Huheey (1977) suggested that preferential right-handedness in man has its evolutionary origin in relation to the tendency of human (and presumably prehuman) mothers to hold infants on the left side. The practice has been ascribed to imprinting and a soothing effect of the sound of the mother's heartbeat on the infant; thus, dextral mothers would be more skillful at manipulation of objects with the free hand and would be selectively favored. Handedness appears to have remained about 93% right-handed over 5,000 years as indicated by a survey of art works (Coren and Porac, 1977).

Laland et al. (1995) presented a model of handedness that proposes that no genetic variation underlies differences in handedness and that variation in handedness among humans is the result of a combination of cultural and developmental factors, with a remaining genetic influence because handedness is a facultative trait.

Klar (1996) presented a genetic model for human handedness that hypothesized the existence of a single gene, designated RGHT (pronounced as right) by him, which confers right-handedness; individuals lacking this gene, RGHT(-)/RGHT(-), display random handedness such that one-half are left-handed (LH) and the other half are right-handed (RH). Tests of the hypothesis were presented using data from Rife (1940). These data involved the families of 687 students attending Ohio State University. Approximately half of the children of LH x LH families were LH and the remainder were RH. Reference was also made to Lefthanders International and the organization's 'Lefthander' magazine, which advertised the survey that was undertaken for these studies.

Geschwind et al. (2002) explored the relative contribution of environmental and genetic influence on cerebral asymmetry by examining the volumes of left and right cerebral cortex in a large cohort of aging identical and fraternal twins and investigated their relationship to handedness. Cerebral lobar volume was found to have a major genetic component, indicating that genes play a large role in changes in brain volume that occur with aging. Shared environment, which likely represents in utero events, had about twice the effect on the left hemisphere as on the right, consistent with less genetic control over the left hemisphere. To test the major genetic models of handedness and cerebral asymmetry, twin pairs were divided into those with 2 right handers and those with at least 1 left hander (nonright handers). Genetic factors contributed twice the influence to left and right cerebral hemispheric volumes in right-handed twin pairs, suggesting a large decrement in genetic control of cerebral volumes in the nonright-handed twin pairs. This loss of genetic determination of left and right cerebral hemispheres in the nonright-handed twin pairs is consistent with models postulating a right-hand/left-hemisphere-biasing genetic influence, a 'right-shift' genotype that is lost in left handers, resulting in decreased cerebral asymmetry.

Bishop (2001) used data from 2 twin studies to address 2 related questions. First, is there any association between handedness and specific speech and language impairment (SSLI) in children? Second, is there genetic influence on individual differences in handedness, and, if so, are the same genes implicated in the cause of SSLI? No handedness differences were found between 58 monozygotic and 26 dizygotic pairs previously recruited for an investigation into the genetic origins of SSLI and singleton controls. To investigate familial transmission of handedness, inventory data for parents and their twins were combined. The most parsimonious model of the findings was one that accounted for parent-child resemblance solely in terms of cultural transmission. Bishop (2001) concluded that, overall, there was no evidence that genes play a role in determining stable individual differences in hand preference.

Handedness is a characteristic, obviously complex in its causation, that may prove amenable to analysis of genetic contribution when a full gene map has been developed (Williamson, 1986). It is a behavioral trait that may be a model for other behavioral traits, normal and abnormal. The observation that the proportion of left-handers in populations decreases with age, diminishing from 13% in 20-year-olds to less than 1% in 80-year-olds, led to the suggestion that sinistrality may be associated with decreased life span. Reduced longevity in left-handers was also suggested by an archival study of records on 2,271 major-league baseball players (Halpern and Coren, 1988). In a questionnaire study of deceased persons identified through death certificates, Halpern and Coren (1991) found significantly more left-handers than right-handers among those who had died in accidents--a result consistent with earlier findings. Age of death in general was lower in left-handers and mixed-handers than in right-handers of either sex. Halpern and Coren (1991) stated that it is likely that the correlates of sinistrality, not sinistrality itself, are responsible for the increased risk; left-handedness may indicate covert neuropathologic features.

Schur (1986) could not demonstrate the association between handedness and an autoimmune disease, systemic lupus erythematosus (152700), which had been proposed by Geschwind and Behan (1982).

In southern Sweden, Olsson and Ingvar (1991) found that left-handedness was significantly less common among patients with breast cancer (1.5%) than among a female referent population (5%); P less than 0.0025. They interpreted the finding as support for theories suggesting that hormonal factors in early life are important both for handedness and for the risk of breast cancer.

Klar (2003) provided evidence for a link between handedness and the orientation of hair whorls on the scalp (139400), suggesting the possibility that the same system that patterns hair may also play a role in left-right asymmetry in the brain. In a sample of the general population, consisting of mostly right-handers (RH), he found that 42 (8.4%) of 500 individuals showed counterclockwise whorl rotation. Non-right-handers (NRH, i.e., left-handers and ambidextrous) displayed a random mixture of clockwise and counterclockwise swirling patterns. Confirming this finding, in another independent sample of individuals chosen because of their counterclockwise rotation, half were found to be NRH. Klar (2003) stated that these findings of coupling in RH and uncoupling in NRH unequivocally established that these traits develop from a common genetic mechanism. Another finding, concerning handedness of the progeny of discordant monozygotic twins, suggested that lefties are 1 gene apart from righties. Together, these results suggested that a single gene controls handedness, whorl orientation, and twin concordance and discordance, and that neuronal and visceral forms of bilateral asymmetry are coded by separate sets of genetic pathways. Klar (2003) discussed the sociologic impact of the results.

MAPPING

In a sample of 195 reading-disabled sib pairs in the United Kingdom, Francks et al. (2002) performed a genomewide quantitative trait locus (QTL) linkage analysis using a continuous measure of relative hand skill (PegQ) rather than treating handedness as a categorical state. A QTL on chromosome 2p12-p11.2 yielded strong evidence for linkage to PegQ and another suggestive QTL on 17p11-q23 was also identified. Relative hand skill therefore appears to be a complex multifactorial phenotype with a heterogeneous background, but nevertheless is amenable to QTL-based gene mapping approaches.

Francks et al. (2003) found evidence supporting their earlier location of a QTL for relative hand skill to chromosome 2p12-q11 in a new sample of 105 pairs of adult brothers drawn from a sample of 168 unrelated male sibships (338 brothers) that was originally collected for investigating X-linked effects on handedness. The evidence of linkage had a P value of 0.00035, thus greatly exceeding significance guidelines for confirmation of linkage (guideline P = 0.01, suggested by Lander and Kruglyak, 1995). Francks et al. (2003) concluded that, although handedness variation may be etiologically complex, there is at least 1 polymorphic genetic influence that is located on 2p12-q11.

Van Agtmael et al. (2002) investigated candidate genes known to be involved in the development of left-right asymmetry in 1 informative extended family and 27 nuclear families of right-handed parents and left-handed children. Segregation analysis in the extended pedigree identified allele sharing in the NODAL (601265) and DNAHC13 regions on chromosome 10 and 1, respectively. Linkage analysis using the models of Klar (1996) and McManus (1985), and nonparametric analysis on nuclear families, subsequently excluded all candidate regions tested. Van Agtmael et al. (2002) concluded that parametric and nonparametric analysis on similar cohorts are powerful enough to identify handedness genes.

Schizophrenia (181500) and non-right-handedness are moderately associated, and both traits are often accompanied by abnormalities of asymmetrical brain morphology or function. Francks et al. (2003) found that in a sample of 191 reading-disabled sib pairs, the relative hand skill of sibs was correlated more strongly with paternal than maternal relative hand skill (p = 0.0000037 for paternal identity-by-descent sharing). Similarly, in affected sib-pair analysis of 241 schizophrenic sib pairs, the authors found linkage to schizophrenia for paternal sharing (lod = 4.72, p = 0.0000016) within 3 cM of the peak linkage to relative hand skill. Francks et al. (2003) suggested that the causative genetic effects on chromosome 2p12-q11 may be related, and they proposed that these linkages may be due to a single maternally imprinted influence on lateralized brain development that contains common functional polymorphisms.

HISTORY

Bodmer and McKie (1994) referred to the left-handedness of the Kerr family which gave rise to the layout of a Kerr castle stronghold, Ferniehirst, on the border between England and Scotland. Whereas in most castles staircases spiral clockwise, Ferniehirst has counterclockwise ones, providing left-handed swordsmen with an advantage, the bends giving a defender's left hand freedom to move over the open railing. The association between the Kerr name and left-handedness was such that throughout Scotland the expression Kerr-handed, or kerry- or corry-fisted, is said to be commonly used to mean left-handed. Bodmer and McKie (1994) quoted a survey of doctors who were asked to note the handedness of any patient bearing the surname Kerr: 'a total of 29.5 percent of the Kerrs were reported, by both British and North American doctors, to be 'left-handed or ambidextrous' compared with only 11% of a control family.' Thus, in the Kerr family, there is still a strong majority of right handers. Furthermore, the left-handedness may have been encouraged from the beginning. 'Andrew Kerr, founder of the family's Ferniehirst dynasty in 1457, was certainly left-handed and found the characteristic a powerful asset in battle.' It appears that he specifically taught his sons and armed men-servants (who, by custom, took the family name) to wield sword and axe with the left hand, and they, in turn, did the same with their sons.

SEE ALSO

Annett (1979); Annett (1973); Annett (1978); Ferronato et al. (1974); Levy (1976); Springer and Searleman (1978)

REFERENCES

1. Annett, M. :
Familial handedness in three generations predicted by the right shift theory. Ann. Hum. Genet. 42: 479-491, 1979.
PubMed ID : 475335

2. Annett, M. :
A model of the inheritance of handedness and cerebral dominance. Nature 204: 59-60, 1964.
PubMed ID : 14240116

3. Annett, M. :
Handedness in families. Ann. Hum. Genet. 37: 93-105, 1973.
PubMed ID : 4759906

4. Annett, M. :
Genetic and nongenetic influences on handedness. Behav. Genet. 8: 227-249, 1978.
PubMed ID : 687316

5. Bishop, D. V. M. :
Individual differences in handedness and specific speech and language impairment: evidence against a genetic link. Behav. Genet. 31: 339-351, 2001.
PubMed ID : 11720120

6. Bodmer, W.; McKie, R. :
The Book of Man: the Quest to Discover Our Genetic Heritage. London: Little, Brown and Co. (pub.) 1994. Pp. 1-5.

7. Coren, S.; Porac, C. :
Fifty centuries of right-handedness: the historic record. Science 198: 631-632, 1977.
PubMed ID : 335510

8. Ferronato, S.; Thomas, D.; Sadava, D. :
Preferences for handedness, arm folding, and hand clasping in families. Hum. Hered. 24: 345-351, 1974.
PubMed ID : 4461659

9. Francks, C.; DeLisi, L. E.; Fisher, S. E.; Laval, S. H.; Rue, J. E.; Stein, J. F.; Monaco, A. P. :
Confirmatory evidence for linkage of relative hand skill to 2p12-q11. (Letter) Am. J. Hum. Genet. 72: 499-502, 2003.
PubMed ID : 12596796

10. Francks, C.; DeLisi, L. E.; Shaw, S. H.; Fisher, S. E.; Richardson, A. J.; Stein, J. F.; Monaco, A. P. :
Parent-of-origin effects on handedness and schizophrenia susceptibility on chromosome 2p12-q11. Hum. Molec. Genet. 12: 3225-3230, 2003.
PubMed ID : 14583442

11. Francks, C.; Fisher, S. E.; MacPhie, I. L.; Richardson, A. J.; Marlow, A. J.; Stein, J. F.; Monaco, A. P. :
A genomewide linkage screen for relative hand skill in sibling pairs. Am. J. Hum. Genet. 70: 800-805, 2002. Note: Erratum: Am. J. Med. Genet. 70: 1074 only, 2002.
PubMed ID : 11774074

12. Geschwind, D. H.; Miller, B. L.; DeCarli, C.; Carmelli, D. :
Heritability of lobar brain volumes in twins supports genetic models of cerebral laterality and handedness. Proc. Nat. Acad. Sci. 99: 3176-3181, 2002.
PubMed ID : 11867730

13. Geschwind, N.; Behan, P. :
Left-handedness: association with immune disease, migraine, and developmental learning disorder. Proc. Nat. Acad. Sci. 79: 5097-5100, 1982.
PubMed ID : 6956919

14. Halpern, D. F.; Coren, S. :
Handedness and life span. (Letter) New Eng. J. Med. 324: 998, 1991.
PubMed ID : 2002827

15. Halpern, D. F.; Coren, S. :
Do right-handers live longer? (Letter) Nature 333: 213, 1988.
PubMed ID : 3367996

16. Hicks, R. E.; Kinsbourne, M. :
Human handedness: a partial cross-fostering study. Science 192: 908-910, 1976.
PubMed ID : 1273577

17. Huheey, J. E. :
Concerning the origin of handedness in humans. Behav. Genet. 7: 29-32, 1977.
PubMed ID : 843315

18. Klar, A. J. S. :
Human handedness and scalp hair-whorl direction develop from a common genetic mechanism. Genetics 165: 269-276, 2003.
PubMed ID : 14504234

19. Klar, A. J. S. :
A single locus, RGHT, specifies preference for hand utilization in humans. Cold Spring Harbor Symp. Quant. Biol. 61: 59-65, 1996.
PubMed ID : 9246435

20. Laland, K. N.; Kumm, J.; Van Horn, J. D.; Feldman, M. W. :
A gene-culture model of human handedness. Behav. Genet. 25: 433-445, 1995.
PubMed ID : 7487840

21. Lander, E.; Kruglyak, L. :
Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nature Genet. 11: 241-247, 1995.
PubMed ID : 7581446

22. Levy, J. :
A review of evidence for a genetic component in the determination of handedness. Behav. Genet. 6: 429-453, 1976.
PubMed ID : 791243

23. Levy, J.; Nagylaki, T. :
A model for the genetics of handedness. Genetics 72: 117-128, 1972.
PubMed ID : 5073852

24. McManus, I. C. :
Handedness, language dominance and aphasia: a genetic model. Psychol. Med. Suppl. 8: Monograph, 1985.

25. Olsson, H.; Ingvar, C. :
Left handedness is uncommon in breast cancer patients. Europ. J. Cancer 27: 1694-1695, 1991.

26. Rife, D. C. :
Handedness with special reference to twins. Genetics 25: 178-186, 1940.
PubMed ID : 17246963

27. Schur, P. H. :
Handedness in systemic lupus erythematosus. Arthritis Rheum. 29: 419-420, 1986.
PubMed ID : 3964317

28. Springer, S. P.; Searleman, A. :
Laterality in twins: the relationship between handedness and hemispheric asymmetry for speech. Behav. Genet. 8: 349-357, 1978.
PubMed ID : 567977

29. Van Agtmael, T.; Forrest, S. M.; Williamson, R. :
Parametric and non-parametric linkage analysis of several candidate regions for genes for human handedness. Europ. J. Hum. Genet. 10: 623-630, 2002.
PubMed ID : 12357333

30. Williamson, R. :
Personal Communication. London, England, 6/1/1986.