α-actinin evolution in humans

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Perhaps your idea of the traditional holiday week involves lounging about with a full belly watching football — not me, though. I think if I did, I’d be eyeing those muscular fellows with thoughts of muscle biopsies and analyses of the frequency of α-actinin variants in their population vs. the population of national recliner inhabitants. I’m sure there’s an interesting story there.

In case you’re wondering what α-actinin is, it’s a cytoskeletal protein that’s important in anchoring and coordinating the thin filaments of actin that criss-cross throughout your cells. It’s very important in muscle, where it’s localized in the Z-disk at the boundaries of sarcomeres, the repeated contractile units of the muscle. This diagram might help you visualize it:

sarcomere.jpeg

Actin (green), myosin (red). Rod-like tropomyosin molecules (black lines). Thin filaments in muscle sarcomeres are anchored at the Z-disk by the cross-linking protein α-actinin (gold) and are capped by CapZ (pink squares). The thin-filament pointed ends terminate within the A band, are capped by tropomodulin (bright red). Myosin-binding-protein C (MyBP-C; yellow transverse lines).

The most prominent elements in the picture are the thin filaments (made of actin) and thick filaments (made of myosin) which slide past each other, driven by motor proteins, to cause contraction and relaxation of the muscle. The α-actinin proteins are the subtle orange lines in the Z disks on the left and right.

The α-actinin proteins are evolutionarily interesting. In vertebrates, there are usually four different kinds: α-actinin 1, 2, 3, and 4. 1 and 4 are ubiquitous in all cells, since all cells have a cytoskeleton, and the α-actinins are important in anchoring the cytoskeleton. α-actinin-2 and -3 are the ones of interest here, because they are specifically muscle actinins. α-actinin-2 is found in all skeletal muscle fibers, cardiac muscle, and also in the brain (no, not muscle in the brain, there isn’t any: in the cytoskeleton of neurons). Just to complicate matters a bit, α-actinin-2 is also differently spliced in different tissues, producing a couple of isoforms from a single gene. α-actinin-3 is not found in the brain or heart, but only in skeletal muscle and specifically in type II fast glycolytic muscle fibers.

Muscle fibers are specialized. Some are small diameter, well vascularized, relatively slow fibers that are optimized for endurance; they can keep contracting over and over again for long periods of time. These are the fibers that make up the dark meat in your Christmas turkey or duck. Other fibers are large diameter, operate effectively anaerobically, and are optimized for generating lots of force rapidly, but they tend to fatigue quickly — and there are more of these in the white meat of your Christmas bird. (There are also intermediate fiber types that we won’t consider here.) Just keep these straight in your head to follow along: the fast type II muscle fibers are the ones that you use to generate explosive bursts of force, and may be enriched in α-actinin-3; the slower fibers are the ones you use to keep going when you run marathons, and contain α-actinin-2. (There are other even more important differences between fast and slow fibers, especially in myosin variants, so differences in α-actinins are not major determinants of muscle type.)

Wait, what about evolution? It turns out that invertebrates only have one kind of α-actinin, and vertebrates made their suite of four in the process of a pair of whole genome duplications. We made α-actinin-2 and -3 in a duplication event roughly 250-300 million years ago, at which time they would have been simple duplicates of each other, but they have diverged since then, producing subtle (and not entirely understood) functional differences from one another, in addition to acquiring different sites of expression. α-actinin-2 and -3 in humans are now about 80% identical in amino acid sequence. What has happened in these two genes is consistent with what we know about patterns of duplication and divergence.

duplication.jpeg

Using sarcomeric α-actinin as an example, after duplication of a gene capable of multiple interactions/functions, there are two possible distinct scenarios besides gene loss. A: Sub-functionalisation, where one interaction site is optimised in each of the copies. B: Neo-functionalisation, where one copy retains the ancestral inter- action sites while the other is free to evolve new interaction sites.

So what we’re seeing in the vertebrate lineage is a conserved pattern of specialization of α-actinin-3 to work with fast muscle fibers — it’s a factor in enhancing performance in the specific task of generating force. The α-actinin-3 gene is an example of a duplicated gene becoming increasingly specialized for a particular role, with both changes in the amino acid sequence that promoted a more specialized activity, and changes in the regulatory region of the gene so that it was only switched on in appropriate muscle fibers.

actn_history.jpeg

Duplication and divergence model proposed by this paper. Before duplication the ancestral sarcomeric α-actinin had the functions of both ACTN2 and ACTN3 in terms of tissue expression and functional isoforms. After duplication, ACTN2 has conserved most of the functions of the preduplicated gene, while ACTN3 has lost many of these functions, which may have allowed it to optimise function in fast fibres.

That’s cool, but what we need is an experiment: we need to knock out the gene and see what happens. Mutations in α-actinin-2 are bad—they cause a cardiomyopathy. Losing α-actinin-4 leads to serious kidney defects (that gene is expressed in kidney tissue). What happens if we lose α-actinin-3?

It turns out you may be a guinea pig in that great experiment. Humans acquired a mutation in the α-actinin-3 gene, called R577X, approximately 40-60,000 years ago, and this mutation is incredibly common: about 50% of individuals of European and Asian descent carry it, and about 10% of individuals from African populations. Furthermore, an analysis of the flanking DNA shows relatively little recombination or polymorphism — which implies that the allele has reached this high frequency relatively recently and rapidly, which in turn implies that there has been positive selection for a nonsense mutation that destroys α-actinin-3 in us. The data suggests that a selective sweep for this variant began in Asia about 33,000 years ago, and in Europe about 15,000 years ago.

There is no disease associated with the loss of α-actinin-3. It seems that α-actinin-2 steps up to the plate and fills the role in type II fast muscle fibers, so everything functions just fine. Except…well, there is an interesting statistical effect.

The presence of a functional α-actinin-3 gene is correlated with athletic performance. A study of the frequency of the R577X mutation in athletes and controls found that there is a significant reduction in the frequency of the mutation among sprinters and power-lifters. At the Olympic level, none of the sprinters in the sample (32 individuals) carried the α-actinin-3 deficiency. Among Olympic power lifters, all had at least one functional copy of α-actinin-3.

Awesome. Now I’m wondering about my α-actinin-3 genotype, and whether I have a good biological excuse for why I always got picked last for team sports in high school gym class. This is also why I’m interested in taking biopsies of football players…both for satisfying a scientific curiosity, and for revenge.

You may be wondering at this point about something: α-actinin-3 has a clear beneficial effect in enhancing athletic performance, and its conservation in other animal species suggests that it’s almost certainly a good and useful protein. So why has there been positive selection (probably) for a knock-out mutation in the human lineage?

There is a weak correlation in that study of athletic performance that high-ranking athletes in endurance sports have an increased frequency of the R577X genotype; it was only seen in female long-distance runners, though. More persuasive is the observation that α-actinin-3 knockouts in mice also produced a shift in metabolic enzyme markers that are indicative of increased endurance capacity. The positive advantage of losing α-actinin-3 may be more efficient aerobic metabolism in muscles, at the expense of sacrificing some strength at the high end of athletic performance.

This is yet another example of human evolution in progress—we’re seeing a shift in human muscle function over the course of a few tens of thousands of years.


Lek M, Quinlan KG, North KN (2009) The evolution of skeletal muscle performance: gene duplication and divergence of human sarcomeric alpha-actinins. Bioessays 32(1):17-25. [Epub ahead of print]

MacArthur DG, Seto JT, Raftery JM, Quinlan KG, Huttley GA, Hook JW, Lemckert FA, Kee AJ, Edwards MR, Berman Y, Hardeman EC, Gunning PW, Easteal S, Yang N, North KN (2007) Loss of ACTN3 gene function alters mouse muscle metabolism and shows evidence of positive selection in humans. Nat Genet.39(10):1261-5.

Yang N, MacArthur DG, Gulbin JP, Hahn AG, Beggs AH, Easteal S, North K (2003) ACTN3 genotype is associated with human elite athletic performance. Am J Hum Genet 73(3):627-31.

11 Comments

Now, this is the kind of science that makes it endlessly fascinating. Without doing a genetic test on myself, I predict that I would have the normal gene. I was always very quick, but not for very long.

PZ sez:

Perhaps your idea of the traditional holiday week involves lounging about with a full belly watching football

What about celebrating Kitzmas??? Nobody posted on the 4th anniversary of K v.D this year… Disappointing…

OgreMkV said:

Now, this is the kind of science that makes it endlessly fascinating. Without doing a genetic test on myself, I predict that I would have the normal gene. I was always very quick, but not for very long.

Well then, I guess you aren’t going to be a porn star or a weight lifter! Now I’m no olympic athlete, but I have always had more quickness than endurance, so maybe I have the mutant allele. As for football players, perhaps the wide receivers have the mutation more often than the lineman. That make make an interesting study. You could also check to see if the muscle proteins were expressed in brain tissue in football players more often than in normal people. (Just kidding. I have the greatest respect for professional football players, some more than others).

But seriously, thanks to PZ for yet another wonderful example of human evolution in action and a good lesson in muscle physiology as well. Once again, the story is the same. Gene duplication followed by divergence of coding and regulatory regions with selection superimposed. There should be an acronym for describing such a mechanism, since it seems so pervasive.

No wonder creationists have so much science envy. They only read one book and it doesn’t have anything new like this.

You can just see it coming; a new nerd pick-up line in the bar, “Are you white meat or dark meat?”

Thanks for the interesting reading. My week has been spent digging out a busted drain pipe. Takes me back to my days as a field archaeologist. We really did “do it dirty.”

KP Wrote:

What about celebrating Kitzmas??? Nobody posted on the 4th anniversary of K v.D this year… Disappointing…

The Curmudgeon did.

But as you know, and contrary to the implications of anti-evolution activists, “Darwinists” have not sat still for 4 years celebrating legal victories and “defending a dying theory.” Rather, as PZ’s article shows, they keep testing the theory. Something anti-evolution activists refuse to do with their “theory,” which is getting more vague every year. What else can they do given the mutual contradictions and easily falsified claims of the various versions?

Frank J said:

What else can (anti-evolutionists) do given the mutual contradictions and easily falsified claims of the various versions?

Bribe and manipulate like-minded politicians and educators into flouting the US Constitution in order to indoctrinate more people into their own painfully narrow and shallow mindset?

Bah! Like that could ever happen.

About Kitzmiller - you can read my blog for a brief summary of what happened on the 4th anniversary.

It’s not clear to me from reading this that positive selection, rather than founder effect and-or genetic drift, would be the obvious explanation for the frequency of the mutant allele in different populations. Modern human populations are descended from fairly small groups of ancestors.

It’s also highly conceivable that self-selection may have played a role. An allele which may be associated with a slight increase in endurance, albeit at a price, being found in populations descended from those who wandered the furthest (in small groups. at a slow pace, over many years) from the ancestral locale.

I bet this is related to the ancient hunting style of simply running down large game that’s still practiced today. As far as I know, only humans hunt like that. And we’re well adapted to it too, one free hand for water + snack, one for a spear. Just keep jogging after that gazelle till it collapses. Works great and only takes a couple hours. Might be also related to humans reaching temperate zones where it’s impossible to survive winter unless you got a hunting style that always works and is actually easier in winter.

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This page contains a single entry by PZ Myers published on December 23, 2009 2:11 PM.

(Creation) science marches on! was the previous entry in this blog.

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