Many Ways There are to Read a Genome

New methods to unravel the code of transcriptional regulators.

When we deciphered the human genome, we came up with three billion letters of its linear code- nice and tidy. But that is not how it is read inside our cells. Sure, it is replicated linearly, but the DNA polymerases don't care about the sequence- they are not "reading" the book, they are merely copying machines trying to get it to the next generation with as few errors as possible. The book is read in an entirely different way, by a herd of proteins that recognize specific sequences of the DNA- the transcription regulators (also commonly called transcription factors [TF], in the classic scientific sense of some "factor" that one is looking for). These regulators- and there are, by one recent estimate, 1,639 of them encoded in the human genome- constitute an enormously complex network of proteins and RNAs that regulate each other, and regulate "downstream" genes that encode everything else in the cell. They are made in various proportions to specify each cell type, to conduct every step in development, and to respond to every eventuality that evolution has met and mastered over the eons.

Loops occur in the DNA between site of regulator binding, in order to turn genes on (enhancer, E, and transcription regulator/factor, TF).

Once sufficient transcription regulators bind to a given gene, it assembles a transcription complex at its start site, including the RNA polymerase that then generates an RNA copy that can float off to be made into a protein, (such as a transcription regulator), or perhaps function in its RNA form as part of zoo of rRNA, tRNA, miRNA, piRNA, and many more that also help run the cell. Some regulators can repress transcription, and many cooperate with each other. There are also diverse regions of control for any given target gene in its nearby non-coding DNA- cassettes (called enhancers) that can be bound by different regulators and thus activated at different stages for different reasons. 

These binding sites in the DNA that transcription regulators bind to are typically quite small. A classic regulator SP1 (itself 785 amino acids long and bearing three consecutive DNA binding motifs coordinated by a zinc ions) binds to a sequence resembling (G/T)GGGCGG(G/A)(G/A)(C/T). So only ten bases are specified at all, and four of those positions are degenerate. By chance, a genome of three billion bases will have such a sequence about 45,769 times. So this kind of binding is not very strictly specified, and such sites tend to appear and disappear frequently in evolution. That is one of the big secrets of evolution- while some changes are hard, others are easy, and it there is constant variation and selection going on in the regulatory regions of genes, refining and defining where / when they are expressed.

Anyhow, researchers naturally have the question- what is the regulatory landscape of a given gene under some conditions of interest, or of an entire genome? What regulators bind, and which ones are most important? Can we understand, given our technical means, what is going on in a cell from our knowledge of transcription regulators? Can we read the genome like the cell itself does? Well the answer to that is, obviously no and not yet. But there are some remarkable technical capabilities. For example, for any given regulator, scientists can determine where it binds all over the genome in any given cell, by chemical crosslinking methods. The prediction of binding sites for all known regulators has been a long-standing hobby as well, though given the sparseness of this code and the lability of the proteins/sites, one that gives only statistical, which is to say approximate, results. Also, scientists can determine across whole genomes where genes are "open" and active, vs where they are closed. Chromatin (DNA bound with histones in the nucleus) tends to be closed up on repressed and inactive genes, while transcription regulators start their work by opening chromatin to make it accessible to other regulators, on active genes.

This last method offers the prospect of truly global analysis, and was the focus of a recent paper. The idea was to merge a detailed library predicted binding sites for all known regulators all over the genome, with experimental mapping of open chromatin regions in a particular cell or tissue of interest. And then combine all that with existing knowledge about what each of the target genes near the predicted binding sites do. The researchers clustered the putative regulators binding across all open regions by this functional gene annotation to come up with statistically over-represented transcription regulators and functions. This is part of a movement across bioinformatics to fold in more sources of data to improve predictions when individual methods each produce sketchy, unsatisfying results.

In this case, mapping open chromatin by itself is not very helpful, but becomes much more helpful when combined with assessments of which genes these open regions are close to, and what those genes do. This kind of analysis can quickly determine whether you are looking at an immune cell or a neuron, as the open chromatin is a snapshot of all the active genes at a particular moment. In this recent work, the analysis was extended to say that if some regulators are consistently bound near genes participating in some key cellular function, then we can surmise that that regulator may be causal for that cell type, or at least part of the program specific to that cell. The point for these researchers is that this multi-source analysis performs better in finding cell-type specific, and function-specific, regulators than is the more common approach of just adding up the prevalence of regulators occupying open chromatin all over a given genome, regardless of the local gene functions. That kind of approach tends to yield common regulators, rather than cell-type specific ones. 

To validate, they do rather half-hearted comparisons with other pre-existing techniques, without blinding, and with validation of only their own results. So it is hardly a fair comparison. They look at the condition systemic lupus (SLE), and find different predictions coming from their current technique (called WhichTF) vs one prior method (MEME-ChIP).  MEME-ChIP just finds predicted regulator binding sites for genomic regions (i.e. open chromatin regions) given by the experimenter, and will do a statistical analysis for prevalence, regardless of the functions of either the regulator or the genes it binds to. So you get absolute prevalence of each regulator in open (active) regions vs the genome as a whole. 

Different regulators are identified from the same data by different statistical methods. But both sets are relevant.

What to make of these results? The MEME-ChIP method finds regulators like SP1, SP2, SP4, and ZFX/Y. SP1 et al. are very common regulators, but that doesn't mean they are unimportant, or not involved in disease processes. SP1 has been observed as likely to be involved in autoimmune encephalitis in mice, a model of multiple sclerosis, and naturally not so far from lupus in pathology. ZFX is also a prominent regulator in the progenitor cells of the immune system. So while these authors think little of the competing methods, those methods seem to do a very good job of identifying significant regulators, as do their own methods. 

There is another problem with the author's WhatTF method, which is that gene annotation is in its infancy. Users are unlikely to find new functions using existing annotations. Many genes have no known function yet, and new functions are being found all the time for those already assigned functions. So if one's goal is classification of a cell or of transcription regulators according to existing schemes, this method is fine. But if one has a research goal to find new cell types, or new processes, this method will channel you into existing ones instead.

This kind of statistical refinement is unlikely to give us what we seek in any case- a strong predictive model of how the human genome is read and activatated by the herd of gene regulators. For that, we will need new methods for specific interaction detection, with a better appreciation for complexes between different regulators, (which will be afforded by the new AI-driven structural techniques), and more appreciation for the many other operators on chromatin, like the various histone modifying enzymes that generate another whole code of locks and keys that do the detailed regulation of chromatin accessibility. Reading the genome is likely to be a somewhat stochastic process, but we have not yet arrived at the right level of detail, or the right statistics, to do it justice.

• Unconscious messaging and control. How the dark side operates.
• Solzhenitsyn on evil.
• Come watch a little Russian TV.
• "Ruthless beekeeping practices"
• The medical literature is a disaster.

On the Spectrum

Autism, broader autism phenotype, temperament, and families. It turns out that everyone is on the spectrum.

The advent of genomic sequencing and the hunt for disease-causing mutations has been notably unhelpful for most mental diseases. Possible or proven disease-causing mutations pile up, but they do little to illuminate the biology of what is going on, and even less towards treatment. Autism is a prime example, with hundreds of genes now identified as carrying occasional variants with causal roles. The strongest of these variants affect synapse formation among neurons, and a second class affects long-term regulation of transcription, such as turning genes durably on or off during developmental transitions. Very well- that all makes a great deal of sense, but what have we gained?

Clinically, we have gained very little. What is affected are neural developmental processes that can't be undone, or switched off in later life with a drug. So while some degree of understanding slowly emerges from these studies, translating that to treatment remains a distant dream. One aspect of the genetics of autism, however, is highly informative, which is the sheer number of low-effect and common mutations. Autism can be thought of as coming in two types, genetically- those due to a high effect, typically spontaneous or rare mutation, and those due to a confluence of common variants. The former tends to be severe and singular- an affected child in a family that is otherwise unaffected. The latter might be thought of as familial, where traits that have appeared (mildly) elsewhere in the family have been concentrated in one child, to a degree that it is now diagnosable.

This pattern has given rise to the very interesting concept of the "Broader Autism Phenotype", or BAP. This stems from the observation that families of autistic children have higher rates where ... "the parents, grandparents, and collaterals are persons strongly preoccupied with abstractions of a scientific, literary, or artistic nature, and limited in genuine interest in people." Thus there is not just a wide spectrum of autism proper, based on the particular confluence of genetic and other factors that lead to a diagnosis and its severity, but there is also, outside of the medical spectrum, quite another spectrum of traits or temperaments which tend toward autism and comprise various eccentricities, but have not, at least to date, been medicalized.

The common nature of these variants leads to another question- why are they persistent in the population? It is hard to believe that such a variety and number of variations are exclusively deleterious, especially when the BAP seems to have, well, rather positive aspects. No, I would suggest that an alternative way to describe BAP is "an enhanced ability to focus", and develop interests in salient topics. Ever meet people who are technically useless, but warm-hearted? They are way off on the non-autistic part of the spectrum, while the more technically inclined, the fixers of the world and scholars of obscure topics, are more towards the "ability to focus" part of the spectrum. Only when such variants are unusually concentrated by the genetic lottery do children appear with frank autistic characteristics, totally unable to deal with social interactions, and given to obsessive focus and intense sensitivities.

Thus autism looks like a more general lens on human temperament and evolution, being the tip of a very interesting iceberg. As societies, we need the politicians, backslappers, networkers, and con men, but we also need, indeed increasingly as our societies and technologies developed over the centuries, people with the ability and desire to deal with reality- with technical and obscure issues- without social inflection, but with highly focused attention. Militaries are a prime example, fusing critical needs of managing and motivating people, with a modern technical base of vast scope, reliant on an army of specialists devoted to making all the machinery work. Why does there have to be this tradeoff? Why can't everyone be James Bond, both technically adept and socially debonaire? That isn't really clear, at least to me, but one might speculate that in the first place, dealing with people takes a great deal of specialized intelligence, and there may not be room for everything in one brain. Secondly, the enhanced ability to focus on technical or artistic topics may actively require, as is implicit in doing science and as was exemplified by Mr. Spock, an intentional disregard of social niceties and motivations, if one is to fully explore the logic of some other, non-human, world.

• Autistic comedy?
• What happened to the war on poverty?
• How to think about cancer treatments.
• 95 year old judges, really? 

The Development of Metamorphosis

Adulting as a fly involves a lot of re-organization.

Humans undergo a slight metamorphosis, during adolescence. Imagine undergoing pupation like insects do and coming out with a totally new body, with wings! Well, Kafka did, and it wasn't very pleasant. But insects do it all the time, and have been doing it for hundreds of millions of years, taking to the air and dominating the biosphere. What goes on during metamorphosis, how complete is its refashioning of the body, and how did it evolve? A recent paper (review) considered in detail how the brains of insects change during metamorphosis, finding a curious blend of birth, destruction, and reprogramming among their neurons.

Time is on the Y axis, and the emergence of later, more advanced types of insects is on the X axis. This shows the progressive elaboration of non-metamorphosis (ametabolous), partially metamorphosing (hemimetabolous), and fully metamorphosing (holometabolous) forms. Dragonflies are only partially metamorphosing in this scheme, though their adult forms are often highly different from their larval (nymph) form.

Insects evolved from crustaceans, and took to land as small silvertail-like creatures with exoskeletons, roughly 450 million years ago. Over 100 million years, they developed the process of metamorphosis as a way to preserve the benefits of their original lifestyle for early development, in moist locations, while conquering the air and distance as adults. Early insect types are termed ametabolous, meaning that they have no metamorphosis at all, developing straight from eggs to an adult-style form. These go through several molts to accommodate growth, but don't redesign their bodies. Next came hemimetabolous development, which is exemplified by grasshoppers and cockroaches. Also dragonflies, which significantly refashion themselves during the last molt, gaining wings. In the nymph stage, those wings were carried around as small patches of flat embryonic tissue, and then suddenly grow out at the last molt. Dragonflies are extreme, and most hemimetabolous insects don't undergo such dramatic change. Last came holometabolous development, which involves pupation and a total redesign of the body that can go from a caterpillar to a butterfly.

The benefit of having wings is pretty clear- it allows huge increases in range for feeding and mating. Dragonflies are premier flying predators. But as a larva, wallowing in fruit juice or leaf sap or underwater, as dragonflies are, wings and long legs would be a hindrance. This conundrum led to the innovation of metamorphosis, based on the already somewhat dramatic practice of molting off the exoskeleton periodically. If one can grow a whole new skeleton, why not put wings on it, or legs? And metamorphosis has been tremendously successful, used by over 98% of insect species.

The adult insect tissues do not come from nowhere- they are set up as arrested embryonic tissues called imaginal discs. These are small patches that exist in the larva at specific positions. During pupation, while much of the rest of the body refashions itself, imaginal discs rapidly develop into future tissues like wings, legs, genitalia, antennas, and new mouth parts. These discs have a fascinating internal structure that prefigures the future organ. The leg disc is concentrically arranged with the more distant future parts (toes) at its center. Transplanting a disc from one insect to another or one place to another doesn't change its trajectory- it will still become a leg wherever it is put. So it is apparent that the larval stage is an intermediate stage of organismal development, where a bunch of adult features are primed but put on hold, while a simpler and much more primitive larval body plan is executed to accommodate its role in early growth and its niche in tight, moist, hidden places.

The new paper focuses on the brain, which larva need as well as adults. So the question is- how does the one brain develop from the other? Is the larval brain thrown away? The answer is that no, the brain is not thrown away at all, but undergoes its own quite dramatic metamorphosis. The adult brain is substantially bigger, so many neurons are added. A few neurons are also killed off. But most of the larval neurons are reprogrammed, trimmed back and regrown out to new regions to do new functions.

In this figure, the neurons are named as mushroom body outgoing neuron (MBON) or dopaminergic neuron (DAN, also MBIN for incoming mushroom body neuron), mushroom body extrinsic neuron to calyx (MBE-CA), and mushroom body protocerebral posterior lateral 1 (PPL1). MBON-c1 is totally reprogrammed, MBON-d1 changes its projections substantially, as do the (teal) incoming neurons, and MBON-12 was not operational in the larval stage at all. Note how MBON-c1 is totally reprogrammed to serve new locations in the adult.

The mushroom body, which is the brain area these authors focus on, is situated below the antennas and mediates smell reception, learning, and memory. Fly biologists regard it as analogous to our cortex- the most flexible area of the brain. Larvae don't have antennas, so their smell/taste reception is a lot more primitive. The mushroom body in drosophila has about a hundred neurons at first, and continuously adds neurons over larval life, with a big push during pupation, ending up with ~2200 neurons in adults. Obviously this has to wire into the antennas as they develop, for instance.

The authors find that, for instance, no direct connections between input and output neurons of the mushroom body (MBIN and MBON, respectively) survive from larval to adult stages. Thus there can be no simple memories of this kind preserved between these life stages. While there are some signs of memory retention for a few things in flies, for the most part the slate is wiped clean. 

"These MBONs [making feedback connections] are more highly interconnected in their adult configuration compared to their larval one: their adult configuration shows 13 connections (31% of possible connections), while their larval configuration has only 7 (17%). Importantly, only three of these connections (7%) are present in both larva and adult. This percentage is similar to the 5% predicted if the two stages were wired up independently at their respective frequencies."

Interestingly, no neuron changed its type- that is, which neurotransmitter it uses to communicate. So, while pruning and rewiring was pervasive, the cells did not fundamentally change their stripes. All this is driven by the hormonal system (juvenile hormone, which blocks adult development, and ecdysone, which drives molting, and in the absence of juvenile hormone, pupation) which in turn drives a program of transcription factors that direct the genes needed for development. While a great deal is known about neuronal pathfinding and development, this paper doesn't comment on those downstream events- how it is that selected neurons are pruned, turned around, and induced to branch out in totally new directions, for instance. That will be the topic of future work.

• Corrupt business practices. Why is this lawful?
• Why such easy bankruptcy for corporations, but not for poor countries?
• Watch the world's mesmerizing shipping.
• Oh, you want that? Let me jack up the price for you.
• What transgender is like.
• "China has arguably been the biggest beneficiary of the U.S. security system in Asia, which ensured the regional stability that made possible the income-boosting flows of trade and investment that propelled the country’s economic miracle. Today, however, General Secretary of the Chinese Communist Party Xi Jinping claims that China’s model of modernization is an alternative to “Westernization,” not a prime example of its benefits."

Molecules That See

Being trans is OK: retinal and the first event of vision.

Our vision is incredible. If I was not looking right now and experiencing it myself, it would be unbelievable that a biological system made up of motley molecules could accomplish the speed, acuity and color that our visual system provides. It was certainly a sticking point for creationists, who found (and perhaps still find) it incredible that nature alone can explain it, not to mention its genesis out of the mists of evolutionary time. But science has been plugging away, filling in the details of the pathway, which so far appear to arise by natural means. Where consciousness fits in has yet to be figured out, but everything else is increasingly well-accounted. 

It all starts in the eye, which has a curiously backward sheet of tissue at the back- the retina. Its nerves and blood vessels are on the surface, and after light gets through those, it hits the photoreceptor cells at the rear. These photoreceptor cells come in two types, rods (non-color sensitive) and cones (sensitive to either red, green, or blue). The photoreceptor cells have a highly polarized and complicated structure, where photosensitive pigments are bottom-most in a dense stack of membranes. Above these is a segment where the mitochondria reside, which provide power, as vision needs a lot of energy. Above these is the nucleus of the cell (the brains of the operation) and top-most is the synaptic output to the rest of the nervous system- to those nerves that network on the outside of the retina. 

A single photoreceptor cell, with the outer segment at the very back of the retina, and other elements in front.

Facing the photoreceptor membranes at the bottom of the retina is the retinal pigment epithelium, which is black with melanin. This is finally where light stops, and it also has very important functions in supporting the photoreceptor cells by buffering their ionic, metabolic, and immune environment, and phagocytosing and digesting photoreceptor membranes as they get photo-oxidized, damaged, and sloughed off. Finally, inside the photoreceptor cells are the pigment membranes, which harbor the photo-sensitive protein rhodopsin, which in turn hosts the sensing pigment, retinal. Retinal is a vitamin A-derived long-chain molecule that is bound inside rhodopsin or within other opsins which respectively confer slightly shifted color sensitivity. 

These opsins transform the tickle that retinal receives from a photon into a conformational change that they, as GPCRs (G-protein coupled receptors), transmit to G-proteins, called transducin. For each photon coming in, about 50 transducin molecules are activated. Each of activated transducin G-protein alpha subunits induce (in its target cGMP phosphodisterase) about 1000 cGMP molecules to be consumed. The local drop in cGMP concentration then closes the cGMP-gated cation channels in the photoreceptor cell membrane, which starts the electrical impulse that travels out to the synapse and nervous system. This amplification series provides the exquisite sensitivity that allows single photons to be detected by the system, along with the high density of the retinal/opsin molecules packed into the photoreceptor membranes.

Retinal, used in all photoreceptor cell types. Light causes the cis-form to kick over to the trans form, which is more stable.

The central position of retinal has long been understood, as has the key transition that a photon induces, from cis-retinal to all-trans retinal. Cis-retinal has a kink in the middle, where its double bond in the center of the fatty chain forms a "C" instead of a "W", swinging around the 3-carbon end of the chain. All-trans retinal is a sort of default state, while the cis-structure is the "cocked" state- stable but susceptible to triggering by light. Interestingly, retinal can not be reset to the cis-state while still in the opsin protein. It has to be extracted, sent off to a series of at least three different enzymes to be re-cocked. It is alarming, really, to consider the complexity of all this.

A recent paper (review) provided the first look at what actually happens to retinal at the moment of activation. This is, understandably, a very fast process, and femtosecond x-ray analysis needed to be brought in to look at it. Not only that, but as described above, once retinal flips from the dark to the light-activated state, it never reverses by itself. So every molecule or crystal used in the analysis can only be used once- no second looks are possible. The authors used a spray-crystallography system where protein crystals suspended in liquid were shot into a super-fine and fast X-ray beam, just after passing by an optical laser that activated the retinal. Computers are now helpful enough that the diffractions from these passing crystals, thrown off in all directions, can be usefully collected. In the past, crystals were painstakingly positioned on goniometers at the center of large detectors, and other issues predominated, such as how to keep such crystals cold for chemical stability. The question here was what happens in the femto- and pico-seconds after optical light absorption by retinal, ensconced in its (temporary) rhodopsin protein home.

Soon after activation, at one picosecond, retinal has squirmed around, altering many contacts with its protein. The trans (dark) conformation is shown in red, while the just-activated form is in yellow. The PSB site on the far end of the fatty chain (right) is secured against the rhodopsin host, as is the retinal ring (left side), leaving the middle of the molecule to convey most of the shape change, a bit like a bicycle pedal.

And what happens? As expected, the retinal molecule twists from cis to trans, causing the protein contacts to shift. The retinal shift happens by 200 femtoseconds, and the knock-on effects through the protein are finished by 100 picoseconds. It all makes a nanosecond seem impossibly long! As imaged above, the shape shift of retinal changes a series of contacts it has with the rhodopsin protein, inducing it to change shape as well. The two ends of the retinal molecule seem to be relatively tacked down, leaving the middle, where the shape change happens, to do most of the work. 

"One picosecond after light activation, rhodopsin has reached the red-shifted Batho-Rh intermediate. Already by this early stage of activation, the twisted retinal is freed from many of its interactions with the binding pocket while structural perturbations radiate away as a transient anisotropic breathing motion that is almost entirely decayed by 100 ps. Other subtle and transient structural rearrangements within the protein arise in important regions for GPCR activation and bear similarities to those observed by TR-SFX during photoactivation of seven-TM helix retinal-binding proteins from bacteria and archaea."

All this speed is naturally lost in the later phases, which take many milliseconds to send signals to the brain, discern movement and shape, to identify objects in the scene, and do all the other processing needed before consciousness can make any sense of it. But it is nice to know how elegant and uniform the opening scene in this drama is.

• Down with lead.
• Medicare advantage, cont.
• Ukraine, cont.
• What the heck is going on in Wisconsin?
• Graph of the week- world power needs from solar, modeled to 2050. We are only scratching the surface so far.

Consciousness and the Secret Life of Plants

Could plants be conscious? What are the limits of consciousness and pain? 

Scientific American recently reviewed a book titled "Planta Sapiens". The title gives it all away, and the review was quite positive, with statements like: 

"Our senses can not grasp the rich communicative world of plants. We therefore lack language to describe the 'intelligence' of a root tip in conversation with the microbial life of the soil or the 'cognition' that emerges when chemical whispers ripple through a lacework of leaf cells."

This is provocative indeed! What if plants really do have a secret life and suffer pain with our every bite and swing of the scythe? What of our vaunted morals and ethics then?

I am afraid that I take a skeptical view of this kind of thing, so let's go through some of the aspects of consciousness, and ask how widespread it really is. One traditional view, from the ur-scientific types like Descartes, is that only humans have consciousness, and all other creatures, have at best a mechanism, unfeeling and mechanical, that may look like consciousness, but isn't. This, continued in a sense by B. F. Skinner in the 20th century, is a statement from ignorance. We can not fully communicate with animals, so we can not really participate in what looks like their consciousness, so let's just ignore it. This position has the added dividend of supporting our unethical treatment of animals, which was an enormous convenience, and remains the core position of capitalism generally, regarding farm animals (though its view of humans is hardly more generous).

Well, this view is totally untenable, from our experience of animals, our ability to indeed communicate with them to various degrees, to see them dreaming, not to mention from an evolutionary standpoint. Our consciousness did not arise from nothing, after all. So I think we can agree that mammals can all be included in the community of conscious fellow-beings on the planet. It is clear that the range of conscious pre-occupations can vary tremendously, but whenever we have looked at the workings of memory, attention, vision, and other components assumed to be part of or contributors to conscious awareness, they all exist in mammals, at least. 

But what about other animals like insects, jellyfish, or bacteria? Here we will need a deeper look at the principles in play. As far as we understand it, consciousness is an activity that binds various senses and models of the world into an experience. It should be distinguished from responsiveness to stimuli. A thermostat is responsive. A bacterium is responsive. That does not constitute consciousness. Bacteria are highly responsive to chemical gradients in their environment, to food sources, to the pheromones of fellow bacteria. They appear to have some amount of sensibility and will. But we can not say that they have experience in the sense of a conscious experience, even if they integrate a lot of stimuli into a holistic and sensitive approach to their environment. 

The same is true of our own cells, naturally. They also are highly responsive on an individual basis, working hard to figure out what the bloodstream is bringing them in terms of food, immune signals, pathogens, etc. Could each of our cells be conscious? I would doubt it, because their responsiveness is mechanistic, rather than being an independent as well as integrated model of their world. Simlarly, if we are under anaesthesia and a surgeon cuts off a leg, is that leg conscious? It has countless nerve cells, and sensory apparatus, but it does not represent anything about its world. It rather is built to send all these signals to a modeling system elsewhere, i.e. our brain, which is where consciousness happens, and where (conscious) pain happens as well.

So I think the bottom line is that consciousness is rather widely shared as a property of brains, thus of organisms with brains, which were devised over evolutionary time to provide the kind of integrated experience that a neural net can not supply. Jellyfish, for instance, have neural nets that feel pain, respond to food and mates, and swim exquisitely. They are highly responsive, but, I would argue, not conscious. On the other hand, insects have brains and would count as conscious, even though their level of consciousness might be very primitive. Honey bees map out their world, navigate about, select the delicacies they want from plants, and go home to a highly organized hive. They also remember experiences and learn from them.

This all makes it highly unlikely that consciousness is present in quantum phenomena, in rocks, in bacteria, or in plants. They just do not have the machinery it takes to feel something as an integrated and meaningful experience. Where exactly the line is between highly responsive and conscious is probably not sharply defined. There are brains that are exceedingly small, and neural nets that are very rich. But it is also clear that it doesn't take consciousness to experience pain or try to avoid it, (which plants, bacteria, and jellyfish all do). Where is the limit of ethical care, if our criterion shifts from consciousness to pain? Wasn't our amputated leg in pain after the operation above, and didn't we callously ignore its feelings? 

I would suggest that the limit remains that of consciousness, not that of responsiveness to pain. Pain is not problematic because of a reflex reaction. The doctor can tap our knee as often as he wants, perhaps causing pain to our tendon, but not to our consciousness. Pain is problematic because of suffering, which is a conscious construct built around memory, expectations, and models of how things "should" be. While one can easily see that a plant might have certain positive (light, air, water) and negative (herbivores, fungi) stimuli that shape its intrinsic responses to the environment, these are all reflexive, not reflective, and so do not appear (to an admittedly biased observer) to constitute suffering that rises to ethical consideration.

The Eye is the Window to the Brain

Alpha oscillations of the brain prefigure the saccades by which our eyes move as we read.

Reading is a complicated activity. We scan symbols on a page, focusing on some in turn, while scanning along for the next one. Data goes to the brain not in full images, but in the complex coding of differences from moment to moment. Simultaneously, various levels of processing in the brain decode the dark and light spots, the letter forms, the word chunks, the phrases, and on up to the ideas being conveyed.

While our brain is not rigidly clocked like a computer, (where each step of computation happens in sync with the master clock), it does have dynamic oscillations at several different frequencies and ranging over variable regions and coalitions of neurons that organize its processing. And the eye is really a part of that same central nervous system- an outpost that conveys so much sensitive information, both in and out.

We take in visual scenes by jerks, or saccades, using our peripheral vision to orient generally and detect noteworthy portions, then bringing our high-acuity fovea to focus on them. The eye moves about four times per second, a span that is used to process the current scene and to plan where to shift next. Alpha oscillations (about 10 per second) in the brain, which are inhibitory, are known to (anti-) correlate with motor control of the saccade period. The processing of the visual sensory system resets its oscillations with each shift in scene, so is keyed to saccades in a receiving sense. Since vision only happens in the rest/focal periods between saccades, it is helpful, conceptually, to coordinate the two processes so that the visual processing system is maximally receptive (via its oscillatory phase) at the same time that the eye comes to rest after a saccade and sends it a new scene. Conversely, the visual sensory system would presumably tell the motor system when it was done processing the last unit, to gate a shift to the next scene.

A recent paper extended this work to ask how brain oscillations relate to the specific visual task of reading, including texts that are more or less difficult to comprehend. They used the non-invasive method of magnetic encephalography to visualize electrical activity within the brains of people reading. The duration of saccades were very uniform, (and short), while the times spent paused on each focal point (word) varied slightly with how difficult the word was to parse. It is worth noting that no evidence supports the lexical processing of words out of the peripheral vision- this only happens from foveal/focused images.

Subjects spent more time focused on rare/difficult words than on easy words, during a free reading exercise (C). On the other hand, the duration of saccades to such words was unchanged (D).

In the author's main finding, alpha oscillations were correlated as the person shifted from word to word, pausing to view each one. These oscillations tracked the pausing more closely when shifting towards more difficult words, rather than to simple words. And these peaks of phase locking happened anatomically in the Brodmann area 7, which is a motor area that mediates between the visual system and motor control of the eye. Presumably this results from communication from the visual processing area to the visual motor area, just next door. They also found that the phase locking was strongest for the start of saccades, not their end, when the scene comes back into focus. This may simply be a timing issue, since there are lags at all points in the visual processing system, and since the saccade duration is relatively fixed, this interval may be appropriate to keep the motor and sensory areas in effective synchronization.

Alpha oscillation locks to some degree with initiation of saccades, and does so more strongly when heading to difficult words, rather than to easy words. Figure B shows the difference in alpha power between the easy and difficult word target. How can this be? 

So while higher frequency (gamma) oscillations participate in sensory processing of vision, this lower alpha frequency is dominant in the area that controls eye movement, in keeping with muscle control mechanisms more generally. But it does raise the question of why they found a signal (phase locking for the initiation of a saccade) for the difficulty of the upcoming word, before it was actually lexically processed. The peripheral visual system is evidently making some rough guess, perhaps by size or some other property, of the difficulty of words, prior to fully decoding them, and it will be interesting to learn where this analysis is done.

• New uses for AI in medicare advantage.
• Some problems with environmental review.
• No-compete "agreements" are no such thing, and worthless anyhow.
• We wanna be free.

An Origin Story for Spider Venom

Phylogenetic analysis shows that the major component of spider venom derives from one ancient ancestor.

One reason why biologists are so fully committed to the Darwinian account of natural selection and evolution is that it keeps explaining and organizing what we see. Despite the almost incredible diversity and complexity of life, every close look keeps confirming what Darwin sensed and outlined so long ago. In the modern era, biology has gone through the "Modern Synthesis", bringing genetics, molecular biology, and evolutionary theory into alignment with mutually supporting data and theories. For example, it was Linus Pauling and colleagues (after they lost the race to determine the structure of DNA) who proposed that the composition of proteins (hemoglobin, in their case) could be used to estimate evolutionary relationships, both among those molecules, and among their host species.

Naturally, these methods have become vastly more powerful, to the point that most phylogenetic analyses of the relationship between species (including the definition of what species are, vs subspecies, hybrids, etc.) are led these days by DNA analysis, which provides the richest possible trove of differentiating characters- a vast spectrum from universally conserved to highly (and forensically) varying. And, naturally, it also constitutes a record of the mutational steps that make up the evolutionary process. The correlation of such analyses with other traditionally used diagnostic characters, and with the paleontological record, is a huge area of productive science, which leads, again and again, to new revelations about life's history.

One sample structure of a DRP- the disulfide rich protein that makes up most of spider venoms.

 The disulfide bond (between two cysteines) is shown in red. There is usually another disulfide helping to hold the two halves of the molecule together as well. The rest of the molecule is (evolutionarily, and structurally) free to change shape and character, in order to carry out its neuron-channel blocking or other toxic function.

One small example was published recently, in a study of spider venoms. Spiders arose, from current estimates, about 375 million years ago, and comprise the second most prevalent form of animal life, second only to their cousins, the insects. They generally have a hunting lifestyle, using venom to immobilize their prey, after capture and before digestion. These venoms are highly complex brews that can have over a hundred distinct molecules, including potassium, acids, tissue- and membrane-digesting enzymes, nucleosides, pore-forming peptides, and neurotoxins. At over three-fourths of the venom, the protein-based neurotoxins are the most interesting and best studied of the venom components, and a spider typically deploys dozens of types in its venom. They are also called cysteine-rich peptides or disulfide-rich peptides (DRPs) due to their composition. The fact that spiders tend to each have a large variety of these DRPs in their collection argues that a lot of gene duplication and diversification has occured.

A general phylogenetic tree of spiders (left). On the right are the signal peptides of a variety of venoms from some of these species. The identity of many of these signal sequences, which are not present in the final active protein, is a sign that these venom genes were recently duplicated.

So where do they come from? Sequences of the peptides themselves are of limited assistance, being small, (averaging ~60 amino acids), and under extensive selection to diversify. But they are processed from larger proteins (pro-proteins) and genes that show better conservation, providing the present authors more material for their evolutionary studies. The figure above, for example, shows, on the far right, the signal peptides from families of these DRP genes from single species. Signal peptides are the small leading section of a translated protein that directs it to be secreted rather than being kept inside the cell. Right after the protein is processed to the right place, this signal is clipped off and thus is not part of the mature venom protein. These signal peptides tend to be far more conserved than the mature venom protein, despite that fact that they have little to do- just send the protein to the right place, which can be accomplished by all sorts of sequences. But this is a sign that the venoms are under positive evolutionary pressure- to be more effective, to extend the range of possible victims, and to overcome whatever resistance the victims might evolve against them. 

Indeed, these authors show specifically that strong positive selection is at work, which is one more insight that molecular data can provide. (First, by comparing the rates of protein-coding positions that are neutral via the genetic code (synonymous) vs those that make the protein sequence change (non-synonymous), and second by the pattern and tempo of evolution of venom sequences compared with the mass of neutral sequences of the species.

"Given their significant sequence divergence since their deep-rooted evolutionary origin, the entire protein-coding gene, including the signal and propeptide regions, has accumulated significant differences. Consistent with this hypothesis, the majority of positively selected sites (~96%) identified in spider venom DRP toxins (all sites in Araneomorphae, and all but two sites in Mygalomorphae) were restricted to the mature peptide region, whereas the signal and propeptide regions harboured a minor proportion of these sites (1% and 3%, respectively)."

 

Phylogenetic tree (left), connecting up venom genes from across the spider phylogeny. On right, some of the venom sequences are shown just by their cysteine (C) locations, which form the basic structural scaffold of these proteins (top figure).

The more general phyogenetic analysis from all their sequences tells these authors that all the venom DRP genes, from all spider species, came from one origin. One easy way to see this is in the image above on the right, where just the cysteine scaffold of these proteins from around the phylogeny are lined up, showing that this scaffold is very highly conserved, regardless of the rest of the sequence. This finding (which confirms prior work) is surprising, since venoms of other animals, like snakes, tend to incorporate a motley bunch of active enzymes and components, sourced from a variety of ancestral sources. So to see spiders sticking so tenaciously to this fundamental structure and template for the major component of their venom is impressive- clearly it is a very effective molecule. The authors point out the cone snails, another notorious venom-maker, originated much more recently, (about 45 million years ago), and shows the same pattern of using one ancestral form to evolve a diversified blizzard of venom components, which have been of significant interest to medical science.

• Example: a spider swings a bolas to snare a moth.

Everything is Alive, but the Gods are all Dead

Barbara Ehrenreich's memoir and theological ruminations in "Living with a Wild God".

It turns out that everyone is a seeker. Somewhere there must be something or someone to tell us the meaning of life- something we don't have to manufacture with our own hands, but rather can go into a store and buy. Atheists are just as much seekers as anyone else, only they never find anything worth buying. The late writer Barbara Ehrenreich was such an atheist, as well as a remarkable writer and intellectual who wrote a memoir of her formation. Unusually and fruitfully, it focuses on those intense early and teen years when we are reaching out with both hands to seize the world- a world that is maddeningly just beyond our grasp, full of secrets and codes it takes a lifetime and more to understand. Religion is the ultimate hidden secret, the greatest mystery which has been solved in countless ways, each of them conflicting and confounding.

Ehrenreich's tale is more memoir than theology, taking us on a tour through a dysfunctional childhood with alcoholic parents and tough love. A story of growth, striking out into the world, and sad coming-to-terms with the parents who each die tragically. But it also turns on a pattern of mystical experiences that she keeps having, throughout her adult life, which she ultimately diagnoses as dissociative states where she zones out and has a sort of psychedelic communion with the world.

"Something peeled off the visible world, taking with it all meaning, inference, association, labels, and words. I was looking at a tree, and if anyone had asked, that's what I would have said I was doing, but the word "tree" was gone, along with all the notions of tree-ness that had accumulated in the last dozen years or so since I had acquired language. Was it a place that was suddenly revealed to me? Or was it a substance- the indivisible, elemental material out of which the entire known and agreed-upon world arises as a fantastic elaboration? I don't know, because this substance, this residue, was stolidly, imperturbably mute. The interesting thing, some might say alarming, was that when you take away all the human attributions- the words, the names of species, the wisps of remembered tree-related poetry, the fables of photosynthesis and capillary action- that when you take all this this away, there is still something left."

This is not very hard to understand as a neurological phenomenon of some kind of transient disconnection of just the kind of brain areas she mentions- those that do all the labeling, name-calling, and boxing-in. In schizophrenia, it runs to the pathological, but in Ehrenreich's case, she does not regard it as pathological at all, as it is always quite brief. But obviously, the emotional impact and weirdness of the experience- that is something else altogether, and something that humans have been inducing with drugs, and puzzling over, forever. 

Source

As a memoir, the book is very engaging. As a theological quest, however, it doesn't work as well, because the mystical experience is, as noted above, resolutely meaningless. It neither compels Ehrenreich to take up Christianity, as after a Pauline conversion, nor any other faith or belief system. It offers a peek behind the curtain, but, stripped of meaning as this view is, Ehrenreich is perhaps too skeptical or bereft of imagination to give it another, whether of her own or one available from the conventional array of sects and religions. So while the experiences are doubtless mystical, one can not call them religious, let alone god-given, because Ehrenreich hasn't interpreted them that away. This hearkens back to the writings of William James, who declined to assign general significance to mystical experiences, while freely admitting their momentous and convincing nature to those who experienced them.

Only in one brief section (which had clearly been originally destined for an entirely different book) does she offer a more interesting and insightful analysis. There, Ehrenreich notes that the history of religion can be understood as a progressive bloodbath of deicide. At first, everything is alive and sacred, to an animist mind. Every leaf and grain of sand holds wonders. Every stream and cloud is divine. This is probably our natural state, which a great deal of culture has been required to stamp out of us. Next is a hunting kind of religion, where deities are concentrated in the economic objects (and social patterns) of the tribe- the prey animals, the great plants that are eaten, and perhaps the more striking natural phenomena and powerful beasts. But by the time of paganism, the pantheon is cut down still more and tamed into a domestic household, with its soap-opera dramas and an increasingly tight focus on the major gods- the head of the family, as it were. 

Monotheism comes next, doing away with all the dedicated gods of the ocean, of medicine, of amor and war, etc., cutting the cast down to one. One, which is inflated to absurd proportions with all-goodness, all-power, all-knowledge, etc. A final and terrifying authoritarianism, probably patterned on the primitive royal state. This is the phase when the natural world is left in the lurch, as an undeified and unprotected zone where human economic greed can run rampant, safe in the belief that the one god is focused entirely on man's doings, whether for good or for ill, not on that of any other creature or feature of the natural world. A phase when even animals, who are so patently conscious, can, through the narcissism of primitive science and egoistic religion, be deemed mere mechanisms without feeling. This process doesn't even touch on the intercultural deicide committed by colonialism and conquest.

This in turn invites the last deicide- that by rational people who toss aside this now-cartoonish super-god, and return to a simpler reverence for the world as we naturally respond to it, without carting in a lot of social power-and-drama baggage. It is the cultural phase we are in right now, but the transition is painfully slow, uneven, and drawn-out. For Ehrenreich, there are plenty of signs- in the non-linear chemical phenomena of her undergraduate research, in the liveliness of quantum physics even into the non-empty vacuum, in the animals who populate our world and are perhaps the alien consciousnesses that we should be seeking in place of the hunt through outer space, and in our natural delight in, and dreams about, nature at large. So she ends the book as atheist as ever, but hinting that perhaps the liveliness of the universe around us holds some message that we are not the only thinking and sentient beings.

"Ah, you say, this is all in your mind. And you are right to be skeptical; I expect no less. It is in my mind, which I have acknowledged from the beginning is a less than perfect instrument. but this is what appears to be the purpose of my mind, and no doubt yours as well, its designed function beyond all the mundane calculations: to condense all the chaos and mystery of the world into a palpable Other or Others, not necessarily because we love it, and certainly not out of any intention to "worship" it. But because ultimately we may have no choice in the matter. I have the impression, growing out of the experiences chronicled here, that it may be seeking us out." 

Thus the book ends, and I find it a rather poor ending. It feels ripped from an X-Files episode, highly suggestive and playing into all the Deepak and similar mystical tropes of cosmic consciousness. That is, if this passage really means much at all. Anyhow, the rest of the trip is well worth it, and it is appropriate to return to the issue of the mystical experience, which is here handled with such judicious care and restraint. Where imagination could have run rampant, the cooly scientific view (Ehrenreich had a doctorate in biology) is that the experiences she had, while fascinating and possibly book-proposal-worthy, did not force a religious interpretation. This is radically unlike the treatment of such matters in countless other hands, needless to say. Perhaps our normal consciousness should not be automatically valued less than more rare and esoteric states, just because it is common, or because it is even-tempered.

• God would like us to use "they".
• If you are interested in early Christianity, Gnosticism is a good place to start.
• Green is still an uphill battle.

A Gene is Born

Yes, genes do develop out of nothing.

The "intelligent" design movement has long made a fetish of information. As science has found, life relies on encoded information for its genetic inheritance and the reliable expression of its physical manifestations. The ID proposition is, quite simply, that all this information could not have developed out of a mindless process, but only through "design" by a conscious being. Evidently, Darwinian natural selection still sticks on some people's craw. Michael Behe even developed a pseudo-mathematical theory about how, yes, genes could be copied mindlessly, but new genes could never be conjured out of nothing, due to ... information.

My understanding of information science equates information to loss of entropy, and expresses a minimal cost of the energy needed to create, compute or transmit information- that is, the Shannon limits. A quite different concept comes from physics, in the form of information conservation in places like black holes. This form of information is really the implicit information of the wave functions and states of physical matter, not anything encoded or transmitted in the sense of biology or communication. Physical state information may be indestructable (and un-create-able) on this principle, but coded information is an entirely different matter.

In a parody of scientific discussion, intelligent design proponents are hosted by the once-respectable Hoover Institution for a discussion about, well, god.

So the fecundity that life shows in creating new genes out of existing genes, (duplications), and even making whole-chromosome or whole-genome duplications, has long been a problem for creationists. Energetically, it is easy to explain as a mere side-effect of having plenty of energy to work with, combined with error-prone methods of replication. But creationistically, god must come into play somewhere, right? Perhaps it comes into play in the creation of really new genes, like those that arise from nothing, such as at the origin of life?

A recent paper discussed genes in humans that have over our recent evolutionary history arisen from essentially nothing. It drew on prior work in yeast that elegantly laid out a spectrum or life cycle of genes, from birth to death. It turns out that there is an active literature on the birth of genes, which shows that, just like duplication processes, it is entirely natural for genes to develop out of humble, junky precursors. And no information theory needs to be wheeled in to show that this is possible.

Yeast provides the tools to study novel genes in some detail, with rich genetics and lots of sequenced relatives, near and far. Here is portrayed a general life cycle of a gene, from birth out of non-gene DNA sequences (left) into the key step of translation, and on to a subject of normal natural selection ("Exposed") for some function. But if that function decays or is replaced, the gene may also die, by mutation, becoming a pseudogene, and eventually just some more genomic junk.

The death of genes is quite well understood. The databases are full of "pseudogenes" that are very similar to active genes, but are disabled for some reason, such as a truncation somewhere or loss of reading frame due to a point mutation or splicing mutation. Their annotation status is dynamic, as they are sometimes later found to be active after all, under obscure conditions or to some low level. Our genomes are also full of transposons and retroviruses that have died in this fashion, by mutation.

Duplications are also well-understood, some of which have over evolutionary time given rise to huge families of related proteins, such as kinases, odorant receptors, or zinc-finger transcription factors. But the hunt for genes that have developed out of non-gene materials is a relatively new area, due to its technical difficulty. Genome annotators were originally content to pay attention to genes that coded for a hundred amino acids or more, and ignore everything else. That became untenable when a huge variety of non-coding RNAs came on the scene. Also, occasional cases of very small genes that encoded proteins came up from work that found them by their functional effects.

As genome annotation progressed, it became apparent that, while a huge proportion of genes are conserved between species, (or members of families of related proteins), other genes had no relatives at all, and would never provide information by this highly convenient route of computer analysis. They are orphans, and must have either been so heavily mutated since divergence that their relationships have become unrecognizable, or have arisen recently (that is, since their evolutionary divergence from related species that are used for sequence comparison) from novel sources that provide no clue about their function. Finer analysis of ever more closely related species is often informative in these cases.

The recent paper on human novel genes makes the finer point that splicing and export from the nucleus constitute the major threshold between junk genes and "real" genes. Once an RNA gets out of the nucleus, any reading frame it may have will be translated and exposed to selection. So the acquisition of splicing signals is a key step, in their argument, to get a randomly expressed bit of RNA over the threshold.

A recent paper provided a remarkable example of novel gene origination. It uncovered a series of 74 human genes that are not shared with macaque, (which they took as their reference), have a clear path of origin from non-coding precursors, and some of which have significant biological effects on human development. They point to a gradual process whereby promiscuous transcription from the genome gave rise by chance to RNAs that acquired splice sites, which piped them into the nuclear export machinery and out to the cytoplasm. Once there, they could be translated, over whatever small coding region they might possess, after which selection could operate on their small protein products. A few appear to have gained enough function to encourage expansion of the coding region, resulting in growth of the gene and entrenchment as part of the developmental program.

Brain "organoids" grown from genetically manipulated human stem cells. On left is the control, in middle is where ENSG00000205704 was deleted, and on the right is where ENSG00000205704 is over-expressed. The result is very striking, as an evolutionarily momentous effect of a tiny and novel gene.

One gene, "ENSG00000205704" is shown as an example. Where in macaque, the genomic region corresponding to this gene encodes at best a non-coding RNA that is not exported from the nucleus, in humans it encodes a spliced and exported mRNA that encodes a protein of 107 amino acids. In humans it is also highly expressed in the brain, and when the researchers deleted it in embryonic stem cells and used those cells to grow "organoids", or clumps of brain-like tissue, the growth was significantly reduced by the knockout, and increased by the over-expression of this gene. What this gene does is completely unknown. Its sequence, not being related to anything else in human or other species, gives no clue. But it is a classic example of gene that arose from nothing to have what looks like a significant effect on human evolution. Does that somehow violate physics or math? Nothing could be farther from the truth.

• Will nuclear power get there?
• What the heck happened to Amazon shopping?

How Recessive is a Recessive Mutation?

Many relationships exist between mutation, copy number, and phenotype.

The traditional setup of Mendelian genetics is that an allele of a gene is either recessive or dominant. Blue eyes are recessive to brown eyes, for the simple reason that blue arises from the absence of an enzyme, due to a loss of function mutation. So having some of that enzyme, from even one "brown" copy of that gene, is dominant over the defective "blue" copy. You need two "blue" alleles to have blue eyes. This could be generalized to most genes, especially essential genes, where lacking both copies is lethal, while having one working copy will get you through, and cover for a defective copy. Most gene mutations are, by this model, recessive. 

But most loci and mutations implicated in disease don't really work like that. Some recent papers delved into the genetics of such mutations, and observed that their recessiveness was all over the map, a spectrum, really, of effects from fully recessive to dominant, with most in the middle ground. This is informative for clinical genetics, but also for evolutionary studies, suggesting that evolution is not, after all, blind to the majority of mutations, which are mostly deleterious, exist most of the time in the haploid (one-copy) state, and would be wholly recessive by the usual assumption.

The first paper describes a large study over the Finnish population, which benefited from several advantages. Finns have a good health system with thorough records which are housed in a national biobank. The study used 177,000 health records and 83,000 variants in coding regions of genes collected from sequencing studies. Second, the Finnish population is relatively small and has experienced bottlenecks from smaller founding populations, which amplifies the prevalence of variants that those founders had. That allows those variants to rise to higher rates of appearance, especially in the homozygous state, which generally causes more noticeable disease phenotypes. Both the detectability and the statistics were powered by this higher incidence of some deleterious mutations (while others, naturally, would have been more rare than the world-wide average, or absent altogether).

Thirdly, the authors emphasize that they searched for various levels of recessive effect, which is contrary to the usual practice of just assuming a linear effect. A linear model says that one copy of a mutation has half the effect of two copies- which is true sometimes, but not most of the time, especially in more typical cases of recessive effect where one copy has a good deal less effect, if not zero. Returning to eye color, if one looks in detail, there are many shades of eyes, even of blue eyes, so it is evident that the alleles that affect eye color are various, and express to different degrees (have various penetrance, in the parlance). While complete recessiveness happens frequently, it is not the most common case, since we generally do not routinely express excess amounts of proteins from our genes, making loss of one copy noticeable most of the time, to some degree. This is why the lack of a whole chromosome, or an excess of a whole chromosome, has generally devastating consequences. Trisomies in only three chromosomes are viable (that is, not lethal), and confer various severe syndromes.

A population proportion plot vs age of disease diagnosis for three different diseases and an associated genetic variant. In blue is the normal ("wild-type") case, in yellow is the heterozygote, and in red the homozygote with two variant alleles. For "b", the total lack of XPA causes skin cancer with juvenile onset, and the homozygotic case is not shown. The Finnish data allowed detection of rather small recessive effects from variations that are common in that population. For instanace, "a" shows the barely discernable advancement of age of diagnosis for a disease (hearing loss) that in the homozygotic state is universal by age 10, caused by mutations in GJB2.

The second paper looked more directly at the fitness cost of variations over large populations, in the heterozygous state. They looked at loss-of-function (LOF) mutations of over 17,000 genes, studying their rate of appearance and loss from human populations, as well as in pedigrees. These rates were turned, by a modeling system, into fitness costs, which are stated in percentage terms, vs wild type. A fitness cost of 1% is pretty mild, (though highly significant over longer evolutionary time), while a fitness cost of 10% is quite severe, and one of 100% is immediately lethal and would never be observed in the population. For example, a mutation that is seen rarely, and in pedigrees only persists for a couple of generations, implies a fitness cost of over 10%.

They come up with a parameter "hs", which is the fitness cost "s" of losing both copies of a gene, multiplied by "h", a measure of the dominance of the mutation in a single copy.

In these graphs, human genes are stacked up in the Y axis sorted by their computed "hs" fitness cost in the heterozygous state. Error bars are in blue, showing that this is naturally a rather error-prone exercise of estimation. But what is significant is that most genes are somewhere on the spectrum, with very few having negligible effects, (bottom), and many having highly significant effects (top). Genes on the X chromosome are naturally skewed to much higher significance when mutated, since in males there is no other copy, and even in females, one X chromosome is (randomly) inactivated to provide dosage compensation- that is, to match the male dosage of production of X genes- which results in much higher penetrance for females as well.

So the bottom line is that while diploidy helps to hide alot of variation in sexual organisms, and in humans in particular, it does not hide it completely. We are each estimated to receive, at birth, about 70 new mutations, of which 1/1000 are the kind of total loss of gene function studied here. This work then estimates that 20% of those mutations have a severe fitness effect of >10%, meaning that about one in seventy zygotes carry such a new mutation, not counting what it has inherited from its parents, and will suffer ill effects immediately, even though it has a wild-type copy of that gene as well.

Humans, as other organisms, have a large mutational load that is constantly under surveillance by natural selection. The fact that severe mutations routinely still have significant effects in the heterozygous state is both good and bad news. Good in the sense that natural selection has more to work with and can gradually whittle down on their frequency without necessarily waiting for the chance of two meeting in an unfortunate homozygous state. But bad in the sense that it adds to our overall phenotypic variation and health difficulties a whole new set of deficiencies that, while individually and typically minor, are also legion.

• Psychological projection, to the max.
• And another murder.
• Next up, book burnings.
• Medicare advantage is a corrupt disaster.
• Corporate health insurance says no.