NCB-IDA Spring 2004 Newsletter: Genes and Dyslexia

Genes and Dyslexia
by Jeffrey W. Gilger, Ph.D.

The normal human genetic complement is approximately 30,000 to 50,000 genes. It is thought that approximately 30% of these genes influence brain development or brain activity directly (Adams et al., 1991; Raff, 1996), while the remaining 70% are involved in other body systems and processes. Some of these other systems or processes may affect the central nervous system (CNS) as well as other structures relevant to reading development (e.g., visual and hearing mechanisms). Genes are involved to some degree in all human behaviors, including learning disabilities (LD), and this makes sense in that we are, after all, organic beings (Gilger, 2000).

What is a Gene? This is not an easy question to answer and advances in our understanding of genes have complicated the matter. The definition of a gene varies with the level of analysis (Hartl & Jones, 2001). For our purposes, a gene is defined as a portion of Deoxyribonucleic Acid (DNA) that contains the code for certain proteins or enzymes that control, moderate, and effect the basic structures and processes of all aspects of what it is to be human (e.g., prenatal brain development, bone growth, pubertal timing, hair color, metabolism, neurochemical production, etc.).

Genes are on chromosomes. We normally have 46 chromosomes (23 pairs, with one member of each pair coming from our fathers and the other from our mothers), each of which is essentially a long strand of DNA. Portions of these DNA strands represent the 40,000 or so distinct genes in the human genome. For a gene to be "active" it goes through a number of steps, including the transcription of DNA into a related molecule called ribonucleic acid or RNA (Hartl & Jones, 2001). RNA is in turn translated into the components of proteins or enzymes that can be used by the human body. There are intervening steps and complexities to the simplified process just de-scribed but for our purposes the process is essentially: DNA to RNA to PROTEIN.

Because we are all human we have many genes in common. For example, we all have genes that affect height and weight, eye color, learning skills, the number of fingers on our hands, and intelligence. However, there are variants of these genes in the population such that people can look different, have different abilities, and so on. Again, we all have the same basic genes, but variations in the DNA code for these genes can yield differences in the product of the gene and/or the gene¹s expression and thus contribute to individual differences in the population for the behavior or trait in question.

There is now solid evidence that various developmental disorders like dyslexia reflect the effects of genes (reviewed in Smith, Gilger & Pennington, 2002; Gerber, 2001). Everyone with an interest in learning disabilities, be they parent, teacher or researcher, should be aware of this fact and as we come to understand more about genetics, the practical role that genetics plays in diagnosis and treatment will likely increase.

How Do Genes Affect Reading-Related Skills?

The answer to this question is complex and not fully understood. For one thing, gene effects only culminate in a behavior after going through a variety of intermediary steps and interactions, including responses to, and interactions with, the environment. Thus, traits with a genetic component are not immutable or predetermined. Rather, they can be modified through the environment and for this reason it is better to speak in terms of probabilities of outcomes and risks due to genes instead of absolutes like genetic causes.

We also know that the process of going from gene to behavior is develop-mental. For instance, we can think of genes affecting the brain and consequently a behavior like reading in a proximal (closely related) or distal (distantly related) manner (Gilger, 1995; Raff, 1996): Different genes turn on and off at different times in our lives such that the structures of, for instance, a school-aged child¹s brain largely reflect the distal effects of genes that become dormant just before birth (e.g., a once active gene that coded for embryologic neuronal cell migration, death, and differentiation in the second trimester in-utero); whereas the functioning of a child¹s brain while he or she is learning to read may reflect more proximal gene effects (e.g., gene actions at the time of the brain-based behavior, such as those of genes that regulate brain activation and the levels of certain neurotransmitters).

Indeed, it is hypothesized that distal gene effects appear to be involved in the micro- and macro-malformations of the "language areas" of the brain often found in individuals with dyslexia (e.g., see Eden and Sherman in this issue; Chase, Rosen & Sherman, 1996; Grigorenko, 2001; Smith, Gilger & Pennington, 2002). During embryogenesis certain cells may fail to properly migrate and make connections in the parts of the brain needed for normal reading-related skills. Thus, much of the neurological mal-development thought to lead to language-based disorders may have occurred during key developmental periods before birth. While there is little hope of directly ameliorating such structural defects in the brain in school-aged children or adults through methodologies currently available, there may be ways to help individuals with dyslexia to use more intact brain systems to compensate for systems that are mal-developed. Standard remediation techniques do in fact have their effect through functional neurocognitive systems mediated by a variety of currently (proximal) and once expressed (distal) genes. (See Eden in this issue for studies that show how the brain can be responsive to remediation. This brain response shown in the images Eden discusses is due to the proximal effects of genes interacting with an environmental input.)

Brief Update on the Genetics of Dyslexia

There is a lot known about the genetics of dyslexia. This paper focuses on two aspects of this area of study: how and if dyslexia runs in families (familial aggregation) and the current status of molecular genetic research where the actual "genes for dyslexia" are being sought.

First, it is abundantly clear that dyslexia can be familial. This fact has implications for clinical work in the areas of diagnosis, prognosis and parent counseling. Moreover, twin and other studies show us that the familiality observed for dyslexia is not due to learning or a "poor" family/reading environment, and instead dyslexia and related disorders run in families primarily because of nature and not nurture (DeFries & Alarcon, 1996; Smith et al., 2002).

Specifically, research indicates that roughly 40-50% of the first-degree relatives (siblings and parents) of an individual with dyslexia are likely to have or have had reading problems. The actual amount of increased risk varies depending on the sex of the relative and the child, and other factors (Smith, Gilger & Pennington, 2002; Scarborough, 1989; Gilger, Pennington & DeFries, 1991).

Some children with dyslexia grow up to be adequate or normal readers as adults and they appear to have "compensated" for their learning disability. One study suggests that a child¹s likelihood to compensate for his or her dyslexia varies with the compensation status of his or her parents (Gilger et al., 1996). Children from families where parents have compensated for their own childhood dyslexia stand a better chance of compensating than do children with parents that have not compensated.

Where are the Genes for Dyslexia? Because dyslexia has a genetic component it is reasonable to look for the genes responsible. Various methods are used in this quest (e.g., linkage and association analyses, candidate gene searches, etc.). All involve extracting DNA (e.g., from blood) and each asks some variation of this basic question: Is dyslexia correlated with, or does it co-occur with a certain area of a chromosome, DNA segment, or a known specific gene? Should a valid correlation be found, the objective is then to characterize these genes and eventually fully understand their role in brain function and development such that reading is affected. This type of work is labor intensive and involves samples of people that are related.

To date no single gene contributing to the risk for dyslexia has been reliably identified, although several "suspect genes" are thought to lie on chromosomes 2, 3, 6, 7, 15, 18, and perhaps others (reviewed in Smith et al., 2002; Grigorenko, 2001; see also Fisher et al., 1998, 2002; Francks et al., 2002; Smith et al., 1998). Among these is a well replicated finding that at least one, as of yet unidentified, gene making people susceptible to dyslexia is located on chromo-some 6 (Smith, Kimberling & Pennington, 1991; Fisher et al., 1998).

This finding is of special interest in that the suspect area of chromosome 6 that may carry the gene (s) is in or near an area on chromosome 6 that carries genes important to the development and function of the immune system/response, and some have noted that immune-related problems are common in people with dyslexia (e.g., Bryden et al., 1994). While this "locational coincidence" is intriguing, it has yet to be fully explored and other research suggests that the immune disorder-dyslexia association is more artifactual than real (Bryden et al., 1994).

Summary

Over the years, the research bridging the fields of genetics and dyslexia has progressed nicely. While there is still much to learn, several conclusions can be drawn from what we now know:

Information acquired from family studies can help with prognostic and diagnostic considerations. For instance, in the future we may regularly use a carefully obtained family history to estimate risk to pre-reading children (i.e., as an index of early identification), make prognostic predictions into adult-hood, and help ascertain if an individual has acquired or develop-mental dyslexia (e.g., given the presence or absence of family history for dyslexia);
There is not a single "dyslexia gene" that insures reading problems. Instead, there are at least several key genes that tend to push an individual toward the low end of the reading continuum. The best model is a probabilistic one, where it is recognized that certain genes, in combination with other factors, add to the risk for dyslexia. This is in contrast to a more disease-oriented single gene model where a gene's effects are more direct and powerful;
More research is needed to better describe and explain the etiology of the individual differences seen in the expression of dyslexia and the "dyslexia genes." While we know that genes and dyslexia are not expressed the same in all people, the mechanisms behind this process are relatively unexplored.

References

Adams, M.D., Kelley, J.M., Gocayne, J.D., Dubnick, M., Polymeropoulos, M.H., Xiao, H., Merril, C.R., Wu, A., Olde, B., Moreno, R.F., Kerlavage, A.R., McCombie, W.R. & Venter, J.C. (1991). Complementary DNA sequencing: Expressed sequence tags and human genome project. Science, 252, 1651-1656.

Bryden, M. P., MacManus, I. C., & Bulman-Fleming, M. B. (1994). Evaluating the empirical support for the Geschwind-Behan-Galaburda model of cerebral lateralization. Brain and Cognition, 26, 103-167.

Chase, C.H., Rosen, G.D. & Sherman, G.F. (Eds.) (1996). Developmental dyslexia: Neural, cognitive, and genetic mechanisms. Baltimore, MD: York Press.

DeFries, J., & Alarcon, M. (1996). Genetics of specific reading disability. Mental Retardation and Developmental Disabilities Research Reviews, 2, 39-47.

Fisher, S. E., Francks, C., Marlow, A. J., MacPhie, I., Newbury, D., Cardon, L. R., Ishikawa-Brush, Y., Richardson, A. J., Talcott, J. B., Gayan, J., Olson, R., Pennington, B. F., Smith, S. D., DeFries, J., Stein, J., & Monaco, A. P. (2002). Independent genomewide scans identify a chromosome 18 quantitative trait locus influencing dyslexia. Nature Genetics, 30, 86-91.

Fisher, S. E., Vargha-Khadem, F., Watkins, K. E., Monaco, A. P., & Pembrey, M. E. (1998). Localization of a gene implicated in a severe speech and language disorder. Nature Genetics, 18, 168-170.

Francks, C., Fisher, S. E., Olson, R. K., Pennington, B. F., Smith, S. D., DeFries, J. C., & Monaco, A. P. (2002). Fine mapping of the chromosome 2p12-16 dyslexia susceptibility locus: Quantitative association analysis and positional candidate genes SEMA4F and OTX1. Psychiatric Genetics, 12, 35-41.

Gerber, S. (2001). Handbook of genetic communicative disorders. Academic Press.

Gilger, J.W. (1995). Behavioral Genetics: Concepts for Research in Language and Language Disabilities. Journal of Speech and Hearing Research, 38, 1126-1142.

Gilger, J.W.(2000) Contribution and promise of human behavioral genetics. Human Biology, 72 (1), 229-255.

Gilger, J.W., Hanebuth, E., Smith, S.D., & Pennington, B.F. (1996). Differential risk for developmental reading disorders in the offspring of compensated versus noncompensated parents. Reading and Writing: An Interdisciplinary Journal, 8, 407-417.

Gilger, J.W., Pennington, B.F., & DeFries, J.C. (1991). Risk for reading disabilities as a function of parental history in three samples of families. Reading and Writing, 3, 205-217.

Grigorenko, E. L. (2001). Developmental dyslexia: An update on genes, brains, and environments. Journal of Child Psychology and Psychiatry, 42, 91-125.

Hartl, D. & Jones, E.W. (2001). Genetics: Analysis of genes and genomes (5th Ed.). Sudbury, MA: Jones and Bartlett, Publishers, Inc.

Raff, M. (1996). Neural development: Mysterious no more? Science, 274, 1063.

Scarborough, H.S. (1989). Prediction of reading disability from familial and individual differences. Journal of Educational Psychology, 81, 101-108.

Smith, S. D., Gilger, J. W., & Pennington, B. F. (2002). Dyslexia and other language/learning disorders. In D.L. Connor & R.E. Pyeritz (Eds.), Emory and Rimoin¹s principles and practices in medical genetics. New York, NY: Livingstone Churchill.

Smith, S. D., Kelley, P. M., & Brower, A. M. (1998). Molecular approaches to the genetic analysis of specific reading disability. Human Biology, 70, 239-256.

Smith, S. D., Kimberling, W. J., & Pennington, B. F. (1991). Screening for multiple genes influencing dyslexia. Reading and Writing: An Interdisciplinary Journal, 3, 285-298.

Jeffrey W. Gilger, Ph.D., is Professor and Chair, Child & Family Studies, California State University at Los Angeles. He is also a Vice-President of IDA and Chair of the IDA Research Subcommittee.

Reprinted with permission from Perspectives

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