Developmental dyslexia: genetic dissection of a complex cognitive trait

Abstract

Developmental dyslexia, a specific impairment of reading ability despite adequate intelligence and educational opportunity, is one of the most frequent childhood disorders. Since the first documented cases at the beginning of the last century, it has become increasingly apparent that the reading problems of people with dyslexia form part of a heritable neurobiological syndrome. As for most cognitive and behavioural traits, phenotypic definition is fraught with difficulties and the genetic basis is complex, making the isolation of genetic risk factors a formidable challenge. Against such a background, it is notable that several recent studies have reported the localization of genes that influence dyslexia and other language-related traits. These investigations exploit novel research approaches that are relevant to many areas of human neurogenetics.

Key Points

  • Despite decades of multidisciplinary investigation, the biological basis of dyslexia — a specific impairment of reading ability — remains obscure. But a series of recent studies has emphasized the contribution of genetic factors to this disorder.

  • Dyslexia runs in families, and studies of monozygotic and dizygotic twins have provided valuable insights into the heritability of the condition. Methods developed for these studies have also aided in the genetic mapping of this reading disability.

  • For several reasons, the genetic analysis of dyslexia is complex. For example, there is no straightforward correspondence between genotype and phenotype, and phenotypic variations can depend on the developmental stage of the subject. Similarly, there is a lack of consensus on the definition of dyslexia, and on whether it is a single trait or a cluster of traits with distinct aetiologies.

  • Successful localization of genes that influence dyslexia has been aided by innovations in three areas. First, methods have been developed for mapping genes that contribute to quantitative variability in reading performance. Second, researchers are dissecting the phenotypic profile into distinct but related components for genetic study. Third, it is now possible to scan all chromosomes of the genome when searching for genes that influence complex traits such as dyslexia.

  • Targeted linkage studies of dyslexia have provided strong evidence that two chromosomal regions — 15q21 and 6p21 — are involved in this syndrome. Similarly, genome-wide scans have identified further regions on chromosomes 2, 3 and 18 that seem to be linked to dyslexia in multiple independent sets of families.

  • Although the linkage results highlight chromosomal regions that are involved in dyslexia susceptibility, finding individual genes that are affected remains a daunting task. So far, no specific dyslexia gene has been identified, but studies of speech and language deficits have found a gene — FOXP2 — that is responsible for a rare form of the disorder.

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Figure 1: IBD allele sharing can be assessed using polymorphic genetic markers.
Figure 2: Methods for QTL-based linkage mapping in humans.
Figure 3: Replicated regions of chromosomes 2, 3, 6, 15 and 18 implicated by linkage studies of dyslexia.
Figure 4: Genetic dissection of dyslexia.

References

  1. 1

    Hinshelwood, J. Word blindness and visual memories. Lancet 2, 1566–1570 (1895).

  2. 2

    Morgan, W. P. A case of congenital word blindness. Br. Med. J. 2, 1378 (1896).

  3. 3

    Orton, S. T. Word-blindness in school children. Arch. Neurol. Psychiatr. 14, 582–615 (1925).

  4. 4

    Snowling, M. J. From language to reading and dyslexia. Dyslexia 7, 37–46 (2001).

  5. 5

    Wolf, M. & Bowers, P. G. Naming-speed processes and developmental reading disabilities: an introduction to the special issue on the double-deficit hypothesis. J. Learn. Disabil. 33, 322–324 (2000).

  6. 6

    Eden, G. F. et al. Abnormal processing of visual motion in dyslexia revealed by functional brain imaging. Nature 382, 66–69 (1996).

  7. 7

    Temple, E. et al. Disruption of the neural response to rapid acoustic stimuli in dyslexia: evidence from functional MRI. Proc. Natl Acad. Sci. USA 97, 13907–13912 (2000).

  8. 8

    Nicolson, R. I., Fawcett, A. J. & Dean, P. Developmental dyslexia: the cerebellar deficit hypothesis. Trends Neurosci. 24, 508–511 (2001).

  9. 9

    Stein, J. & Walsh, V. To see but not to read; the magnocellular theory of dyslexia. Trends Neurosci. 20, 147–152 (1997).

  10. 10

    Hari, R. & Renvall, H. Impaired processing of rapid stimulus sequences in dyslexia. Trends Cogn. Sci. 5, 525–532 (2001).

  11. 11

    Habib, M. The neurological basis of developmental dyslexia. An overview and working hypothesis. Brain 123, 2373–2399 (2000).A comprehensive discussion of multidisciplinary investigations into the aetiology of dyslexia.

  12. 12

    Thomas, C. J. Congenital 'word-blindness' and its treatment. Ophthalmoscope 3, 380–385 (1905).

  13. 13

    Stephenson, S. Six cases of congenital word-blindness affecting three generations of one family. Ophthalmoscope 5, 482–484 (1907).

  14. 14

    Hallgren, B. Specific dyslexia ('congenital word blindness'): a clinical and genetic study. Acta Psychiatr. Neurol. Scand. 65 (Suppl.), 1–287 (1950).

  15. 15

    Finucci, J. M., Guthrie, J. T., Childs, A. L., Abbey, H. & Childs, B. The genetics of specific reading disability. Ann. Hum. Genet. 40, 1–23 (1976).

  16. 16

    Lewitter, F. I., DeFries, J. C. & Elston, R. C. Genetic models of reading disabilities. Behav. Genet. 10, 9–30 (1980).

  17. 17

    Vogler, G. P., DeFries, J. C. & Decker, S. N. Family history as an indicator of risk for reading disability. J. Learn. Disabil. 18, 419–421 (1985).

  18. 18

    Pennington, B. F. et al. Evidence for major gene transmission of developmental dyslexia. JAMA 266, 1527–1534 (1991).

  19. 19

    Wolff, P. H. & Melngailis, I. Family patterns of developmental dyslexia: clinical findings. Am. J. Med. Genet. 54, 122–131 (1994).

  20. 20

    Bakwin, H. Reading disability in twins. Dev. Med. Child Neurol. 15, 184–187 (1973).

  21. 21

    Stevenson, J., Graham, P., Fredman, G. & McLoughlin, V. A twin study of genetic influences on reading and spelling ability and disability. J. Child Psychol. Psychiatry 28, 229–247 (1987).

  22. 22

    DeFries, J. C., Fulker, D. W. & LaBuda, M. C. Evidence for a genetic aetiology in reading disability of twins. Nature 329, 537–539 (1987).

  23. 23

    DeFries, J. C. & Alarcón, M. Genetics of specific reading disability. Ment. Retard. Dev. Disabil. Res. Rev. 2, 39–47 (1996).

  24. 24

    Pennington, B. F. & Lefly, D. L. Early reading development in children at family risk for dyslexia. Child Dev. 72, 816–833 (2001).

  25. 25

    DeFries, J. C. & Fulker, D. W. Multiple regression analysis of twin data. Behav. Genet. 15, 467–473 (1985).

  26. 26

    DeFries, J. C. & Gillis, J. J. in Nature, Nurture, and Psychology (eds Plomin, R. & McClearn, G.) 121–145 (American Psychiatric Association, Washington DC, 1993).

  27. 27

    Gayán, J. & Olson, R. K. Genetic and environmental influences on orthographic and phonological skills in children with reading disabilities. Dev. Neuropsychol. 20, 483–507 (2001).

  28. 28

    Bishop, D. V. M. et al. Different origin of auditory and phonological processing problems in children with language impairment: evidence from a twin study. J. Speech Lang. Hear. Res. 42, 155–168 (1999).

  29. 29

    Stevenson, J. Evidence for a genetic etiology in hyperactivity in children. Behav. Genet. 22, 337–344 (1992).

  30. 30

    Fisher, S. E. & Smith, S. D. in Dyslexia: Theory and Good Practice (ed. Fawcett, A. J.) 39–64 (Whurr, London, UK, 2001).

  31. 31

    Fisher, S. E. in Behavioral Genetics in the Postgenomic Era (eds Plomin, R., DeFries, J. C., Craig, I. W. & McGuffin, P.) 205–226 (American Psychiatric Association, Washington DC, 2002).

  32. 32

    Smith, S. D., Kimberling, W. J., Pennington, B. F. & Lubs, H. A. Specific reading disability: identification of an inherited form through linkage analysis. Science 219, 1345 (1983).

  33. 33

    Cardon, L. R. et al. Quantitative trait locus for reading disability on chromosome 6. Science 266, 276–279 (1994).An early demonstration of the value of applying QTL mapping methods to continuous measures of cognitive ability. Strong evidence was provided for a locus on 6p, which was subsequently verified in several independent populations.

  34. 34

    Cardon, L. R. et al. Quantitative trait locus for reading disability: correction. Science 268, 1553 (1995).

  35. 35

    Grigorenko, E. L. et al. Susceptibility loci for distinct components of developmental dyslexia on chromosomes 6 and 15. Am. J. Hum. Genet. 60, 27–39 (1997).This paper proposed the intriguing idea that differing aspects of the dyslexia profile might link to distinct genetic loci. Although some conclusions from this study have been criticized, it raised the key question of whether we can reliably dissect complex cognitive phenotypes using genetic linkage data.

  36. 36

    Field, L. L. & Kaplan, B. J. Absence of linkage of phonological coding dyslexia to chromosome 6p23–p21.3 in a large family data set. Am. J. Hum. Genet. 63, 1448–1456 (1998).

  37. 37

    Fisher, S. E. et al. A quantitative trait locus on chromosome 6p influences different aspects of developmental dyslexia. Am. J. Hum. Genet. 64, 146–156 (1999).

  38. 38

    Bisgaard, M. L., Eiberg, H., Moller, N., Niebuhr, E. & Mohr, J. Dyslexia and chromosome 15 heteromorphism: negative lod score in a Danish sample. Clin. Genet. 32, 118–119 (1987).

  39. 39

    Froster, U., Schulte-Körne, G., Hebebrand, J. & Remschmidt, H. Cosegregation of balanced translocation (1;2) with retarded speech development and dyslexia. Lancet 342, 178–179 (1993).

  40. 40

    Schulte-Körne, G. et al. Evidence for linkage of spelling disability to chromosome 15. Am. J. Hum. Genet. 63, 279–282 (1998).

  41. 41

    Fagerheim, T. et al. A new gene (DYX3) for dyslexia is located on chromosome 2. J. Med. Genet. 36, 664–669 (1999).The successful genome-wide application of traditional parametric methods led to the localization of a dyslexia risk gene in a single large pedigree.

  42. 42

    Nopola-Hemmi, J. et al. A dominant gene for developmental dyslexia on chromosome 3. J. Med. Genet. 38, 658–664 (2001).A genome-wide study of a large extended family identified a susceptibility locus for dyslexia on chromosome 3. References 41 and 42 provide a clear example of genetic heterogeneity, even when investigating multigenerational pedigrees.

  43. 43

    Castles, A. & Coltheart, M. Varieties of developmental dyslexia. Cognition 47, 149–180 (1993).

  44. 44

    Castles, A., Datta, H., Gayán, J. & Olson, R. K. Varieties of developmental reading disorder: genetic and environmental influences. J. Exp. Child Psychol. 72, 73–94 (1999).

  45. 45

    Lander, E. S. & Schork, N. J. Genetic dissection of complex traits. Science 265, 2037–2048 (1994).An excellent introduction to key concepts of complex genetic analysis.

  46. 46

    Haseman, J. K. & Elston, R. C. The investigation of linkage between a quantitative trait and a marker locus. Behav. Genet. 2, 3–19 (1972).

  47. 47

    Cardon, L. R. & Fulker, D. W. The power of interval mapping of quantitative trait loci, using selected sib pairs. Am. J. Hum. Genet. 55, 825–833 (1994).

  48. 48

    Amos, C. I. Robust variance-components approach for assessing genetic linkage in pedigrees. Am. J. Hum. Genet. 54, 535–543 (1994).

  49. 49

    Allison, D. B. et al. Testing the robustness of the likelihood-ratio test in a variance-component quantitative-trait loci-mapping procedure. Am. J. Hum. Genet. 65, 531–544 (1999).

  50. 50

    Fisher, S. E. et al. Independent genome-wide scans identify a chromosome 18 quantitative-trait locus influencing dyslexia. Nature Genet. 30, 86–91 (2002).This paper reported the first QTL-based genome-wide linkage scans for dyslexia, yielding robust evidence for a chromosome 18 locus influencing dyslexia in three independent samples of sib-pairs, and implicating a number of other potential loci of interest.

  51. 51

    Gayán, J. et al. Quantitative trait locus for specific language and reading deficits on chromosome 6p. Am. J. Hum. Genet. 64, 157–164 (1999).

  52. 52

    Davis, C. J. et al. Etiology of reading difficulties and rapid naming: the Colorado Twin Study of Reading Disability. Behav. Genet. 31, 625–635 (2001).

  53. 53

    Wijsman, E. M. et al. Segregation analysis of phenotypic components of learning disabilities. I. Nonword memory and digit span. Am. J. Hum. Genet. 67, 631–646 (2000).

  54. 54

    Raskind, W. H., Hsu, L., Berninger, V. W., Thomson, J. B. & Wijsman, E. M. Familial aggregation of dyslexia phenotypes. Behav. Genet. 30, 385–396 (2000).

  55. 55

    Marlow, A. J. et al. Investigation of quantitative measures related to reading disability in a large sample of sib-pairs from the UK. Behav. Genet. 31, 219–230 (2001).

  56. 56

    Fisher, S. E., Stein, J. F. & Monaco, A. P. A genome-wide search strategy for identifying quantitative trait loci involved in reading and spelling disability (developmental dyslexia). Eur. Child Adolesc. Psychiatry 8 (Suppl. 3), 47–51 (1999).

  57. 57

    Kruglyak, L. & Lander, E. S. Complete multipoint sib-pair analysis of qualitative and quantitative traits. Am. J. Hum. Genet. 57, 439–454 (1995).

  58. 58

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

  59. 59

    The SLI consortium. A genomewide scan identifies two novel loci involved in specific language impairment. Am. J. Hum. Genet. 70, 384–398 (2002).

  60. 60

    Lander, E. & Kruglyak, L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nature Genet. 11, 241–247 (1995).A technical overview of central concerns in the sound interpretation of linkage data when analysing complex traits.

  61. 61

    Altmüller, J., Palmer, L. J., Fischer, G., Scherb, H. & Wjst, M. Genomewide scans of complex human diseases: true linkage is hard to find. Am. J. Hum. Genet. 69, 936–950 (2001).

  62. 62

    Rabin, M. et al. Suggestive linkage of developmental dyslexia to chromosome 1p34–p36. Lancet 342, 178 (1993).

  63. 63

    Smith, S. D., Kimberling, W. J. & Pennington, B. F. Screening for multiple genes influencing dyslexia. Read. Writ. 3, 285–298 (1991).

  64. 64

    Fulker, D. W. et al. Multiple regression of sib-pair data on reading to detect quantitative trait loci. Read. Writ. 3, 299–313 (1991).

  65. 65

    Grigorenko, E. L., Wood, F. B., Meyer, M. S. & Pauls, D. L. Chromosome 6p influences on different dyslexia-related cognitive processes: further confirmation. Am. J. Hum. Genet. 66, 715–723 (2000).

  66. 66

    Geschwind, N. & Behan, P. Left-handedness: association with immune disease, migraine, and developmental learning disorder. Proc. Natl Acad. Sci. USA 79, 5097–5100 (1982).

  67. 67

    Gilger, J. W. et al. A twin and family study of the association between immune system dysfunction and dyslexia using blood serum immunoassay and survey data. Brain Cogn. 36, 310–333 (1998).

  68. 68

    Petryshen, T. L., Kaplan, B. J., Liu, M. F. & Field, L. L. Absence of significant linkage between phonological coding dyslexia and chromosome 6p23–21.3, as determined by use of quantitative-trait methods: confirmation of qualitative analyses. Am. J. Hum. Genet. 66, 708–714 (2000).

  69. 69

    Grigorenko E. L. et al. Linkage studies suggest a possible locus for developmental dyslexia on chromosome 1p. Am. J. Med. Genet. 105, 120–129 (2001).

  70. 70

    Petryshen T. L. et al. Evidence for a susceptibility locus on chromosome 6q influencing phonological coding dyslexia. Am. J. Med. Genet. 105, 507–517 (2001).

  71. 71

    Francks, C. et al. Quantitative association analysis within the chromosome 2p12–16 dyslexia susceptibility region: microsatellite markers and candidate genes SEMA4F and OTX1. Psychiatr. Genet. 12, 35–41 (2002).

  72. 72

    Petryshen, T. L., Kaplan, B. J., Hughes, M. L., Tzenova, J. & Field, L. L. Supportive evidence for the DYX3 dyslexia susceptibility gene in Canadian families. J. Med. Genet. 39, 125–126 (2002).

  73. 73

    Nopola-Hemmi, J. et al. Two translocations of chromosome 15q associated with dyslexia. J. Med. Genet. 37, 771–775 (2000).

  74. 74

    Cardon, L. R. & Bell, J. I. Association study designs for complex diseases. Nature Rev. Genet. 2, 91–99 (2001).

  75. 75

    Morris, D. W. et al. Family-based association mapping provides evidence for a gene for reading disability on chromosome 15q. Hum. Mol. Genet. 9, 843–848 (2000).Converging evidence for a locus on 15q has been revealed by complementary approaches to linkage mapping, including this report of association and a study of chromosomal abnormalities (reference 73).

  76. 76

    Kaplan, D. E. et al. Evidence for linkage and association with reading disability on 6p21.3–22. Am. J. Hum. Genet. 70, 1287–1298 (2002).

  77. 77

    Pennington, B. F. Using genetics to dissect cognition. Am. J. Hum. Genet. 60, 13–16 (1997).An insightful critique of the suggestion that genes might show simple mapping to individual cognitive processes that underlie dyslexia.

  78. 78

    Goring, H. H., Terwilliger, J. D. & Blangero, J. Large upward bias in estimation of locus-specific effects from genomewide scans. Am. J. Hum. Genet. 69, 1357–1369 (2001).

  79. 79

    Willcutt, E. G. et al. Quantitative trait locus for reading disability on chromosome 6p is pleiotropic for attention-deficit/hyperactivity disorder. Am. J. Med. Genet. 114, 260–268 (2002).

  80. 80

    Lai, C. S. L. et al. The SPCH1 region on human 7q31: genomic characterization of the critical interval and localization of translocations associated with speech and language disorder. Am. J. Hum. Genet. 67, 357–368 (2000).

  81. 81

    Lai, C. S. L., Fisher, S. E., Hurst, J. A., Vargha-Khadem, F. & Monaco, A. P. A forkhead-domain gene is mutated in a severe speech and language disorder. Nature 413, 519–523 (2001).This paper reports the identification of the FOXP2 gene and shows that its disruption causes one form of speech and language impairment. This is the only known case of a direct link between a specific gene and this type of developmental disorder.

  82. 82

    Newbury, D. F. et al. FOXP2 is not a major susceptibility gene for autism or Specific Language Impairment (SLI). Am. J. Hum. Genet. 70, 1318–1327 (2002).

  83. 83

    Nokelainen, P. & Flint, J. Genetic effects on human cognition: lessons from the study of mental retardation syndromes. J. Neurol. Neurosurg. Psychiatry 72, 287–296 (2002).

  84. 84

    Thomson, M. E. The assessment of children with specific reading disabilities (dyslexia) using the British Ability Scales. Br. J. Psychol. 73, 461–478 (1982).

  85. 85

    Siegel, L. S. & Himel, N. Socioeconomic status, age and the classification of dyslexics and poor readers: the dangers of using IQ scores in the definition of reading disability. Dyslexia 4, 90–103 (1998).

  86. 86

    Pennington, B. F., Gilger, J. W., Olson, R. K. & DeFries, J. C. The external validity of age- versus IQ-discrepancy definitions of reading disability: lessons from a twin study. J. Learn. Disabil. 25, 562–573 (1992).

  87. 87

    Shapiro, B. K. Specific reading disability: a multiplanar view. Ment. Retard. Dev. Disabil. Res. Rev. 7, 13–20 (2001).

  88. 88

    Shaywitz, S. E. et al. Persistence of dyslexia: the Connecticut Longitudinal Study at adolescence. Pediatrics 104, 1351–1359 (1999).

  89. 89

    Nehls, M., Pfeifer, D., Schorpp, M., Hedrich, H. & Boehm, T. New member of the winged-helix protein family disrupted in mouse and rat nude mutations. Nature 372, 103–107 (1994).

  90. 90

    Nishimura, D. Y. et al. The forkhead transcription factor gene FKHL7 is responsible for glaucoma phenotypes which map to 6p25. Nature Genet. 19, 140–147 (1998).

  91. 91

    Fang, J. et al. Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema–distichiasis syndrome. Am. J. Hum. Genet. 67, 1382–1388 (2000).

  92. 92

    Brunkow, M. E. et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nature Genet. 27, 68–73 (2001).

  93. 93

    Crisponi, L. et al. The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome. Nature Genet. 27, 159–166 (2001).

  94. 94

    Hurst, J. A., Baraitser, M., Auger, E., Graham, F. & Norell, S. An extended family with a dominantly inherited speech disorder. Dev. Med. Child Neurol. 32, 347–355 (1990).

  95. 95

    Vargha-Khadem, F., Watkins, K., Alcock, K., Fletcher, P. & Passingham, R. Praxic and nonverbal cognitive deficits in a large family with a genetically transmitted speech and language disorder. Proc. Natl Acad. Sci. USA 92, 930–933 (1995).

  96. 96

    Bishop, D. V. M. Putting language genes in perspective. Trends Genet. 18, 57–59 (2002).An interesting discussion of what the discovery of FOXP2 might tell us about speech and language development.

  97. 97

    Fisher S. E. in Neurosciences at the Postgenomic Era (eds Mallet, J. & Christen, Y.) (Springer–Verlag, Heidelberg, Germany, 2002).

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Acknowledgements

S.E.F. is a Royal Society Research Fellow. J.C.D. is supported by a centre grant from the National Institute of Child Health and Human Development.

Author information

Correspondence to Simon E. Fisher.

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DATABASES

LocusLink

FOXP2

OMIM

ADHD

dyslexia

OMIM Gene Map

1p22

1p34–36

2p15–16

2q31

3p12–q13

6p21.3

6q12

15q21

18p11.2

FURTHER INFORMATION

Encyclopedia of Life Sciences

language

quantitative genetics

MIT Encyclopedia of Cognitive Sciences

dyslexia

language impairment, developmental

reading

visual word recognition

Wellcome Trust Centre for Human Genetics

FOXP2 in Speech and Language Disorder

Genetics of Developmental Dyslexia

Genetics of Specific Language Impairment

Glossary

PHONEMES

Individual units of speech sound that combine to make words.

MENDELIAN

A trait resulting from changes in a single gene that has a significant effect on the phenotype and is inherited in a simple pattern that is similar or identical to those described by Gregor Mendel. Also referred to as monogenic.

PROBAND

Usually, the person who serves as the starting point of a genetic study.

MONOZYGOTIC

Twins that develop from a single fertilized egg cell through its division into two genetically identical parts.

DIZYGOTIC

Twins that develop during the same pregnancy as the result of two separate eggs being fertilized by two separate sperm.

HERITABILITY

The proportion of variability in a particular characteristic that can be attributed to genetic influences. This is a statistical description that applies to a specific population and might change if the environment is altered.

SPECIFIC LANGUAGE IMPAIRMENT

A significant deficit in language development in children with normal non-verbal intelligence that cannot be attributed to hearing loss, inadequate educational opportunity or obvious neurological impairment.

ATTENTION-DEFICIT/HYPERACTIVITY DISORDER

A common disorder with childhood onset, in which persistent inattention and/or hyperactive–impulsive behaviour leads to impaired social and/or academic functioning.

CANDIDATE GENE

A gene that encodes a protein, the expected or known function of which indicates that it might be responsible for a disease or trait in a population of individuals. Pure candidate-gene approaches do not exploit or require information on chromosomal location (in contrast to 'positional cloning').

POLYMORPHIC GENETIC MARKERS

Naturally occurring variants in DNA sequence that can be used to track the inheritance pattern of a particular chromosomal location.

POSITIONAL CLONING

A strategy for the identification of disease genes on the basis of marker inheritance data from affected families that does not require any prior knowledge of the underlying biological pathways or gene function (in contrast to 'candidate-gene' approaches). In recent years, a blend of positional cloning and candidate-gene approaches (sometimes referred to as a 'positional-candidate' strategy) has often been used, involving the combined use of data on map location and expected gene function.

GENOTYPE

The genetic constitution of an individual. This can refer to the entire complement of genetic material or to a specific gene (or set of genes).

PHENOTYPE

The appearance of an individual in terms of a particular characteristic (physical, biochemical, physiological and so on), resulting from interactions between the individual's genotype and the environment.

PENETRANCE

The probability that an individual with a particular genotype manifests a given phenotype. Complete penetrance corresponds to the situation in which every individual with the same specific genotype manifests the phenotype in question.

PHENOCOPIES

People who manifest the same phenotype as other individuals of a particular genotype, but do not possess this genotype themselves. For example, this might occur when environmental influences alone evoke a developmental trait that has a similar genetic counterpart.

OLIGOGENICITY

When a few different genes work together to contribute to a particular phenotype.

POWER

The probability of correctly rejecting the null hypothesis when it is truly false. For linkage studies, the null hypothesis is that of 'no linkage', so the power represents the probability of correctly detecting a genuine linkage.

QUANTITATIVE TRAIT LOCUS

(QTL). A genetic locus or chromosomal region that contributes to variability in a complex quantitative trait (such as body weight), as identified by statistical analysis.

POLYGENIC

The effects of a large number of different genes, each of which has a slight influence on the phenotypic outcome.

GRAPHEME

A written symbol, or group of symbols, that is used to represent a specific phoneme.

MULTIPOINT ANALYSIS

The use of data obtained from multiple neighbouring genetic markers on the same chromosome to extract linkage information at many points across a genomic region.

SINGLE-POINT ANALYSIS

The investigation of linkage at one point on a chromosome, using data from a single marker.

LOD SCORE

Linkage mapping involves comparing two likelihoods. The first is the likelihood of the data, under the hypothesis that there is linkage between inheritance of the trait and that of the chromosomal region in question. The second is the likelihood of the data, under the null hypothesis that there is no linkage. The lod score is the logarithm of the likelihood ratio; if it exceeds a given threshold, the null hypothesis can be rejected.

CHROMOSOMAL HETEROMORPHISM

Natural variation in the shape or staining pattern of a chromosome, as viewed under the microscope.

CENTROMERE

The constricted region of a chromosome that includes the site of attachment to the mitotic or meiotic spindle. Geneticists divide the chromosome into 'short' and 'long' arms, which are separated by this centromere.

CENTIMORGAN

A standard measure of genetic distance that is derived from observations of recombination between neighbouring loci. The relationship to actual physical distance along a chromosome varies throughout the genome; on average, 1 centimorgan corresponds to around one million bases of DNA.

HLA COMPLEX

A well-studied region of chromosome 6p that contains many loci, such as the human leukocyte antigen (HLA) genes, which encode key components of the immune system. Also known as the major histocompatibility complex (MHC).

AUTOSOMAL DOMINANT

One type of inheritance pattern that is observed for monogenic traits. Autosomes are any chromosomes in a cell that are not sex chromosomes. Autosomal dominant transmission results when an abnormal copy of an autosomal gene from a single parent gives rise to the trait, even though the copy inherited from the other parent is normal.

TRANSLOCATION

A genetic rearrangement in which part of a chromosome is detached by breakage and becomes attached to another part of the same chromosome, or to a different chromosome.

DUPLICATION

A genetic rearrangement that involves the doubling or repetition of part of a chromosome.

DELETION

A genetic rearrangement that involves the loss of part of a chromosome.

INVERSION

A genetic rearrangement in which part of a chromosome is reversed, so that the genes within that part are in inverse order.

BREAKPOINT

The specific site of chromosomal breakage that is associated with a particular chromosomal rearrangement.

LINKAGE DISEQUILIBRIUM

Non-random association between specific allelic variants at one genetic locus and those at another genetic locus that maps nearby.

EFFECT SIZE

A standardized measure of effect that is adopted when different scales are used to measure an outcome. In QTL analyses, the effect size is the proportion of variability in a measure that is attributable to the genetic locus of interest.

TRANSCRIPTION FACTOR

A DNA-binding protein that regulates gene expression.

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