Visualizing and teaching evolution through synteny

Embracing the rationalist and empirically-based perspective of science is not easy. Modern science generates disconcerting ideas that can be difficult to accept and often upsetting to philosophical or religious views of what gives meaning to existence [link]. In the context of biological evolutionary mechanisms, the fact that variation is generated by random (stochastic) events, unpredictable at the level of the individual or within small populations, led to the rejection of Darwinian principles by many working scientists around the turn of the 20th century (see Bowler’s The Eclipse of Darwinism + link).  Educational research studies, such as our own “Understanding randomness and its impact on student learning“, reinforce the fact that ideas involving stochastic processes relevant to evolutionary, as well as cellular and molecular, biology, are inherently difficult for people to accept (see also: Why being human makes evolution hard to understand). Yet there is no escape from the science-based conclusion that stochastic events provide the raw material upon which evolutionary mechanisms act, as well as playing a key role in a wide range of molecular and cellular level processes, including the origin of various diseases, particularly cancer [Cancer is partly caused by bad luck](1).

Teach Evolution

All of which leaves the critical question, at least for educators, of how to best teach students about evolutionary mechanisms and outcomes. The problem becomes all the more urgent given the anti-science posturing of politicians and public “intellectuals”, on both the right and the left, together with various overt and covert attacks on the integrity of science education, such as a new Florida law that lets “anyone in Florida challenge what’s taught in schools”.

Just to be clear, we are not looking for students to simply “believe” in the role of evolutionary processes in generating the diversity of life on Earth, but rather that they develop an understanding of how such processes work and how they make a wide range of observations scientifically intelligible. Of course the end result, unless you are prepared to abandon science altogether, is that you will find yourself forced to seriously consider the implications of inescapable scientific conclusions, no matter how weird and disconcerting they may be.

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There are a number of educational strategies, in part depending upon one’s disciplinary perspective, on how to approach teaching evolutionary processes. Here I consider one, based on my background in cell and molecular biology.  Genomicus is a web tool that “enables users to navigate in genomes in several dimensions: linearly along chromosome axes, transversely across different species, and chronologically along evolutionary time.”  It is one of a number of  web-based resources that make it possible to use the avalanche of DNA (gene and genomic) sequence data being generated by the scientific community. For example, the ExAC/Gnomad Browser enables one to examine genetic variation in over 60,000 unrelated people. Such tools supplement and extend the range of tools accessible through the U.S. National Library of Medicine / NIH / National Center for Biotechnology Information (NCBI) web portal (PubMed).

In the biofundamentals / coreBio course (with an evolving text available here), we originally used the observation that members of our subfamily of primates,  the Haplorhini or dry nose primates, are, unlike most mammals, dependent on the presence of vitamin C (ascorbic acid) in their diet. Without vitamin C we develop scurvy, a potentially lethal condition. While there may be positive reasons for vitamin C dependence, in biofundamentals we present this observation in the context of small population size and a forgiving environment. A plausible scenario is that the ancestral Haplorhini population the lost the L-gulonolactone oxidase (GULO) gene (see OMIM) necessary for vitamin C synthesis. The remains of the GULO gene found in humans and other Haplorhini genomes is mutated and non-functional, resulting in our requirement for dietary vitamin C.

How, you might ask, can we be so sure? Because we can transfer a functional mouse GULO gene into human cells; the result is that vitamin C dependent human cells become vitamin C independent (see: Functional rescue of vitamin C synthesis deficiency in human cells). This is yet another experimental result, similar to the ability of bacteria to accurately decode a human insulin gene), that supports the explanatory power of an evolutionary perspective (2).


In an environment in which vitamin C is plentiful in a population’s diet, the mutational loss of the GULO gene would be benign, that is, not strongly selected against. In a small population, the stochastic effects of genetic drift can lead to the loss of genetic variants that are not strongly selected for. More to the point, once a gene’s function has been lost due to mutation, it is unlikely, although not impossible, that a subsequent mutation will lead to the repair of the gene. Why? Because there are many more ways to break a molecular machine, such as the GULO enzyme, but only a few ways to repair it. As the ancestor of the Haplorhini diverged from the ancestor of the vitamin C independent Strepsirrhini (wet-nose) group of primates, an event estimated to have occurred around 65 million years ago, its ancestors had to deal with their dietary dependence on vitamin C either by remaining within their original (vitamin C-rich) environment or by adjusting their diet to include an adequate source of vitamin C.

At this point we can start to use Genomicus to examine the results of evolutionary processes (see a YouTube video on using Genomicus)(3).  In Genomicus a gene is indicated  by a pointed box  ; for simplicity all genes are drawn as if they are the same size (they are not); different genes get different colors and the direction of the box indicates the direction of RNA synthesis, the first stage of gene expression. Each horizontal line in the diagram below represents a segment of a chromosome from a particular species, while the blue lines to the left represent phylogenic (evolutionary) relationships. If we search for the GULO gene in the mouse, we find it and we discover that its orthologs (closely related genes) are found in a wide range of eukaryotes, that is, organisms whose cells have a nucleus (humans are eukaryotes).

We find a version of the GULO gene in single-celled eukaryotes, such as baker’s yeast, that appear to have diverged from other eukaryotes about ~1.500,000,000 years ago (1500 million years ago, abbreviated Mya).  Among the mammalian genomes sequenced to date, the genes surrounding the GULO gene are (largely) the same, a situation known as synteny (mammals are estimated to have shared a common ancestor about 184 Mya). Since genes can move around in a genome without necessarily disrupting their normal function(s), a topic for another day, synteny between distinct organisms is assumed to reflect the organization of genes in their common ancestor. The synteny around the GULO gene, and the presence of a GULO gene in yeast and other distantly related organisms, suggests that the ability to synthesize vitamin C is a trait conserved from the earliest eukaryotic ancestors.GULO phylogeny mouse
Now a careful examination of this map (↑) reveals the absence of humans (Homo sapiens) and other Haplorhini primates – Whoa!!! what gives?  The explanation is, it turns out, rather simple. Because of mutation, presumably in their common ancestor, there is no functional GULO gene in Haplorhini primates. But the Haplorhini are related to the rest of the mammals, aren’t they?  We can test this assumption (and circumvent the absence of a functional GULO gene) by exploiting synteny – we search for other genes present in the syntenic region (↓). What do we find? We find that this region, with the exception of GULO, is present and conserved in the Haplorhini: the syntenic region around the GULO gene lies on human chromosome 8 (highlighted by the red box); the black box indicates the GULO region in the mouse. Similar syntenic regions are found in the homologous (evolutionarily-related) chromosomes of other Haplorhini primates.synteny-GULO region

The end result of our Genomicus exercise is a set of molecular level observations, unknown to those who built the original anatomy-based classification scheme, that support the evolutionary relationship between the Haplorhini and more broadly among mammals. Based on these observations, we can make a number of unambiguous and readily testable predictions. A newly discovered Haplorhini primate would be predicted to share a similar syntenic region and to be missing a functional GULO gene, whereas a newly discovered Strepsirrhini primate (or any mammal that does not require dietary ascorbic acid) should have a functional GULO gene within this syntenic region.  Similarly, we can explain the genomic similarities between those primates closely related to humans, such as the gorilla, gibbon, orangutan, and chimpanzee, as well as to make testable predictions about the genomic organization of extinct relatives, such as Neanderthals and Denisovians, using DNA recovered from fossils [link].

It remains to be seen how best to use these tools in a classroom context and whether having students use such tools influences their working understanding, and more generally, their acceptance of evolutionary mechanisms. That said, this is an approach that enables students to explore real data and to develop  plausible and predictive explanations for a range of genomic discoveries, likely to be relevant both to understanding how humans came to be, and in answering pragmatic questions about the roles of specific mutations and allelic variations in behavior, anatomy, and disease susceptibility.spacer bar

Some footnotes (figures reinserted 2 November 2020, with minor edits)

(1) Interested in a magnetic bumper image? visit: http://www.cafepress.com/bioliteracy

(2) An insight completely missing (unpredicted and unexplained) by any creationist / intelligent design approach to biology.

(3) Note, I have no connection that I know of with the Genomicus team, but I thank Tyler Square (now at UC Berkeley) for bringing it to my attention.

The trivialization of science education

It’s time for universities to accept their role in scientific illiteracy.  

There is a growing problem with scientific illiteracy, and its close relative, scientific over-confidence. While understanding science, by which most people seem to mean technological skills, or even the ability to program a device (1), is purported to be a critical competitive factor in our society, we see a parallel explosion of pseudo-scientific beliefs, often religiously held.  Advocates of a gluten-free paleo-diet battle it out with orthodox vegans for a position on the Mount Rushmore of self-righteousness, at the same time astronomers and astrophysicists rebrand themselves as astrobiologists (a currently imaginary discipline) while a subset of theoretical physicists, and the occasional evolutionary biologist, claim to have rendered ethicists and philosophers obsolete (oh, if it were only so). There are many reasons for this situation, most of which are probably innate to the human condition.  Our roots are in the vitamin C-requiring Haplorhini (dry nose) primate family, we were not evolved to think scientifically, and scientific thinking does not come easy for most of us, or for any of us over long periods of time (2). The fact that the sciences are referred to as disciplines reflects this fact, it requires constant vigilance, self-reflection, and the critical skepticism of knowledgeable colleagues to build coherent, predictive, and empirically validated models of the Universe (and ourselves).  In point of fact, it is amazing that our models of the Universe have become so accurate, particularly as they are counter-intuitive and often seem incredible, using the true meaning of the word.

Many social institutions claim to be in the business of developing and supporting scientific literacy and disciplinary expertise, most obviously colleges and universities.  Unfortunately, there are several reasons to question the general efficacy of their efforts and several factors that have led to this failure. There is the general tendency (although exactly how wide-spread is unclear, I cannot find appropriate statistics on this question) of requiring non-science students to take one, two, or more  “natural science” courses, often with associated laboratory sections, as a way to “enhance literacy and knowledge of one or more scientific disciplines, and enhance those reasoning and observing skills that are necessary to evaluate issues with scientific content” (source).

That such a requirement will “enable students to understand the current state of knowledge in at least one scientific discipline, with specific reference to important past discoveries and the directions of current development; to gain experience in scientific observation and measurement, in organizing and quantifying results, in drawing conclusions from data, and in understanding the uncertainties and limitations of the results; and to acquire sufficient general scientific vocabulary and methodology to find additional information about scientific issues, to evaluate it critically, and to make informed decisions” (source) suggests a rather serious level of faculty/institutional distain or apathy for observable learning outcomes, devotional levels of wishful thinking,  or simple hubris.  To my knowledge there is no objective evidence to support the premise that such requirements achieve these outcomes – which renders the benefits of such requirements problematic, to say the least (link).

On the other hand, such requirements have clear and measurable costs; going beyond the simple burden of added and potentially ineffective or off-putting course credit hours. The frequent requirement for multi-hour laboratory courses impacts the ability of students to schedule courses.  It would be an interesting study to examine how, independently of benefit, such laboratory course requirements impact students’ retention and time to degree, that is, bluntly put, costs to students and their families.

Now, if there were objective evidence that taking such courses improved students’ understanding of a specific disciplinary science and its application, perhaps the benefit would warrant the cost.  But one can be forgiven if one assumes a less charitable driver, that is, science departments’ self-interest in using laboratory and other non-major course requirements as means to support graduate students.  Clearly there is a need for objective metrics for scientific, that is disciplinary, literacy and learning outcomes.

And this brings up another cause for concern.  Recently, there has been a movement within the science education research community to attempt to quantify learning in terms of what are known as “forced choice testing instruments;” that is, tests that rely on true/false and multiple-choice questions, an actively anti-Socratic strategy.  In some cases, these tests claim to be research based.  As one involved in the development of such a testing instrument (the Biology Concepts Instrument or BCI), it is clear to me that such tests can serve a useful role in helping to identify areas in which student understanding is weak or confused [example], but whether they can provide an accurate or, at the end of the day, meaningful measure of whether students have developed an accurate working understanding of complex concepts and the broader meaning of observations is problematic at best.

Establishing such a level of understanding relies on Socratic, that is, dynamic and adaptive evaluations: can the learner clearly explain, either to other experts or to other students, the source and implications of their assumptions?  This is the gold standard for monitoring disciplinary understanding. It is being increasingly side-lined by those who rely on forced choice tests to evaluate learning outcomes and to support their favorite pedagogical strategies (examples available upon request).  In point of fact, it is often difficult to discern, in most science education research studies, what students have come to master, what exactly they know, what they can explain and what they can do with their knowledge. Rather unfortunately, this is not a problem restricted to non-majors taking science course requirements; majors can also graduate with a fragmented and partially, or totally, incoherent understanding of key ideas and their empirical foundations.

So what are the common features of a functional understanding of a particular scientific discipline, or more accurately, a sub-discipline?  A few ideas seem relevant.  A proficient needs to be realistic about their own understanding.  We need to teach disciplinary (and general) humility – no one actually understands all aspects of most scientific processes.  This is a point made by Fernbach & Sloman in their recent essay, “Why We Believe Obvious Untruths.”  Humility about our understanding has a number of beneficial aspects.  It helps keep us skeptical when faced with, and asked to accept, sweeping generalizations.

Such skepticism is part of a broader perspective, common among working scientists, namely the ability to distinguish the obvious from the unlikely, the implausible, and the impossible. When considering a scientific claim, the first criterion is whether there is a plausible mechanism that can be called upon to explain it, or does it violate some well-established “law of nature”. Claims of “zero waste” processes butt up against the laws of thermodynamics.

Going further, we need to consider how the observation or conclusions fits with other well established principles, which means that we have to be aware of these principles, as well as acknowledging that we are not universal experts in all aspects of science.  A molecular biologist may recognize that quantum mechanics dictates the geometries of atomic bonding interactions without being able to formally describe the intricacies of the molecule’s wave equation. Similarly, a physicist might think twice before ignoring the evolutionary history of a species, and claiming that quantum mechanics explains consciousness, or that consciousness is a universal property of matter.  Such a level of disciplinary expertise can take extended experience to establish, but is critical to conveying what disciplinary mastery involves to students; it is the major justification for having disciplinary practitioners (professors) as instructors.

From a more prosaic educational perspective other key factors need to be acknowledged, namely a realistic appreciation of what people can learn in the time available to them, while also understanding at least some of their underlying motivations, which is to say that the relevance of a particular course to disciplinary goals or desired educational outcomes needs to be made explicit and as engaging as possible, or at least not overtly off putting, something that can happen when a poor unsuspecting molecular biology major takes a course in macroscopic physics, taught by an instructor who believes organisms are deducible from first principles based on the conditions of the big bang.  Respecting the learner requires that we explicitly acknowledge that an unbridled thirst for an empirical, self-critical, mastery of a discipline is not a basic human trait, although it is something that can be cultivated, and may emerge given proper care.  Understanding the real constraints that act on meaningful learning can help focus courses on what is foundational, and help eliminate the irrelevant or the excessively esoteric.

Unintended consequences arise from “pretending” to teach students, both majors and non-science majors, science. One is an erosion of humility in the face of the complexity of science and our own limited understanding, a point made in a recent National Academy report that linked superficial knowledge with more non-scientific attitudes. The end result is an enhancement of what is known as the Kruger-Dunning effect, the tendency of people to seriously over-estimate their own expertise: “the effect describes the way people who are the least competent at a task often rate their skills as exceptionally high because they are too ignorant to know what it would mean to have the skill”.

A person with a severe case of Kruger-Dunning-itis is likely to lose respect for people who actually know what they are talking about. The importance of true expertise is further eroded and trivialized by the current trend of having photogenic and well-speaking experts in one domain pretend to talk, or rather to pontificate, authoritatively on another (3).  In a world of complex and arcane scientific disciplines, the role of a science guy or gal can promote rather than dispel scientific illiteracy.

We see the effects of the lack of scientific humility when people speak outside of their domain of established expertise to make claims of certainty, a common feature of the conspiracy theorist.  An oft used example is the claim that vaccines cause autism (they don’t), when the actual causes of autism, whether genetic and/or environmental, are currently unknown and the subject of active scientific study.  An honest expert can, in all humility, identify the limits of current knowledge as well as what is known for certain.  Unfortunately, revealing and ameliorating the levels of someone’s Kruger-Dunning-itis involves a civil and constructive Socratic interrogation, something of an endangered species in this day and age, where unseemly certainty and unwarranted posturing have replaced circumspect and critical discourse.  Any useful evaluation of what someone knows demands the time and effort inherent in a Socratic discourse, the willingness to explain how one knows what one thinks one knows, together with a reflective consideration of its implications, and what it is that other trained observers, people demonstrably proficient in the discipline, have concluded. It cannot be replaced by a multiple choice test.

Perhaps a new (old) model of encouraging in students, as well as politicians and pundits, an understanding of where science comes from, the habits of mind involved, the limits of, and constraints on, our current understanding  is needed.  At the college level, courses that replace superficial familiarity and unwarranted certainty with humble self-reflection and intellectual modesty might help treat the symptoms of Kruger-Dunning-itis, even though the underlying disease may be incurable, and perhaps genetically linked to other aspects of human neuronal processing.


some footnotes:

  1. after all, why are rather distinct disciplines lumped together as STEM (science, technology, engineering and mathematics).
  2.  Given the long history of Homo sapiens before the appearance of science, it seems likely that such patterns of thinking are an unintended consequence of selection for some other trait, and the subsequent emergence of (perhaps excessively) complex and self-reflective nervous system.
  3.  Another example of Neil Postman’s premise that education is be replaced by edutainment (see  “Amusing ourselves to Death”.