1) The neutral theory never predicts that sequences under purifying selection are equally suitable for building phylogenetic trees, even if just for the topology part of it. The key concept of the neutral theory is that most observed natural variants are not under purifying selection. Most are neutral and some (very few) are beneficial. The new data on Y chr invalidate the neutral theory. And if the neutral theory is invalid, all molecular trees today would have no sound theoretical basis. In fact, in our view, the neutral theory was mistaken right from the start when it mistakenly interpreted the genetic equidistance result that got the field started. That result was the best evidence for purifying selection and absence of junk/neutral DNAs.

2) Common purifying selection would lead to common shared sequences, which would dramatically affect topology. (It may be easier for you to imagine shared sequences due to positive selection. But it really is pretty easy to think the same for purifying selection.) Thus, the close similarity between human and chimpanzee in fast evolving sequences including the Y, which are all under purifying selection, merely indicates common purifying selection rather than common ancestry. Our recent paper in Science China shows that when using slow evolving sequences not under selection, chimp and human can be shown to belong to separate clades with all three great apes in the pongid clade.

3) If population A has high genetic diversity while B low in most genome sequences, the typical interpretation today is that A evolved longer than B and gave rise to B. But this topology could be completely reversed if most sequences are under purifying selection with A under more relaxed selection than B. Here the true topology as revealed by the slow evolving sequences may show that B evolved first and has higher genetic diversity in the informative sequences. We will soon have a paper to this effect.

4) Nothing is truly neutral. All variants, being random and disorderly in origin, have a deleterious aspect. A major effect variant causing great harm never has a chance to behave as neutral and is negatively selected immediately within one generation after it emerges. In contrast, most minor effect variants would exist as neutral for a long time or many generations before being negatively selected when the accumulation of too many such variants exceeds the maximum tolerable level that an organism can tolerate. Simple organisms can tolerate more. Therefore, only slow evolving sequences that have variant numbers still below the maximum tolerable level are informative to tree topology as well as timing. That more slow evolving and hence more conserved sequences have apparently observed neutral variants may seem counter-intuitive but actually makes sense. Since changes in the slow evolving sequences take long time, they may be too slow to meet adaptive needs to be under positive selection. Given the apparent slow rate and absence of positive selection, they are also unlikely to reach excess levels to cause harm or be under negative selection.

5) Nearly all the ‘surprise’ results reported at the ASHG2012 meeting can be easily explained by purifying selection and the MGD. Iceman Otzi from ~5000 years ago was found not to show similarity to Europeans today in Central Europe in most fast evolving sequences, but rather to Sardinians, which is considered surprising. Also, Iceman is related to other Central European farmers (but not hunter gathers) from 5000 years ago. Even more surprising is that the mtDNA of Iceman does not resemble any humans today. Well, all these are evidence for the MGD. The sequences under purifying selection 5000 years ago are of course expected to be very different from those of today. My graduate students are right now busy verifying that the Iceman will be inseparable from Central Europeans today in slow evolving sequences.

lol. i *am* old fwiw :=) (e.g., older than dgmacarthur i believe)

#7, agreed.

Yes I think I have a particularly poor aptitude for recognizing faces. The constant presence of name tags at conferences is a life-saver to me. I also have a habit of constructing a model of someone’s voice and mannerisms based on their writing that I don’t realise exists until I actually meet them – and for some reason my internal model of you came out as older, more severe and (inexplicably) more British than the reality.

On a few occasions I saw you on twitter and intended to intercept you at the end of a session, but I underestimated my ability to navigate quickly around a large crowd littered with people who I only see once a year.

One of the most notable trends was a huge focus on ever more sophisticated methods for IBD estimation. I suspect that these will soon converge into a single gold standard and researchers will shift their attention to novel population genetic questions not covered by substructure/relatedness work.

Your comment about purifying selection will not affect Y trees but only positive selection will maybe mistaken. Purifying selection means that genetic diversity may not increase with time anymore once reaching a maximum level (maximum genetic diversity, MGD). Anything higher will be negatively selected. Thus, genetic diversity level observed today for humans may have been the maximum or at this level some unknown number of years ago. This is especially true if the sequences are fast evolving, which is the case for most Y STR markers.

There are only one scientific theory known so far that advocates no junk DNAs, i.e., the MGD hypothesis. Much work in recent years have essentially killed the junk DNA concept, most recently by the ENCODE finding of at least 80% human genome being functional. But the theory that predicts the neutral and junk DNA concept still remains to be overthrown. The MGD represents the best chance to explain nearly 100% functional genome and to supercede the neutral theory.