issue that he rants about. It's not rocket science. The law isn't that hard to understand.

Maybe there's something about being religious that clouds the mind?

Listen for the following words from attorney Megan Kelley, "I've never met a non-lawyer who argues the law so confidently, albeit, so wrongly."

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[Hat Tip: Friendly Atheist: You Are Wrong! You Are *So* Wrong!]

Get a Job

 

Canada Research Chair (Tier I)
in Comparative Genomics and Evolutionary Bioinformatics
at Dalhousie University, Halifax, Canada
The Faculty of Medicine at Dalhousie University is seeking to attract an outstanding individual eligible for nomination for a Tier I Canada Research Chair faculty position in the area of comparative genomics and evolutionary bioinformatics. The successful candidate will be recognized internationally as a leader in this research area and will join the newly formed Centre for Comparative Genomics and Evolutionary Bioinformatics (http://cgeb.dal.ca/), an interdisciplinary research group with diverse and complementary interests in molecular evolution, microbial diversity, protistology, phylogenetics, genomics, proteomics and bioinformatics. Dalhousie is a leading Canadian research-oriented University, located in Halifax on the scenic Atlantic coast of Nova Scotia.

The Canada Research Chairs program was established by the Government of Canada to foster world class centres of research excellence in a global, knowledge-based economy (www.chairs.gc.ca). Applicants should have a Ph.D. in Biochemistry/Molecular Biology or a related discipline, and currently hold the rank of Professor or Associate Professor (with expectation of promotion to Professor within 1-2 years). The successful candidate will be offered a tenured or tenure-track appointment in the Department of Biochemistry & Molecular Biology (www.biochem.dal.ca/) with limited teaching responsibilities. Preference will be given to applicants with interdisciplinary expertise in both laboratory-based biochemical/molecular biological approaches as well as bioinformatics and/or computer science.

To apply send a curriculum vitae, a brief outline of research achievements and goals, and arrange for three letters of reference to be sent, under separate cover, to: Dr. David M. Byers (Chair, Search Committee), Department of Biochemistry & Molecular Biology, Dalhousie University, Sir Charles Tupper Medical Building, 5850 College Street, Halifax, NS, B3H 1X5 Canada. Interviews may commence as early as January 15th, however we will continue to receive applications until a successful candidate has been chosen up to March 1, 2009. All Chairs are subject to review and final approval by the CRC Secretariat.

Dalhousie University is an Employment Equity/Affirmative Action employer. The University encourages applications from qualified Aboriginal people, persons with a disability, racially visible persons and women.

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Get a Job

 

Assistant Professor, Tenure Stream
in Cellular and Molecular Biology of Lipids
Department of Pediatrics, Atlantic Research Centre
Dalhousie University
Halifax, Nova Scotia, Canada

The Department of Pediatrics at Dalhousie University invites applications for a probationary tenure-track position at the rank of Assistant Professor. Candidates should have demonstrated potential to develop a nationally and internationally recognized research program in the field of lipid metabolism, signaling or transport, with emphasis on human diseases such as cancer, obesity, diabetes or cardiovascular. The successful candidate will join an established, interactive group of investigators with complementary research interests at the Atlantic Research Centre (ARC). Members of the ARC have ready access to established core research facilities that include: tissue culture and animal care, cellular imaging (confocal and electron microscopy, flow cytometry), mass spectrometry and microarray technology.

Applicants must hold a PhD degree or equivalent and have at least three years post-doctoral training in biomedical sciences. The successful applicant will be expected to compete for external research and salary support, supervise graduate students and contribute to the teaching activities of the Department. Salary will be commensurate with qualifications and experience. Further information concerning this position, the Department and the ARC may be obtained by consulting arc.medicine.dal.ca and associated links.

Dalhousie University is a research-intensive institution located in the historic port city of Halifax, Nova Scotia, which boasts excellent recreational, cultural and lifestyle opportunities (www.halifax.ca/visitors.asp).

Interested applicants should submit a CV as well as send a statement outlining their research and teaching interests. They should have three letters of reference sent under separate cover directly to the Chair of the Search Committee. At least 2 of these references must come from academic referees.

Chair, Search Committee
Atlantic Research Centre
Room C302, CRC Building, 5849 University Avenue,
Dalhousie University
Halifax, Nova Scotia,
Canada B3H 4H7
Closing date for receipt of applications is January 31, 2009. Starting dates are negotiable; the positions may be filled by Sept. 1, 2009.

All qualified candidate are encouraged to apply; however, Canadians and permanent residents will be given priority. Dalhousie University is an Employment Equity/Affirmative Action employer. The University encourages applications from qualified Aboriginal people, persons with a disability, racially visible persons and women.

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Get a Job

 

Department of Biochemistry
College of Medicine
University of Saskatchewan
Assistant Professor
The Department of Biochemistry invites applications for a tenure-track position at the level of Assistant Professor. Candidates must have a Ph.D. with at least 2 years of post-doctoral experience. The successful applicant is expected to establish a strong, independent and externally funded research program in biochemistry, preferably in a research area related to metabolism, gene expression, lipid and carbohydrate biochemistry or the biochemical basis of diseases. An interest and/or experience in bioinformatics would be an asset.

In addition, participation in teaching of both the undergraduate medical and biochemistry curricula will be required. The successful applicant will have a broad range of collaborative possibilities on campus with scientists in other departments and colleges, including the Canadian Light Source (www.cls.usask.ca/) and the Saskatchewan Structural Sciences Centre (www.usask.ca/sssc/).

Please submit both electronic and signed hard copies of the application, including curriculum vitae; a detailed statement on research interests and of previous teaching experience in a single PDF document to:

Dr. R.L. Khandelwal
Head, Department of Biochemistry, College of Medicine
University of Saskatchewan
107 Wiggins Road, Saskatoon, SK S7N 5E5 Canada.
E-mail: ramji.khandelwal@usask.ca
Phone:(306) 966-4368
Fax: (306) 966-4390
Applicants should also arrange for three confidential letters of reference to be sent separately to the same address.

The closing date for receipt of applications is February 1, 2009. The effective date for appointment is between April 1, 2009 and July 1, 2009.

All qualified candidates are encouraged to apply. However, Canadian citizens and permanent residents will be given priority. The University of Saskatchewan is committed to Employment Equity. Members of Designated Groups (women, Aboriginal people, people with disabilities and visible minorities) are encouraged to self-identify on their applications.

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Nobel Laureate: Fred Sanger

 

The Nobel Prize in Chemistry 1980.

"for their contributions concerning the determination of base sequences in nucleic acids"



Frederick Sanger (1918 - ) was awarded the Nobel Prize for developing the chain termination, or dideoxy, method of sequencing DNA (The Sanger Method of DNA Sequencing). The method relies on synthesis of DNA in vitro using dideoxynucleotides that cause chain termination from time to time. The original method has been adapted to high throughput methods that are fully automated.

Fred Sanger shared the Nobel Prize with Walter Gilbert. It was Sanger's second Nobel Prize, his first was for developing methods to sequence proteins.

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The images of the Nobel Prize medals are registered trademarks of the Nobel Foundation (© The Nobel Foundation). They are used here, with permission, for educational purposes only.

[Photo Credit: The photograph show Fred Sanger in front of the Wellcome Trust Sanger Institute.]

Testing Natural Selection: Part 1

 
The latest issue of Scientific American has an interesting article by H. Allen Orr entitled Testing Natural Selection.

Biologists working with the most sophisticated genetic tools are demonstrating that natural selection plays a greater role in the evolution of genes than even most evolutionists had thought.

Orr is an adaptationist. His perspective on evolution focuses on natural selection as the predominant mechanism. He tends to dismiss all other mechanisms as either uninteresting or unimportant.

I though it might be interesting to compare what a pluralist might say about some of the things in the article. It's one way of highlighting the difference between the two points of view.

Naturally, as a pluralist, I disagree with some statements. My main beef, however, is with the growing tendency to over-emphasize natural selection as we approach the 200th anniversary of Darwin's birth and the 150th anniversary of publication of On the Origin of Species. I think it's possible to describe the differences between evolution in the eighteenth century and evolution in the 21st century without diminishing Darwin's contributions.

Orr begins his article by describing natural selection. He explains that there are several kinds of mutations ...

Most important, we know something about the effects of mutations on fitness. The overwhelming majority of mutations are harmful—that is, they reduce fitness; only a tiny minority are beneficial, increasing fitness.

That's not exactly how I would put it. I would have added that there's a third type of mutation that is neither harmful nor beneficial—neutral mutations.

Furthermore, I would have explained that the frequency of these three different kinds of mutations can vary considerably from one species to the next depending on the organization of the genome. In animals and plants, for example, most of the DNA does not seem to be essential so that the overwhelming majority of mutations are neutral and a smaller number—those that interfere with an essential function—are deleterious. A few mutations can be beneficial.

Orr goes on to say ....

Most mutations are bad for the same reason that most typos in computer code are bad: in finely tuned systems, random tweaks are far more likely to disrupt function than to improve it.

I would not use this analogy because it emphasizes something that I think is false; namely that organisms are "fine tuned systems." I tend to think of them as sloppy Rube Goldberg machines and not as well-tested computer code.

I would say that most mutations in essential regions of the genome are deleterious because random hits in DNA are more likely to make things worse than to make things better. The distinction is subtle, but important. Many adaptationists use language implying that living organisms are almost perfectly adapted to their present environment.

In the next section, Orr describes the advances of population genetics and its influence on how we understand natural selection. I would have described how population genetics led to an understanding of all type of evolution, and not just natural selection. Here's what Orr says,

Population geneticists have also provided insight into natural selection by describing it mathematically. For example, geneticists have shown that the fitter a given type is within a population, the more rapidly it will increase in frequency; indeed, one can calculate just how quickly the increase will occur. Population geneticists have also discovered the surprising fact that natural selection has unimaginably keen “eyes,” which can detect astonishingly small differences in fitness among genetic types. In a population of a million individuals, natural selection can operate on fitness differences as small as one part in a million.

I would have said that the growth of population genetics in the early part of the 20th century led to the recognition of random genetic drift as an important mechanism of evolution. Models were developed to explain how natural selection affected the increase in frequency of a beneficial allele and how neutral alleles could also increase in frequency even though they were invisible to natural selection.

The population geneticists also discovered that harmful alleles could become fixed by accident, although that turns out to be a rare event. More importantly, they discovered that natural selection has a stochastic component. Beneficial alleles will only become fixed part of the time. The probability depends on the fitness advantage. For example, if an allele has a fitness advantage of 10% then it will only become fixed 20% of the time. In 80% of cases when such an allele arises in a population it will be lost by random genetic drift before it becomes fixed.¹

As the fitness advantage diminishes, the probability of fixation becomes lower and lower so that alleles with small fitness advantages (<1%) will hardly ever change the species. That's what population geneticists discovered about natural selection.

The probability of fixation of neutral alleles (or nearly neutral alleles) is very low but since there are so many more of them than beneficial alleles, much of evolution is characterized by changes due to random genetic drift.

The next section is "How Common Is Natural Selection?". This is where Orr asks the key question ...

One of the simplest questions biologists can ask about natural selection has, surprisingly, been one of the hardest to answer: To what degree is it responsible for changes in the overall genetic makeup of a population? No one seriously doubts that natural selection drives the evolution of most physical traits in living creatures—there is no other plausible way to explain such large-scale features as beaks, biceps and brains. But there has been serious doubt about the extent of the role of natural selection in guiding change at the molecular level. Just what proportion of all evolutionary change in DNA is driven, over millions of years, by natural selection—as opposed to some other process?

We've discussed this distinction between molecular changes and physical traits many times. One of the most annoying characteristics of adaptationists is that they insist on relegating other mechanisms of evolution to the level of DNA sequences but refuse to consider anything but natural selection when it comes to visible phenotypes. There is no justification for this assumption. Many physical traits can be neutral or even deleterious. They were not fixed by natural selection.²

What Orr says is simply not true. There are many biologists who seriously doubt that natural selection drives the evolution most physical traits, even though such pluralists readily agree that most adaptions are due to natural selection. Random genetic drift is a plausible way to explain many physical traits.

Until the 1960s biologists had assumed that the answer was “almost all,” but a group of population geneticists led by Japanese investigator Motoo Kimura sharply challenged that view. Kimura argued that molecular evolution is not usually driven by “positive” natural selection—in which the environment increases the frequency of a beneficial type that is initially rare. Rather, he said, nearly all the genetic mutations that persist or reach high frequencies in populations are selectively neutral—they have no appreciable effect on fitness one way or the other. (Of course, harmful mutations continue to appear at a high rate, but they can never reach high frequencies in a population and thus are evolutionary dead ends.) Since neutral mutations are essentially invisible in the present environment, such changes can slip silently through a population, substantially altering its genetic composition over time. The process is called random genetic drift; it is the heart of the neutral theory of molecular evolution.

As I've already pointed out, random genetic drift was discovered in the 1920s and it was incorporated into the first version of the Modern Synthesis in the 1940s. It dropped out of favor when the synthesis hardened at the time of the Darwin centennial in 1959.

Random genetic drift was revived in the late 1960's with the discovery of neutral alleles. Drift is the way in which selectively neutral alleles become fixed in a population. Random genetic drift and neutral theory are not synonyms.

As I indicated above, since the vast majority of animal and plant genomes is non-essential, it stands to reason that the vast majority of alleles will be neutral. Thus at the molecular level, at least, random genetic drift must be the dominant mechanism of evolution.

By the 1980s many evolutionary geneticists had accepted the neutral theory. But the data bearing on it were mostly indirect; more direct, critical tests were lacking. Two developments have helped fix that problem. First, population geneticists have devised simple statistical tests for distinguishing neutral changes in the genome from adaptive ones. Second, new technology has enabled entire genomes from many species to be sequenced, providing voluminous data on which these statistical tests can be applied. The new data suggest that the neutral theory underestimated the importance of natural selection.

Hmmm ... I could see where this was going even before I read it. Orr is about to quote the infamous work of Drosophila geneticists who have devised complicated tests to show that some synonymous mutations might confer a selective advantage in one species but not in another closely related species. Some of the papers claim that many alleles in coding regions are not neutral even thought they don't change the amino acid. There's no question that this is true in some cases.

It's also true that mutations altering the amino acid are sometimes beneficial, and therefore selected. However, if you align the amino acid sequences of a given gene from hundreds of species and map them on to the structure of the protein it becomes readily apparent that most substitutions cannot have a significant effect on the function of the protein. They must be neutral, or nearly neutral. As a matter of fact, in most proteins it is difficult to find any clearly beneficial alleles present in one species and not in the others.

In one study a team led by David J. Begun and Charles H. Langley, both at the University of California, Davis, compared the DNA sequences of two species of fruit fly in the genus Drosophila. They analyzed roughly 6,000 genes in each species, noting which genes had diverged since the two species had split off from a common ancestor. By applying a statistical test, they estimated that they could rule out neutral evolution in at least 19 percent of the 6,000 genes; in other words, natural selection drove the evolutionary divergence of a fifth of all genes studied. (Because the statistical test they employed was conservative, the actual proportion could be much larger.) The result does not suggest that neutral evolution is unimportant—after all, some of the remaining 81 percent of genes may have diverged by genetic drift. But it does prove that natural selection plays a bigger role in the divergence of species than most neutral theorists would have guessed. Similar studies have led most evolutionary geneticists to conclude that natural selection is a common driver of evolutionary change even in the sequences of nucleotides in DNA.

Pluralists disagree. We still think that random genetic drift is by far the dominant mechanism at the molecular level and that it even plays a significant role at the level of visible phenotypes.

In addition, we like to remind adaptationists that most beneficial alleles are eliminated by random genetic drift before they ever become fixed in a population.

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1. Many biologists, and most evolutionary psychologists, do not understand this important point. They think that all they have to do is identify some (real or imagined) benefit and it will automatically take over the population no matter how small the benefit.

2. I know that Orr said "most" physical traits and not "all" physical traits. It's a distinction without meaning since the percentage of non-adaptive changes that adaptationists are willing to admit, grudgingly, is not much different than zero.

The Sanger Method of DNA Sequencing

 

In 1976 Frederick Sanger developed a method for sequencing DNA enzymatically using the Klenow fragment of E. coli DNA polymerase I. Sanger was awarded his second Nobel Prize for this achievement (he received his first Nobel Prize for developing a method for sequencing proteins). The advantage of using the Klenow fragment for this type of reaction is that the enzyme lacks the 5′ → 3′ exonuclease activity, which could degrade newly synthesized DNA. However, one of the disadvantages is that the Klenow fragment is not very processive and is easily inhibited by the presence of secondary structure in the single-stranded DNA template. This limitation can be overcome by adding SSB or analogous proteins, or more commonly, by using DNA polymerases from bacteria that grow at high temperatures. Such polymerases are active at 60° to 70°C, a temperature at which secondary structure in single-stranded DNA is unstable.

The Sanger sequencing method uses 2′,3′-dideoxynucleoside triphosphates (ddNTPs), which differ from the deoxyribonucleotide substrates of DNA synthesis by lacking a 3′-hydroxyl group (see below). The dideoxyribonucleotides, which can serve as substrates for DNA polymerase, are added to the 3′ end of the growing chain. Because these nucleotides lack a 3′-hydroxyl group, subsequent nucleotide additions cannot take place and incorporation of a dideoxynucleotide terminates the growth of the DNA chain. When a small amount of a particular dideoxyribonucleotide is included in a DNA synthesis reaction, it is occasionally incorporated in place of the corresponding dNTP, immediately terminating replication. The length of the resulting fragment of DNA identifies the position of the nucleotide that should have been incorporated.

Chemical structure of a 2′,3′-dideoxynucleoside triphosphate.
B represents any base.

DNA sequencing using ddNTP molecules involves several steps (as shown below). The DNA is prepared as single-stranded molecules and mixed with a short oligonucleotide complementary to the 3′ end of the DNA to be sequenced. This oligonucleotide acts as a primer for DNA synthesis catalyzed by DNA polymerase. The oligonucleotide-primed material is split into four separate reaction tubes. Each tube receives a small amount of an α[³²P]-;abelled dNTP whose radioactivity allows the newly synthesized DNA to be visualized by autoradiography.

Next, each tube receives an excess of the four nonradioactive dNTP molecules and a small amount of one of the four ddNTPs. For example, the A reaction tube receives an excess of nonradioactive dTTP, dGTP, dCTP, and dATP mixed with a small amount of ddATP. DNA polymerase is then added to the reaction mixture. As the polymerase replicates the DNA, it occasionally incorporates a ddATP residue instead of a dATP residue, and synthesis of the growing DNA chain is terminated. Random incorporation of ddATP results in the production of newly synthesized DNA fragments of different lengths, each ending with A (i.e., ddA). The length of each fragment corresponds to the distance from the 5′-end of the primer to one of the adenine residues in the sequence.

Adding a different dideoxyribonucleotide to each reaction tube produces a different set of fragments: ddTTP produces fragments that terminate with T, ddGTP with G, and ddCTP with C. The newly synthesized chains from each sequencing reaction are separated from the template DNA.

Finally, the mixtures from each sequencing reaction are subjected to electrophoresis in adjacent lanes on a sequencing gel, where the fragments are resolved by size. The sequence of the DNA molecule can then be read from an autoradiograph of the gel.


This technique has also been modified to allow automation for high throughput applications like genomic sequencing. Instead of using radioactivity automated sequencing relies on fluorescently labeled dideoxynucleotides (four colors, one for each base) to detect the different chain lengths. In this system the gel is “read” by a fluorimeter and the data are stored in a computer file. Additionally, the sequencing machine can also provide a graphic chromatogram that shows the location and size of each fluorescent peak on the gel as they passed the detector.

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The bottom figure is from Wikipedia. The other figures and the text are from Horton, H.R., Moran, L.A., Scrimgeour, K.G., Perry, M.D., and Rawn, J.D. (2006) Principles of Biochemistry 4th edition, Pearson Prentice Hall, Upper Saddle River, New Jersey, USA.
© Laurence A. Moran, Pearson Prentice Hall