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Inheritance of randomness
Medical Hypotheses (1996) 47, 23-26 © Pearson Professional Ltd 1996
Inheritance of Randomness B. A. AFZELIUS Department of Ultrastructure Research, Stockholm University, S-106 91 Stockholm, Sweden (Correspondence to: Department of Biological Ultrastructure, Biology Building E 4, Stockholm University, S-106 91 Stockholm, Sweden (Tel: (+46) 8 16 40 91; Fax: (+46) 8 15 98 71; e-mail: bafz@zub,su.se)
Abstract - - The mouse mutant iv is characterized by 'a random determination of a developmental process' in that 50 rather than 100% of the homozygotes have situs inversus. The same explanation is given to the inheritance of situs inversus in the human immotile-cilia syndrome. There are probably two alleles of the responsible gene, one for control of the proper asymmetry and one without control and hence resulting in equal numbers of situs solitus and situs inversus in the homozygote. Left-handedness may be similarly inherited; furthermore, because of its high prevalence (around 10-12%) it has been assumed that there is an advantage of carrying both alleles ('balanced polymorphism'). With these two assumptions, a prevalence of left-handedness of 12.5% is expected, a 50% chance of lefthandedness in matings between two left-handed persons, and equal numbers of discordant and left-handed concordant monozygotic twins. These values are close to those actually found. As the values for (female) homosexuality are similar to those of left-handedness a similar inheritance is proposed.
The problem of left or right is an intriguing one. It has, for instance, been observed that it would be impossible to inform an extraterrestrial civilisation about the right (or the left) direction without providing a drawing. And even on this planet there are several problems connected with laterality. To be left-handed in a world of right-handed people undoubtedly must be a handicap. So why does lefthandedness occur? And what is its genetics? The following facts may be considered:
2. 3.
4.
1. The genus Homo seems to have been right-handed from its beginning two million years ago, although
5.
Date received 6 December 1995 Date accepted 21 December 1995
23
the existence of 10-20% left-handed people has been inferred from marks in flint tools dating from 150 000-200 000 years ago (l). Left-handedness occurs in all cultures and probably with the same prevalence (around 10%) (2). Children who have one left-handed parent are left-handed in a higher-than-average proportion (see below) (3). About 50% of children with two left-handed parents are left-handed (3). This indicates a genetic basis of left-handedness. There is no obvious association in handedness between monozygotic twins (3,4). According to
24
MEDICAL HYPOTHESES
general wisdom, this fact would exclude a genetic basis.
Situs inversus
Twenty years ago, two papers were published that both dealt with the inheritance of another problem of laterality, namely situs inversus and situs solitus (5,6). Situs solitus is the normal asymmetry of the viscera, situs inversus the reversed position of viscera. One of the papers, by Layton (5), deals with an inbred mouse strain, called iv/iv (for inversed viscera). Mating between two homozygotes was shown to produce an offspring in which 50% had situs inversus. The proportion is the same whether the two mated parents themselves have situs inversus or have situs solitus. Thus, rather than a gene for situs inversus and gene for situs solitus, there is a gene, which in single or double copy will control situs solitus - and an allele of the gene, which cannot control visceral laterality, but will give a 50% chance of situs inversus. Hence the title of Layton's paper 'Random determination of a developmental process'. The other paper (6) describes a human syndrome in which cilia lack their main motor protein, dynein, and as a consequence are immotile. Half the number of patients with this 'immotile-cilia syndrome' have situs inversus, half have situs solitus. It was concluded that 'chance alone will determine whether viscera take up the normal of the reversed position during embryogenesis, when normal dynein arms are missing.' The trait immotile cilia is likely to have a normal Mendelian inheritance, usually autosomal recessive, although the trait situs inversus is randomly determined in cases of immotile-cilia syndrome. Torgersen (7) has reviewed the literature on situs inversus in twins and found that twelve pairs of probably monozygotic twins were known, out of which six pairs consisted of two sibs both with situs inversus and six pairs of one sib with situs inversus and one with situs solitus. The trait thus shows a 50% discordance.
Left-handedness
The above data on situs inversus were used by McManus (8), who postulated a similar random deterruination for left-handedness and that randomness in homozygotes comes from a chance accumulation of noise that will give equally many cases of left or right. Annett (9) accepted this explanation and made a further assumption. She assumed that the reason why left-handedness survives in mankind in spite of its
disadvantages is that the gene exists in two allelic forms: one allele concerned with the control of righthandedness (and presumably with other functions as well), and another allele, which although it is unable to exert control of handedness, is equally useful to the individual carrying it. This phenomenon is called 'balanced polymorphism' and is a feature similar to the well-known advantage of being heterozygote for the sickle-cell disease in countries with malaria. Annett's hypothesis can now be tested against the data on genetics of left-handedness obtained by Rife (3), who found that the number of left-handed children after matings between: • two right-handed parents was 159 out of 1993, thus 8%; • one right-handed and one left-handed parent was 34 out of 174, thus 20%; • two left-handed parents was 6 out of 11, thus 55%. If it is assumed that the two allelic forms of the gene (control-gene and no control, or plus-gene and minus-gene) are equally common in the population, then the situation can be illustrated with a simple diagram (Figure). The assumption is thus made that 50% of the minusminus individuals are left-handed, and that 4 out of 7 alleles in the population of right-handed persons are of the plus-type (the control-gene). Three of 7 alleles are the minus-type (no control). This means that a
+
+
+
+
+
Figure A scheme with two assumptions: (1) The population contains an equal proportion of a control allele (a plus-gene) and a no-control allele (a minus-gene); (2) With no control there are equally many cases of right-handed and left-handed asymmetries. Three out of seven alleles in the population with 'correct asymmetry' will be of the no-control type.
25
INHERITANCE OF RANDOMNESS
mating between two right-handed persons results in a 3/7 x 3/7 chance of getting two genes that lack control: 50% of them will be left-handed, thus 1/2 x 3/7 x 3/7 = 9%. This figure is to be compared with the 8% found by Rife. Mating between one left-handed and one righthanded person will give 1/2 x 3/7 = 21% left-handed children, to be compared with 20% found by Rife. Mating between two left-handed persons will give a 50% chance of left-handedness as no allele for handedness control is present (to be compared with the 55% found by Rife). The theoretical values obtained in this calculation are reasonably close to those found by Rife. It should be remarked, however, that the percentages of lefthandedness found by Rife are somewhat lower than the figures obtained in later studies. Left-handedness (or non-right-handedness) sometimes is not easy to diagnose and older figures tend to give too low values, presumably because left-handedness was more strongly oppressed at an earlier date than it is today. Tambs et al (10) thus found that the prevalence of left-handedness (as defined by the person writing with the left hand) has increased from about 1% to about 10% in just two generations. Another model for the genetics of handedness has been proposed by Levy and Nagylaki (11), whereas Tambs et al (10) advocate an environmental hypothesis. If inheritance of randomness plays a role in these cases of human laterality, it might occur also in the animal kingdom. Attempts to inbreed platy fish with situs inversus resulted in a maximum of 50% situs inversus (12). In a recessive mutant of the Drosophila fruitfiy the abdomen is rotated to the right and a cross between two heterozygotes gave 397 out of 3256 flies having a dextral rotation (13). This ratio, 12.2%, is close to the expected 12.5% for a trait with random determination. The homozygote strain was claimed to consist only of individuals with dextral rotation, however, so there might not be a random orientation in this case. Other examples of asymmetries have been described from most animal groups (14), but only rarely have crosses been made between animals with different lateralities, such as wingfolding in bugs (15).
Homosexuality The inheritance pattern in the case of left-handedness is unlikely to be unique. It might exist also in other cases, where there is a choice between two alternatives. I suggest that heterosexuality versus homosexuality may be another such trait. Consider the following list: 1. Although it is a reproductive disadvantage to be
2.
3.
4.
5.
homosexual, this trait has been recognized as far back as any stone age rock carving or any written record will take us. Homosexuality occurs in all cultures, although by necessity more hidden in some cultures than in others. The incidence of women in the USA or western Europe with any homosexual experience has been estimated to be 10--12% (16 quoted from Ref. 17). This figure should be compared to the expected 12.5% that is evident from the scheme by Annett (9) (Figure). If one of the parents is homosexual, the child is more likely also to be homosexual (18). This indicates a genetic basis. Among monozygotic twin sisters of lesbian women, 48% were themselves lesbian. This indicates a random determination. For other sisters of a lesbian woman, the figure is 15% and for unrelated adoptive sisters 6% (17).
It is believed that genetic factors contribute both to female and male homosexuality but that the factors for these two orientations differ (17). Evidence has also been provided for an environmental factor for male homosexuality (19). There are presumably other genes that will entail a random determination of traits other than those that control (or cannot control) laterality of viscera or of handedness. A search for such traits is probably best performed by looking for a 50% occurrence of the trait in homozygotes (in the case of animals) or among twins (in the case of our own species).
References 1. Comford J M. Specialized resharpening techniques and evidence of handedness. In: Callow P, Cornford J M, ads. La Cotte de St Brelade 1961-1978. Norwich: Geo Books, 1986. 2. Corballis M C. The Lopsided Ape. Evolution of the Generative Mind. Oxford: Oxford University Press, 1991. 3. Rife D C. Handedness, with special reference to twins. Genetics 1940; 25: 178-186. 4. Hay D A, Howie P M. Handedness and difference in birthweight of twins. Perceptual Motor Skill 1980; 51: 666. 5. Layton W M. Random determination of a developmental process. J. Hered. 1976; 67: 336-338. 6. Afzelius B A. A human syndrome caused by immotile cilia. Science 1976; 193: 317-319. 7. Torgersen J. Situs inversus, asymmetry and twinning. Am J Hum Gen 1950; 2: 361-370. 8. McManus I C. The biology of asymmetry. PhD Thesis, University of Cambridge, 1978. 9. Annett M. Left, right, hand and brain. The right shift theory. London: Erlbaum, 1985. 10. Tambs K, Magnus P, Berg K. Left-handadncss in twin families. Support of an environmental hypothesis. Perception Motor Skill 1987; 64: 155-170.
26 11. Levy J, Nagylaki T A. A model for the genetics of handedness. Genetics 1972; 72:117-128. 12. Baker-Cohen K F. Visceral and vascular transposition in fishes, and a comparison with similar anomalies in man. Am J Anat 1961; 109: 37-55. 13. Beliajeff N K. Erbliche Asymmetric bei Drosophila. Biol Zentralbl 1931; 51: 701-708. 14. Ludwig W. Das Rechts-Links Problem in Tierreich und beim Menschen. Berlin: Springer Verlag, 1932 (reprinted 1970). 15. Ludwig W. Die Fliigellage der Feuerwanze. Ein Beitrag zum Rechts-Links Problem. Verhandl Deut Zool Ges 1931; 34: 213-219.
MEDICAL HYPOTHESES
16. Gebhard P H. Incidence of overt homosexuality in the United States and western Europe. In: Livingood J M, ed. NIMH Task Force on Homosexuality. Final Report and Background Papers. Washington DC: Dept of HEW, 1972: 22-29. 17. Bailey J M, Pillard R C, Neale M, Agyei Y. Heritable factors influence sexual orientation in women. Arch Gen Psychiatr 1993; 50: 217-223. 18. Pillard R C, Weinrich J D. Evidence of familial nature of male homosexuality. Arch Gen Psychiatr 1986; 43: 808-812. 19. Bailey J M. A test of the maternal stress hypothesis for human male homosexuality. Behav Gen 1989; 19: 744.
Inheritance of Randomness B. A. AFZELIUS Department of Ultrastructure Research, Stockholm University, S-106 91 Stockholm, Sweden (Correspondence to: Department of Biological Ultrastructure, Biology Building E 4, Stockholm University, S-106 91 Stockholm, Sweden (Tel: (+46) 8 16 40 91; Fax: (+46) 8 15 98 71; e-mail: bafz@zub,su.se)
Abstract - - The mouse mutant iv is characterized by 'a random determination of a developmental process' in that 50 rather than 100% of the homozygotes have situs inversus. The same explanation is given to the inheritance of situs inversus in the human immotile-cilia syndrome. There are probably two alleles of the responsible gene, one for control of the proper asymmetry and one without control and hence resulting in equal numbers of situs solitus and situs inversus in the homozygote. Left-handedness may be similarly inherited; furthermore, because of its high prevalence (around 10-12%) it has been assumed that there is an advantage of carrying both alleles ('balanced polymorphism'). With these two assumptions, a prevalence of left-handedness of 12.5% is expected, a 50% chance of lefthandedness in matings between two left-handed persons, and equal numbers of discordant and left-handed concordant monozygotic twins. These values are close to those actually found. As the values for (female) homosexuality are similar to those of left-handedness a similar inheritance is proposed.
The problem of left or right is an intriguing one. It has, for instance, been observed that it would be impossible to inform an extraterrestrial civilisation about the right (or the left) direction without providing a drawing. And even on this planet there are several problems connected with laterality. To be left-handed in a world of right-handed people undoubtedly must be a handicap. So why does lefthandedness occur? And what is its genetics? The following facts may be considered:
2. 3.
4.
1. The genus Homo seems to have been right-handed from its beginning two million years ago, although
5.
Date received 6 December 1995 Date accepted 21 December 1995
23
the existence of 10-20% left-handed people has been inferred from marks in flint tools dating from 150 000-200 000 years ago (l). Left-handedness occurs in all cultures and probably with the same prevalence (around 10%) (2). Children who have one left-handed parent are left-handed in a higher-than-average proportion (see below) (3). About 50% of children with two left-handed parents are left-handed (3). This indicates a genetic basis of left-handedness. There is no obvious association in handedness between monozygotic twins (3,4). According to
24
MEDICAL HYPOTHESES
general wisdom, this fact would exclude a genetic basis.
Situs inversus
Twenty years ago, two papers were published that both dealt with the inheritance of another problem of laterality, namely situs inversus and situs solitus (5,6). Situs solitus is the normal asymmetry of the viscera, situs inversus the reversed position of viscera. One of the papers, by Layton (5), deals with an inbred mouse strain, called iv/iv (for inversed viscera). Mating between two homozygotes was shown to produce an offspring in which 50% had situs inversus. The proportion is the same whether the two mated parents themselves have situs inversus or have situs solitus. Thus, rather than a gene for situs inversus and gene for situs solitus, there is a gene, which in single or double copy will control situs solitus - and an allele of the gene, which cannot control visceral laterality, but will give a 50% chance of situs inversus. Hence the title of Layton's paper 'Random determination of a developmental process'. The other paper (6) describes a human syndrome in which cilia lack their main motor protein, dynein, and as a consequence are immotile. Half the number of patients with this 'immotile-cilia syndrome' have situs inversus, half have situs solitus. It was concluded that 'chance alone will determine whether viscera take up the normal of the reversed position during embryogenesis, when normal dynein arms are missing.' The trait immotile cilia is likely to have a normal Mendelian inheritance, usually autosomal recessive, although the trait situs inversus is randomly determined in cases of immotile-cilia syndrome. Torgersen (7) has reviewed the literature on situs inversus in twins and found that twelve pairs of probably monozygotic twins were known, out of which six pairs consisted of two sibs both with situs inversus and six pairs of one sib with situs inversus and one with situs solitus. The trait thus shows a 50% discordance.
Left-handedness
The above data on situs inversus were used by McManus (8), who postulated a similar random deterruination for left-handedness and that randomness in homozygotes comes from a chance accumulation of noise that will give equally many cases of left or right. Annett (9) accepted this explanation and made a further assumption. She assumed that the reason why left-handedness survives in mankind in spite of its
disadvantages is that the gene exists in two allelic forms: one allele concerned with the control of righthandedness (and presumably with other functions as well), and another allele, which although it is unable to exert control of handedness, is equally useful to the individual carrying it. This phenomenon is called 'balanced polymorphism' and is a feature similar to the well-known advantage of being heterozygote for the sickle-cell disease in countries with malaria. Annett's hypothesis can now be tested against the data on genetics of left-handedness obtained by Rife (3), who found that the number of left-handed children after matings between: • two right-handed parents was 159 out of 1993, thus 8%; • one right-handed and one left-handed parent was 34 out of 174, thus 20%; • two left-handed parents was 6 out of 11, thus 55%. If it is assumed that the two allelic forms of the gene (control-gene and no control, or plus-gene and minus-gene) are equally common in the population, then the situation can be illustrated with a simple diagram (Figure). The assumption is thus made that 50% of the minusminus individuals are left-handed, and that 4 out of 7 alleles in the population of right-handed persons are of the plus-type (the control-gene). Three of 7 alleles are the minus-type (no control). This means that a
+
+
+
+
+
Figure A scheme with two assumptions: (1) The population contains an equal proportion of a control allele (a plus-gene) and a no-control allele (a minus-gene); (2) With no control there are equally many cases of right-handed and left-handed asymmetries. Three out of seven alleles in the population with 'correct asymmetry' will be of the no-control type.
25
INHERITANCE OF RANDOMNESS
mating between two right-handed persons results in a 3/7 x 3/7 chance of getting two genes that lack control: 50% of them will be left-handed, thus 1/2 x 3/7 x 3/7 = 9%. This figure is to be compared with the 8% found by Rife. Mating between one left-handed and one righthanded person will give 1/2 x 3/7 = 21% left-handed children, to be compared with 20% found by Rife. Mating between two left-handed persons will give a 50% chance of left-handedness as no allele for handedness control is present (to be compared with the 55% found by Rife). The theoretical values obtained in this calculation are reasonably close to those found by Rife. It should be remarked, however, that the percentages of lefthandedness found by Rife are somewhat lower than the figures obtained in later studies. Left-handedness (or non-right-handedness) sometimes is not easy to diagnose and older figures tend to give too low values, presumably because left-handedness was more strongly oppressed at an earlier date than it is today. Tambs et al (10) thus found that the prevalence of left-handedness (as defined by the person writing with the left hand) has increased from about 1% to about 10% in just two generations. Another model for the genetics of handedness has been proposed by Levy and Nagylaki (11), whereas Tambs et al (10) advocate an environmental hypothesis. If inheritance of randomness plays a role in these cases of human laterality, it might occur also in the animal kingdom. Attempts to inbreed platy fish with situs inversus resulted in a maximum of 50% situs inversus (12). In a recessive mutant of the Drosophila fruitfiy the abdomen is rotated to the right and a cross between two heterozygotes gave 397 out of 3256 flies having a dextral rotation (13). This ratio, 12.2%, is close to the expected 12.5% for a trait with random determination. The homozygote strain was claimed to consist only of individuals with dextral rotation, however, so there might not be a random orientation in this case. Other examples of asymmetries have been described from most animal groups (14), but only rarely have crosses been made between animals with different lateralities, such as wingfolding in bugs (15).
Homosexuality The inheritance pattern in the case of left-handedness is unlikely to be unique. It might exist also in other cases, where there is a choice between two alternatives. I suggest that heterosexuality versus homosexuality may be another such trait. Consider the following list: 1. Although it is a reproductive disadvantage to be
2.
3.
4.
5.
homosexual, this trait has been recognized as far back as any stone age rock carving or any written record will take us. Homosexuality occurs in all cultures, although by necessity more hidden in some cultures than in others. The incidence of women in the USA or western Europe with any homosexual experience has been estimated to be 10--12% (16 quoted from Ref. 17). This figure should be compared to the expected 12.5% that is evident from the scheme by Annett (9) (Figure). If one of the parents is homosexual, the child is more likely also to be homosexual (18). This indicates a genetic basis. Among monozygotic twin sisters of lesbian women, 48% were themselves lesbian. This indicates a random determination. For other sisters of a lesbian woman, the figure is 15% and for unrelated adoptive sisters 6% (17).
It is believed that genetic factors contribute both to female and male homosexuality but that the factors for these two orientations differ (17). Evidence has also been provided for an environmental factor for male homosexuality (19). There are presumably other genes that will entail a random determination of traits other than those that control (or cannot control) laterality of viscera or of handedness. A search for such traits is probably best performed by looking for a 50% occurrence of the trait in homozygotes (in the case of animals) or among twins (in the case of our own species).
References 1. Comford J M. Specialized resharpening techniques and evidence of handedness. In: Callow P, Cornford J M, ads. La Cotte de St Brelade 1961-1978. Norwich: Geo Books, 1986. 2. Corballis M C. The Lopsided Ape. Evolution of the Generative Mind. Oxford: Oxford University Press, 1991. 3. Rife D C. Handedness, with special reference to twins. Genetics 1940; 25: 178-186. 4. Hay D A, Howie P M. Handedness and difference in birthweight of twins. Perceptual Motor Skill 1980; 51: 666. 5. Layton W M. Random determination of a developmental process. J. Hered. 1976; 67: 336-338. 6. Afzelius B A. A human syndrome caused by immotile cilia. Science 1976; 193: 317-319. 7. Torgersen J. Situs inversus, asymmetry and twinning. Am J Hum Gen 1950; 2: 361-370. 8. McManus I C. The biology of asymmetry. PhD Thesis, University of Cambridge, 1978. 9. Annett M. Left, right, hand and brain. The right shift theory. London: Erlbaum, 1985. 10. Tambs K, Magnus P, Berg K. Left-handadncss in twin families. Support of an environmental hypothesis. Perception Motor Skill 1987; 64: 155-170.
26 11. Levy J, Nagylaki T A. A model for the genetics of handedness. Genetics 1972; 72:117-128. 12. Baker-Cohen K F. Visceral and vascular transposition in fishes, and a comparison with similar anomalies in man. Am J Anat 1961; 109: 37-55. 13. Beliajeff N K. Erbliche Asymmetric bei Drosophila. Biol Zentralbl 1931; 51: 701-708. 14. Ludwig W. Das Rechts-Links Problem in Tierreich und beim Menschen. Berlin: Springer Verlag, 1932 (reprinted 1970). 15. Ludwig W. Die Fliigellage der Feuerwanze. Ein Beitrag zum Rechts-Links Problem. Verhandl Deut Zool Ges 1931; 34: 213-219.
MEDICAL HYPOTHESES
16. Gebhard P H. Incidence of overt homosexuality in the United States and western Europe. In: Livingood J M, ed. NIMH Task Force on Homosexuality. Final Report and Background Papers. Washington DC: Dept of HEW, 1972: 22-29. 17. Bailey J M, Pillard R C, Neale M, Agyei Y. Heritable factors influence sexual orientation in women. Arch Gen Psychiatr 1993; 50: 217-223. 18. Pillard R C, Weinrich J D. Evidence of familial nature of male homosexuality. Arch Gen Psychiatr 1986; 43: 808-812. 19. Bailey J M. A test of the maternal stress hypothesis for human male homosexuality. Behav Gen 1989; 19: 744.