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.

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.

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.

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.

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.

*Edit July 2020: The series was consolidated into a single article on the BioLogos site. The link now goes to that single article.

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.

New limbs from old fins, part 2

Titktaalik roseae.
Image from
https://tiktaalik.uchicago.edu/index.html

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 final installment of the series at BioLogos.

*Edit July 2020: The series was consolidated into a single article on the BioLogos site. The link now goes to that single article.

"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.