An overnight recipe for a new gene: change the frame

Can a new protein-coding gene be born overnight? That's the theme of this series. The answer, remarkably, is yes, and the Arhgap11b gene is the recent case I'm considering. After surveying the ways that this could happen, I narrowed the possible mechanisms to three:

There are really just three kinds of change that can get it done. All three are mutations that change how the DNA sequence that's already there gets decoded into protein. They are: 1) tiny mutations that shift the reading frame; 2) tiny mutations that change splicing; and 3) large-ish rearrangements that create new combinations of code.

Before looking at the details, let's take note of the fact that the genomes of animals and plants typically have gigantic amounts of DNA that does not code for protein. Humans are merely typical in this regard—at least 95% of the human genome is non-coding DNA, but there are organisms with a lot more and some with a lot less. The point here is not about "junk" or function, it's more basic: an animal genome contains vast amounts of DNA that could code for a protein, but doesn't. A new gene doesn't have to be magicked into a genome, by a demon or by a virus. A new gene can enter the gene library simply by becoming a new way of reading a pre-existing text. This is almost certainly how the vast majority of new genes have arisen in animals and plants for at least half a billion years. And the basic mechanism applies to all living things, for 3-ish billion years: any DNA sequence can become a protein-coding sequence, and those that already do code for protein can be straightforwardly modified to make completely different proteins.

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Gene-making: some questions answered

In my previous post I attempted to identify all the ways that a new gene can come about, after defining what I meant by "new" and "gene." Two questions came up, one a comment on the post, and the other via Facebook.

1. What about exon shuffling? Isn't that a mechanism by which new genes are made?

Exon shuffling is, roughly, the creating of new coding sequences (genes, as I'm defining them in this series) by the rearrangement of pieces of coding sequence. (An exon is a piece of coding sequence in DNA or RNA.) It's a nice descriptive phrase: the exons are gene pieces, and they can be moved around to make new cominbations that code for new proteins. So is this an additional mechanism for the creation of genes?

No, it's not.

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Can someone make me a new gene?

What would it take to make a completely new gene?

Interesting question, but first let's agree on roughly what we mean by a "new gene." Here is how I defined the topic when discussing unique human attributes:

A truly new and unique human gene, for my purposes here, would be a gene that makes a protein that is unique to humans—a protein never before seen, not something merely tweaked from a precursor.

"Creation of Eve." Was she completely new?

So you see we mean something a lot more "new" than, for example, the human-specific version of the FoxP2 gene, which I have discussed before. And we mean something that is born overnight. After all, incremental changes over eons can result in a gene being transformed into something utterly different. That's interesting, of course, but it's not what we mean by a "new gene." We are discussing genes that appear suddenly and code for protein, and we want them to truly "appear" and not merely move from one species to another.

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Does it take special genes to make a special human?

We humans think we're pretty special. Here's Hamlet, in the speech that gave this blog its name:

What a piece of work is a man! How noble in reason! how infinite in faculty! in form, in moving, how express and admirable! in action how like an angel! in apprehension how like a god! the beauty of the world! the paragon of animals!

—Hamlet, Act II, Scene II, The Oxford Shakespeare

Kemble in the role of Hamlet.
Courtesy of Wellcome Images.

It is common, at least in the West, to consider humans "the paragon of animals," typically making reference to the ancient idea of "God's image." I won't address here whether humanity is a paragon, but here's a more tractable question: what are the facets that distinguish humans from other animals? Biologically speaking, what is special about humans that sets them apart from other apes?

Anatomically, we're pretty unremarkable apes. We have enlarged gluteal muscles and other adaptations that make us good distance runners. We have fancy thumbs that make us good tool users. We have a tweaked larynx that facilitates speech. We have spineless penises that facilitate other things. And of course we have what Hamlet was talking about: big brains and associated cognitive abilities.

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A mystery gene in human brain development: discovering ARHGAP11b

The human brain is often described using literally cosmic superlatives. Here is V.S. Ramachandran, a renowned neuroscientist:

The human brain, it has been said, is the most complexly organised structure in the universe and to appreciate this you just have to look at some numbers. The brain is made up of one hundred billion nerve cells or "neurons" which is the basic structural and functional units of the nervous system. Each neuron makes something like a thousand to ten thousand contacts with other neurons and these points of contact are called synapses where exchange of information occurs. And based on this information, someone has calculated that the number of possible permutations and combinations of brain activity, in other words the numbers of brain states, exceeds the number of elementary particles in the known universe.

That's some serious complexity there, yes, but hidden in the description is a mundane reality: the human brain is made of neurons which make synapses with other neurons, which means that it's made of the same stuff as the brain of a sloth or a goldfish or an earthworm. (Or even a parasitic mite on an earthworm.) Still, whether or not the human brain is really special or just big, something has caused it to grow in ways that differ from its predecessors. Especially at key junctures in the process, human brain development must depart from boring old mammalian brain development. And this should be reflected by — and perhaps explained by — patterns of gene expression.

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When a GAP is not a GAP: ARHGAP11B, the mysterious human-specific gene

A truly human-specific gene, not merely a human-specific version of an animal gene or a mammal gene or a primate gene — that is something particularly interesting. Given that the human genome is 96% identical to that of our closest relatives (chimps and bonobos), and given that so much of those genomes is composed of mobile elements that are unlikely to end up being genes at all, I and perhaps others long thought that human-specific genes would be something pretty rare.

But there they are — genes by every definition, that code for protein and are expressed in human tissues, that are unique in humans. One of the most interesting is a gene that brings together some of my personal favorite topics in biology: brain development, cellular signaling systems, and of course evolution. The gene goes by the unfortunate "name" of ARHGAP11B.

I do consider ARHGAP11B to be a unique human gene, but its name betrays its evolutionary history and its membership in a family of genes, so it's not completely unique (specifics to come). That family is the family of GAPs, a group of proteins that were the focus of my postdoctoral research years ago. GAP stands for "GTPase-activating protein," and besides being a typical morsel of biochemical jargon, the phrase is a bit of an insult to the roles played by these proteins in cellular signaling systems.

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Relaunch in 10...9...8...

Quintessence of Dust has been on hiatus for more than five years. It's time to resurrect it. Why now? Because it's 2017, and 2017 is not a time to be quiet.

The first project involves some remodeling. Quintessence of Dust was built almost ten years ago, with a set of themes and goals that don't all fit in 2017. Most notably, the blog was conceived when I was a Christian, and for five years addressed issues and questions that I knew to be of interest to evangelical Christians. I am happily no longer a Christian, and will remodel the blog to reflect that. I do still live in the United States, in 2017, where evangelical Christianity exerts significant influence. And I know a lot about that world. So religion will be an occasional, if tangential, topic. But now I will write as a skeptic, as one who has transitioned from Christian humanism to just plain humanism. The remodeling of the site is mostly to make this clear. I do think I'll keep the Celtic cross in the banner.

In parallel with the remodeling I'll start writing about cool science. And I've already found the topic of my first post or two: a paper from last month that identifies a single mutation in the human genome that may explain (at least in part) the dramatic expansion of the cerebral cortex that occurred in our lineage. The story is a remarkable confluence of topics very dear to me: evolution, developmental neurobiology, and cellular signaling systems. The protein at the center of the story is closely related to the proteins that I spent my postdoctoral fellowship trying to understand. I'll explain all of this in the posts to come.

If you want to have a peek at the story, check out the news piece at the BBC, or the new paper itself (it's open access). The first part of the saga, in which the protein's role in brain development was discovered, was published in 2015 (also open access but requires free registration).

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Image: By Internet Archive Book Images [No restrictions], via Wikimedia Commons

December 2014 update: Quintessence of Dust is on a long-term hiatus, but I haven't closed it down just yet. I have some new writing projects in various stages of planning, in collaboration with some old friends. See my About page for information about me and the blog, including current contact information.

If it's not natural selection, then it must be...

The folks at the Discovery Institute (DI) are engaged in an extensive attempt to rebut my friend Dennis Venema's critiques of Stephen Meyer's surprisingly lame ID manifesto, Signature in the Cell. There are several aspects of this conversation that I hope to address in the coming days and weeks, but one jumped out at me today: the consistent confusion about natural selection in depictions of evolutionary theory by design advocates.

Consider this excerpt from a recent blog post by a writer at the Discovery Institute:

...we need a brief primer in fundamental evolutionary theory. Natural selection preserves randomly arising variations only if those variations cause functional differences affecting reproductive output.

A few sentences later, the same claim is repeated:

Indeed, given that natural selection favors only functionally advantageous variations, ...

Those claims were first made in a piece written by unnamed DI "fellows" mocking the work and conclusions of Joe Thornton, an evolutionary biologist at the University of Oregon and the University of Chicago. And the claims are badly misleading.

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Common ancestry, bottlenecks, and human evolution

Human evolution has been in the news quite a lot recently.

• New genetic data suggest that ancient humans included both Neanderthals and Denisovans, which colonized different parts of the world but subsequently interbred with so-called modern humans and left telltale traces of this history in the genomes of living humans.
• New analysis of current genetic diversity suggests that human population size underwent interesting fluctuations throughout the history of our species, but concludes that the population never dipped below a few thousand reproducing individuals.

Unsurprisingly, these findings have been discussed in the context of Christian views of human origins. In the context of some of these discussions (among Catholics, for example), I have noticed some confusion regarding the implications of common ancestry. I will illustrate the error with a stylized example, then explain why it is an error.

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Harmful genes, and sneaky, too: Genetic hitchhiking in the human genome

Genetic hitchhiking is thought to be an inevitable result of strong positive selection in a population. The basic idea is that if a particular gene is strongly selected for (as opposed to selected against), then the chunk of the genome that carries that gene will become very common in the population. The result is a local loss of genetic diversity: all (or nearly all) of the individuals in the population will have that same chunk of genetic information, whereas before the selection process acted, there might have been a lot of variation in that chunk throughout the population. And this means that areas of the human genome that are less variable between people are suspected sites of recent positive selection. Within that chunk, there are potentially many genes and genetic elements that became more common in the population by virtue of their placement near the gene that was actually selected for. Those other genes are the hitchhikers. And it's likely that some hitchhikers are bad news – they're harmful mutations that would normally become rare or extinct in the population, but instead have become common by hitchhiking.

In the last few years, large amounts of genetic information have become available that have enabled biologists to look for evidence of such phenomena in the human genome. Specifically, two major projects have collected genetic data for the purpose of analyzing genetic variation among humans. One project, the International HapMap Project, mapped and quantified sites in the human genome that are known to vary among humans by a single genetic letter. These sites are called single nucleotide polymorphisms, or SNPs (pronounced "snips"). The project has mapped millions of these sites in a group of 270 humans representing various lineages. Another project that has made the news recently is the 1000 Genomes Project, which also seeks to provide a picture of human genetic variation using more people (more than 1000 at present) and slightly different technology. Efforts like these have taken analysis of the human genome to a new level. No longer do we merely wonder what "the" human genome is like – we can begin to learn about how genetic differences give rise to biological differences such as susceptibility to particular diseases.

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New limbs from old fins, part 3

The third installment of my series at BioLogos is now up. It discusses the developmental mechanisms that underlie the construction of limbs, and the striking fact that these mechanisms are the same ones used to construct fish fins. Watch for an appearance by Sonic Hedgehog.

Genetic hitchhiking in English

The next post will discuss recent evidence for genetic hitchhiking in humans. So, what do we mean when we say that genes can hitchhike? To make sense of this phenomenon, we first need to review chromosomes and sexual reproduction.

Most people know that sexual reproduction creates offspring that are genetically distinct from both of the their parents. That's true, but the genetic scrambling that occurs is more significant than is sometimes reported. Let's start by looking at chromosomes.

Like every other animal (or plant or pretty much any other organism), your genetic endowment is carried in chunks of DNA called chromosomes. You have 23 of these chunks, which are rather like volumes in a set of encyclopedias. More completely, you have 23 pairs of these volumes; one set was contributed by your mother and the other by your father. Each of your parents had a complete set, also consisting of a set from Mom and a set from Dad. When your mother made the egg that became the zygote that became you, she provided you with one copy of each volume in the set, and she chose those copies randomly. For example, she may have chosen her dad's copy of chromosome 1, but her mom's copy of chromosome 2. Just by virtue of this random picking process, she made an egg with a shuffled version of her own genetic cards. Dad did the same when he made his sperm, and so your genetic complement is an amalgamation of your parents' genomes which were amalgamations of your grandparents' genomes, and so on.

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New limbs from old fins, part 2

The second post in my series on limb evolution is now up at the BioLogos site. This installment reviews the fossil evidence on fin-to-limb evolution, introducing the famous Tiktaalik. Next up: evidence from developmental biology.

The first post at BioLogos outlined limb structure and some historical background. The series at BioLogos was spawned by an idea here at QoD, which aimed to discuss some new findings in the fins-to-limbs story. Those new findings will be discussed in the fifth installment of the series at BioLogos.

Please comment! You can leave comments here or at BioLogos.

"The stamp of one defect": an endless series on harmful mutations

Not surprisingly, Hamlet weighed in on the nature vs. nurture question, at least once.

So, oft it chances in particular men,
That for some vicious mole of nature in them,
As, in their birth,―wherein they are not guilty,
Since nature cannot choose his origin,―
By the o’ergrowth of some complexion,
Oft breaking down the pales and forts of reason,
Or by some habit that too much o’er-leavens
The form of plausive manners; that these men,
Carrying, I say, the stamp of one defect,
Being nature’s livery, or fortune’s star,
Their virtues else, be they as pure as grace,
As infinite as man may undergo,
Shall in the general censure take corruption
From that particular fault: the dram of eale
Doth all the noble substance of a doubt,
To his own scandal.

– Hamlet, Act I, Scene IV, The Oxford Shakespeare

It is certainly true that "the stamp of one defect" can wreak havoc on the scale that Hamlet describes, and whether the result is a debilitating physical limitation or damage to "the pales and forts of reason," the outcome is tragic by any measure.

Reflecting on the reality of inherited dysfunction, we might be tempted to assume that a "vicious mole of nature" is something seen only "in particular men," and that those who are not so characterized (let's call them "normal people") have been dealt a genetic hand that lacks such devilish cards. Normal people don't have bad genes.

Okay, so in the real world I suspect that most people are not so naïve; if you're reading this blog, then you probably know that bad genes can be carried by normal, healthy people. Nevertheless, when we think about bad genes – or more technically, deleterious mutations – we are likely to think that they are not very common.

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New limbs from old fins, part 1

Last month, I started a series on the topic of limb evolution, here at Quintessence of Dust. That series has been transformed (through a series of intermediates) into a series of posts at the BioLogos site. The first installment is now up, and it provides an expanded introduction to the topic and a little historical context. Subsequent posts will tackle fossils, developmental biology, genetics, the explanatory role of design, and related themes.

So go check out the introduction, and feel free to contribute comments, questions and suggestions here. And enjoy the image below, from Wellcome Images, which is featured in the post at BioLogos. Cool, huh?

Molecular evolution: improve a protein by weakening it

In the cartoon version of evolution that is often employed by critics of the theory, a new protein (B) can arise from an ancestral version (A) by stepwise evolution only if each of the intermediates between A and B are functional in some way (or at least not harmful). This sounds reasonable enough, and it's a good starting point for basic evolutionary reasoning.

But that simple version can lead one to believe that only those mutations that help a protein, or leave it mostly the same, can be proposed as intermediates in some postulated evolutionary trajectory. There are several reasons why that is a misleading simplification – there are in fact many ways in which a mutant gene or protein that seems to be partially disabled might nevertheless persist in a population or lineage. Here are two possibilities:

1. The partially disabled protein might be beneficial precisely because it's partially disabled. In other words, sometimes it can be valuable to turn down a protein's function.

2. The effects of the disabling mutations might be masked, partially or completely, by other mutations in the protein or its functional partners. In other words, some mutations can be crippling in one setting but not in another.

In work just published by Joe Thornton's lab at the University of Oregon, reconstruction of the likely evolutionary trajectory of a protein family (i.e., the steps that were probably followed during an evolutionary change) points to both of those explanations, and illustrates the increasing power of experimental analyses in molecular evolution.

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Let's see a show of autopods. Part 1.

The discovery of deep homology was a milestone in the history of evolutionary thought. Anatomical structures in distantly related organisms, structures with only the barest of functional similarities, were found to be constructed under the influence of remarkably similar genetic pathways. The original and classic example from 1989 involves genes controlling pattern in both insects and mammals – the famous Hox genes. Another great example emerged from the study of limb development and evolution in vertebrates, work beautifully described by Neil Shubin in Your Inner Fish.

The idea that the limbs of various animals are homologous – meaning that they are variations on a theme inherited from common ancestors – is certainly not new, with roots in the exploration of 'archetypes' by the great Sir Richard Owen. But deep homology goes, well, deeper, suggesting that even basic themes like 'limb' or 'eye' or even just 'thing-sticking-out-of-the-body-wall' can be identified and seen to be conserved throughout the biological world. And, importantly, deep homology points to genetic mechanisms that underlie basic themes, structural concepts so distinct that they would not be judged to be related by structural criteria alone. Consider, for example, limb development in vertebrates.

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What a selfish little piece of...

"The Selfish Gene." "Selfish DNA." Oh, how such phrases can get people bent out of shape.  Stephen Jay Gould hated such talk (see a little book called The Panda's Thumb), and Richard Dawkins devoted more time to answering critics of his use of the term 'selfish' than should have been necessary. Dawkins' thesis was pretty straightforward, and he provided real examples of "selfish" behavior of genes in both The Selfish Gene and its superior sequel, The Extended Phenotype. But there have always been critics who can't abide the notion of a gene behaving badly.

Leaving aside silly bickering about the attribution of selfishness or moral competence to little pieces of DNA, let's consider what we might mean if we tried to imagine a really selfish piece of DNA. I mean a completely self-centered, utterly narcissistic little piece of DNA, one that not only seeks its own interest but does so with rampant disregard for other pieces of DNA and even for the organism in which it travels. Can we imagine, for example, a piece of DNA that deliberately harms its host in order to propagate itself?

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Evolution cheats, or how to get an old enzyme to do new tricks

It is of course a cliche to state that eukaryotic cells (i.e., cells that are not bacteria) are complex. In the case of an animal, tens of thousands of proteins engage in fantastically elaborate interactions that somehow coax a single cell into generating a unique and magnificent organism. These interactions are often portrayed as exquisitely precise, using metaphorical images such as 'lock-and-key' and employing diagrams that resemble subway maps.

Many of these interacting proteins are enzymes that modify other proteins, and many of those enzymes are of a particular type called kinases. Kinases do just one thing: they attach phosphate groups to other molecules. This kind of modification is centrally important in cell biology, and one way to tell is to look at how many kinases there are: the human genome contains about 500 kinase genes.

Now, kinases tend to be pretty picky about who they stick phosphate onto, and this specificity is known to involve the business end of the kinase, called the active site. The active site is (generally) the part of the kinase that physically interacts with the target and transfers the phosphate. You might think that this interaction, between kinase and target, through the active site, would be by far the most important factor in determining the specificity of kinase function. But that's probably not the case.

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