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Psychology 325: Psychobiology

Second Project

The Genetic Basis of Intelligence

Gene Loci and Intelligence: Shaw Gillespie

Given the research presently available, there seems to be ample evidence supporting the conclusion that genetic factors play, at least, a moderate role in determination of intelligence and cognitive ability. Bouchard and McGue (1981) conducted a review of family studies on IQ, and found that results obtained from many of the studies were consistent with the polygenetic theory of inheritance because the correlation between family member's scores on intelligence measures roughly corresponded to the proportion of genes shared between those family members.

One of the most well researched genes known to play a role in cognitive ability is the fragile X mental retardation gene FMR1 located on the X chromosome. Fragile X syndrome is characterized by x linked physical characteristics such as macroorchidism (increased testicular volume), long face, large protruding ears, and social eye gaze avoidance (De Vries et. al., 1997). The cognitive phenotype of the fragile X syndrome includes deficits in executive function, decrease in attention and viseo spatial memory, and decreased IQ (Menon et. al., 2000).

The FMR1 gene is associated with a series of trinucleotide repeats (CGG). Normal FMR1 genes are associated with 6 to 54 repeats, but can also expand to a length of 50 to 200 repeats in phenotypically normal individuals (Fu, et. al., 1991). The full mutation of FMR1 can contain as many as 2000 repeats, and individuals with the full mutation almost always show IQ scores in the mentally retarded range (Daniels, et. al., 1998). However, the length of the trinucleotide repeat series in those who do not carry the full mutation was not found to have any significant correlation with intelligence scores in those individuals (Franke et. al., 1999).

Menon et. al. (2000) found that disruption in FMR1 gene expression leads to decreased levels of FMR1 protein (FMRP) levels in the brain. The mutated gene form contains an area within the gene that prevents transcription of the gene leading to a decreased level of FMRP in the brain, which has been linked to abnormal formation of dendritic spines in the cortex which may impede learning and memory (Hinton et. al., 1991).

Additionally, the FMR2 gene, which lies distal to FMR1 along the X chromosome, has been implicated in fragile X syndrome. FMR2 is similar to FMR1 in that it contains a series of trinucleotide repeats (CGG) that result in expression of the fragile X phenotype in mutations containing over 200 repeats. As with FMR1, however, normal variation in the size of the gene is not associated with variation in intellectual performance (Mazzocco and Reiss, 1999).

While fragile X syndrome is the leading cause of inherited familial mental retardation, there are also a number of other genes present on the X chromosome that seem to play a role in intelligence and cognitive ability. For instance, Borjeson Forssman Lehmann syndrome (BFLS) is a syndromal X linked mental retardation involving a gene coding for fibroplast growth factor homologous factor 2 (FGF2) (Baker et al, 1999). Also, Hamel et al (1997) describe a syndrome involving X linked mental retardation, ataxia, loss of vision, and a fatal course in early childhood. This syndrome was linked to a gene (Xq21.33 to q24) that codes for two myelin proteins in the central nervous system. Finally, Nussbaum et al (1997) have linked the oculocerebrorenal syndrome of Lowe (OCRL), a rare X linked disorder characterized by mental retardation, congenital cataracts, and a disorder of the renal system, to a gene on the X chromosome (Xq25 to 26). However, they have not yet uncovered the action of the gene, nor have they uncovered its effects on the body's systems.

Another effort to track down genes that may play a role in intelligence is the IQ quantitative trait loci project, an association study examining gene markers of neurological relevance linked with intelligence (Plomin et al, 1994). Thus far, the study has singled out three markers that seem to have a significant association with IQ; the HLA A (B) allele; CTG B33, a trinucleotide repeat; and EST00083, a marker associated with mitochondrial DNA.

The HLA A (B) allele has been associated, along with the apolipoprotein E (ApoE) gene, with the age of onset of Alzheimer's disease. The e4 allele of the ApoE gene has been shown to be one of the factors considered to increase the risk and decrease the age of onset of Alzheimer's disease in direct proportion to the number of e4 alleles expressed (Owen, Liddell, and McGuffin, 1994). ApoE is present in cerebrospinal fluid and is thought to have a stimulatory effect in promoting structural changes following brain injury and neurodegeneration (Turic et al, 2001). Less is known about the HLA A (B) gene, but studies have associated it with late onset Alzheimer's in ApoE negative subjects (Lehmann et al, 2001). However, no associated between general intelligence scores and HLA A or ApoE genes has been found in the general population (Jacomb et al., 1999; Turic et al., 2001).

Additionally, little is yet known about the other two markers uncovered by the IQ quantitative trait loci project: CTG B33, and the mitochondrial EST00083. Moises et al (1999) examined EST00083, but found no association with high versus average IQ in the general population. Jacomb et al (1999) also examined CTG B33 polymorphisms and found no association with variation in IQ.

Monogenetic vs Polygenetic Debate: Gary Van Horn

Since the discovery that tiny chains of proteins called genes were responsible for determining which traits a plant or animal would possess there has been debate over whether a single gene could have such a large effect on something which seems so complicated as height, or if there were multiple genes involved with each adding a small contribution to the overall encoding of the trait. Many years, many debates, and stacks of research articles have done little to determine the overall focus of the debate, whether or not a trait can be controlled by a single gene; however, thanks to research done as to the source of "the most highly inheritable mental attribute known" it can be said with a large degree of certainty that human intelligence "is a complex phenomenon, governed by hundreds or even thousands of genes (Wright, 1999)."

The fact that intelligence is a polygenetic trait would seem like common sense to some because it is thought of as "traditionally defined in dictionaries and by many experimental biologists as problem solving ability" which can involve many factors such as learning, memory, "reasoning, analytical skills, and the ability to generalize previously learned information (Tsien, 2000)." A list of traits that diverse does not seem to lend itself well to a monogenetic explanation.

Monogenetic explanations do lend themselves to disease, for example

"the malfunction of a single essential gene can cause a distinctive pathological phenotype, that is, a monogenetic disease such as phenylektonuria, which alone outweighs the effect of all other intelligence determining genes and causes mental retardation (Henn, 2000)."

Theoretical Arguments Concerning Genes Involvement in Human Behavior: Gary Van Horn

Discoveries regarding changes in the genetic codes of mice, a close genetic relative of the human, have shown that there is definitely an effect on the level of overall intelligence of a genetically altered mouse, and that this effect can be either good or bad depending on how and which gene is effected. For example Joe Z. Tsien of Princeton University was "able to describe how the addition of a single gene endowed mice with superior memory and learning ability" by "adding the gene for a protein that helps brain cells communicate," known as NMDA receptors (Travis, 1999).

Studies concerning knocking out genes for intelligence also seem to prove the point that genes are involved in human behavior. For instance, due to the increased focus on the NMDA receptor genes, on group of researchers decided to attempt to "knockout" or "delete a subunit of the NMDA receptor. The researchers found that "the knockout mice [had] lost the capacity to change the strength of the neuronal connections in the CA1 regions of their brains" and as a result exhibited abnormal spatial memory ability.

In light of this research it is hard to deny that our genetic codes influence our intelligence level to some degree, however it is still hard to determine whether the complex phenomenon of intelligence can be attributed wholly to genetics or wholly to environment. The answer which seems to be forming out of continued research in intelligence is that intelligence is formed by a combination of both, in relatively equal amounts, "many experts . . . think 50 percent is the most likely figure. (Physical attributes such as height and weight can be up to 90 percent heritable.) (Wright, 1999)."

Effect of Genes on the Phenotype: Gary Van Horn

Phenotype is defined as the observable physical or biochemical characteristics of an organism, as determined by both genetic makeup and environmental influences. So one cannot look simply at a change in the IQ level of a subject as a change in phenotype, but instead at a change in some factor which is related to that difference in IQ. For example if one changes the genotype of a mouse so that it has a large cranial volume in the hopes that the added area will provide for a more intelligent mouse, then that person would be changing the phenotype of cranial volume.

It would seem that when talking about changes in the phenotype of subjects, both human and otherwise, that the most observable of the traits are the least important when it comes to actually changes in intelligence levels. For example the larger cranial volume of the mouse mentioned before has been shown to have little effect on overall intelligence. On a similar note, brain size and weight has also been shown to have little effect (Pile). What seems to matter the most is the level of microscopic changes that occur, such as an increase in receptor sites, or in the production of a certain chemical. (Wright, 1999)

Research designs, Strengths and Weaknesses: John Meyer

Introduction

In an attempt to understand the genetic contribution to complex behaviors--such as intellect-- studies have been devised to evaluate genetic and environmental influences on behavior. These studies include twin, adoption, and familily studies. These are known as traditional methods and are less complicated and controversial as the modern methods; therefore, as lay-person in the field of genetics, I will not venture past the boundaries of these traditional methods. The following is a brief overview of the research designs of three methods of genetic investigation of intelligence.

Twin studies

One of the simplest research designs for assessing the hereditary vs environmental influences on complex behaviors, such as intellect, is in the longitudinal study of twins. Monozygotic twin pairs have 100% of their genes in common, and dizygotic pairs only have 50% in common (Province, M.A.1999). For monozygotic twins there is a correlation of 80-90% on IQ test-- this is true even if they are reared apart. Dizygotic twins have a correlation of only about 50% on IQ tests. Therefore, the overall heredibility of intelligence is estimated at 50-70% (Clothier, J.L.1997). One inherent limitation is that twins are rare, so it is hard to even begin such a study. also, parents tend to treat twins as the same,and thereby effect the environmental relationship in a problematic way. However, the strengths of these studies lies in the ability to judge the relative influence of genetics, in other words, heritability of complex traits.

Adoption studies

One of the most powerful research designs for assessing hereditary vs environmental influences on intelligence is in the full adoption study. Within such studies it is assumed that any behavioral similarities between adopted child and biological parent is due only to genetic effects, and similarities between adopted child and adoptive parent is purely environmental(Province, M.A.1999).Strengths in this design lies in it's ability to: identify specific environmental influences unconfounded by heredity, analyze the role of heredity in environmental relationships, and assess genotype-environment interactions and correlation(Sherman S.L. et al. 1997). The Limitations include: difficulties in obtaining both biological parents of the adoptees, and finding adoptions that occurred directly after birth ( to assure only environmental effects).

Family studies

A research design that shows the extent of behavioral similarity in relatives that share the same genes and environment-- in comparison to unrelated individuals-- is found in the family study. Some have asserted that heritability of IQ is quite high and their is a tendency for those similar in ability to marry and that the innate cognitive ability of the offspring will be reinforced by the supportive environments of the "intellectually elite", such as: separate neighborhoods , private schools, special interest groups, etc.(Herrnstien and Murray 1995). Limitations in this type of study include the difficulty in ascertaining whether factors such as socioeconomic status (SES), or similar variables, are causing spurious results. Strengths of the design are in its finding of zero coorelations between unrelated individuals raised together who share family environment but not genetics; therefore, the correlation between family SES and offspring IQ is due, to some extent , to genetic influence.

References

Gecz, J., Baker, E., Donnelly, A., Ming, J., McDonald McGinn, D., Spinner, N., Zackai, E., Sutherland, G., Mulley, J., Fibroplast growth factor homologous factor 2 (FHF2) gene structure, expression, and mapping to the Borjeson Forssman Lehmann syndrome region in Xq26 delineated by duplication breakpoint in a BFLS like patient. Human Genetics, 1999, v104, 56 to 63.

Bouchard, T., and McGue, M., Familial studies of intelligence. Science, 1981, v212, 1055 to 1059.Daniels, J., McGuffin, P., Owen, M., Plomin, R., Molecular genetic studies of cognitive ability. Human Biology, 1998, v70, 281 to 296.

De Vries, B., Van Den Ouweland, A., Mohkamsing, S., Screening and diagnosis for the fragile X syndrome among the mentally retarded. American Journal of Human Genetics, 1997, v61, 660 to 667.

Franke, P. Leboyer, M., Hardt, J., Sohne, E., Weiffenbach, O., Biancalana, V, Cornillet Lefebre, P., Delobel, B., Froster, U., Schwab, S., Poustka, F., Hautzinger, M., Maier, W., Neuropsychological profiles of FMR1 premutation and full mutation carrier females. Psychiatry Research, 1999, v87, 223 to 231.

Fu, Y., Kuhl, D., Pizzuti, A., Variation of the CGG repeat at the fragile X site results in genetic instability. Cell, 1991, v67, 1047 to 1058.

Hamel, K., Van den Helm, B., De Wijs, J., Sistermans, E., Ropers, h., Mariman, E., Localization of the gene for a syndrome with X linked mental retardation, ataxia, weakness, hearing impairment, loss of vision, and a fatal course in early childhood. Human Genetics, 1996, v98, 513 to 517.

Hinton, V., Brown, W., Wisniewski, K. Rudelli, R., Analysis of neocortex in three males with the fragile X syndrome. American Journal of Medical Genetics, 1991, v41, 289 to 294.

Jacomb, P., Jorm, A., Croft, L., Gao, X., Easteal, S., HLA A and CTGB33 polymorphisms and variation in IQ scores. Personality and Individual Differences, 1999, v26, 795 to 799.

Lehmann, D., Wiebusch, H., Marshall, S., Johnston, C., Warden, D., Morgan, K., Schnappert, K., Poirier, J., Xuereb, N., Kalsheker, N., Welsh, K., Smith, A., HLA class I, II, & III genes in confirmed late onset Alzheimer's disease. Neurobiology of Aging, 2001, v22, 71 to 77.

Mazzocco, M., Reiss, A., Normal Variation in size of the FMR2 gene is not associated with variation in intellectual performance. Intelligence, 1999, v27, 175 to 182.

Menon, V., Kxon, H., Eliez, S., Taylor, A., Reiss, A., Functional brain activation during cognition is related to FMR1 gene expression. Brain Research, 2000, v877, 367 to 370.

Moises, H., Yang, L., Kohnke, M., Vetter, P., Neppert, J., Petrill, S., Plomin, R., Mitochondrial DNA marker EST00083 is not associated with high vs. average IQ in a German sample. Intelligence, 1999, v26, 344 to 382.

Nussbaum, R., Orrison, B., Janne, P., Charnas, L., Chinault, A., Physical mapping and genomic structure of the Lowe syndrome gene. Human Genetics, 1997, v99, 145 to 150.

Owen, M., Liddell, M., and McGuffin, P., Alzheimer's Disease: an association with apolipoprotein E4 may help unlock the puzzle. British Medical Journal, 1994, v308, 672 to 673.

Plomin, R., McClearn, G., Smith, D., DNA markers associated with high versus low IQ. Behavioral Genetics, 1994, 24, 107 to 118.

Turic, D., Fisher, P., Plomin, R., Owen, M., No association between apolipoprotein E polymorphisms and general cognitive ability in children. Neuroscience Letters, 2001, v299, 97 to 100.

Wright, Karen (1999)Why are you so smart?, Discover, Vol.20 Issue 10, p40.

Tsien, Joe Z. (2000)Building a Brainier Mouse, Scientific American, Vol.282 Issue 4, p62.

Henn, Wolfram (2000)Consumerism in prenatal diagnosis: a challenge for ethical quidelines Journal of Medical Ethics, Vol.26, p444-446.

Travis, J. (1999)Gene tinkering makes memorable mice...Science News, Vol. 156 Issue 10, p149.

Clothier, J. L. (1997). Behavioral genetics. Genetics. Dept. of Psychiatry. www. uams.edu.1-6

Herrnstien R.J., Murray C. The Bell Curve: Intelligence and Class Structure in American Life . New york: Free Press ,1994. 845 pp. ISBN

Kalet J.W. Biological Pychology . Pacific Grove: Brooks Cole publishing,1998. pp.135-145

Sherman S.L., Defries, J.C.(1997) Behavioral genetics '97 ASHG Statement. Recent developements in human behavioral genetics : past accomplishments and future directions. American Journal of Human Genetics. 60: 1265-1275.

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