Key Gene Associated With Hominin Leap ID'd

What is it that makes humans different from other extant primates?

A new study points the finger at a small number of genes associated with brain development which are also have some connections to common developmental disorders and mental health conditions, and in particular to a gene called SRGAP2 which is one of the several dozen genes that seem to be most plausible candidates for genes that distinguish hominins from other great apes.

[L]oss of SRGAP2 function accelerates neurons' migration in the developing brain, potentially helping them reach their final destination more efficiently. Moreover, neurons that have decreased SRGAP2 function, due to expression of the human-specific SRGAP2 display more knob-like extensions or spines on their surfaces, making the neurons appear much more like those found in the human brain. These spines enable connections between neurons to form.

The authors of the study think the effect of this mutation would have been dramatic as soon as it emerged.  "If this gene duplication did indeed produce an immediate effect during evolution . . . there must have been a fascinating period in human history characterized by "huge variation" in human cognition and behavior." 

Brain Parasites That Affect Dopamine Found In 2/9th of Americans

[I]nfection by the brain parasite Toxoplasma gondii, found in 10-20 per cent of the UK's population, directly affects the production of dopamine, a key chemical messenger in the brain. . . . Toxoplasmosis, which is transmitted via cat faeces (found on unwashed vegetables) and raw or undercooked infected meat, is relatively common, with 10-20% of the UK population and 22% of the US population estimated to carry the parasite as cysts. Most people with the parasite are healthy, but for those who are immune-suppressed -- and particularly for pregnant women -- there are significant health risks that can occasionally be fatal.

The parasite infects the brain by forming a cyst within its cells and produces an enzyme called tyrosine hydroxylase, which is needed to make dopamine. Dopamine's role in mood, sociability, attention, motivation and sleep patterns are well documented and schizophrenia has long been associated with dopamine, which is the target of all current schizophrenia drugs on the market.

From here.

The role of dopamine in ADHD and schizophrenia is discussed here.

I certainly admit to being absolutely shocked to discover that there is any brain parasite in human beings that can impact an important brain subsystem with observable effects is anywhere near as common as Toxoplasma gondii. It brings to mind a subplot of some of Isaac Asimov's Foundation series in which a communicable disease affecting the brain is intentionally employed to prevent humanity from making certain kinds of scientific progress.

Usually the brain is unusually free of outside agents because the brain-blood barrier does a better job of keeping these agents out than the systems that protect the rest of the body. But, these cysts somehow manage to cross that barrier.

I would very much like to know if there are other common brain parasites out there, what percentage of carriers of this parasite suffer any symptoms from it, and what kind of diagnosis and treatment regimes are out there to deal with it. Even a quite low percentage of cases that are symptomatic could conceivably account for a quite high percentage of dopamine related conditions that do not have a clear genetic basis, and if I've never heard of it, the odds that it is not widely considered as a possibility by mental health professionals is substantial. This kind of causation suggests a very different treatment regime than the default assumption in mental health circles that a condition is congenital. More here (from 2007).

Dementia Deadly?

Nearly 4,000 people between the ages of 60 to 102 years, initially seen from 1991 to 1993 by primary care physicians at Wishard Health Services, a large public hospital with community health centers in Indianapolis, participated in the study. The patients were followed for 13 years. . . . The study followed 3,957 patients. At screening, 3,157 had no cognitive impairment, 533 had mild impairment, and 267 had moderate to severe impairment. During follow-up, 57 percent of patients with no impairment died, compared with 68 percent of those with mild impairment and 79 percent of those with moderate to severe impairment. Median survival time was 138 months for patients with no impairment, 106 months for those with mild impairment, and 63 months for those with moderate to severe impairment.

Study participants were screened for cognitive impairment using an easy-to-administer 10-question mental status questionnaire. On the basis of the number of errors patients made on this test, they were categorized as having no, mild, or moderate to severe cognitive impairment. . . .  Cognitive impairment affects memory and thinking. Approximately 4 million to 5 million people in the United States have dementia, and the number of individuals affected is significantly higher if individuals with milder forms of cognitive impairment are included.

From here.

Cause and effect aren't necessarily easy to separate here because dementia is a well documented consequence of the aging process and the aging process also tends to bring a parade of horribles. It might be partially accurate to see the onset of dementia as a general indicator of the extent to which a person is suffering from geriatric disorders, although there are certainly many ways that cognitive impairment can causally lead to bodily harm.

Rare Gene Variants And Genetic Conditions

An important class of genetic conditions are caused by myriad rare genetic mutations that may emerge for the first time when the person who has it is born, or may be limited to small extended lineages or fairly small populations, rather than to all of humanity.

A small number of rare genetic mutations are produced in each new generation. Advanced parental age and environmental exposures and stresses can increase their frequency, the absence of these factors can reduce their frequency.

The most harmful of these rare genetic mutations are never passed on in the gene pool because they produce miscarriages or cognenital defects that cause someone to die before reproducing or to be infertile or both. Others appear where they are mostly harmless, for example in an inactivated gene or one triggered by environmental conditions that are absent (e.g. a gene that weakens ability to handle thin oxygen at high altitude in someone who lives on a flat Pacific island), and are passed on from generation to generation as little more than evolutionarily neutral ancestry informative markers.

Certain genes are more sensitive to disruption than others. The most sensitive genes code intricate biological processes that call upon many genes to work together to function properly which can be interrupted by defects in that biological system at a great many different points. Thus, interruptions to the same system at any of these different points is going to appear phenotypically as a similar syndrome associated with the overall complex biological system's failure to work properly due to some rare genetic variant.

Autism and schizophrenia are two of many conditions that seem to fit the profile of having overwhelmingly genetic causes that act on the same or interrelated groups of biological systems in a personn causing phenomenologically similar symptoms, but in which the specific mutations that cause the syndrome vary almost as widely as the number of extended families that have cases of it.

These genetic syndromes (as noted by my source linked above) adhere to "the “Anna Karenina principle”, based on Tolstoy’s famous opening line:
“Happy families are all alike; every unhappy family is unhappy in its own way”, people without these syndromes are are alike in the relevant genes (or least exhibit a handful of common variations in those genes); people with these syndromes all differ from this fixed standard in their own way.

These conditions can be among the most severely impairing of genetic conditions, because they rely for a substantial share of their prevalance on new mutations at each generation rather than Mendelin inheritance from parents. They don't have to be fitness enhancing to endure.

In contrast, genetic conditions whose prevalance relies on the precisely same mutation being passed on from parent to child need to either be genetic fitness neutral, or genetic fitness enhancing (at least at a long run multi-generational, extended familiy level of analysis), or the genetic fitness disadvantage nature of the mutation will cause its frequency in the population to decline unless other unrelated genetic fitness boosts cause the individual's population to expand notwithstanding its other faults.

The prevalance of these conditions is a product of mutation rates per generation and the proportion of the genome that constitutes a target area that would induce these conditions if a random mutation of some type arose there. The larger the group of genes required to code a biological function, the more vulnerable it is to this kind of condition. Given the extremely complexity of the brain relative to that of the brains of most other animals, and relative to many other parts of our bodies, it isn't too surprising that many of these rare gene variant disruptions of complex systems conditions give rise to mental health conditions.

Even if every known sufferer from autism and schizophrenia and everyone who was a potential carrier of those conditions was removed from a sufficiently control population, that control population would develop new autistic and schizophrenic individuals in the very next generation and would in not many generations after that have the same prevalance of autism and schizophrenia as the source populations if environmental factors that impact mutation rates were held constant between the source and control populations.

Spontaneous v. Familial Inheritance As A Matter of Degree

Of course, Mendelin inheritance models and sponanteous rare genetic variant models are merely ideal types. Every Mendelin inherited genetic variant started at some point as a spontaneously arising rare genetic mutation. Every rare genetic variant that is passed on to at least one child has a Mendelin inheritance element.

Rare genetic variants that are dominant in expression get noticed and classified by the conditions they give rise to, and have negative fitness effects, are going to have predominantly sporadic rather than familial prevalance patterns even though they are genetic.

Recessive rare genetic variants considered

Rare genetic variants that are recessive in expression are invisible until (1) inbreeding causes someone to have two copies of the recessive gene, probably many generations later, (2) someone who has already inherited a recessive gene from a parent spontaneously has a germline mutation in the same gene from another parent (either the same, or a functionally equivalent version), or (3) two independent lineages each have mutations in the same gene (possibly many generations apart from each other) in a manner that are recessive in effect and admixture of those lineages gives rise to an individual who expresses the recessive gene variant's effect.

Given the fairly modest number of mutations per generation (IIRC about 2500) out of 3 billion genetic bases in an individual's genome, method (1), or method (3) with different versions of the recessive mutation that have the same effect, are likely to be much more common than the alternatives and from the point of view of an individual born with a recessive genetic condition it is almost always going to look like a predominantly Mendelin inheritance based genetic condition.

The odds of one novel germ line mutation from a father and one novel germline mutation from a mother of the same recessive mutation in the same gene arising at the same time in the same individual is almost nil unless it is the product of intentional manipulation or a highly targeted environmental effect (e.g. lateral gene transfer as a result of a shared germ line retroviral infection, or an environmental effect that only impacts the very end point of a chromosome for chemical geometry reasons of some kind). There is some circumstantial evidence that a retrovirus carried by a seasonal germ vector like lice may account for the seasons variation in schizophrenia (and perhaps also autism) prevalence.

Also, recessive conditions, as a result, are likely to start somewhere and see their prevalance slowly grow in a particular reproductive population due to population expansion and founder effects, or due to major selective advantages associated with them, rather than having the more random, generally global prevalance one expects in syndroms caused by rare genetic variants that influence complex biological systems that have themselves reached fixation or near fixation on a species or population.

Tell Tale Symptoms Of New Mutation Rare Gene Variant Syndromes

Strongly hereditary conditions that show similar prevalance in all global populations, like schizophrenia, are more likely to be dominant genetic conditions caused to a great extent by new rare gene variant mutations in large complex biological systems, while strongly hereditary conditions that show major frequency variations between different populations are more likely to be associated with Mendelin recessive genes.

Rare gene variants that are fitness enhancing in almost all circumstances, in contrast, whether dominant additive, or recessive, such as new mutations that enhance intelligence, should have strongly familial inheritance patterns. Every time one of these arises, it should tend to stay in the genome and should tend to stall on the road to fixation only if it interfers with some other fitness enhancing gene (perhaps either gene individually changes brain chemistry in a positive way but the presence of both genes at the same time has no effect or a negative effect) or has other negative side effects (e.g. an enhancement of connective tissue development that fosters brain connectivity but also increases the risk at any given point in life of developing connective tissue cancer, a scenario that has been proposed as a hypothetical basis for the fairly rapid spread of one of the breast cancer risk genes).

Schizophrenia Causation Better Understood

About 80% of schizophrenia cases are estimated to be hereditary. The other 20% of cases are sporadic, not having an apparent familial cause.

A new study suggests that at least half of sporadic cases are attributable to genetic mutations that arise for the first time in them and are not present in their parents, something that tends to have an elevated frequency in children with older fathers (the risk factor is called advanced paternal age).

Thus, at least 90% of schizophrenia cases are genetic, even though just 80% are hereditary. Evidence has also pointed to seasonal tick infections around the start of a pregnancy, low vitamin D levels during pregnancy, and rare recessive genes of inbred individuals as possible causes of sporadic schizophrenia.

This combined pattern of causes make schizophrenia makes its causes better understood than almost any other mental health condition, which is appropriate because schizophrenia is quite common, with about 2.2 million Americans affected.

Adventures In Chemicals The Affect The Brain And Seasonal Birth Effects

I've abstracted a hodgepodge of interesting new research studies on the impact of chemicals and birthdays on mental health.  We a finally reaching the frontier where the actual biological mechanism behind mental health conditions long believed to have a biological basis are understood in a meaningful fashion with clinical applications.

Cortisol hormone response patterns linked to temperament in toddlers

Cortisol responses to stress in toddlers reflect their temperaments and may also have significant environmental responses. Personality traits which otherwise seem to have only suggestive oppositions to each other seem to have a biological root as different dimensions of cortisol responses to stress. In particular, anxiety and depression may be the opposite side of the coin the same trait that at the other extreme may be associated with ADHD. It wouldn't overstate the matter to infer that the Big Five personality trait conscientiousness may also be linked to this tendency that is present in very early childhood.

Is your kid a "dove" -- cautious and submissive when confronting new environments, or perhaps you have a "hawk" -- bold and assertive in unfamiliar settings? . . .

Children exposed to high levels of interparental aggression at home showed different reactions to [a staged] telephone quarrel. Doves with parents who fought violently produced elevated levels of cortisol, a hormone that is thought to increase a person's sensitivity to stress. Hawks from such stressful home environments put the breaks on cortisol production, which is regarded as a marker for diminishing experiences of danger and alarm.

Heightened cortisol levels characteristic of the doves were related to lower attention problems but also put them at risk for developing anxiety and depression over time. By contrast, the lower cortisol levels for hawks in aggressive families were associated with lower anxiety problems; however, at the same time, these children were more prone to risky behavior, including attention and hyperactivity problems.

Previous research has focused more on neurotransmitters and general stimulants in these conditions.

Dopamine flows from anticipation of reward, not the reward itself.

The treatment of psychiatric conditions like depression or schizophrenia often revolves around regulating monoamine neurotransmitters like serotonin, norepinephrine and dopamine.

Dopamine is an important neurotransmitter that functions in a lot of behaviors and reactions, such as movement, lactation, aggression, fear, etc. In diseases like Parkinson, dopamine levels lower and movement becomes uncontrolled. In other diseases like schizophrenia, either dopamine levels are high or response to dopamine is higher, and paranoia & hallucinations manifest. Treating schizophrenia involves blocking dopamine receptors. As you can imagine, a common side effect of antipsychotics is movement disorders — or Parkinsonism. . . .

Our cultural and behavioral predisopostions ultimately boil down to chemicals in our brain interacting and stimulating other areas. One of the most important functions of dopamine is in the reward system of the brain, an area called the nucleus accumbens that primes pleasurable behavior to repeat, such as sex, eating, and drugs. . . .

Robert Sapolsky of Stanford Neurology makes the distinction between how dopamine levels rise in the anticipation of pleasure and not as a response to pleasure.

From here.

Drug Addition Linked To Salt Appetite System

[T]he gene patterns activated by stimulating an instinctive behavior, salt appetite, [a]re the same groups of genes regulated by cocaine or opiate (such as heroin) addiction.

"[B]locking addiction-related pathways . . . powerfully interfere[s] with sodium appetite. . . . [The] findings . . . could lead to a new understanding of addictions and the detrimental consequences when obesity-generating foods are overloaded with sodium. . . . Though instincts like salt appetite are basically genetic neural programs, they may be substantially changed by learning and cognition . . . Once the genetic program is operating, experiences that are part of the execution of the program become embodied in the overall patterns of an individual's behavior, and some scientists have theorized that drug addiction may use nerve pathways of instinct. . . . one classic instinct, the hunger for salt, is providing neural organization that subserves addiction to opiates and cocaine."

From here.

Ketamine Has Different Roles At Different Doses

Ketamine is finding new applications in both legal and illegal applications.

The anesthetic ketamine works against depression by quickly boosting levels of a brain compound that has been linked to the condition . . . [which] may lead to highly effective and fast-acting antidepressants that provide relief within hours instead of weeks. . . . Traditional antidepressants can be effective but often take weeks or months to improve symptoms. . . . “Here is increasing evidence that you can go more directly at the target, and that’s maybe why you get more of a rapid antidepressant effect.”

Mice receiving a single injection of ketamine showed fewer signs of depression just half an hour after the shot, and they continued to show multiple signs of reduced depression for a week. . . .

At high doses, ketamine renders a person unconscious. At lower doses, the drug can induce euphoria, hallucinations and out-of-body experiences, properties that make “Special K” a popular drug of abuse. . . . the study . . . used low doses that wouldn’t induce psychotic effects.

They found that ketamine kicks off a series of biochemical changes in the brain that culminate in the production of a protein called BDNF. Low BDNF levels have been linked to depression. . . . mice genetically engineered to be unable to produce BDNF didn’t respond to ketamine.

From here.

A small trial reported in 2010 found Ketamine to be safe and effective in treating treatment-resistant bipolar patients, suggesting that it acts on a different mechanism than existing depression treatments. Unlike traditional anti-depressants, whose efficacy has been seriously questioned as being little more than placebo effect in a significant class of patients treated with them, Ketamine's effect is so rapid and pronounced that its short term effectiveness is beyond question, although its tendency to be associated with mild psychiotic side effects is a concern.

British drug enforcement authorities have seen increased abuse of ketamine:

Once seen as a drug exclusively for the rave and dance scene, its popularity is now growing among Britain's middle-class users due to its price – a gram of ketamine costs £20, half as much as the same amount of cocaine – and the fact that it is seen as a "safe" and "clean" drug. . .

a survey carried out by Professor David Nutt, the chairman of the Government's drug advisory panel, ranks the class C drug as the sixth most dangerous illegal drug available – more harmful than Ecstasy and cannabis. The mistaken belief that the substance is risk-free is encouraging more young people to try ketamine and to take it in increasingly higher doses. . . . it can cause heart or lung failure and point to the fact that it has been linked to 23 deaths between 1993 and 2006. In 2006 it was classified as a class C drug [in the U.K.] . . . the drug, which can be snorted, swallowed, injected and even smoked, . . . [had] an estimated 60,000 users [in the U.K.] between 1998 and 2000 . . . [and] about 113,000 in 2008. . . .

Originally used to treat injured soldiers in Vietnam, ketamine is most commonly used now as a horse tranquilliser. It has also been experimented with to treat depression and alcohol and heroin addiction. It was classified as an illegal drug in 2006 by the UK Government. It is usually sold in powder or liquid form for about £20 per gram. Unlike cocaine and heroin, it is not physically addictive, but, like cannabis and Ecstasy, it is psychologically addictive.

David first tried ketamine as a 20-year-old student at university in London. Now a 27-year-old marketing executive, living in Shoreditch, east London, he still takes the drug once a month. "I see it as a fun, sociable drug," he said. "I do it at house parties or if I'm having a big night out. I used to do cocaine, but I suppose I gradually replaced coke with ket. Coke is much more expensive and it generally makes everyone very loud and aggressive. Ket is different. It costs less and you use it in smaller quantities so it lasts a lot longer. The feeling you get is different too. It makes you feel anaesthetised to your worries. You forget about your normal life and everything is euphoric. Sometimes I've had bad trips, but I've never felt angry when on ketamine. I think it is a lot safer too. I've read it can have long-term effects on your health, but it doesn't seem as dangerous as cocaine. When on coke I used to feel my heart pounding and it didn't feel right. The other reason I changed is because of the classification. I've got a proper job and a career and I don't want to lose that. Ketamine is a class C drug so if I get caught I'm probably only going to get a slap on the wrist."

Hallucinating Computers

Efforts to create neural network computer models of the brain's circuits for processing language in an effort to understand schizophrenic auditory hallucinations have managed to reproduce the phenomena of coherent auditory hallucinations (i.e. hearing voices) by both of two different mechanisms suspected to be a work in this phenomena in the real world.

Hearing voices is a hallmark of schizophrenia and other psychotic disorders, occurring in 60-80% of cases. These voices are typically identified as belonging to other people and may be voicing the person’s thoughts, commenting on their actions or ideas, arguing with each other or telling the person to do something. Importantly, these auditory hallucinations are as subjectively real as any external voices. They may in many cases be critical or abusive and are often highly distressing to the sufferer.

However, many perfectly healthy people also regularly hear voices – as many as 1 in 25 according to some studies, and in most cases these experiences are perfectly benign. In fact, we all hear voices “belonging to other people” when we dream – we can converse with these voices, waiting for their responses as if they were derived from external agents. Of course, these percepts are actually generated by the activity of our own brain, but how?

The two different models that were both supported in the computerized neural network were as follows:

There are two major hypotheses that were modelled: the first is that networks in schizophrenia are “over-pruned”. This fits with a lot of observations, including neuroimaging data showing reduced connectivity in the brains of people suffering with schizophrenia. It also fits with the age of onset of the florid expression of this disorder, which is usually in the late teens to early twenties. This corresponds to a period of brain maturation characterised by an intense burst of pruning of synapses – the connections between neurons.

In schizophrenia, the network may have fewer synapses to begin with, but not so few that it doesn’t work well. This may however make it vulnerable to this process of maturation, which may reduce its functionality below a critical threshold. Alternatively, the process of synaptic pruning may be overactive in schizophrenia, damaging a previously normal network. (The evidence favours earlier disruptions).

The second model involves differences in the level of dopamine signalling in these circuits. Dopamine is a neuromodulator – it alters how neurons respond to other signals – and is a key component of active perception. It plays a particular role in signalling whether inputs match top-down expectations derived from our learned experience of the world. There is a wealth of evidence implicating dopamine signalling abnormalities in schizophrenia, particularly in active psychosis. Whether these abnormalities are (i) the primary cause of the disease, (ii) a secondary mechanism causing specific symptoms (like psychosis), or (iii) the brain attempting to compensate for other changes is not clear.

Birth Season Effects On Mental Health

A causal mechanism isn't obvious, but some mental health conditions so seasonal effects.

Anorexia nervosa is more common among people born in the spring. . . . [Researchers] found an excess of anorexia births between March and June, and a deficit from September to October. . . . A number of previous studies have found that mental illnesses such as schizophrenia, bipolar disorder and major depression are more common among those born in the spring -- so this finding in anorexia is perhaps not surprising. . . .researchers believe that environmental factors around the time of conception or when the baby is developing in the womb may be responsible. . . . Seasonal changes in temperature, sunlight exposure and vitamin D levels, maternal nutrition and exposure to infections are all possible risk factors. Identifying these risk factors is important in helping us understand and maybe even prevent illness in future.

Meanwhile:

An examination of the birth records of the more than 7 million children born in the state of California during the 1990s and early 2000s has found a clear link between the month in which a child is conceived and the risk of that child later receiving a diagnosis of autism." The risk of having a child with an autism spectrum disorder grew progressively throughout the fall and winter to early spring, with children conceived in March having a 16 percent greater risk of later autism diagnoses, when compared with July conceptions.

The researchers said the finding suggests that environmental factors, for example, exposure to seasonal viruses like influenza, might play a role in the greater risk they found of children conceived during the winter having autism.

"The study finding was pronounced even after adjusting for factors such as maternal education, race /ethnicity, and the child's year of conception." . . . Each month was compared with July, with an 8 percent higher incidence in December, increasing to 16 percent higher in March.

The study lacked the means to discern if conception or some later point in pregnancy was the source of the vulnerability.

When Is a Genetic Condition Not Hereditary?

Normally, people think of genetic conditions and hereditary conditions as identical. But, this isn't necessarily so. There are two main ways that someone can end up with genes that do not come from their parents.

First, there can be a mutation in a germline cell (i.e. a sperm or egg) that is not present in the rest of the genome of the parent. This is the mechanism suspected in almost all congenital conditions that are associated with advanced paternal age (i.e. with old fathers).

Second, a retrovirus can infect a person and change their genome during their life. These kinds of viruses are rare, but not unknown and their existence is fundamental to almost all proposed gene therapies, something done routinely in lab rats but only a few times on a therapeutic clinical basis in human subjects.

The distinction is important in interpreting a recent study of autistic twins in in California and receiving developmental disability assistance from the state that purport to show about 55% of autism is attributable to shared environment, rather than to hereditary causes or non-shared environment. Previous studies had suggested that autism was 90%+ genetic.

If there really is a large shared environment effect, it is probably a neo-natal environmental exposure situation, perhaps, for example, due mostly to pregnant women taking SSRI drugs. But, genetic factors like first generation germline cell mutations attributable to advanced paternal age and possibly also to the environmental exposures that the father has received would look mostly like a shared environment effect in the simple heredity analysis used in twin studies.

This method of analysis ignores first generation germline mutations, which is often a sensible thing to do, but is probably not appropriate in the case of conditions where there is an epidemiology that shows a strong advanced paternal age effect. Most serious dominant gene developmental disorders are probably predominantly due to first generation germline mutations, so excluding that possibility in a twin study analyzing autism causation is probably not reasonable.

The emerging consensus model of autism causation sees this syndrome as being caused by mutations in any of a very large number of genes (perhaps hundreds) that must all be perfectly in harmony to carry out the part of brain function that is atypical in autism, but can be mitigated if one or more "protective" genes are present (possibly an X-chromosome linked gene that could account for the differing rates of autism in boys and girls, since boys are less likely to have at least one copy of the protective X-linked gene).

In this model, most autism cases arise from first generation dominant gene germline mutations, and a minority of cases arise from inheritance from a parent who may be a carrier due to the presence of a protective gene that silences or mitigates the effect of the germline mutation that person received. The relative number of inherited and first generation mutations can be inferred by the extent to which advanced paternal age is a risk factor in autism.