Homology for Dummies

Current Biology likes to give its readers primers on various concepts. The topic in the May 4 issue is homology.¹ Caleb Webber and Chris P. Ponting explain this important evolutionary term for the rest of us. The Q&A format also introduces homology’s siblings: analogy, orthology, paralogy, xenology, and synteny.

Some readers may not realize that the term homology was first coined by a Christian creationist, Richard Owen, Britain’s foremost paleontologist in Darwin’s day. Owen, who despised Darwin’s book, defined homologous structures as similarities descended from a common archetypal body plan. The Darwinians co-opted the term to mean descended from a common ancestor. Analogous structures, by contrast, came to mean similarities not due to common ancestry, but rather to convergence (evolution toward similarity from different directions).

The other words are derivatives of these key concepts.

• Orthology means similarities on the same branch of the phylogenetic tree
• Paralogy means similarity due to gene duplication
• Xenology means similarity arising from lateral gene transfer
• Synteny can mean either genes that reside on the same chromosome, or, more generally, genes in the same orthologous order within the same genomic regions.  The terms can be applied to visible structures, like vertebrate limbs and plant leaves, but are more commonly used to describe gene sequences.

Now that you know the words, how are they used in practice by biologists?

Is Homology a Useful Concept?

The authors seem to be eager to dismiss charges that the terminology provides an ostentatious distraction from evolutionary assumptions. No, it is truly useful, as a famous biologist once said:

Differentiating between homology and analogy is not mere pedantry²: homology allows Darwinian evolutionary theory to be applied accurately across the biosciences. And, as Theodosius Dobzhansky (1900–1975) famously remarked, “Nothing in biology makes sense except in the light of evolution.”

With that understood, the authors point out occasions where lack of understanding of the ancestry can trip up the observer. Sequence similarity, for instance, is not the same thing as homology: “Sequence similarity is a quantity that is agnostic of evolution. In contrast, homology is a property that describes evolutionary history.” In other words, sequences can look homologous but not really be related in the family tree. Even evolutionary scientists goof on this point sometimes:

Just as with bird wings and bat wings, perceived similarities between sequences need not be due to a common evolutionary origin. Research papers sometimes wrongly quote values of ‘percent homology’. In these cases ’percent identity’ is meant, as two genes either have a common ancestor or they do not. The only appropriate use of ‘percent homology’ is when separate portions of a gene have distinct evolutionary histories, for example as a result of a gene fusion event.

That raises the next obvious question; “How can one be sure beyond reasonable doubt that two similar sequences are homologous?” To answer it requires a little high school algebra.  Hang on:

Using statistics you can estimate how likely it is that randomly composed sequences yield alignment scores that are at least as high as that obtained between the real sequences in question. For example, the BLAST program reports an Expect (or E) value for each alignment (with score x), which is the number of times sequences are expected, with scores >=x, to crop up in a search just by chance. As E gets closer to zero, the more confident one should be in a prediction of homology. Many users cautiously consider only those alignments with E-values lower than 10^-3 as substantiating evidence for homology.

Now that that’s clear, what about proteins? They can have similar folds; does that indicate homology? Not necessarily. They warn that “once again we are faced with ‘similarities’: we cannot be sure that just because two proteins fold up in the same way it means they arose from a common ancestor. Nevertheless, spatial coincidence of active or binding sites, or unusual structure, can boost the odds of a homology prediction being correct.”

Convergent Evolution

Then there is the puzzle of convergence:

What about convergent evolution? As far as we can tell, the convergence of gene sequences is extremely rare. It is, by far, ‘easier’ for Nature to duplicate a gene than invent similar genes on two separate occasions. By contrast, independent invention of protein structure is often suggested to have occurred, yet for most of these cases the evolutionary provenance is unclear.

Next, they describe how orthology, paralogy and xenology are best illustrated with a phylogenetic tree, and draw one to make it clear. “However,” they caution, “lineage-specific gene deletion, pseudogenisation, duplication, conversion and rapid sequence divergence can all confuse phylogenetic tree reconstruction.” Better leave that to the experts. They provide examples of confusion that can arise from gene duplication and deletion.

Note that these relationships [orthologs, paralogs etc.] are defined with respect to evolution, and not function. Nevertheless, they are useful in predicting function as the more recently two genes shared a common ancestor, the more likely it is that they have retained similar functions. Moreover, orthologous genes that have been spared by natural selection from deletion or duplication over many millions of years are also likely to share overlapping functions.

Well, that about wraps up this lesson. One more issue is the need for such jargon. How useful are these words, really? Why not invent a new term that avoids evolutionary assumptions altogether?

Do we need new terms (neologies)? Some would say that we do. They argue that we should coin terms to describe similarities — in sequence or structure, for example — between biological molecules regardless of whether these arose by divergence from a common ancestor. Only definitions that are useful will survive, they suggest, while those that are not will be dropped (a linguistic mimicking of purifying selection). We believe that there is too much bewilderment already in the use of homology, orthology and paralogy, so introducing yet more terms appears to be asking for trouble. Moreover, the terms in current use are sufficient, when applied appropriately, to qualitatively describe the consequences of gene duplication (homologs), speciation (orthologs), intragenome duplication (paralogs) and horizontal transfer (xenologues), which are four of the major evolutionary forces acting on genes.

Coincidentally, the same week, Nature³ posted a story about a case of apparent convergent evolution. The abstract states, “Swift-swimming, open-ocean hunters such as mako sharks and tunas need a big engine. Despite their long separation in evolutionary terms, the internal drive systems adopted by these fishes are much the same…. after 400 million years of separate evolutionary trajectories, these two high-speed predators have converged on solutions to the problem of swimming fast that go from skin to skeleton.” Don’t forget that certain extinct marine reptiles with similar body shapes that probably also “converged” on these solutions independently.

¹Caleb Webber and Chris P. Ponting, “Magazine: Genes and homology,” Current BiologyVol 14, R332-R333, 4 May 2004.
²Pedantry, n., pedantic presentation or application of knowledge or learning. Pedantic, adj., or, relating to, or being a pedant. Pedant, n., 2. a. one who parades his learning. b. one who is unimaginative or who unduly emphasizes minutiae in the presentation or use of knowledge. Pedantic can also mean: narrowly, stodgily, and often ostentatiously learned: e.g., ontogeny recapitulates phylogeny.
³Adam P. Summers, “Fast Fish,” Nature 429, 31 – 33 (06 May 2004); doi:10.1038/429031a.

Well, now I’m more bewildered than ever. Didn’t they just say that we need the evolutionary terms with their evolutionary baggage so that we can describe evolutionary forces in evolutionary terms? This has me going around in so many circles I’m getting dizzy.

I hope you got the gist of this tale. Webber and Ponting just bluffed their way past the pedantry of the terminology, claimed without evidence that it is useful, supported it by an argument from authority, and then assumed evolution to explain everything in an evolutionary way, no matter how contradictory the evidence. Basically, they used evolutionary assumptions to create evolutionary lingo such that any kind of data yields an evolutionary explanation. This is why they said, “homology allows Darwinian evolutionary theory [read: belief] to be applied accurately [read: forceably] across the biosciences.” What a con job! Since we already agree a priori that nothing makes sense except in the light of evolution, as Dobzhansky “famously remarked,” well by golly we’re going to make sure that nothing makes sense except in the light of evolution, and we’ll even invent the words to enforce it. Look, we can even throw in some worthless algebra to impress the peasants – that will make them afraid to use common sense.

This is how they can get away with murdering the data. They’ve put their opponents into a catch-22. Unless the opponent comes up with an evolutionary explanation, he’s disqualified, because he or she is not applying evolutionary theory accurately across the biosciences. They can’t lose. Similarities due to prior belief in common ancestry? No problem: homologous. Similarities due to prior belief they are not related by common ancestry? Oh, those are analogous. Convergent evolution took care of it. “Nature” was clever and “invented” it twice; it’s rare, but trust us, it just happens sometimes. Sequence similarity? Well, it might be homologous, or it might not; better leave that to the wizards (who have already sworn allegiance to Charlie). See?  Everything makes perfect sense. Nothing makes sense except in the light of evolution. But couldn’t we just try to use terms that describe the similarities without any evolutionary presuppositions? Well, now, the peasants are already bewildered by the words we have. It’s a nice suggestion, but… I think we should just leave things alone. Everything is fine.

In his book Icons of Evolution (Regnery, 2000, p. 248), Jonathan Wells* turned Dobzhansky’s famous line around into something more akin to the spirit of true science: “Nothing makes sense except in the light of evidence.”