Until fairly recently in human history, the brain’s function was misunderstood. Many humans associated emotions and thoughts with the heart, as is evident on Valentine’s day, even today. Many argued that thought could never be explained by any physical organ but required the action of spirit. We now know that the brain is a biological organ where sensations are detected, motor commands are generated, memories are stored, and where our emotions are determined. In the past, many argued that a material organ could never be capable of determining what they viewed to be supernatural attributes of the soul.

In the study of patients who have suffered a stroke, it is clear that damage to a certain area of the brain. Strokes in specific areas can cause personality changes (frontal lobe), emotional changes (limbic system), the loss of motor control in a body region (the motor cortex), loss of sensation in a body region (somatasensory cortex), the loss of the ability to understand speech (gnostic area), etc. Some strokes have resulted in a variety of odd effects in patients:

--hemineglect: (esp. strokes in right parietal lobe) indifference to left side of visual field: shave or apply makeup to right side only, leave left arm out of sleeve

--difficulty in naming objects (stroke in temporal lobes)

--finger agnosia: can’t name the finger you point to

--dyscalculia: problems with obvious math problems although understanding of math (place value, etc.) left unaffected

--mirror agnosia: patients try to reach for images in mirror

--anosognosia (esp. after right hemisphere damage): unaware of illness--left side is paralyzed and the patient is unaware (may even make excuses “I’ve never been ambidexterous”, --someone put a cadaver’s arm in my bed@)

--Capgras’s syndrome: the feeling that close relatives are imposters (perhaps because no emotions are felt with reference to these people only; one patient killed his father thinking he was an android and opened his skull looking for the microchip)

--fregoli: patient sees the same face everywhere

--Cotard’s syndrome: patient asserts that they are dead (perhaps no longer feel any emotion)

--epileptic seizures in temporal lobe can cause intense spiritual experiences during the seizure; leads to “temporal lobe personality”--heightened emotions and great significance attached to trivial events, humorless, decreased sexual desire, often maintain extensive diaries

--some areas of temporal lobe can cause preoccupation with sex




In many ways, the debate over “nature” vs. “nurture” is silly given how intimately the two can interact with each other. However, there are a few points which would be useful to make before pursuing this issue.

1) Brain Regions are involved in Behavior

Thought, behavior, emotions, etc. occur in the brain. Damage to the brain affects these mental activities as do changing levels of hormones, neurotransmitters, or the use of drugs which alter hormone and neurotransmitter levels. In that sense, thought, emotions, and personality are biological phenomena. But what makes one brain’s activity different from that of another’s? What controls neurotransmitter release? Nature? Nurture?


2) What do you mean by Nature? Genes or the Biological Tissues of the Brain?

  • Genes

Can genes determine behavior and personality? The effect of genes is obvious in abnormal cases since there are genes which cause behavioral disorders.

--Alzheimers Disease: 4 genes known to be involved: beta APP (amyloid precursor protein; chr 21), apolipoprotein E (chr 19), Presenilin 1 (chr 14), Presenilin 2 (chr 1)

--Lesch-Nyhan syndrome--symptoms include self mutilation (children bite off pieces of fingers, lips, and cheeks)


--manic depression: MAFD2

--narcolepsy: a gene for a human leukocyte antigen (HLA DQB1*0602) involved; possibly an autoimmune disease

--familial insomnia: prion protein gene on chromosome 20; mutations may make the protein protease resistant (mutations in codons 178 and 200 can cause either familial insomnia or the Creutzfeldt-Jakob dementia; a mutation at codon 129 determines which of the two disorders results)

--Williams Syndrome: a small deletion on chromosome 7 (7q11.32) produces mild retardation with deficits primarily in visual spatial relationships; affected individuals are friendly, social, empathetic, and some have extraordinary music ability

--Tourettes syndrome: motor and vocal tics; often frequent outbursts of obscenities

-- Huntington disease: HD

--psychosis: PPMX

--Parkinson disease: PRKN, SNCA, PARK3, PPND

--Prader-Willi syndrome: NDN, SNRPN, PWCR

--schizophrenia: SCZD1, SCZD4, APP, CHRNA7, SCZD3, PENK, NTF3, HTR2A, APP, PRNP

--spastic paraplegia: L1CAM, PLP, SPG3A, SPG4, SPG5A, SPG6, PGN

--speech-language disorder: SPCH1


  • the Brain?

Autistic savants sometimes have mental abilities which are almost unbelievable. One calculated the cube root of a 6 figure number; one could double a 7 digit number 24 times in several seconds; one blind boy incapable of tying shoes could play any piece of music like a professional after one listen, some produce wonderful artwork as children, and one could give the exact time of day to the second without a clock (even mumbling in his sleep). Are genes responsible for autism? Although at some level, genes are responsible for virtually everything in the body, it may be the environment which changes which genes are active.

The brain’s activity is not only guided by its genetic makeup, but also by experience. Experience changes the structure and activity of the brain (nurture determines nature)and these changes then affect future interactions with the environment (more nurture). For example; drug abuse can alter neurotransmitter secretion patterns and the loss of limb causes a reorganization of neuronal projections onto the sensory cortex. In children, damage to the left hemisphere causes the right to take over the language capabilities and the commissures in children (but not adults) enlarge in response to a damaged corpus callosum to allow communication between hemispheres. One child even suffered the removal of his entire left hemisphere (due to deterioration) but later scored above average on intelligence tests, completed college and grad school, and became an executive even though half his skull is full of cerebrospinal fluid only.

It should be stressed that although a specific feature of the brain might be biological and involve genes, it is not necessarily an inherited condition.


3) Interaction between Nature and Nurture

Genes commonly interact with the environment before determining phenotype. Frequently the most important question is not whether a given feature is due to nature or nurture, but rather in what way have nature and nurture interacted to produce this phenotype. In the following examples, note that the genes do not determine the characteristics of the individual themselves: individuals in one environment would develop one way, while those in a different environment would develop a different way.

In humans, nutrition obviously affects final height and brain development, traits which are also affected by genetic makeup. The condition xeroderma pigmentosum can lead to skin cancer after sun exposure but humans who inherit this gene can, by staying out of the sun, prevent cancer.

All infants born in the U.S. are tested for phenylketonuria. If a child has this genetic disorder, there is an amino acid byproduct which they cannot break down. It accumulates to levels in their brain which will cause retardation. However, children who are placed on a special diet are normal.

The presence of certain DRD2 receptors may predispose an individual to a variety of addictions and genes affecting alcohol metabolism can predispose an individual to alcoholism. Obviously neither of these phenotypes will be displayed if the individual avoids alcohol and drugs.


4) Nature can Influence Nurture

Anxiety, temperament, harm-avoidance, risk-taking, shyness, sexuality, libido are not only aspects of personality which have a genetic component (nature), they also influence the life situations we later find ourselves in (nurture). For example, there may be a genetic component in determining the degree of colic in infants. What effect does extreme colic in a child have on parental interaction with the child? Can anyone say that parents would treat a happy child and a child who is always crying exactly the same? If not, then the environment of the child (nurture) will be influenced by his or her nature.


5) Nature and Nurture are difficult to study separately

Often the nature/nurture distinction is difficult since relatives often grow up in similar environments. For example, one study once concluded the following that if one individual is homosexual, the likelihood of an identical twin being homosexual is 52%, a fraternal twin 22%, and nonrelated adopted sibling of same age 11%. Does this answer the question as to whether sexuality is determined by genes or the environment? No. Not only does genetic relatedness decrease as one considers, identical twins, fraternal twins, and adopted siblings, the shared aspects of their environment might also decrease as well.



Nurture can determine nature, nature can determine nurture, nature and nurture must interact to produce some phenotypes, and the two are difficult to study separately. In studying behavior and the brain, some traits may have a strong genetic component while others primarily determined by the environment.



--A 1997 book raised an interesting question. There are many genes which interact with environmental variables to control height, producing a Bell curve of phenotypes. Even if only the upper 1% of the curve are called giants, there are individuals in the upper third of the distribution that have a number of the tall alleles and share some of the phenotype. Does this principle apply to personality traits?

--Is a sad personality a shadow form of depression?

--Is hypomania (over-elation) with its upswings and downswings a shadow form of bipolar disorder in which the swings can be devastating?

--Is intermittent rage disorder a shadow form of more psychotic forms of anger?

--Is hyperactivity in adults a shadow form of attention deficit disorder?

--Is a lifetime of being socially awkward a shadow form of autism?

If these personality traits are influenced by multiple genes, what would mild forms of these disorders look like? Would it ever be helpful to have a bit of the elation of mania or be a bit pessimistic as in depression or be not too slow to anger? What shadow syndromes might you have?



1) fetal environment

A number of factors can affect the development of a fetus’ brain during development such as alcohol, cocaine, lead, and toxic compounds of metabolism (i.e. in phenylketonuric women who aren’t sticking to their special diet). Fetal alcohol syndrome often includes lifelong brain abnormalities, including retardation. “Crack babies” undergo withdrawal and schools report them to be withdrawn, impulsive, and hyperactive. Events at birth can affect the fetal brain such as low oxygen (cocaine may also cause this).

2) hormones:

Similar fetuses exposed to different hormones will express different behaviors; some of these hormones may come from a maternal disorder, anabolic steroids or other medication, etc.

3) critical periods

Much of the nervous system is not “hard wired” but develops according to early inputs. For some traits, critical stimuli must occur during a certain developmental stage or else normal development can never be attained.

  • Vision: Covering an eye or leaving a crossed eye uncorrected during the first two years of life
  • Language: If language does not develop by a certain stage (often about age 6), it will never be normal. Some children have been raised in isolation (even as part of experiments: an Egyptian pharaoh wanted to determine if Egyptian was humanity’s innate language, a Scottish king had similar ideas about Hebrew). Children who gradually become deaf by the age of 2 but were exposed to language learn sign language more quickly than those deaf from birth.
  • Attachment: there is an optimal period shortly after birth in which a young animal attaches to a mother (or imprints on any figure in some species) if normal development is to occur afterwards.
  • Sexual differentiation: in 4 mammals studied (including rhesus monkey), there is a critical period for the effects of sex hormones on the brain. In children (and to a lesser degree in adults although women fare better than men) the brain retains plasticity: brain areas may compensate for damage in other areas and perform processing that they otherwise would not have.

4) infant care and beyond:

In mice, neurons are smaller and there are fewer glial cells when mice mature in solitary confinement; neurological development (and weight gain) is more rapid in animals (including human babies) that are handled. Unresponsive mothers may increase “insecure attachment” in their children (from human and primate studies) in which the young are less likely to explore a new environment and more easily frightened; secure attachment has been shown to promote social competence in toddlers. In sad cases where children have been raised in neglect, children are often withdrawn, frightened, even speechless; despite adoption, they may have permanent psychological scars. Monkeys raised in total isolation react aggressively to other monkeys; most were incapable of mating as adults; artificially impregnated females often neglectful, cruel, or even murderous of children; most abusive parents admit that they had also been abused.

The frequency of psychological disorders (e.g. depression, anxiety, post-traumatic distress disorder) increases after traumatic experiences such as a natural disaster, war, or a sexual assault.



These are examples of how nurture can become nature--the early environment of a child may guide brain development during critical periods and thus become hard wired in the brain.




While the messages which spread along a nerve cell electrical, the messages which pass from nerve cells to muscle cells, gland cells, or other nerve cells are chemical messages, transmitted by molecules called neurotransmitters and neuropeptides. These molecules would be useless as messengers if the cells receiving these messages did not have receptors for neurotransmitters and neuropeptides. G protein coupled receptors (GPCRs) are the receptors for most of these signals, and they mediate the signals of the nervous system which result in muscle contraction, hormone secretion, sensory awareness, emotions, memory, and personality.



The neurotransmitter dopamine is involved in the perception and pursuit of pleasure. It is involved in almost every type of addiction and dopamine treatment can decrease addiction. Its release increases sex drive, is a factor in orgasm, and may cause premature ejaculation. Higher than normal levels occur through cocaine use, sexual activity, periods of increased sexual receptivity, and in response to testosterone. Much of the feeling of euphoria associated with cocaine use results from the blocking of the reabsorption of dopamine. Since dopamine receptors are expressed in both the brain and on white blood cells, there may be a link between personality and immune function (Czermak, 2004).


There are a number of dopamine receptors (DRD1 through DRD5). Different alleles of these receptor genes affect a number of aspects of brain function ranging from neurological disorders to normal personality traits.


DRD1 receptors are expressed in the brain’s nucleus accumbens, caudate nucleus, and the olfactory tubercle and are also expressed in the ovary. Dopamine is used in the kidney to regulate sodium and DRD1 mutations can affect sodium transport (OMIM). The DRD1 gene is located in the region linked to bipolar disorder in some studies. Bipolar disorder affects about 1% of the population and dopamine signaling is affected by medications which treat bipolar disorder (Ni, 2002).



DRD2 alleles have been linked to schizophrenia, recurrent major depression, and adolescent emotional disorders. Some studies have found associations between certain alleles and alcoholism and Parkinson-like disorders. DRD2 receptors function in the coordination of movement and mutations may cause myoclonus dystonia. Some mutations in mice cause abnormalities similar to those observed in Parkinsons disease. In mice some mutations affect the response to morphine when used as a reward (but not other rewards such as food). Some antipsychotic drugs act by blocking DRD2.

The A1 allele of DRD2 is more common in those addicted to alcohol, cigarettes, opiates, and other substances and is associated with high novelty seeking and high harm avoidance (Berman, 2002). The Ser311Cys allele of DRD2 is more common in those with persecution delusional disorder (Morimoto, 2002). The density of DRD2 receptors in the striatum is correlated with the personality trait of detachment as are variants of the promoter which affect the density of receptors produced. Novelty seeking is associated with density of DRD2 receptors in the right insular cortex as is increased blood flow to this region (Jonsson, 2003).

Investigations into the contribution of DRD2 in schizophrenia have led to conflicting results, with some studies suggesting a link between DRD2 polymorphisms and the disorder. A polymorphism in a gene located 3’ to DRD2, named “X-kinase” is linked to schizophrenia (Dubertret, 2004). Different alleles of DRD2 seem to contribute to the difference in the effectiveness of medication which treats post-traumatic stress disorder (Lawford, 2003; Jonsson, 2003).

The first documentation of interaction between different alleles of a gene and the environment was the 2000 report that children with minor alleles of DRD2 had greater extraversion when living in an alcoholic home while the opposite was true of children with major alleles of DRD2 (Ozkaragoz, 2000).




DRD3 receptors are expressed in the limbic system and are involved in cognition, emotions, and hormone release. Drugs which treat Parkinsons disease and psychosis may act on DRD3 receptors. Increased expression of DRD3 receptors may be a factor in causing schizophrenia. Polymorphisms in DRD3 and DRD4 are linked to avoidant and obsessive personality traits (Joyce, 2003). Reduction in the density of D3 receptors is involved in antipsychotic treatment (Seretti, 2000). The DRD3 gene is highly concentrated in the parts of the limbic system associated with reward. It doesn’t seem to be involved in alcohol addiction (Gorwood, 2001). DRD3 polymorphisms linked to the trait of persistence (Czermak, 2004). The BalI polymorphism (which converts a serime to a glycine in condon 9 of the first exon of DRD3) is linked to schizophrenia (Petronis, 2000). Studies have linked the 102T/C polymorphism of DRD3 to schizophrenia with the C allele being more frequently found in schizophrenics (Petronis, 2000).



DRD4 receptors are expressed in the limbic system and affect cognition, emotions, and anger. This gene is one of the most variable human genes known with most of the variation occurring in exon 3. Different alleles of DRD4 are associated with scores on personality tests related to novelty seeking (high scores with novelty seeking are correlated with impulsive and exploratory behaviors; low scores are correlated with being stoic, loyal, and frugal). Increased expression of receptors may be a factor in schizophrenia and certain alleles may affect ADHD. Some mutations in humans affect the functioning of the autonomic nervous system and some mutations in mice affect activity levels and sensitivity to drugs (OMIM). Although DRD4 alleles were associated with variations in smoking prevalence in humans, this link was lost after controlling for novelty-seeking (Elovainio, 2004).

Several drugs used to treat schizophrenia act on DRD4 and analysis of the brains of schizophrenics indicates that DRD4 expression is higher in schizophrenics (Xing, 2003). A polymorphism upstream of the DRD4 region which may affect transcription rates is linked to schizophrenia. This may explain the inconsistent findings of polymorphisms within the gene contributing to schizophrenia (Xing, 2003).



DRD5 receptors are expressed in the cortex, dentate gyrus, hippocampus, and substantia nigra. There are a number of pseudogenes of DRD5, some of which are still transcribed in some tissues. One allele of DRD5 is associated with a disorder which affects the eye muscles known as plepharospasm (Misbahuddin, 2002). The human genome contains 2 DRD5 pseudogenes (Nguyen, 1991).





Epinephrine is not only a neurotransmitter, but it also functions as a hormone when released from the adrenal glands during the fight or flight response. Blood concentrations of neurepinephrine increase in ADHD. Some learning disabilities and some of the variations in NE receptors are correlated with ADHD, especially when accompanied with learning disabilities. Antidepressants such as Elavil prevent the reuptake of NE and serotonin form the synaptic cleft; prolonging their elevating effects. Some antihypertensive drugs act in the PNS, blocking NE's stimulation of smooth muscle by binding to NE receptors. Amphetamines resemble NE and dopamine which are used at pleasure center (OMIM).


GABA (gamma amino butyric acid)

GABA is the major inhibitory neurotransmitter of the vertebrate brain. More than a dozen genes code for the subunits which can be combined to form the receptor protein. GABA receptors interact with barbituates, ethanol, and benzodiapezine. Tranquilizers such as valium and librium bind to GABA receptors, enhancing its inhibitory effect (OMIM). GABA receptor polymorphisms have been linked to anxiety and the effects of alcoholism (Reif, 2003).


GABRA2 is expressed in the limbic system and it mediates the effects of anti-anxiety drugs.

GABRA5 is located in the region which is deleted in the Prader-Willi and Angelman syndromes and may be responsible for some of the effects of these disorders. One study correlated a CA repeat in this gene to bipolar disorder.


GABRB3 mutations have been linked to insomnia and autism.


GABRE is expressed in the brain, heart, and placenta and alternate splicing can produce tissue specific forms. Mutations may be involved in retardation and early onset Parkinsons disease.


GABRG2 and GABRG1 mediate the effects of the drug benzodiapezine. One of the splicing variants of GABRG2 interacts with ethanol. Mutations can cause epilepsy and febrile seizures.



GABA B Receptor 1 GABBR1 is expressed throughout the brain, small intestine, and uterus. Mutations in mice result in seizures, memory problems, and EEG abnormalities.




Glutamate is the major excitory neurotransmitter in the mammalian brain. There are two classes of glutamate receptor, ionotropic and metabotropic. The ionotropic receptors are divided into the NMDA receptors and the non-NMDA receptors (such as GRIA and GRIK). The metabotropic receptors can be grouped on the basis of structure and function (GRM1 and 5 are grouped together, as are GRM 2 and 3, and GRM 4 and 6).



NMDA receptors are involved in associative memory.


GRIN1 is the major subunit in all NMDA receptors; one or more of the following GRIN receptors are also incorporated into the protein. NMDA receptors located at synapses increase the activity of CREB and BDNF genes (involved in learning), and are antiapoptotic (prevent cell death). NMDA receptors which are not located at synapses are activated in hypoxia, inducing membrane potential changes in the mitochondria and apoptosis (programmed cell death). A decrease in NMDA receptors may be a factor in schizophrenia.


GRIN2A mutations in mice interfere with memory.


GRIN2B mutations cause death in homozygous mice. Transgene mice which expressed increased amounts of GRIN2B performed better at memory tasks than wild type mice.






GRIA1 mutations in mice interfere with learning.


GRIA2 is essential for normal brain function and is also involved in the perceived reward from cocaine.


GRIA3 mutations cause Rasmussen encephalitis whose effects include inflammation, epilepsy, and dementia.


GRIK1 receptors are expressed in the ventral horn of the spinal chord. Mutations can cause juvenile absence epilepsy.


GRIK2 polymorphisms affected the age of onset of Huntingdon disease.



GRM1 mutations cause learning and motor abnormalities.


GRM4 is expressed most highly in the cerebellum. Mutations affect learning.



Endorphins, enkalphins, and dynorphin are our brain’s own opiates that reduce our sensitivity to pain (may be felt during exercise [“runner’s high”] and the fight or flight response). Enkalphins are secreted during labor. Opioid receptors mediate the effects of endogenous opiates (enkalphins, endorphins, dynorphin) as well as those of morphine, heroin, and methadone.


OPRM1 is the major receptor site for the binding of heroin, morphine, and methadone. There are ethnic differences is the distribution of OPRM1 alleles and some alleles increase vulnerability to these drugs. One mutant receptor binds beta-endorphin three times the degree observed in wild type receptors. Mutations can cause epilepsy (OMIM).




The neurotransmitter serotonin inhibits sex drive and orgasm; promotes contentment, causes cravings for sweets and has been used to treat depression, obsessive-compulsive disorder, panic, anxiety, PMS. Prozac increases serotonin levels and dieting decreases them. Receptors for serotonin are involved in the regulation of sleep, appetite, thermoregulation, pain, and sexual drives. Abnormalities in serotonin pathways can result in depression, migraine, and obsessive-compulsive behavior. LSD binds to serotonin receptors, blocking the inhibition of some pathways. Some sensory information is no longer filtered resulting in a sensory overload (OMIM).

Serotonin receptors are expressed in the CNS, PNS, and other tissues and are involved in depression, anxiety, schizophrenia, obsessive-compulsive disorders, panic disorders, migraine, hypertension, eating disorders, and irritable bowel syndrome (Hoyer, 2002). Studies have suggested that abnormalities in the serotonin system may be a factor in aggression and pedophilia (Maes, 2001).



Mutations in 5HT 1A receptors in mice increased levels of anxiety (Reif, 2003).


HTR1B is most highly expressed in the striatum. Mutations in 5HT 1B receptors in mice increase aggression, exploratory behavior, and the susceptibility to addition to cocaine and alcohol. Variants of the 5HT 1B receptor have been linked to increased frequency of alcoholism in two human populations (Reif, 2003).


HTR1C variants can cause audiogenic seizures and visual hallucinations.


HTR2A receptors are imprinted and only the maternal allele is expressed. One variant is associated with schizophrenia and with auditory and visual hallucinations. A G/A polymorphism in the promoter of serotonin 2A receptor gene (position -1438) has been correlated with seasonal affective disorder, anorexia, and obsessive compulsive disorder (although other studies have produced negative results). Studies of prison inmates have also shown differences in the frequency of alleles at this site compared to control populations (Beggard, 2003).


HTR2C mutations in mice cause seizures (including audiogenic seizures) and weight gain. Variants in 5HT 2c receptors and DRD4 receptors may interact to determine reward dependence and persistence (Reif, 2003).


HTR3A is located on the region of chromosome 11 which some have linked to schizophrenia and bipolar disorder.





There are more than 60 neuropeptides in the mammalian brain; most of them act through GPCRs. In mammals, neuropeptides function in a variety of neural pathways, including those involving feeding and sleep (Nathoo, 2001).


Galanin is expressed in the diencephalon and in other brain regions and in the gastrointestinal tract. It effects neurotransmitter release, pain, appetite, growth hormone secretion, heartbeat, gastric motility, and sexual activity. GPRs 40 through 43 are located in a cluster on chromosome 19q13.



Cannabinoid receptors respond to endogenous neuropeptides whose effects are anti-inflammatory, immunosuppressive, anticonvulsive, and can relieve intraocular pressure in glaucoma. They also affect memory. Both of the receptors are involved in the extinction of aversive memories (OMIM). CB1 and CB2 are the GPCRs which respond to marijuana and endocannibinoids (those produced by the body). CB1 is most highly expressed in the hippocampus and cerebellum but is also expressed outside the brain in the spleen, testis, and white blood cells. CB2 is primarily expressed in white blood cells. Both are expressed in the placenta (Onaivi, 2002).

Endocannibinoids are modified eicosinoid-like fatty acids. Given the production of encannibinoids in the fetal brain, these substances may function in development. Endocannibinoids also seem to function in immunity, cell growth, learning, and inflammatory reactions. They may be produced from cell membrane lipids after receptor-ligand interaction and function as a retrograde signal (Onaivi, 2002). . Marijuana use can alter memory and learning pathways (Onaivi, 2002).



Current evidence suggests that personality traits are not determined by single genes but rather by the additive functions of a number of genes, many of which are polymorphic in human populations (and which will likely be shown to interact with the environment). Some personality traits seem to be more affected by genes and others more affected by the environment. Some personality disorders may reflect the extreme expression of normal components of personality (Reif, 2003). It is thought that any single gene does not typically cause more than 1-2% the observed variance of a personality trait (Czermak, 2004).



Although variations in serotonin receptors can affect behavior, there are other proteins involved in the use of serotonin as a neurotransmitter whose variations are also significant. Low serotonin levels or turnover have been linked to suicide, impulsive behavior, aggression, and low social status (the latter observed in primates) (Reif, 2003). Harm avoidance is determined by serotonin (Berman, 2002).


The enzyme tryptophan hydroxylase, located only in neurons of the raphe nucleus, catalyzes the most important of the two reactions which convert tryptophan to 5HT (serotonin). Variations in tryptophan hydroxylase (TPH) have been linked to aggression and suicidal behavior (Reif, 2003).

Once serotonin is released as a neurotransmitter, it can be reabsorbed for subsequent reuse by the neuron using a 5HT transporter (5HTT) or degraded to 5HIAA by monoamine oxidase A (MAO-A) (Reif, 2003). The 5HTT gene is regulated by an upstream polymorphic repetitive element (known only in humans and simian primates). Variants in this transporter repetitive element (5HTTLPR) have been linked to neuroticism, agreeableness, and anxiety. The concentration of 5HIAA (the breakdown product of serotonin) in cerebrospinal fluid has been shown to vary in monkeys depending on whether young rhesus monkeys were raised by their mothers or their peers, but only in monkeys the s allele of the serotonin reuptake transporter repetitive element. These alleles also influence the age at which rhesus monkeys leave their group (Reif, 2003).



Although variations in dopamine receptors can affect behavior, there are other proteins involved in the use of dopamine as a neurotransmitter whose variations are also significant.


Dopamine converted from tyrosine by the enzyme tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (Reif, 2003). Variants in the TH gene have been linked to neuroticism, angry hostility, vulnerability, suicidal behavior, and alcoholism (Reif, 2003). Tyrosine hydroxylase controls the synthesis of E and NE is a factor in some mood disorders (Seretti, 2000).


Catecol-O-methyltransferase (COMT) is an enzyme which breaks down dopamine, epinephrine, and neurepinephrine. Deletions in the region of this gene are associated with psychosis (Collier, 2003).


Although both serotonin and dopamine are perceived by multiple receptors, both are reabsorbed into neurons by a single reuptake transporter. There is some evidence that variations in the dopamine transporter (DAT) may influence personality such as avoidant behavior (Reif, 2003).

Monoamines are deaminated by MAO-A and the catecholamines are methylated by COMT. There are two genes for monoamine oxidase, MAO-A and MAO-B. Deletions of MAO-A in humans result in mental retardation, autistic behavior, and other abnormalities (Reif, 2003). Mutations in MAO-A and 5TTT affect the organization of the cerebral cortex in mice (Reif, 2003).

The absence of MAO-A expression in mice results in increased levels of some neurotransmitters (dopamine, serotonin, and NE), higher aggression, and inappropriate sexual activity in males. In humans, a mutation in MAO-A causes Brunner syndrome in which males suffer from mild retardation and display a variety of aggressive and hypersexual behaviors (in addition to other behaviors ranging from arson to suicidal behavior). This is the only example known which fulfills the OGOD (one gene, one disease) model for behavioral disorders. Variations in the promoter region are known to affect panic and depression in females and aggression in males (Reif, 2003).

COMT variations have been shown to affect aggression in males and females. Gene interaction (epistasis) has been observed between DRD4 and polymorphisms of the 5HTTLPR and COMT (Reif, 2003).



GABA levels are inversely associated with aggression and the interaction of GABA A receptors with alcohol, bezodiazepines, and barbiturates, can increase aggressive behavior. The brain actually synthesizes steroid hormones which can interact with GABA A receptors (Miezek, 2003).


The neurotransmitter norepinephrine is synthesized from dopamine by dopamine β-hydroxylase (DBH). Variant forms of this enzyme may affect irritability (Reif, 2003).


Of course, there are many factors other than genetics which can affect personality and the biochemistry of the brain. Schizophrenia may affect up to 1% of the world’s population. Non-genetic contributions may arise from problems during pregnancy and delivery, urban environments, childhood viral infections, marijuana use, and the age of the father (Collier, 2003). Season of birth has been implicated in variations in schizophrenia, bipolar disorder, circadian rhythms, novelty seeking, neurotransmitter metabolism, and suicidal tendency (Chotai, 2003).




Estrogen Receptor

Estrogen causes sexual differentiation in many vertebrates (Wu, 2003). About 60% serum estradiol is bound to albumin, 38% is bound to sex-hormone binding globulin, and about 2% is dissolved in plasma. Estrogen can be synthesized from testosterone in both men and women by the brain, adipose, and the liver by the aromatase cytochrome P450 19 enzyme (Osterlund, 2001). Mice without estrogen are infertile (both genders) and have abnormalities of the skeletal system, gonads, and mammary glands. Mutations in mice also alter lipid metabolism and susceptibility to obesity. Estrogen affects both the testis and prostate in males. Estrogens cause growth and differentiation of female reproductive structures, maintain bone mass, serve to lessen cardiovascular disease, and influence mood, cognition, and hormone release (Osterlund, 2001).

There are two genes for estrogen receptors, ESRA and ESRB. These receptors are not expressed to the same degree throughout the body: The ovaries and uterus express ESRA more than ESRB; the vagina expresses ERGA only; and the testis expresses ESRB in more regions than ESRA. Both receptors are expressed in growing bone but with distinct distributions. The two estrogen receptors can both form homodimers and heterodimers (Osterlund, 2001).

Variations in ESRA have been linked to bone density variations in women and men and the onset of menopause in women. Estrogen receptors can vary in the number of TA repeats (ESRA) and CA repeats (ESRB) they contain. Shorter ESRB receptors are associated with higher levels of circulating androgen. Human mutations suggest that ESRA may offer some protection from heart disease and ESRB may offer some protection from prostate cancer in males (OMIM). The highest expression of ESRα in the brain occurs in the hypothalamus and amygdale while the highest expression of ESRβ occurs in the hippocampus, thalamus, and entorhinal complex. Mammals in general express estrogen receptors in the limbic areas of the brain (Osterlund, 2001).


Androgen Receptor

The gene which codes for the two isoforms of androgen receptor is located on chromosome Xq11. The receptor protein can be cleaved by caspase 3 to produce fragments which can be toxic to the cell (a “death substrate”) utilized in programmed cell death.

Some mutations in androgen receptors result in small testis and prostate size. Some mutations cause constitutive activity of the receptor (in which the receptor is always active even when it has not bound to androgen hormones) and are a cause of prostate cancer. Two mutations are known resulting in a “promiscuous receptor” which can bind to estrogen and progesterone and these mutations also increase the likelihood of prostate cancer (OMIM; Han, 2005) .

The normal gene possesses two regions of tandem trinucleotide repeats and (one type of mutation observed in this gene is an amplification of the number of CAG repeats). While 11 to 33 repeats can be considered normal, those with a larger number of repeats are more susceptible to mutation. Some repeats have been linked to mental retardation and, as the number of repeats increases, the likelihood of males suffering from partly/unfuses scrotum, micropenis, and azoospermia increases. Although the number of CAG repeats is not a major cause of infertility, normal men with lower repeat numbers have higher sperm counts than those with higher repeat numbers. Women who have lower repeat numbers in the androgen receptor gene have higher levels of androgens in the blood and lower levels of LH (OMIM).

Shorter androgen receptor proteins increase the activity of the receptor and are associated with an earlier age of onset and increased severity of prostate cancer. Longer proteins can cause infertility. There are ethnic differences in the number of repeats found in androgen receptors (OMIM).




Although estrogen (and testosterone) affect the tissues of the reproductive system, they also affect other tissues including the brain. The receptors for sex steroids are more abundant in certain parts of the brain including the hypothalamus, amygdala, and hippocampus (Steiner, 2003). Since the regions of the brain include those which control emotions and drives, it is not surprising that the secretion patterns of steroid hormones are implicated in both normal fluctuations in mood and in mood disorders (affective disorders). In females, secretion of estrogen seems to begin after birth and is maintained at a low level throughout childhood. With the onset of puberty, the secretion of estrogen generally increases and undergoes monthly fluctuations (Ramirez, 2003).

Affective disorders are the most common mental disorders and women are afflicted at twice the rate as men (with an 8% lifetime risk as opposed to 4% in males). Decreased estrogen levels are a factor in postnatal depression and post-menopausal depression (Steiner, 2003). Low concentrations estrogen have been associated with PMS, postnatal depression, and postmenopausal depression and estrogen can be used to treat the latter two. About 75% women experience some form of PMS and 3-8% of these women suffer from the more serious emotional and behavioral symptoms of PMDD (premenstrual dysphoric disorder) (Steiner, 2003; Osterlund, 2001). PMDD affects 5% of women in reproductive years (Shors, 2003).

A number of studies show that estrogen can relieve depression. Reduction of serotonin (or the tryptophan it is derived from) increases irritability and the severity of PMS. Estrogen increases serotonin synthesis, uptake and receptor number, and functions as an antidepressant. Evidence suggests that estrogen decreases the expression of 5-HT1A serotonin receptors and increases the expression of 5-HT2A receptors (Steiner, 2003; Osterlund, 2001; Genazzani, 2002). Estrogen affects synthesis of serotonin through TH (tryptophan hydrozxylase) and can increase serotonin receptors in areas of the brain known to affect mood (Shors, 2003). Given that estrogen can both increase body fat and fight depression, there actually may have been some observational evidence which gave rise to past sterotypes linking body size and disposition (Oinonen, 2001).

In general, estrogen seems to offer some protection from schizophrenia. Schizophrenia symptoms are milder in women and onset occurs about 4 years later in women than men. Estrogen also seems to decrease susceptibility to Alzheimer’s disease (Osterlund, 2001). Estrogen in mice affects learning (Shors, 2003). Estrogen improves some cognitive functions, such as memory, which is not surprising given that it increases ACh formation in neurons, such as ACh neurons which project to the hippocampus (Genazzani, 2002).

The loss of gonadal hormones at menopause affects mood, libido, and some aspects of cognition. The mood and emotional changes also seem to involve changes in the serotoin, noradrenaline, dopamine, and opiate pathways. (Genazzani, 2002). After menopause, the rate of depression in females approaches that seen in men (Shors, 2003). A polymorphism in the estrogen receptor alpha is associated with variation in some of the characteristics of menopause such as vaginal dryness and hot flashes (Malacara, 2004).


Depression can be associated with altered mood, changes in sleep patterns, changes in appetite, and suicidal thoughts. In patients with depression, abnormalities in brain blood flow and glucose metabolism have been observed, in regions such as the amygdale, hippocampus, and prefrontal cortex. Drugs which increase the activity of norepinephrine and serotonin have an antidepressant effect. Serotonin levels are lower in the brains of those who commit suicide and increased intake of serotonin precursors (such as tryptophan and 5-hydroxytryptophan) can combat depression (Kalia, 2005; Hamet, 2005).

The short form of the 5-HTTLPR transporter gene is linked to neuroticism (with its association with anger, anxiety, and pessimism), depression, and smoking dependence (Brody, 2005). Those who are homozygous or heterozygous for the short form of the transporter gene display stronger reactions to fearful stimuli by the amygdala and are more likely to undergo depression in response to stressful life situations (Wurtman, 2005). Heterozygous women, but not men, displayed higher levels of anxiety and this difference may be a factor in the observed gender differences in the frequency of depression (Mizuno, 2006).


Other genes have been shown to be associated with depression and anxiety. Leptin and cholesterol levels can be lower in patients with major depressive disorder (but higher in patients with schizophrenia) (Jow, 2006). The A1 allele of the DRD2 gene is associated with anxiety, insomnia, depression, and difficulty in social interaction (Lawford, 2005). The transcription factor CREB is among the genes associated with depression and antidepressant drugs typically increase CREB activity (Blendy, 2006). Stressful situations can increase inflammatory mechanisms in the body and depression (which often follows a stressful life situation) can be associated with increased levels of inflammatory signals (cytokines) and cell adhesion molecules (Raison, 2006). Mutations in the Bcl-2 gene may also affect personality traits such as anxiety (Einat, 2005).

Progesterone can cause depression and increases monoamine oxidase activity (which breaks down serotonin) (Steiner, 2003). Progesterone opposes estrogen’s effects in the brain and can alter mood, increasing the risk of depression (Genazzani, 2002). Individuals suffering from depression have higher levels of adrenal hormones and corticotrophin releasing factor (CRF). Male and female mice react to stressful stimuli with different hormones (Shors, 2003).



The production of testosterone increases in the male fetus early in the third month of development through birth. It mediates effects on the male genetalia and hypothalamus during this time. About 2 months after birth there is another surge in testosterone production which last several months although its significance is not understood. The final surge in testosterone production occurs during puberty where it contributes to growth, development of the primary sex organs and secondary sexual characteristics, and influences sexuality, personality, violence, and other cognitive aspects (Ramirez, 2003).

Androgens increase sex drive in both men and women and also increase irritability. High levels of androgens may be associated with some of the increased drive and irritability of some parts of the menstrual cycle in females (Steiner, 2003). In men, chemical castration is linked to increased risk of depression and anxiety. Ending chemical castration coincides with improved performance in memory. Decreased testosterone levels are linked to depression (Almeida, 2004). Testosterone supplementation improves some types of cognitive ability (Almeida, 2004). Androgens are used to treat the loss of libido in postmenopausal women (Genazzani, 2002). The “feminine”/“masculine” behavior of young girls has been linked in some studies to both non-biological phenomena (such as the existence of older male siblings) and to levels of testosterone. Maternal testosterone levels may increase later in life (or at least the ratio of testosterone to estrogen can increase) and this may have an effect on fetal development (Ramirez, 2003).



Although it can reasonably be expected that increased levels of testosterone in humans correlate with increased violence given such observations in other mammals, this correlation seems to be weak in humans. Testosterone levels are higher in adolescent boys perceived to be socially dominant. In other species, aggressive acts are often initiated by males of lower social status in an attempt to be more socially dominant. Therefore, the lack of strong evidence for a direct correlation between testosterone levels and aggression may be influenced by the aggression committed by adolescents of a lesser perceived social status (with lower levels of testosterone) who are trying to become more dominant (Ramirez, 2003).

There are studies which have concluded that males who commit violent acts (including domestic violence) have higher testosterone levels and some males with high testosterone levels display high irritability (George, 2001). In humans, high doses of anabolic steroids has been linked to indiscriminate violence sometimes referred to as “’roid rage”. Studies have shown that anabolic steroids increase the incidence of verbal aggression, fighting, homicidal behavior and violence towards women. Studies with rats also indicate that anabolic steroids increase aggression (McGinnis, 2002).


There are a number of hormones which can affect aggression and violence in addition to testosterone. Increased aggressive behavior may also be linked to lower levels of DHEAS, a lower ratio of testosterone to estrogen, lower levels of FSH, and higher levels of LH, androstenedione, and DHEA.

The adrenal gland secretes several hormones which are called androgens because of the similarities of their actions to those of testosterone, androstenedione, DHEA (dehyroepiandrostenedione), and DHEAS (dehyroepiandrostenedione sulfate). Their effects are more easily observed in females since in males their effects are overshadowed by the testosterone secreted by the testes. There is some evidence suggesting that higher levels of adrenal androgens are factors in increased aggression and antisocial behavior (Ramirez, 2003).


Nitric oxide serves three main functions in the body. Outside of the nervous system, macrophages can synthesize it to destroy tumor cells and endothelial cells can secrete it to relax blood vessels. In the brain, nitric oxide can affect the activity of neurons and the enzyme which synthesizes it, nitric oxide synthase (NOS), is concentrated in regions of the brain which determine emotions. In animal studies, mutations in NOS greatly increase male aggression, but not female aggression. Testosterone is required for this increase; no such increase is observed in castrated males. In fact, normal female mice do display maternal aggressiveness toward intruders which is reduced in NOS mutant females. Thus it appears that the activity of NOS affects aggression but has opposite effects in males and females. Androgens tend to inhibit NOS and estrogens tend to increase its activity. The increased aggression in male mice due to mutations in the nitric oxide synthase gene is apparently mediated through reductions in serotonin levels and serotonin receptor function. Although decreased serotonin system activity is also a feature of depression, the behavior of these mice is distinct from that behavioral “despair” in mice. In female mice, nitric oxide mutations actually decrease the normal amounts of aggression (Chiavegatto, 2003; Nelson 2005; Reif, 2003).

Sex steroids are involved in aggression. Young animals exposed to androgens alter the distribution of the varieties of serotonin receptors. Both estrogen and testosterone increase levels of serotonin receptors although estrogen may interfere with the binding of serotonin to its receptor (Chiavegatto, 2003).

Decreasing the activity of serotonin pathways is known to increase aggression in both humans and other animals. Increased aggression occurs when brain the levels of serotonin precursors decrease, under the influence of drugs which decrease serotonin synthesis, in response to tryptophan-free diets, and when neurons which produce serotonin are destroyed by lesions. Increasing serotonin levels has been observed to decrease aggression (Chiavegatto, 2003).


Aggression can also be increased through environmental variables. Mice become more aggressive when isolated and isolation is required for increased aggression in nitric oxide synthase mutants to become manifest (Chiavegatto, 2003).

Alleles of the dopamine receptor D2 and dopamine transporter genes are associated with increased aggression in humans (Chen, 2005).


A certain allele of the serotonin 2A receptor gene is more likely to be found in criminals and psychiatric patients than in control groups. This variation has no other observable affect on personality scores (Berggard, 2003).


Low levels of cortisol are associated with increased aggression. This reduction in cortisol secretion can be observed in children and may thus be a predictor of aggressive behavior. Interestingly, there seems to be an interaction between culture and cortisol levels. For example, differences in the rise of cortisol levels after experiencing insult have been observed between adolescents raised in the Northern U.S. compared to the Southern U.S. (Ramirez, 2003).


Pituitary hormones may also be factors in aggression. Studies have linked increased aggression to lower levels of FSH and prolactin and higher levels of LH and DHEA (Ramirez, 2003).


In primates, lower cholesterol levels are associated with increased aggression. In humans, a number of studies have shown lower cholesterol levels are linked to increased levels of violence and death by violence (Golomb, 2000).



The nervous system depends on sodium, potassium, and calcium channels to transmit electrical messages and a diversity of these channels can be found throughout the nervous system. Mutations in individual channels can have a range of effects, such as epilepsy, febrile seizures, migraines, and hypertension (OMIM).


OBESITY (included here because of its frequent past association with temptation, willpower, etc.)

The obese gene (that’s the name of the gene in mice where it was discovered) codes for the protein leptin. Leptin is a secreted protein from fat cells that seems to serve as a "lipostat" (the human gene is named leptin). The diabetic gene in mice and fatty gene in rats codes for leptin receptor, OB-R, which is expressed in the hypothalamus (human version LEPR). The hypothalamus responds to leptin by secreting neuropeptide Y. Adipocyte fatty acid binding protein is in a pathway that links obesity to insulin resistance and diabetes Other genes involved in fat metabolism include UCP-3 (uncoupling proteins), ASIP, CPE, TUB, MC3R & MC4R (meolanocortin receptors), POMC, MSTN, and TNFA (tumor necrosis factor).



The diverse features of Angelman syndrome (which include microcephaly, abnormal movements, failure of speech development, and abnormally happy disposition are caused by mutations in the ubiquitin ligase gene (Williams, 2005).



Among neurological disorders, autism spectrum disorders have a high heritability. In monozygotic twins, the concordance for autism (if the definition of autism spectrum includes language delay) has been reported to be between 60% and 90%. While the general risk of autism spectrum disorder is about 0.5%, the risk for an individual with an affected sibling is 2 to 6%. The symptoms of autism can occur with other disorders such as fragile X syndrome, tuberous sclerosis complex, Rett syndrome, neurofibromatosis, and duplications of the 15q chromosomal region (Spence, 2004; Volkmar, 2003). A major factor in autism seems to be abnormal fetal neural development. Genes (such as HOXA1) and drugs (such as ethanol, valproic acid, thalidomide, and misoprostol) which mediate their effects early in fetal development can cause autism (Conciatori, 2004).

Autism may involve brain abnormalities such as an increase of brain size by 2-10% and abnormalities (such as fewer neurons or decreased neuronal branching) in specific areas such as the amygdale, hippocampus, septum and anterior cingulated. Autistic patients may also display abnormal cerebellar development, consistent with the association of mutations in the genes reelin and engrailed2 with autism. In monkeys, lesions of the amygdale and hippocampus have produced behavior comparably to those observed in autism (Volkmar, 2003; Bartlett, 2005).

Autism is not inherited in a Mendelian fashion and gender affects susceptibility given that only 20% of those affected are female. The genes which have been identified as being associated with autism include genes involved in brain development (such as homeobox genes HoxA1 and engrailed 2, the extracellular matrix gene reelin, and the forkhead transcription factor FOXP2), genes involved in neurotransmitter action (such as the serotonin transporter SCL6A4, GABA receptor GABRB3, glutamate receptor GluR6, arginine vasopressin receptor AVPR1a, and serotonin precursor enzyme tyrptophan 2,3 dioxygenase), genes involved in immune disorders (such as HLA-DR4, HLA-DR13, and the MHC III complex complement gene HLA C4B) and other genes expressed in the brain (such as adenosine deaminase ADA and UBE2H which causes the Angelman syndrome) (Spence, 2004; Odell, 2005; Torres, 2002; Serajee, 2006; Bartlett, 2005; Li, 2005). Rare variants of the secretin gene may contribute to autism ( Yamagata, 2002). Mutations in the gene AHI1 not only causes retardation but also autism-like behaviors. It has undergone selection in the human lineage and may be a candidate for a gene involved in allowing human social interaction (Hill, 2005).


Autistic patients frequently may possess an abnormal skull shape (trigonocephaly). Hoxa1 and MECP2 mutations are both associated with autism (the latter being the cause of Rett syndrome) and can cause abnormal skull shape (Ijichi, 2002).

Oxytocin and vasopressin are known to mediate a variety of social behaviors such as courtship and parental care in vertebrates as diverse as fish and mammals. Oxytocin mutations in mice cause social deficits which may be related to autism in humans as do mice with mutations in the Fmr gene which causes fragile X syndrome (Winslow, 2002; Lim, 2005; Mineur 2005).

Fragile X syndrome, caused by a trinucleotide expansion of the FMR gene, is the most common inherited disorder causing mental retardation and is also associated with autism, attention deficit hyperactivity disorder, delayed language development, anxiety, and abnormal social interactions (Berry-Kravis, 2002).




Schizophrenia is a serious genetic disorder affecting about 1% of the population. Although a large number of genes have been associated with increasing the risk of schizophrenia, many of these analyses have had difficulty being replicated and few genes have strong support as causative agents. The candidate genes include dysbindin (which interacts with the dystrophin complex in hippocampal synapses), neuroregulin 1 (whose diverse forms perform a variety of functions in the development of the nervous system, neuronal cell interaction, and synapse function), disrupted in schizophrenia 1 (a cytoskeletal protein functioning in neural development), D-amino oxidase, interleukin-10, and regulator of G-protein signaling 4 (Owen, 2005; Harrison, 2006; Sawa, 2005; He, 2006). The onset of schizophrenia is thought to demonstrate an environmental influence which may be mediated by thyroid hormones and retinoids which a critical for brain development and whose pathways have been associated with schizophrenia in genome analyses (Palha, 2005). In patients with schizophrenia, abnormal expression of cytomatrix proteins has been observed in the amygdale (Weidenhofer, 2006).

The human genome possesses four proteins known as neuregulins which bind to ErbB receptor tyrosine kinases. Structurally, they possess an EGF-like domain and, depending on how the 20 exons are spliced, may possess an immunoglobulin domain as well. The expression patterns of two of the immunoglobulin-containing isoforms (Types I and IV) of Neuregulin 1 seem to play a role in susceptibility to schizophrenia. The EGF domain interacts with the ErbB3 and ErbB4 receptors, which then interact with ErbB2 ( Harrison, 2006).





Bipolar disorder is a serious mood disorder both because of its worldwide prevalence (estimated at 3-5%) and its implication in the suicide of untreated patients. The regions of the brain which seem most responsible for the features of bipolar disorder are the amygdale, hippocampus, basal ganglia, and prefrontal cortex. Although it clearly has a genetic component, causative genes have not yet been clearly identified. A number of gene variants have been associated with bipolar which include serotonin receptors (HTR3A and HTR4) and the serotonin transporter, GABA receptor (GABRA5) hormones and neuropeptides (corticotrophin-releasing hormone and proenkaphalin), and NCAM1 (Shastry, 2005; Otani, 2005).

Schizophrenia and bipolar disorder may share some of the same susceptibility genes, such as the G72 protein (D-amino oxidase activator) which interacts with D-amino acid oxidase (DAO) in the oxidation of D-serine (which can subsequently interact with NMDA receptors) (Addington, 2004).



It is obvious that genes can affect intelligence, given the many mutations which lead to retardation.

-- FMR-1 gene (fragile X syndrome), the most common form of inherited retardation

--Rubinstein-Taybi syndrome: the cause of 1/300 institutionalized cases; a gene on chromosome 16 involved in the switching on of other genes

--there are over 70 different x-linked conditions causing mental retardation; over 100 different retardation causing mutations have been identified


--Mutations in the human homolog of the Drosophila Aristaless gene, named Aristaless related homeobox gene ARX, can cause mental retardation, epileptic seizures, and infantile spasms (Stromme, 2002).


--in laboratory organisms, mutations in certain genes (CREB genes, dunce, rutabaga, turnip, and others) decrease learning potential

All heritability studies indicate a genetic component to IQ scores, ranging between .6 and .8 (heritability is a measure of the percentage of a variation in a given population that is caused by genetic factors; it is not a measure of what percentage of intelligence in genetic in origin). Unfortunately, this topic is certainly a difficult one to study and is clouded by past failures. Measurements of intelligence in the past (whether through phrenology, head circumference, or early forms of IQ tests) have been highly erroneous and often based on (or reinforced) societal predjudices.



Microcephaly is a disorder in which head and brain size are significantly reduced. Microcephalic humans have brain sizes equivalent to those of chimpanzees and gorillas. The cerebral cortex’s gyral pattern is less complex than normal. Primary microcephaly involves a reduction in the number of neurons during fetal development while secondary microcephaly involves a reduction in neuronal branching and synapse formation after birth. Severe forms of human microcephaly may also involve lissencephaly, the formation of a smooth cerebral surface.

Abnormal spindle-like microcephaly associated ASPM is a large protein which interacts with microtubules and is expressed in areas where new neurons are produced. Its homolog in flies is known to function in the organization of microtubules during cell division. Microcephalin (MCPH1) is related to topoisomerase II-binding protein and BRCA1. It regulates chromosome condensation in mitosis and DNA repair. Homologs exist in bilateran animals. Other genes which cause microcephaly function in cell division and include cyclin dependent kinase 5 regulatory associated protein (homologous to centrosomin in flies) and centromere associated protein J (homologous to CENPJ in flies) (Woods, 2004; Bond, 2006; Ponting , 2005 ). CDK5RAP2 has also undergone an advanced evolutionary rate in primates (or the human lineage more specifically) and mutations in this gene can cause microencephaly (Evans, 2006).