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.

In an age of rampant narcissism and social cheating – the importance of teaching social evolutionary mechanisms.

As socioeconomic inequality grows,  the publicly acknowledged importance of traits such as honesty, loyalty, self-sacrifice, and reciprocity appears to have fallen out of favor with some of our socio-economic and political elites. How many people condeHutton quotemn a person as dishonest one day and embrace them the next? Dishonesty and selfishness no longer appear to be taboo, or a source of shame that needs to be expurgated (perhaps my Roman Catholic upbringing is bubbling to the surface here).  A disavowal of shame and guilt and the lack of serious social censure appears to be on the rise, particularly within the excessively wealthy and privileged, as if the society from which they extracted their wealth and fame does not deserve their active participation and support [link: Hutton, 2009].  They have embraced a “winning takes all” strategy.

birds in a flockIf an understanding of evolutionary mechanisms is weak within the general population [link], the situation is likely to be much worse when it comes to an understanding of the role and outcomes of social evolutionary mechanisms. Yet, the evolutionary origins of social systems, and the mechanisms by which such systems are maintained against the effects of what are known as “social cheaters”, are critical to understanding and defending, human social behaviors  such as honesty, cooperation, loyalty, self-sacrifice, self-restraint, mutual respect, responsibility and kindness.

While evolutionary processes are often caricatured as favoring selfish behaviors, the facts tell a more complex, organism-specific story [link: Aktipis 2016]. Cooperation between organisms underlies a wide range of behaviors, from sexual reproduction and the formation of multicellular organisms (animals, plants, and people) to social systems, ranging from microbial films to bee colonies and construction companies [see Bourke, 2011: Principles of Social Evolution] [Wikipedia link].

One of the best studied of social systems involves the cellular slime mold Dictyostelium discoideum [Wikipedia link].  When life is good, that is when the world is moist and bacteria, the food of these organisms, are plentiful, D. discoideum live and reproduce happily as single celled amoeba-like individuals in soil.  Given their small size (~5 μm diameter), they cannot travel far, but that does not matter as long as their environment is hospitable.  When the environment turns hostile, however, an important survival strategy is to migrate to a new location – but what is a little guy to do?  The answer in this species is to cooperate.  Individual amoeba begin to secrete a chemical that acts to attract others; eventually thousands of individuals aggregate to form a multicellular “slug”; slugs migrate around to 1066px-Dicty_Life_Cycle_H01.svgfind a hospitable place and then differentiate into a fruiting body that stands ~1mm (20x the size of an individual amoeba) above the ground.  To form the stalk that lifts the “fruiting body” into the air, a subset of cells (once independent individuals) change shape. These stalk cells die, while the rest of the cells form the fruiting body, which consists of spores – cells specialized to survive dehydration.  Spores are released into the air where they float and are dispersed over a wide range.  Those spores that land in a happy place (moist and verdant), revert to the amoeboid life style, eat, grow, divide and generate a new (clonal) population of amoeboid cells: they have escaped from a hostile environment to inhabit a new world, a migration made possible by the sacrifice of the cells that became the stalk (and died in the process).  Similar types of behavior occur in a wide range of macroscopic organisms [Scrambling to the top: link].  Normally, who becomes a stalk cell and who becomes a spore is a stochastic process [see previous PLoS blog post on stochastics and biology education].

Cheaters in the slime mold system are individuals who take part in the aggregation process (they respond to the migration signal and become part of the slug), but have altered their behavior to avoid becoming a stalk cell – no self-sacrifice for them. Instead they become spores.  In the short run, such a strategy can be beneficial to the individual, after all it has a better chance of survival if it can escape a hostile environment.  But imagine a population made up only of cheaters – no self-sacrifice, no stalk, no survival advantage = death [see link: Strassmann & Queller, 2009].

A classic example of social cheating with immediate relevance to the human situation is cancer.  Within a sexually reproducing multicellular organism, reproduction is strictly restricted to the cells of the germ line – eggs and sperm.  The other cells of the organism, known collectively as somatic cells, have ceded their reproductive rights to the organism as a whole.  While somatic cells can divide, they divide in a controlled and strictly regulated (unselfish) way.  Somatic cells do not survive the death of the organism – only germ line cells (sperm and eggs) are able to produce a new organism.  In the end cellular cooperation has been a productive strategy, as witness the number of different types of multicellular organisms, including humans.  If a somatic cell breaks the social contract and cheats, that is, begins to divide (asexually) in an independent manner, it can lead to the formation of a  tumor and later, if the cells of the tumor start to migrate within the organism, to metastatic cancer.  More rarely (apparently) such cells can migrate between organisms, as in the case of transmissible cancers in dogs, Tasmanian Devils, and clams [see links: Murchison 2009 and Ujvari et al 2016).  The growth and evolution of the tumor cell leads to the death of the organism and the cancer cells’ own extinction, another example of the myopic nature of evolutionary processes.

In the case of cancer the organism’s defenses against social cheaters comes in two forms, intrinsic to the individual cheater cells, in the form of cell suicide (known through a number of technical terms including apoptosis, anoikis and necroptosis)[link: Su et al., 2015] and extrinsic and organismic processes, such as the ability of the organism’s immune system to identify and kill cancer cells – a phenomena with therapeutically relevant implications [link: Ledford, 2014].  We can think of these two processes as guilt + shame (leading to cellular suicide) and policing + punishment (leading to immune system killing).  For a cell to escape growth control and to evolve to produce metastatic disease, it needs to inactivate or ignore intrinsic cell death systems and to evade the immune system.

To consider another example, social systems are based on cooperation, often involving the sharing of resources with those in need.  A recent example is the sharing of food (blood) between vampire bats [see link: Carter & Wilkinson, 2013].  The rules, as noted by Aktipis, are simple, 1) ask only when in need and 2) give when asked and able.  In this context, we can identify two types of social cheaters – those who ask when they do not need and those you fail to give when asked and able.  People who refuse to work even when they can and when jobs are available fall into the first group, the rich who avoid taxes and fail to donate significant funds to charities the other.  It is an interesting question of how to characterize those who borrow money and fail to repay it.  Bankruptcy laws that protect the wealth of the borrower while leading to losses to the lender might be seen as acting to undermine the social contract (clearly philosophers’ and economists’ comments here would be relevant).

Given that social systems at all levels are based on potentially costly traits, such as honesty, loyalty, self-sacrifice, and reciprocity, the evolutionary origins of social systems must lie in their ability to increase reproductive success, either directly or through effects on relatives, a phenomena known as inclusive fitness [Wikipedia link]. Evolutionary processes also render social systems vulnerable to cheating and so have driven the development of a range of defenses against various forms of social cheaters (see above).  But recent political and cultural events appear to be acting to erode and/or ignore society’s defenses.

So what to do?  Revolution? From a PLoS Science education perspective, one strategy suggests itself:  to encourage (require) that students and the broader public be introduced to effective instruction on social evolutionary mechanisms, the traits they can generate (various forms of altruism and cooperation), the reality and pernicious effects of social cheaters, and the importance of defenses against them.  In this light, it appears that social evolutionary processes are missing from the Next Generation Science Standards [NGSS link]. Understanding the biology, together with effective courses in civics [see link: Teaching Civics in the Year of The Donald] might serve to bolster the defense of civil society.

December 22, 2016, minor update 23 October 2020 – Mike Klymkowsky

Featured image is used with permission from Matthew Lutz (Princeton University).

Army ants’ ‘living’ bridges span collective intelligence, ‘swarm’ robotics (PNAS)