Aging and Death

Our fate was sealed a very long time ago.

Why do we die? It seems like a cruel and wasteful way to run a biosphere, not to mention a human life. After we have accumulated a lifetime of experience and knowledge, we age, decline, and sign off, whether to go to our just reward, or into oblivion. What is the biological rationale and defense for all this, which the biblical writers assigned to the fairy tale of the snake and the apple?

A recent paper ("A unified framework for evolutionary genetic and physiological theories of aging") discusses evolutionary theories of aging, but in typical French fashion, is both turgid and uninteresting. Aging is widely recognized as the consequence of natural selection, or more precisely, the lack thereof after organisms have finished reproducing. Thus we are at our prime in early adulthood, when we seek mates and raise young. Evolutionarily, it is all downhill from there. In professional sports, athletes are generally over the hill at 30, retiring around 35. Natural selection is increasingly irrelevant after we have done the essential tasks of life- surviving to mate and reproduce. We may participate in our communities, and do useful things, but from an evolutionary perspective, genetic problems at this phase of life have much less impact on reproductive success than those that hit earlier. 

All this is embodied in the "disposable soma" theory of aging, which is that our germ cells are the protected jewels of reproduction, while the rest of our bodies are, well, disposable, and thus experience all the indignities of age once their job of passing on the germ cells is done. The current authors try to push another "developmental" theory of aging, which posits that the tradeoffs between youth and age are not so much the resources or selective constraints focused on germ cell propagation vs the soma, but that developmental pathways are, by selection, optimized for the reproductive phase of life, and thus may be out of tune for later phases. Some pathways are over-functional, some under-functional for the aged body, and that imbalance is sadly uncorrected by evolution. Maybe I am not doing justice to these ideas, which maybe feed into therapeutic options against aging, but I find this distinction uncompelling, and won't discuss it further.

A series of unimpressive distinctions in the academic field studying aging from an evolutionary perspective.

Where did the soma arise? Single cell organisms are naturally unitary- the same cell that survives also mates and is the germ cell for the next generation. There are signs of aging in single cell organisms as well, however. In yeast, "mother" cells have a limited lifespan and ability to put out daughter buds. Even bacteria have "new" and "old" poles, the latter of which accumulate inclusion bodies of proteinaceous junk, which apparently doom the older cell to senescence and death. So all cells are faced with processes that fail over time, and the only sure bet is to start as a "fresh" cell, in some sense. Plants have taken a distinct path from animals, by having bodies and death, yes, but being able to generate germ cells from mature tissues instead of segregating them very early in development into stable and distinct gonads.

Multicellularity began innocently enough. Take slime molds, for example. They live as independent amoebae most of the time, but come together to put out spores, when they have used up the local food. They form a small slug-like body, which then grows a spore-bearing head. Some cells form the spores and get to reproduce, but most don't, being part of the body. The same thing happens with mushrooms, which leave a decaying mushroom body behind after releasing their spores. 

We don't shed alot of tears for the mushrooms of the world, which represent the death-throes of their once-youthful mycelia. But that was the pattern set at the beginning- that bodies are cells differentiated from the germ cells, that provide some useful, competitive function, at the cost of being terminal, and not reproducing. Bodies are forms of both lost energy and material, and lost reproductive potential from all those extra cells. Who could have imagined that they would become so ornate as to totally overwhelm, in mass and complexity, the germ cells that are the point of the whole exercise? Who could have imagined that they would gain feelings, purposes, and memories, and rage against the fate that evolution had in store for them?

On a more mechanistic level, aging appears to arise from many defects. One is the accumulation of mutations, which in soma cells lead to defective proteins being made and defective regulation of cell processes. An extreme form is cancer, as is progeria. Bad proteins and other junk like odd chemicals and chemically modified cell components can accumulate, which is another cause of aging. Cataracts are one example, where the proteins in our lenses wear out from UV exposure. We have quite intricate trash disposal processes, but they can't keep with everything, as we have learned from the advent of modern chemistry and its many toxins. Another cause is more programmatic: senescent cells, which are aged-out and have the virtue that they are blocked from dividing, but have the defect that they put out harmful signals to the immune system that promote inflammation, another general cause of aging.

Aging research has not found a single magic bullet, which makes sense from the evolutionary theory behind it. A few things may be fixable, but mostly the breakdowns were never meant to be remedied or fixed, nor can they be. In fact, our germ cells are not completely immune from aging either, as we learn from older fathers whose children have higher rates of autism. We as somatic bodies are as disposable as any form of packaging, getting those germ cells through a complicated, competitive world, and on to their destination.

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Putting Body Parts in Their Places

How HOX genes run development, on butterfly wings.

I have written about the HOX complex of genes several times, because they constitute a grail of developmental genetics- genes that specify the identity of body parts. They occupy the middle of a body plan cascade of gene regulation, downstream from broader specifiers for anterior/posterior orientation, regional and segment specification, and in turn upstream of many more genes that specify the details of organ and tissue construction. Each of the HOX genes encodes a transcriptional regulator, and the name of one says it all- antennapedia. In fruit flies, where all this was first discovered, loss of antennapedia converts some legs into antennae, and extra expression of antennapedia converts antennae on the head into legs.

The HOX complex (named for the homeobox DNA binding motif of the proteins they encode) is linear, arranged from head-affecting genes (labial, proboscipedia) to abdomen-affecting genes (abdominal A, abdominal B; evidently the geneticist's flair for naming ran out by this point). This arrangement is almost universally conserved, and turns out to reflect molecular mechanisms operating on the complex. That is, it "opens" in a progressive manner during development, on the chromosome. Repression of chromatin is a very common and sturdy way to turn genes off, and tends to affect nearby genes, in a spreading effect. So it turns out to be easy, in some sense, to set up the HOX complex to have this chromatin repression lifted in a segmental fashion, by upstream regulators, whereby only the head sections are allowed to be expressed in head tissues, but all the genes are allowed to be expressed in the final abdominal segment. That is why the unexpected expression of antennapedia, which is the fifth of eight HOX genes, in the head, leads to a thoracic tissue (legs) forming on the head.

A recent paper delved a little more deeply into this story, using butterflies, which have a normal linearly conserved HOX cluster and are easy to diagnose for certain body part transformations (called homeotic) on their beautiful wings. The main thing these researchers were interested in is the genetic elements that separate one part of the HOX cluster from other parts. These are boundary or "insulator" elements that separate topologically associated domains (called TADs). Each HOX gene is surrounded by various regulatory enhancer and inhibitor sites in the DNA that are bound by regulatory proteins. And it is imperative that these sites be directed only to the intended gene, not neighboring genes. That is why such TADs exist, to isolate the regulation of genes from others nearby. There are now a variety of methods to map such TADs, by looking where chromatin (histones) are open or closed, or where DNA can be cut by enzymes in the native chromatin, or where crosslinks can be formed between DNA molecules, and others.

The question posed here was whether a boundary element, if deleted, would cause a homeotic transformation in the butterflies they were studying. They found, unfortunately, that it was impossible to generate whole animals with the deletions and other mutations they were engineering, so they settled for injecting the CRISPER mutational molecules into larval tissues and watching how they affected the adults in mosaic form, with some mutant tissues, some wild-type. The boundary they focused on was between antennapedia (Antp) and ultrabithorax (Ubx), and the tissues the forewings, where Ubx is normally off, and hindwings, where Ubx is normally on. Using methods to look at the open state of chromatin, they found that the Ubx gene is dramatically opened in hindwings, relative to forewings. Nevertheless, the boundary remains in place throughout, showing that there is a pretty strong isolation from Antp to Ubx, though they are next door and a couple hundred thousand basepairs apart. Which in genomic terms is not terribly far, while it leaves plenty of space for enhancers, promotes, introns, boundary elements, and other regulatory paraphernalia.

Analysis of the site-to-site chromosomal closeness and accessibility across the HOX locus of the butterfly Junonia coenia. The genetic loci are noted at the bottom, and the site-to-site hit rates are noted in the top panels, with blue for low rates of contact, and orange/red for high rates of contact. At top is the forewing, and at bottom is the hindwing, where Ubx is expressed, thus the high open-ness and intra-site contact within its topological domain (TAD). Yet the boundary between Ubx and Anp to its left (dotted lines at bottom) remains very strong in both tissues. In green is a measure of transcription from this DNA, in differential terms hindwing minus forewing, showing the strong repression of Ubx in the forewing, top panel.

The researchers naturally wanted to mutate the boundary element, (Antp-Ubx_BE), which they deduced lay at a set of binding sites (featuring CCCTC) for the protein CTCF, a well-known insulating boundary regulator. Note, interestingly, that in the image above, the last exon (blue) of Ubx (transcription goes right to left) lies across the boundary element, and in the topological domain of the Antp gene. This means that while all the regulatory apparatus of Ubx is located in its own domain, on the right side, it is OK for transcription to leak across- that has no regulatory implications. 

Effects of removing the boundary element between Ubx and Antp. Detailed description is in the text below. 

Removal of this boundary element, using CRISPER technology in portions of the larval tissues, had the expected partial effects on the larval, and later adult, wings of this butterfly. First, note that in panel D insets, the wild type larval forewing shows no expression of Ubx, (green), while the wild type hind wing shows wide-spread expression. This is the core role of the HOX locus and the Ubx gene- locate its expression in the correct body parts to then induce the correct tissues to develop. The larval wing tissue of the mosaic mutant, also in D, shows, in the forewing, extensive patchy expression of Ubx. This is then reflected in the adult (different animals) in the upper panels, in the mangled eyespot of the fully formed wing (center panel, compared to wild-type forewing and hindwing to each side). It is a small effect, but then these are small mutations, done in only a fraction of the larval cells, as well.

So here we are, getting into the nuts and bolts of how body parts are positioned and encoded. There are large regions around these genes devoted to regulatory affairs, including the management of chromatin repression, the insulation of one region from another, the enhancer and repressor sites that integrate myriad upstream signals (i.e. other DNA binding proteins) to come up with the detailed pattern of expression of these HOX genes. Which in turn control hundreds of other genes to execute the genetic program. This program can hardly be thought of as a blueprint, nor a "design" in anyone's eye, divine or otherwise. It resembles much more a vast pile of computer code that has accreted over time with occasional additions of subroutines, hacks, duplicated bits, and accidental losses, adding up to a method for making a body that is robust in some respects to the slings and arrows of fortune, but naturally not to mutations in its own code.

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The Long Tail of Genome Duplication

A new genomic sequence of hagfish tells us a little about our origins.

Hagfish- not a fish, and not very pretty, but it occupies a special place in evolution, as a vertebrate that diverged very early (along with lampreys, forming the cyclostome branch) from the rest of the jawed vertebrates (the gnathostome branch). The lamprey has been central to studies of the blood clotting system, which is a classic story of gradual elaboration over time, with more steps added to the cascade, enabling faster clotting and finer regulation.

A highly schematic portrayal (not to scale!) of the evolutionary history of animal life on earth.

A recent paper reported a full genome sequence of hagfish, and came up with some interesting observations about the history of vertebrate genomes. At about three billion nucleotides, this genome is about as large as ours. (Yet again, size doesn't see, to matter much, when it comes to genomes.) They confirm that lampreys and hagfish make up a single lineage, separate from all other animals and especially from the jawed vertebrates. For example, though lampreys have 84 chromosomes to the hagfish's 17, this resulted from repeated splitting of chromosomes, and each lamprey chromosome can be mostly mapped to one hagfish chromosome, accepting that a lot of other gene movement and change has taken place in the roughly 460 million years since these lineages diverged. 

Hagfish (bottom) and lamprey (top) chromosomes pretty much line up, indicating that despite the splitting of the lamprey genome, there hasn't been a great deal of shuffling over the intervening 460 million years.

The most important parts of this paper are on the history of genome duplications that happened during this early phase of vertebrate evolution. Whole genome duplications are an extremely powerful engine of change, supplying the organism with huge amounts of new genetic material. Over time, most of the duplicated genes are discarded again (in a process they call re-diploidization). But many are not, if they have gained some foothold in providing more of an important product, or differentiated themselves from each other in some other way. Our genomes are full of families, some extremely large, of related genes that have finely differentiated functions. Many of these copies originated in long-ago genome duplications, while others originated in smaller duplication accidents. It is startling to hear from self-labeled scientists in the so-called intelligent design movement that there is some rule or law against such copying of information, by their ridiculous theories of specified information. Hagfish certainly never heard of such a thing.

At any rate, these researchers confirm that the earliest vertebrate lineage, around 530 million years ago, experienced two genome duplications which led to a large increment of new genes and evolutionary innovation. What they find now is that the cyclostome lineage experienced another genome three-fold duplication (near its origin, about 460 million years ago, leading to another round of copies and innovation. And lastly, the gnathostome lineage separately experienced its own genome four-fold duplication around the same time, after it had diverged from the cyclostome lineage. One might say that the gnathostomes made better use of their genomic manna, generating jaws, teeth, ears, thymus, better immune systems, and the other features that led them to win the race of the animal kingdom. But hagfish are still around, showing that primitive forms can find a place in the scheme of things, as the biosphere gets larger and more diverse over time.

A classic example of gene replication is the Hox cluster, which are a set of genes that have the power of dictating what body part occurs where. They are gene regulators that function in the middle of the developmental sequence, after determination of the overall body axis and segmentation, and themselves regulating downstream genes governing features as they occur in different segments, such as limbs, parts of the head, fingers, etc. Flies have one Hox cluster, split into two parts. The extremely primitive chordate amphioxus, which far predates the cyclostomes, also has one complete Hox cluster, as diagrammed below. Most other vertebrates, including us, have four Hox clusters, amounting to over thirty of these transcription regulators. These four clusters arose from the inferred genome duplications very early in the vertebrate lineage, prior to the advent of the cyclostomes. 

Hox clusters and their origins, as inferred by the current authors. The red/blue points at the left mark whole genome duplications (or more) that have been inferred by these or other authors. More description is in the main text below.

The inferred genome duplications during early chordate evolution, noted on the far left of the diagram above, led to duplicated clusters of Hox genes. Amphioxus (top) is the earliest branching chordate, and has only one full Hox cluster of transcription regulators, which, in general terms, control, during development, the expression of body parts along the body axis, with the order of genes in the cluster paralleling expression and action along the body axis. Chicken as a gnathostome has four copies of the cluster, with a few of the component genes lost over time. Hagfish have six copies of this Hox cluster, some rather skeletal, stemming from its genome duplication events. Clearly several whole clusters have also been lost, as in some cases the genome duplications experienced by the cyclostomes resolved back to diploidy without leaving an extra copy of this cluster. The net effect is to allow all these organisms greater options for controlling the identity and form of different parts of the body, particularly, in the case of gnathostomes, the head.

Genome duplications are one of those fast events in evolution that are highly influential, unlike the usual slow and steady selection and optimization that is the rule in the Darwinian theory. Unlike mass extinction, another kind of fast event in evolution, genome duplications are highly constructive, providing fodder on a mass (if microscopic) scale for new functions and specializations that help account for some of the more rapid events in the history of life, such as the rise of chordates and then vertebrates in the wake of the Cambrian explosion.

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Where Did Flowers Come From?

Are angiosperms 135 million years old, or 275 million years old?

We live among a hodgepodge of plants from different evolutionary epochs, with flowering plants being the most recent, (including the even more recently evolved grasses), alongside the more ancient conifers, cycads, ferns, mosses, and lichens. All have a place in diverse ecosystems, but what is their true history? This has been difficult to establish in more than broad outlines, due, as usual, to the patchy nature of the fossil record, and the difficulties of aligning it with what we now have as the molecular record. Angiosperms have been a particular sore spot, ever since Darwin, who recognized that the sudden appearance and radiation of flowering plants, roughly 130 million years ago, was a problem for evolutionary theory.

A paper from a few years back offered a carefully aligned molecular and fossil analysis of angiosperms, coming to the conclusion that they actually originated ~275 million years ago (MYA), and must have persisted in some cryptic fashion through the ensuing 150 MY before making a splash in the fossil record. How is this kind of analysis done? First, the best early fossils are tabulated, with secure dating and clear characteristics that include them among angiosperms. The most ancient example is a sample of pollen, from roughly 125 million years, which looks strongly like it came from angiosperms. These fossils are also assigned to plant lineages, so that their appearance can inform the branching points of the phylogenetic diagram, whether that diagram is based purely on these fossils and their morphology, or based on molecular data.

Then a set of gene sequences is collected, which are conserved between all the surveyed species, and aligned so that their changes can be fed into a program that counts all the differences. It was clear through this work that some lineages changed faster than other ones (the faster ones are marked with blue flares towards the right. Since the sampled species are all ones that exist now (time 0), being able to provide DNA, and since the branch points are in any case shared between the lineages that descend from them(at their origination points), faster change / evolution in one lineage vs another will be readily apparent, and the researchers just have to make up some rules to judge where to come down in time assignments when faced with such discrepancies. The more serious problem is that such different speeds can totally derange this kind of analysis, making a faster-changing lineage seem much older than it is. So pinpointing the branch points between lineages is extremely important to pin down such hard-to gauge branch lengths. 

Biologically, it is now well known that lineages vary substantially (up to ten fold, less so in longer lineages and time spans) in their speed of molecular change.. molecular evolution is not a clock. Faster change tends to happen when populations are small, and when big evolutionary transitions have happened. For example, plants, and specifically angiosperms, have gone through whole-genome duplications that represent major evolutionary watersheds. These duplications supplied raw material for countless diversifications and specializations of genes, with especially rapid change in molecular sequences either released from previous selective constraints, or subject to new ones via new roles.

Integrated phylogenetic diagram of the evolution of angiosperms, marking key fossils that inform branch point timing (lettered blue circles), and ranges of possible branch points derived from the molecular alignments (red circles). At bottom is time, in millions of years before present.

What can explain the big gap in estimated angiosperm origins? There are three basic hypotheses. First is that the molecular data is correct, which implies that there is an extremely long (150 million years) history of cryptic angiosperms that have not (yet) been detected in the fossil record. There are smatterings of findings in the literature that suggest that such fossils may be (or may have been) found, but I don't think these have been widely accepted yet (especially when they come from highly questionable sources).

The second hypothesis is that something about the very early evolution of angiosperms (like the very early evolution of eukaryotes, and the very early diversification of macroscopic animals) was accelerated in molecular terms, (as discussed above in terms of differing rates between lineages), rendering the apparent molecular phylogeny much longer than the real one. That includes the prodigious radiation of the many lineages in the diagram above, all before the first fossil is found.

The third hypothesis, much beloved of creationists, is that god did it. A mystery like this is ripe for invoking the solution to all mysteries, which is it does not need to be explained in the normal mechanistic terms of the natural world, but rather can be chalked up to the author of all things, god. While this hypothesis, at least for believers, solves this one nagging mystery, it brings on a few others. Why does the rest of biology through this vast lineage still follow the plodding path of gradual (if uneven) development? Why jump in to create this mystery when so many other lineages in the fossil record do not present similar mysteries? Why did god insist upon, (presumably for the ultimate appearance of us as humans), the whole four billion year process of life's plodding development, when the whole thing could have been authored at once and at the start? What amazing societies we could have developed with a four billion year head start!

It is clear, therefore, that some hypotheses create more problems than they solve. Inviting scientists to consider and comment on harebrained hypotheses is not going to end well. The solution to this problem is going to be some combination of the first two hypotheses, of rapid molecular evolution at the start of a major radiation, and some as-yet missing material in the fossil record. Innovative organisms are very likely to be rare, though whole cryptic lineages surviving for many tens of millions of years is hard to posit without more evidence. Yet it is also a given that fossils will necessarily appear after the actual events of lineage branching, thus will always post-date the calculated molecular branching point.

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Ruffling the Feathers of Dinosaurs

The origin of birds remains uncertain, as does the status of feathers on dinosaurs. Review of "Riddle of the Feathered Dragons", by Alan Feduccia. 

As regular readers can surmise, I was raised (scientifically) in an empirical, experimental tradition- that of molecular biology. In that field there is little drama, since any dispute can be taken back to the lab for adjudication. No titanic battles of conflicting interpretations happen, and extremely high standards pervade the field, since any lapse is easily discovered and replicated. Despite the dominant position of molecular biology in the major journals, due to its high productivity, it is thus rarely in the public spotlight. It has been a bit of a culture shock to realize that other areas of science have significantly different standards and epistemology. Many fields (such as astronomy or paleontology) are at heart observational rather than experimental, or have other restrictions or conflicts (medical science, nutrition studies) that impair their ability to find the truth, leading to a great deal more interpretation, drama, and sometimes, rampant speculation.

Paleontology, and the study of the past in general, has an intrinsic lack of data. If the fossils are missing, what can one do but to wonder and speculate what could have happened during that gap? And when fossils do turn up, they still lack alot of information about their unfortunate contributor- they are only the bare bones, after all. They may be in bad condition and particularly hard to interpret. Whole genera or above may be represented by a tooth or single bone. Millions of years may go by with nothing to show for it. No wonder speculation fills the gap- but is that science? Incidentally, I have to thank the Discovery Insitute, with its keen nose for scientific controversy, for pointing me to today's author, who disputes the now-conventional view that birds arose from dinosaurs. While Alan Feduccia has nothing to do with Creationism and its offshoots, and is a perfectly respectable paleontologist, he is, in the course of at least four books on the subject, (of which this is the third), clearly frustrated with the reigning interpretations of his field, which has jumped to what he regards as unwarranted conclusions that have led to a flurry of portrayals of feathered dinosaurs.

The Archaeopteryx fossil, Berlin specimen, which dates to roughly 150 million years ago.

The first bird, more or less, was Archaeopteryx. Its Berlin fossil, found about 1875, and dating to roughly 150 million years ago (mya) is perhaps the most beautiful, and informative, fossil ever found- a complete bird, with fully spread flight feathers on its arms and legs, a long tail, claws on its hands,and teeth in its mouth. It had the precisely the in-between characteristics of both reptiles and birds that gave immediate validation to Charles Darwin's theory of evolution by gradual change and natural selection. But where did it come from? That is the big question. While a great many other fossil birds have been found, none substantially predate Archaeopteryx, (other than perhaps Anchiornis, very similar to Archaeopterix, and dating to roughly 160 mya), and thus we really do not know (as yet) from fossils how birds originated. 

Feathers are one diagnostic feature in this lineage. Archaeopterix and many later birds found in China and Mongolia from the Cretaceous have feathers, clearly marking them as birds and as lineally related. But other allied fossils have been found, nominally described as dinosaurs, which are described to have feathers as well. One is shown below. 

Fossil of Sinosauropteryx, which dates roughly to 124 million years ago.

Closeup of the hair-like impressions on the tail of Sinosauropteryx.

Whether these structures are feathers, or related to them, is quite debatable. They look more like hairs, and Feduccia claims that they do not even occur outside the body wall. Some experimentation by others has shown that sub-dermal collagen can form this kind of hair-like fuzz during some forms of decay and fossilization, given proper squashing. Current conventional wisdom, however, describes them as filament-like feathers used for insulation or display. My take, looking closely at these pictures, is that they are not feathers, but are outside the body wall, which, on the tail certainly, would have been very close to the bone. Additionally, as these specimens are all rather late, they could easily be descended from birds, while being large and flightless. Feduccia points out that while land-based animals have never gained/regained flight, flightlessness has evolved many times through the bird lineages. Similarly, extensive lineages of secondarily flightless birds may have developed in the Mesozoic, that conventional paleontologists call dinosaurs, (often with feathers), and posit as evidence that the reverse happened- that birds evolved from dinosaurs. For example, the conventional view of dinosaurs and birds draws on many later fossils from the Cretaceous (such as Deinonychus), which had both bird-like and dinosaur-like features: the "raptors". 

Another character at issue is flight itself. If birds are basal- that is, they arose prior to or separately from the other dinosaurs- then they could easily have developed from small arboreal lizards that learned to glide from place to place. On the other hand, dinosaurs are all relatively large and bipedal. So conventional paleontologists have labored to come up with ways that flight could have developed "from the ground up". Such theories as insect trapping by nascent small wings, or occasional tree climbing with tiny wings, to escape predators, have been invoked as rationales for feathers and wings to develop in terrestraial bipedal dinosaurs. Feduccia counters that in the whole history of flight, all animals (birds, bats, squirrels, others) have developed flight from gliding, not from the ground up. Indeed, there are countless flightless birds, and none of them have resumed flight, despite presumably having much of the genetic wherewithal to do so.

Given patchy data, the leading method to make sense of it and organize organisms from the fossil record into a phylogenetic story is the cladistic method. Practitioners choose a wide range of "characters", (such as the lengths, angles, holes, and other morphologies in the available bones) and tabluate their values from all the proposed species. Then they can mathematically just total up who is more distant from whom. Feducci emphasizes that this is an excellent method for ordering closely related genera and species. But over the long run, evolution repeats itself alot, making numerous flightless birds, for example, or similarly shaped swimming animals, not all of which are as closely related as they might look morphologically. Cladistics is a classic case of garbage-in-garbage-out analysis, and has routinely been overturned by molecular evidence when, among extant species, genomic data is available. Sadly, genomic data is not available for the fossils from the Mesozoic (the age of the dinosaurs, which encompasses, in order, the Triassic (245 mya to 208 mya), the Jurassic (208 to 144 mya) and the Cretaceous (144 to 65 mya) periods), nor from any living descendants of the dinosaurs... other than their putative decendants, birds.

As an aside, molecular phylogenies are also at heart cladistic in their theory and method. They just have a lot more "characters"- i.e. the letters of the DNA sequences in homologous / aligned sequences. But even more importantly, since a large proportion of these characters are neutral, (to natural selection), and thus vary (in sort-of clock-like fashion) no matter what convergent evolution might happen morphologically, molecular phylogenies can easily resolve difficult questions of phylogeny on the short to medium geologic terms. When it comes to the deepest phylogenies, however, going over a billion years, neutral characters become wholly useless due to homogenization by the vast times that have passed, so for such time periods these methods become less incisive.

Crude cladogram illustrating the alternative hypotheses- that birds are descended from theropod dinosaurs, or that birds arise from a basal lineage of their own, directly from the common stem of archosaurs. In the latter hypothesis, numerous bird-like lineages currently construed as dinosaurs might be secondarily flightless birds.

It is cladistics (along with other evidence) that has enshrined birds within the dinosaur lineage, finding that theropods came first, and the avians came later on. (With a contrasting view, and a critique of the contrasting view.) Theropods and birds are certainly similar, compared to their crocodilian / archosaur antecedents. They are bipedal, with similar hip structures, neck structures, and hands/feet reduced from five to three toes. But if much of what we take to be the dinosaurs (those with feathers and the whole so-called "raptor" class), are actually secondarily flightless birds, then one can make a lot of sense of some of these similarities, while casting the origin of birds quite a bit father back in time, more or less co-incident with the origin of true dinosaurs. Such as in the diagram above.

The problem with all this is again time. The early Jurassic and Triassic, amounting to almost one hundred million years before Archaeopterix, provide a lot of evidence for dinosaurs. They first appear roughly 240 mya, and flourish after the major exinction event that ended the Triassic, at 201 mya. The stark lack of evidence for birds, and widespread evidence for dinosaurs, including the lineage (theropods) that are most related to birds, suggests strongly that birds did not originate back in the Triassic, in parallel with the core dinosaur lineages. It suggests, rather, that among the many theropod dinosaurs during the ten or twenty million years before Archaeopterix were some small enough to take to the trees, grow longer arms, and be in position for flight. There were doubtless plenty of insects up there, at least until just about this time of the late-Jurassic, when birds started to eat them! Fossil record gaps are treacherous things, but this one indicates strongly that birds evolved in the middle Jurassic, along with (and within) the wider adaptive radiation of dinosaurs.

"Yet Archaeopteryx is still the classic urvogel- the oldest well-studied bird yet discovered, perhaps some 25 or more million years older than most of the Early Cretaceous Chinese fossils. As we saw in chapter 3, the Solnhofen urvogel is a mosaic of reptilian and avian features, a true bird, and the more it is studied, the more and more birdlike it is revealed to be. Ignoring the element of geologic time, however, many paleontologists have proposed that the Liaoning fossils provide evidence for all the stages of the evolution not only of birds and bird flight but also of feathers, from fiberlike protofeathers to pennaceous, asymmetrical flight remiges. Such a claim is remarkable and would be astounding in any fauna, but is especially so for a fauna so temporally removed from the time of avian origins, presumably before the Middle Jurassic and perhaps well back into the Triassic. 

University of Pennsylvania paleontologist Peter Dodson, remarking on the inadequacies of cladistic methodology, tells us: 'To maintain that the problem of the origin of birds has been solved when the fossil record of the Middle or Late Jurassic bird ancestors is nearly a complete blank is completely absurd. The contemporary obsession with readily available computer-assisted algorithms that yield seemingly precise results that obviate the need for clear-headed analysis diverts attention away fron the effort that is needed to discover the very fossils that may be the true ancestors of birds. When such fossils are found, will cladistics be able to recognize them? Probably not.'"

Feducci makes a lot of insightful points and hits some sensitive marks, in addition to all the trash-talk. Cladistics has problems, hairs are not feathers, and Cretaceous birds don't tell us much about the evolution of bird flight, which doubtless began as gliding between trees tens of millions of years earlier. And he is right that the hunt for clear antecedents of Archaeopterix, whether far in the past or near, should be the focus of this field. But overall, it is hard to fully credit the "birds early" story. 

• Of course animals are conscious.
• Only a minority of House Republicans supported the Ukraine aid bill.
• A pessimistic mood.
• The bitter end of colonialism.
• Beautiful views down under.
• Price fixing- a new epoch of screwing consumers.

How Does Speciation Happen?

Niles Eldredge and the theory of punctuated equilibrium in evolution.

I have been enjoying "Eternal Ephemera", which is an end-of-career memoir/intellectual history from a leading theorist in paleontology and evolution, Niles Eldredge. In this genre, often of epic proportions and scope, the author takes stock of the historical setting of his or her work and tries to put it into the larger context of general intellectual progress, (yes, as pontifically as possible!), with maybe some gestures towards future developments. I wish more researchers would write such personal and deeply researched accounts, of which this one is a classic. It is a book that deserves to be in print and more widely read.

Eldredge's claim to fame is punctuated equilibrium, the theory (or, perhaps better, observation) that evolution occurs much more haltingly than in the majestic gradual progression that Darwin presented in "Origin of Species". This is an observation that comes straight out of the fossil record. And perhaps the major point of the book is that the earliest biologists, even before Darwin, but also including Darwin, knew about this aspect of the fossil record, and were thus led to concepts like catastrophism and "etagen". Only Lamarck had a steadfastly gradualist view of biological change, which Darwin eventually took up, while replacing Lamarck's mechanism of intentional/habitual change with that of natural selection. Eldridge unearths tantalizing and, to him, supremely frustrating, evidence that Darwin was fully aware of the static nature of most fossil series, and even recognized the probable mechanism behind it (speciation in remote, peripheral areas), only to discard it for what must have seemed a clearer, more sweeping theory. But along the way, the actual mechanism of speciation got somewhat lost on the shuffle.

Punctuated equilibrium observes that most species recognized in the fossil record do not gradually turn into their descendents, but are replaced by them. Eldredge's subject of choice is trilobites, which have a long and storied record for almost 300 million years, featuring replacement after replacement, with species averaging a few million years duration each. It is a simple fact, but one that is a bit hard to square with the traditional / Darwinian and even molecular account of evolution. DNA is supposed to act like a "clock", with constant mutational change through time. And natural selection likewise acts everywhere and always... so why the stasis exhibited by species, and why the apparently rapid evolution in between replacements? That is the conundrum of punctuated equilibrium.

There have been lot of trilobites. This comes from a paper about their origin during the Cambrian explosion, arguing that only about 20 million years was enough for their initial speciation (bottom of image).

The equilibrium part, also termed stasis, is seen in the current / recent world as well as in the fossil record. We see species such as horses, bison, and lions that are identical to those drawn in cave paintings. We see fossils of animals like wildebeest that are identical to those living, going back millions of years. And we see unusual species in recent fossils, like saber-toothed cats, that have gone extinct. We do not typically see animals that have transformed over recent geological history from one (morphological) species into another, or really, into anything very different at all. A million years ago, wildebeest seem to have split off a related species, the black wildebeest, and that is about it.

But this stasis is only apparent. Beneath the surface, mutations are constantly happening and piling up in the genome, and selection is relentlessly working to ... do something. But what? This is where the equilibrium part comes in, positing that wide-spread, successful species are so hemmed in by the diversity of ecologies they participate in that they occupy a very narrow adaptive peak, which selection works to keep the species on, resulting in apparent stasis. It is a very dynamic equilibrium. The constant gene flow among all parts of the population that keeps the species marching forward as one gene pool, despite the ecological variability, makes it impossible to adapt to new conditions that do not affect the whole range. Thus, paradoxically, the more successful the species, and the more prominent it is in the fossil record, the less change will be apparent in those fossils over time.

The punctuated part is that these static species in the fossil record eventually disappear and are replaced by other species that are typically similar, but not the same, and do not segue from the original in a gradual way that is visible in the fossil record. No, most species and locations show sudden replacement. How can this be so if evolution by natural selection is true? As above, wide-spread species are limited in what selection can do. Isolated populations, however, are more free to adapt to local conditions. And if one of those local conditions (such as arctic cold) happens to be what later happens to the whole range (such as an ice age), then it is more likely that a peripherally (pre-)adapted population will take over the whole range, than that the resident species adapts with sufficient speed to the new conditions. Range expansion, for the peripheral species, is easier and faster than adaptation, for the wide-ranging originating species.

The punctuated equilibrium proposition came out in the 1970's, and naturally followed theories of speciation by geographic separation that had previously come out (also resurrected from earlier ideas) in the 1930's to 1950's, but which had not made much impression (!) on paleontologists. Paleontologists are always grappling with the difficulties of the record, which is partial, and does not preserve a lot of what we would like to know, like behavior, ecological relationships, and mutational history. But they did come to agree that species stasis is a real thing, not just, as Darwin claimed, an artifact of the incomplete fossil record. Granted- if we had fossils of all the isolated and peripheral locations, which is where speciation would be taking place by this theory, we would see the gradual change and adaptation taking place. So there are gaps in the fossil record, in a way. But as long as we look at the dominant populations, we will rarely see speciation taking place before our eyes, in the fossils.

So what does a molecular biologist have to say about all this? As Darwin insisted early in "Origin", we can learn quite a bit from domesticated animals. It turns out that wild species have a great amount of mostly hidden genetic variation. This is apparent whenever one is domesticated and bred for desired traits. We have bred dogs, for example, to an astonishingly wide variety of traits. At the same time, we have bred them out to very low genetic diversity. Many breeds are saddled with genetic defects that can not be resolved without outbreeding. So we have in essence exchanged the vast hidden genetic diversity of a wild species for great visible diversity in the domesticated species, combined with low genetic diversity.

What this suggests is that wild species have great reservoirs of possible traits that can be selected for the purposes of adaptation under selective conditions. Which suggests that speciation in range edges and isolated environments can be very fast, as the punctuated part of punctuated equilibrium posits. And again, it reinforces the idea that during equilibrium with large populations and ranges, species have plenty of genetic resources to adapt and change, but spend those resources reinforcing / fine tuning their core ecological "franchise", as it were.

In population genetics, it is well known that mutations arise and fix (that is, spread to 100% of the population on both alleles) at the same rate no matter how large the population, in theory. That is to say- bigger populations generate more mutations, but correspondingly hide them better in recessive form (if deleterious) and for neutral mutations, take much longer to allow any individual mutation to drift to either extinction or fixation. Selection against deleterious mutations is more relentless in larger populations, while relaxed selection and higher drift can allow smaller populations to explore wider ranges of adaptive space, perhaps finding globally higher (fitness) peaks than the parent species could find.

Eldredge cites some molecular work that claims that at least twenty percent of sequence change in animal lineages is due specifically to punctuational events of speciation, and not to the gradual background accumulation of mutations. What could explain this? The actual mutation rate is not at issue, (though see here), but the numbers of mutations retained, perhaps due to relaxed purifying selection in small populations, and founder effects and positive selection during the speciation process. This kind of phenomenon also helps to explain why the DNA "clock" mentioned above is not at all regular, but quite variable, making an uneven guide to dating the past.

Humans are another good example. Our species is notoriously low in genetic diversity, compared to most wild species, including chimpanzees. It is evident that our extremely low population numbers (over prehistoric time) have facilitated speciation, (that is, the fixation of variants which might be swamped in bigger populations), which has resulted in a bewildering branching pattern of different hominid forms over the last few million years. That makes fossils hard to find, and speciation hard to pinpoint. But now that we have taken over the planet with a huge population, our bones will be found everywhere, and they will be largely static for the foreseeable future, as a successful, wide-spread species (barring engineered changes). 

I think this all adds up to a reasonably coherent theory that reconciles the rest of biology with the fossil record. However, it remains frustratingly abstract, given the nature of fossils that rarely yield up the branching events whose rich results they record.

• TV in China.
• How now at the Supreme Court?
• Tears are powerful.

The Way We Were: Origins of Meiosis and Sex

Sex is as foundational for eukaryotes as are mitochondria and internal membranes. Why and how did it happen?

Sexual reproduction is a rather expensive proposition. The anxiety, the dating, the weddings- ugh! But biologically as well, having to find mates is no picnic for any species. Why do we bother, when bacteria get along just fine just dividing in two? This is a deep question in biology, with a lot of issues in play. And it turns out that bacteria do have quite a bit of something-like-sex: they exchange DNA with each other in small pieces, for similar reasons we do. But the eukaryotic form of sex is uniquely powerful and has supported the rapid evolution of eukaryotes to be by far the dominant domain of life on earth.

A major enemy of DNA-encoded life is mutation. Despite the many DNA replication accuracy and repair mechanisms, some rate of mutation still occurs, and is indeed essential for evolution. But for larger genomes, the mutation rate always exceeds the replication rate, (and the purifying natural selection rate), so that damaging mutations build up and the lineage will inevitably die out without some help. This process is called Muller's ratchet, and is why all organisms appear to exchange DNA with others in their environment, either sporadically like bacteria, or systematically, like eukaryotes.

An even worse enemy of the genome is unrepaired damage like complete (double strand) breaks in the DNA. These stop replication entirely, and are fatal. These also need to be repaired, and again, having extra copies of a genome is the way to allow these to be fixed, by processes like homologous recombination and gene conversion. So having access to other genomes has two crucial roles for organisms- allowing immediate repair, and allowing some way to sweep out deleterious mutations over the longer term.

Our ancestors, the archaea, which are distinct from bacteria, typically have circular, single molecule genomes, in multiple copies per cell, with frequent gene conversions among the copies and frequent exchange with other cells. They routinely have five to twenty copies of their genome, and can easily repair any immediate damage using those other copies. They do not hide mutant copies like we do in a recessive allele, but rather by gene conversion (which means, replicating parts of a chromosome into other ones, piecemeal) make each genome identical over time so that it (and the cell) is visible to selection, despite their polyploid condition. Similarly, taking in DNA from other, similar cells uses the target cells' status as live cells (also visible to selection) to insure that the recipients are getting high quality DNA that can repair their own defects or correct minor mutations. All this ensures that their progeny are all set up with viable genomes, instead of genomes riddled with defects. But it comes at various costs as well, such as a constant race between getting lethal mutation and finding the DNA that might repair it. 

Both mitosis and meiosis were eukaryotic innovations. In both, the chromosomes all line up for orderly segregation to descendants. But meiosis engages in two divisions, and features homolog synapsis and recombination before the first division of the parental homologs.

This is evidently a precursor to the process that led, very roughly 2.5 billion years ago, to eukaryotes, but is all done in a piecemeal basis, nothing like what we do now as eukaryotes. To get to that point, the following innovations needed to happen:

• Linearized genomes, with centromeres and telomeres, and >1 number of chromosomes.
• Mitosis to organize normal cellular division, where multiple chromosomes are systematically lined up and distributed 1:1 to daughter cells, using extensive cytoskeletal rearrangements and regulation.
• Mating with cell fusion, where entire genomes are combined, recombined, and then reduced back to a single complement, and packaged into progeny cells.
• Synapsis, as part of meiosis, where all sister homologs are lined up, damaged to initiate DNA repair and crossing-over.
• Meiosis division one, where the now-recombined parental homologs are separated.
• Meiosis division two, which largely follows the same mechanisms as mitosis, separating the reshuffled and recombined sister chromosomes.

This is a lot of novelty on the path to eukaryogenesis, and is just a portion of the many other innovations that happened in this lineage. What drove all this, and what were some plausible steps in the process? The advent of true sex generated several powerful effects:

1. A definitive solution to Muller's ratchet, by exposing every locus in a systematic way to partial selection and sweeping out deleterious mutations, while protecting most members of the population from those same mutations. Continual recombination of the parental genomes allows beneficial mutations to separate from deleterious ones and be differentially preserved.
2. Mutated alleles are partially, yet systematically, hidden as recessive alleles, allowing selection when they come into homozygous status, but also allowing them to exist for limited time to buffer the mutation rate and to generate new variation. This vastly increases accessible genetic variation.
3. Full genome-length alignment and repair by crossing over is part of the process, correcting various kinds of damage and allowing accurate recombination across arbitrarily large genomes.
4. Crossing over during meiotic synapsis mixes up the parental chromosomes, allowing true recombination among the parental genomes, beyond just the shuffling of the full-length chromosomes. This vastly increases the power of mating to sample genetic variation across the population, and generates what we think of as "species", which represent more or less closed interbreeding pools of genetic variants that are not clones but diverse individuals.

The time point of 2.5 billion years ago is significant because this is the general time of the great oxidation event, when cyanobacteria were finally producing enough oxygen by photosynthesis to alter the geology of earth. (However our current level of atmospheric oxygen did not come about until almost two billion years later, with rise of land plants.) While this mainly prompted the logic of acquiring mitochondria, either to detoxify oxygen or use it metabolically, some believe that it is relevant to the development of meiosis as well. 

There was a window of time when oxygen was present, but the ozone layer had not yet formed, possibly generating a particularly mutagenic environment of UV irradiation and reactive oxygen species. Such higher mutagenesis may have pressured the archaea mentioned above to get their act together- to not distribute their chromosomes so sporadically to offspring, to mate fully across their chromosomes, not just pieces of them, and to recombine / repair across those entire mated chromosomes. In this proposal, synapsis, as seen in meiosis I, had its origin in a repair process that solved the problem of large genomes under mutational load by aligning them more securely than previously. 

It is notable that one of the special enzymes of meiosis is Spo11, which induces the double-strand breaks that lead to crossing-over, recombination, and the chiasmata that hold the homologs together during the first division. This DNA damage happens at quite high rates all over the genome, and is programmed, via the structures of the synaptonemal complex, to favor crossing-over between (parental) homologs vs duplicate sister chromosomes. Such intensive repair, while now aimed at ensuring recombination, may have originally had other purposes.

Alternately, others suggest that it is larger genome size that motivated this innovation. This origin event involves many gene duplication events that ramified the capabilities of the symbiotic assemblage. Such gene dupilcations would naturally lead to recombinational errors in traditional gene conversion models of bacterial / archaeal genetic exchange, so there was pressure to generate a more accurate whole-genome alignment system that confined recombination to the precise homologs of genes, rather than to any similar relative that happened to be present. This led to the synapsis that currently is part of meiosis I, but it is also part of "parameiosis" systems on some eukaryotes, which, while clearly derived, might resemble primitive steps to full-blown meiosis.

It has long been apparent that the mechanisms of meiosis division one are largely derived from (or related to) the mechanisms used for mitosis, via gene duplications and regulatory tinkering. So these processes (mitosis and the two divisions of meiosis) are highly related and may have arisen as a package deal (along with linear chromosomes) during the long and murky road from the last archaeal ancestor and the last common eukaryotic ancestor, which possessed a much larger suite of additional innovations, from mitochondria to nuclei, mitosis, meiosis, cytoskeleton, introns / mRNA splicing, peroxisomes, other organelles, etc.  

Modeling of different mitotic/meiotic features. All cells modeled have 18 copies of a polypoid genome, with a newly evolved process of mitosis. Green = addition of crossing over / recombination of parental chromosomes, but no chromosome exchange. Red = chromosome exchange, but no crossing over. Blue = both crossing over and chromosome exchange, as occurs now in eukaryotes. The Y axis is fitness / survival and the X axis is time in generations after start of modeling.

A modeling paper points to the quantitative benefits of the mitosis when combined with the meiotic suite of innovations. They suggest that in a polyploid archaean lineage, the establishment of mitosis alone would have had revolutionary effects, ensuring accurate segregation of all the chromosomes, and that this would have enabled differentiation among those polyploid chromosome copies, since they would be each be faithfully transmitted individually to offspring (assuming all, instead of one, were replicated and transmitted). Thus they could develop into different chromosomes, rather than remain copies. This would, as above, encourage meiosis-like synapsis over the whole genome to align all the (highly similar) genes properly.

"Modeling suggests that mitosis (accurate segregation of sister chromosomes) immediately removes all long-term disadvantages of polyploidy."

Additional modeling of the meiotic features of chromosome shuffling, and recombination between parental chromosomes, indicates (shown above) that these are highly beneficial to long-term fitness, which can rise instead of decaying with time, per the various benefits of true sex as described above. 

The field has definitely not settled on one story of how meiosis (and mitosis) evolved, and these ideas and hypotheses are tentative at this point. But the accumulating findings that the archaea that most closely resemble the root of the eukaryotic (nuclear) tree have many of the needed ingredients, such as active cytoskeletons, a variety of molecular antecedents of ramified eukaryotic features, and now extensive polyploidy to go with gene conversion and DNA exchange with other cells, makes the momentous gap from archaea to eukaryotes somewhat narrower.

• SNL says goodbye to George Santos.
• Surveillance vs spying.
• The South China Sea.

Are Archaea Archaic?

It remains controversial whether the archaeal domain of life is 1 or 4.5 billion years old. That is a big difference!

Back in the 1970's, the nascent technologies of molecular analysis and DNA sequencing produced a big surprise- that hidden in the bogs and hot springs of the world are micro-organisms so extremely different from known bacteria and protists that they were given their own domain on the tree of life. These are now called the archaea, and in addition to being deeply different from bacteria, they were eventually found to be the progenitors of eukaryotic cell- the third (and greatest!) domain of life that arose later in the history of the biosphere. The archaeal cell contributed most of the nuclear, informational, membrane management, and cytoskeletal functions, while one or more assimilated bacteria (most prominently the future mitochondrion and chloroplast) contributed most of the metabolic functions, as well as membrane lipid synthesis and peroxisomal functions.

Carl Woese, who discovered and named archaea, put his thumb heavily on the scale with that name, (originally archaebacteria), suggesting that these new cells were not just an independent domain of life, totally distinct from bacteria, but were perhaps the original cell- that is, the LUCA, or last universal common ancestor. All this was based on the sequences of rRNA genes, which form the structural and catalytic core of the ribosome, and are conserved in all known life. But it has since become apparent that sequences of this kind, which were originally touted as "molecular clocks", or even "chronometers" are nothing of the kind. They bear the traces of mutations that happen along the way, and, being highly important and conserved, do not track the raw mutation rate, (which itself is not so uniform either), but rather the rate at which change is tolerated by natural selection. And this rate can be wildly different at different times, as lineages go through crises, bottlenecks, adaptive radiations, and whatever else happened in the far, far distant past.

Carl Woese, looking over filmed spots of 32P labeled ribosomal RNA from different species, after size separation by electrophoresis. This is how RNAs were analyzed, back in 1976, and such rough analysis already suggested that archaea were something very different from bacteria.

There since has been a tremendous amount of speculation, re-analysis, gathering of more data, and vitriol in the overall debate about the deep divergences in evolution, such as where eukaryotes come from, and where the archaea fit into the overall scheme. Compared with the rest of molecular biology, where experiments routinely address questions productively and efficiently due to a rich tool chest and immediate access to the subject at hand, deep phylogeny is far more speculative and prone to subjective interpretation, sketchy data, personal hobbyhorses, and abusive writing. A recent symposium in honor of one of its more argumentative practitioners made that clear, as his ideas were being discarded virtually at the graveside.

Over the last decade, estimates of the branching date of archaea from the rest of the tree of life have varied from 0.8 to 4.5 Gya (billion years ago). That is a tremendous range, and is a sign of the difficulty of this field. The frustrations of doing molecular phylogeny are legion, just as the temptations are alluring. Firstly, there are very few landmarks in the fossil record to pin all this down. There are stromatolites from roughly 3.5 Gya, which pin down the first documented life of any kind. Second are eukaryotic fossils, which start, at the earliest, about 1.5 Gya. Other microbial fossils pin down occasional sub-groups of bacteria, but archaea are not represented in the fossil record at all, being hardly distinguishable from bacteria in their remains. Then we get the Cambrian explosion of multicellular life, roughly 0.5 Gya. That is pretty much it for the fossil record, aside from the age of the moon, which is about 4.5 Gya and gives us the baseline of when the earth became geologically capable of supporting life of any kind.

The molecules of living organisms, however, form a digital record of history. Following evolutionary theory, each organism descends from others, and carries, in mutated and altered form, traces of that history. We have parts of our genomes that vary with each generation, (useful for forensics and personal identification), we have other parts that show how we changed and evolved from other apes, and we have yet other areas that vary hardly at all- that carry recognizable sequences shared with all other forms of life, and presumably with LUCA. This is a real treasure trove, if only we can make sense of it.

But therein lies the rub. As mentioned above, these deeply conserved sequences are hardly chronometers. So for all the data collection and computer wizardry, the data itself tells a mangled story. Rapid evolution in one lineage can make it look much older than it really is, confounding the whole tree. Over the years, practitioners have learned to be as judicious as possible in selecting target sequences, while getting as many as possible into the mix. For example, adding up the sequences of 50-odd ribosomal proteins can give more and better data than assembling the 2 long-ish ribosomal RNAs. They provide more and more diverse data. But they have their problems as well, since some are much less conserved than others, and some were lost or gained along the way. 

A partisan of the later birth of archaea provides a phylogenetic tree with countless microbial species, and one bold claim: "inflated" distances to the archaeal and eukaryotic stems. This is given as the reason that archaea (lower part of the diagram, including eukaryotes, termed "archaebacteria"), looks very ancient, but really just sped away from its originating bacterial parent, (the red bacteria), estimated at about 1 Gya. This tree is based on an aligned concatentation of 26 universally conserved ribosomal protein sequences, (51 from eukaryotes), with custom adjustments.

So there has been a camp that claims that the huge apparent / molecular distance between the archaea and other cells is just such a chimera of fast evolution. Just as the revolution that led to the eukaryotic cell involved alot of molecular change including the co-habitation of countless proteins that had never seen each other before, duplications / specializations, and many novel inventions, whatever process led to the archaeal cell (from a pre-existing bacterial cell) might also have caused the key molecules we use to look into this deep time to mutate much more rapidly than is true elsewhere in the vast tree of life. What are the reasons? There is the general disbelief / unwillingness to accept someone else's work, and evidence like possible horizontal transfers of genes from chloroplasts to basal archaea, some large sequence deletion features that can be tracked through these lineages and interpreted to support late origination, some papering over of substantial differences in membrane and metabolic systems, and there are plausible (via some tortured logic) candidates for an originating, and late-evolving, bacterial parent. 

This thread of argument puts the origin of eukaryotes roughly at 0.8 Gya, which is, frankly, uncomfortably close to the origination of multicellular life, and gives precious little time for the bulk of eukaryotic diversity to develop, which exists largely, as shown above, at the microbial level. (Note that "Animalia" in the tree above is a tiny red blip among the eukaryotes.) All this is quite implausible, even to a casual reader, and makes this project hard to take seriously, despite its insistent and voluminous documentation.

Parenthetically, there was a fascinating paper that used the evolution of the genetic code itself to make a related point, though without absolute time attributions. The code bears hallmarks of some amino acids being added relatively late (tryptophan, histidine), while others were foundational from the start (glycine, alanine), when it may have consisted of two RNA bases (or even one) rather than three. All of this took place long before LUCA, naturally. This broad analysis of genetic code usage argued that bacteria tend to use a more ancient subset of the code, which may reflect their significantly more ancient position on the tree of life. While the full code was certainly in place by the time of LUCA, there may still at this time have been, in the inherited genome / pool of proteins, a bias against the relatively novel amino acids. This finding implies that the time of archaeal origination was later than the origination of bacteria, by some unspecified but significant amount.

So, attractive as it would be to demote the archaea from their perch as super-ancient organisms, given their small sizes, small genomes, specialization in extreme environments, and peripheral ecological position relative to bacteria, that turns out to be difficult to do. I will turn, then, to a very recent paper that gives what I think is much more reasoned and plausible picture of the deeper levels of the tree of life, and the best general picture to date. This paper is based on the protein sequences of the rotary ATPases that are universal, and were present in LUCA, despite their significant complexity. Indeed, the more we learn about LUCA, the more complete and complex this ancestor turns out to be. Our mitochondrion uses a (bacterial) F-type ATPase to synthesize ATP from the food-derived proton gradient. Our lysosomes use a (archaeal) V-type ATPase to drive protons into / acidify the lysosome in exchange for ATP. These are related, derived from one distant ancestor, and apparently each was likely to have been present in LUCA. Additionally, each ATPase is composed of two types of subunits, one catalytic, and one non-catalytic, which originated from an ancient protein duplication, also prior to LUCA. The availability of these molecular cousins / duplications provides helpful points of comparison throughout, particularly for locating the root of the evolutionary tree.

Phylogenetic trees based on ATP synthase enzymes that are present in all forms of life. On left is shown the general tree, with branch points of key events / lineages. On right are shown sub-trees for the major types of the ATP synthase, whether catalytic subunit (c), non-catalytic (n), F-type, common in bacteria, or V type, common in archaea. Note how congruent these trees are. At bottom right in the tiny print is a guide to absolute time, and the various last common ancestors.

This paper also works quite hard to pin the molecular data to the fossil and absolute time record, which is not always provided The bottom line is that archaea by this tree arise quite early, (see above), co-incident with or within about 0.5 Gy of LUCA, which was bacterial, at roughly 4.4 Gya. The bacterial and archaeal last common ancestors are dated to 4.3 and 3.7 Gya, respectively. The (fused) eukaryotic last common ancestor dates to about 1.9 Gya, with the proto-mitochondrion's individual last common ancestor among the bacteria some time before that, at roughly 2.4 Gya. 

This time line makes sense on many fronts. First, it provides a realistic time frame for the formation and diversification of eukaryotes. It puts their origin right around the great oxidation event, which is when oxygen became dominant in earth's atmosphere, (about 2 to 2.4 Gya), which was a precondition for the usefulness of mitochondria to what are otherwise anaerobic archaeal cells. It places the origin of archaea (LACA) a substantial stretch after the origin of bacteria, which agrees with the critic's points above that bacteria are the truly basal lineage of all life, and archaea, while highly different and pretty archaic, also share a lot of characteristics with bacteria, and perhaps more so with certain early lineages than with others that came later. The distinction between LUCA and the last common bacterial ancestor (LBCA) is a technical one given the trees they were working from, and are not, given the ranges of age presented, (see figure above), significantly different.

I believe this field is settling down, and though this paper, working from only a subset of the most ancient sequences plus fossil set-points, is hardly the last word, it appears to represent a consensus view and is the best picture to date of the deepest and most significant waypoints in the deep history of life. This is what comes from looking through microscopes, and finding entire invisible worlds that we had no idea existed. Genetic sequencing is another level over that of microscopy, looking right at life's code, and at its history, if darkly. What we see in the macroscopic world around us is only the latest act in a drama of tremendous scale and antiquity.

• Platitude.
• There are a lot of single-celled eukaryotes.
• Hitting bottom.