Hum. Genet. 50, 227--230 (1979)
© by Springer-Veriag1979
Original Investigations
Another Elliptocytosis Locus on Chromosome 1? Bronya J. B. Keats Population Genetics Laboratory, University of Hawaii, Honolulu, Hawaii 96822, USA
Summary. Analysis of pedigrees given in the literature suggests that a second elliptocytosis locus (not linked to Rh) may be linked to Duffy (Z = 1.97 at d = 0.0), and therefore on chromosome 1. Significant heterogeneity is found between the EI~ and El2 total lod scores with Fy.
Our linkage data base described by Rao et al. (1978) has been extended to give standard lod tables for 2331 pairs of loci (Keats et al., 1979). Many pedigrees from the literature have been analysed according to our modified version of LIPED (Ott, 1974), and lod scores for each sex have been obtained by means of an approximate factorization that gives the correct maximum likelihood estimates, but the lod surface is not precisely recovered (Morton, 1979). Analysis of these lod scores suggested that a second elliptocytosis locus, not linked to Rh, may be closely linked to the Duffy (Fy) blood group, and therefore on chromosome 1. Attempts to obtain unpublished pedigrees informative for Fy and elliptocytosis were unsuccessful. The few published scores are therefore summarized here to stimulate further studies of elliptocytosis pedigrees so that this possible linkage may be confirmed or rejected. Since Morton (1956) showed that there are at least two loci for elliptocytosis, one linked to the Rh locus, many studies have reported pedigrees together with Rh types. In 12 cases the results of testing for the Fya antigen are also given. Although the heterogeneity among the 12 pedigrees is not significant (Z21=9.25, P > 0.5) for the elliptocytosis/Fy linkage, they may be divided into two groups based on the level of recombination between Rh and elliptocytosis: (a) those unlinked or loosely linked to Rh (El2) and (b) those closely linked to Rh (Ell). Recombination of less than 10% was taken as evidence for linkage to Rh. Within each of these groups the heterogeneity among pedigrees is not significant for either elliptocytosis/Rh or elliptocytosis/Fy. Table 1 gives the lod scores (sexes pooled) between Fy and elliptocytosis for these two groups, together with Z and 0 for Rh and elliptocytosis. The maximum lod score of 1.97 at 0 = 0 for Fy/EI2
0340-6717/79/0050/0227/$ 01.00
228
B.J.B. Keats
Table 1. Lod scores for Duffy and elliptocytosis (sexes pooled), together with Z, t~for Rh and elliptocytosis Pedigreea Z
0
Recombination fraction (0) 0.05
EljRh
0.1
0.2
0.3
0.4
0.15 0.58 -0.32 0.79 0.71 -0.17
0.12 0.50 -0.25 0.67 0.63 -0.17
0.07 0.33 -0.14 0.45 0.45 -0.14
0.03 0.17 -0.06 0.25 0.25 -0.08
0.01 0.05 -0.02 0.10 0.07 -0.02
Z
a) El2 B1 B2 B3 B4 MO 2
0.17 0.65 0 0.91 0.78 0
0 0 0.5 0 0 0.5
Total
1.97
0.00
1.74
1.50
1.02
0.56
0.19
b) Ell 3 4 5 6 DeJ II
0.34 0 0 0.03 0.30 0.08
0 0.5 0.5 0.41 0.25 0.25
0.30 -0.23 -0.13 -0.54 - 0.45 -0.71
0.26 -0.20 -0.10 -0.30 0.00 -0.24
0.21 -0.15 -0.05 -0.10 0.27 0.06
0.15 -0.10 -0.02 -0.01 0.28 0.07
0.08 -0.05 -0.01 0.03 0.17 -0.01
Total
0.37
0.28
- 1.76
- 0.58
0.24
0.37
0.21
0 0 0 0.30 0 0.15
0.5 0.5 0.5 0.21 0.5 0.39
Ell/Rh 5.11 2.07 3.48 0.27 7.58 2.36
0 0.08 0.04 0 0.05 0
a The references to the pedigrees are as follows: B1, B2, B3, B4, Bannerman and Renwick (1962); MO, De J, Geerdink et al. (1967); 2, Chalmers and Lawler (1953); 3, Goodall et al. (1953); 4, Goodall et al. (1954); 5, 6, LaMer and Sandier (1954); II, Lovric et al. (1965)
suggests t h a t these two loci m a y be linked. A test o f heterogeneity ( M o r t o n , 1956) b e t w e e n the Fy/E12 a n d F y / E l l linkages yielded Z~ = 4.95, which is significant ( P < 0.02). T h e i n f o r m a t i o n on the R h / E l l linkage for pedigree 6 is very sparse, so its classification as Ell is uncertain. O m i t t i n g it, however, still gives significant h e t e r o g e n e i t y b e t w e e n the Fy/E12 a n d F y / E l l linkages (Z12 = 4 . 4 1 ; P < 0.03). T a b l e 2 gives the l o d scores for males a n d females separately. T h e r e is no certain r e c o m b i n a n t for either sex. A s s u m i n g t h a t the p r i o r p r o b a b i l i t y o f linkage in m a n is 0.054, the reliability o f the linkage test ( R a o et al., 1978) at Z = 1.97 is 0.84, indicating that the m a j o r i t y o f pairs o f loci with a l o d score o f at least 1.97 are expected to be true. R a o et al. (1979) c o n s t r u c t e d a m a x i m u m l i k e l i h o o d m a p o f c h r o m o s o m e 1 giving m a p l o c a t i o n s for 13 m a r k e r s . F o r El2 to be on this m a p , it is necessary t h a t the r e c o m b i n a t i o n values between E12 a n d the 13 m a r k e r s be consistet with the m a p . T h e o b s e r v e d values for E12 are 0m = 0 r = 0 with Fy, a n d 0m = 0 f = 0 . 5 with Rh, a n d the t o t a l o f the m a x i m u m o b s e r v e d l o d scores is 2.07. W h e n the p o s i t i o n o f E12 is estimated, c o n s t r a i n i n g it to lie o n the m a p with 13 fixed locations, the m a x i m u m p r e d i c t e d ( m a p - c o n s t r a i n e d ) l o d score is 2.06, which is suggestive o f El2 being on c h r o m o s o m e 1, b u t does n o t reach the c o n v e n t i o n a l level o f 3.
229
Another Elliptocytosis Locus on Chromosome 1? Table 2. Lod scores for Duffy and Elz (sexes separate) Pedigree
Z
0
0.05
0.1
0.2
0.3
0.4
Male B1 B2 B3 B4 MO 2
0.08 0.21 0 0.28 0.85 .
0 0 0.5 0 0
0.06 0.18 -0.15 0.24 0.78 .
0.05 0.14 -0.12 0.21 0.71 .
0.03 0.08 -0.07 0.15 0.56 .
0.01 0.04 -0.03 0.09 0.39
0.00 0.01 -0.01 0.04 0.20
Total
1.23
0.00
1.11
0.99
0.75
0.50
0.24
Female B1 B2 B3 B4 MO 2
0.08 0.21 0.00 0.78 0.18 0
0 0 0.47 0 0 0.5
0.06 0.18 -0.20 0.69 0.17 -0.17
0.05 0.14 -0.16 0.61 0.16 -0.17
0.03 0.08 -0.09 0.44 0.13 -0.14
0.01 0.04 -0.03 0.28 0.09 -0.08
0.00 0.01 -0.01 0.13 0.04 -0.02
Total
0.84
0.00
0.73
0.63
0.45
0.31
0.15
.
.
.
Other elliptocytosis pedigrees reported in the literature include one by C h a g a n t i et al. (1975), for which there is very little i n f o r m a t i o n o n linkage with Rh: two n o n r e c o m b i n a n t s a n d one r e c o m b i n a n t . This elliptocytosis, however, shows no evidence of linkage to the centromeric h e t e r o m o r p h i s m (01q12) of c h r o m o s o m e 1. If it is El2, this result would not be compatible with close linkage of El2 to Fy, a n d the m a p - c o n s t r a i n e d lod score would be reduced to 0.4. If linkage between Fy a n d El2 is confirmed, then each a r m of c h r o m o s o m e 1 will have been shown to carry a n elliptocytosis locus. This a r r a n g e m e n t is also f o u n d on the X c h r o m o s o m e for two loci for mental r e t a r d a t i o n (Lubs et al., 1968; Fried a n d Sanger, 1973), a n d family data suggest that the loci for the two hemophilias a n d also the two types of muscular dystrophy (Becker a n d D u c h e n n e ) m a y be o n different arms of the X c h r o m o s o m e , suggesting insertional duplication.
Acknowledgments. This work was supported by grants GM 23021 from the U.S. National Institutes of Health and 1-475 from the National Foundation. This publication is PGL paper no. 204.
References Bannerman, R. M., Renwick, J. H.: The hereditary elliptocytoses: clinical and linkage data. Ann. Hum. Genet. 26, 23--38 (1962) Chaganti, R. S. K., Weitkamp, L. R., Fleming, J., Miller, G., German, J.: Polymorphic chromosomes and gene assignment in man. Rotterdam Conference (1974): Second International
230
B.J.B. Keats
Workshop on Human Gene Mapping. Birth Defects: Original Article Series, XI (3), 93--98, 1975. The National Foundation, New York Chalmers, J. N. M:, Lawler, S. D.: Data on linkage in man: elliptocytosis and blood groups. I. Families 1 and 2. Ann. Eugen. 17, 267--271 (1953) Fried, K., Sauger, R.: Possible linkage between Xg and the locus for a gene causing mental retardation with or without hydrocephalus. J. Med. Genet. 10, 172-18 (1973) Geerdink, R. A., Nijenhuis, L. E., Huizinga, J.: Hereditary eUiptocytosis: linkage data in man. Ann. Hum. Genet. 30, 363--378 (1967) Goodall, H. B., Hendry, D. W. W,, Lawler, S. D., Stephen, S. A.: Data on linkage in man: elliptocytosis and blood groups. II. Family 3. Ann. Eugen. 17, 272--278 (1953) Goodall, H. B., Hendry, D. W. W., Lawler, S. D., Stephen, S. A.: Data on linkage in man: elliptocytosis and blood groups. III. Family 4. Ann. Eugen. 18, 325--327 (1954) Keats, B. J. B., Morton, N. E., Rao, D. C., Williams, W. R.: A source book for linkage in man. Baltimore: Johns Hopkins University Press 1979 Lawler, S. D., Sandler, M.: Data on linkage in man: elliptocytosis and blood groups. IV. Families 5, 6 and 7. Ann. Eugen. 18, 328--334 (1954) Lovric, V. A., Walsh, R. J., Bradley, M. A.: Hereditary elliptocytosis: genetic linkage with the Rh chromosome. Aust. Ann. Med. 14, 162--166 (1965) Lubs, H. A.: A marker X chromosome. Am. J. Hum. Genet. 21, 231--244 (1969) Morton, N. E.: The detection and estimation of linkage between the genes for elliptocytosis and the Rh blood type. Am. J. Hum. Genet. 8, 80--96 (1956) Morton, N. E.: Analysis of crossingover in man. In: Winnipeg Conference (i977): Fourth International Workshop on Human Gene Mapping. Birth Defects: Original Article Series 1979. The National Foundation, New York Ott, J.: Estimation of the recombination fraction in human pedigrees: efficient computation of the likelihood for human linkage studies. Am. J. Hum. Genet. 26, 588--597 (1974) Rao, D. C., Keats, B. J. B., Laloud, J. M., Morton, N. E., Ye% S,: A maximum likelihood map of chromosome 1. Am.J. Hum. Genet. 31 (in press, 1979) Rao, D. C., Keats, B. J. B., Morton, N. E., Yee, S., Lew, R.: Variability of human linkage data. Am. J. Hum. Genet. 30, 516--529 (1978)
Received January 19 / Revised March 15, 1979
© by Springer-Veriag1979
Original Investigations
Another Elliptocytosis Locus on Chromosome 1? Bronya J. B. Keats Population Genetics Laboratory, University of Hawaii, Honolulu, Hawaii 96822, USA
Summary. Analysis of pedigrees given in the literature suggests that a second elliptocytosis locus (not linked to Rh) may be linked to Duffy (Z = 1.97 at d = 0.0), and therefore on chromosome 1. Significant heterogeneity is found between the EI~ and El2 total lod scores with Fy.
Our linkage data base described by Rao et al. (1978) has been extended to give standard lod tables for 2331 pairs of loci (Keats et al., 1979). Many pedigrees from the literature have been analysed according to our modified version of LIPED (Ott, 1974), and lod scores for each sex have been obtained by means of an approximate factorization that gives the correct maximum likelihood estimates, but the lod surface is not precisely recovered (Morton, 1979). Analysis of these lod scores suggested that a second elliptocytosis locus, not linked to Rh, may be closely linked to the Duffy (Fy) blood group, and therefore on chromosome 1. Attempts to obtain unpublished pedigrees informative for Fy and elliptocytosis were unsuccessful. The few published scores are therefore summarized here to stimulate further studies of elliptocytosis pedigrees so that this possible linkage may be confirmed or rejected. Since Morton (1956) showed that there are at least two loci for elliptocytosis, one linked to the Rh locus, many studies have reported pedigrees together with Rh types. In 12 cases the results of testing for the Fya antigen are also given. Although the heterogeneity among the 12 pedigrees is not significant (Z21=9.25, P > 0.5) for the elliptocytosis/Fy linkage, they may be divided into two groups based on the level of recombination between Rh and elliptocytosis: (a) those unlinked or loosely linked to Rh (El2) and (b) those closely linked to Rh (Ell). Recombination of less than 10% was taken as evidence for linkage to Rh. Within each of these groups the heterogeneity among pedigrees is not significant for either elliptocytosis/Rh or elliptocytosis/Fy. Table 1 gives the lod scores (sexes pooled) between Fy and elliptocytosis for these two groups, together with Z and 0 for Rh and elliptocytosis. The maximum lod score of 1.97 at 0 = 0 for Fy/EI2
0340-6717/79/0050/0227/$ 01.00
228
B.J.B. Keats
Table 1. Lod scores for Duffy and elliptocytosis (sexes pooled), together with Z, t~for Rh and elliptocytosis Pedigreea Z
0
Recombination fraction (0) 0.05
EljRh
0.1
0.2
0.3
0.4
0.15 0.58 -0.32 0.79 0.71 -0.17
0.12 0.50 -0.25 0.67 0.63 -0.17
0.07 0.33 -0.14 0.45 0.45 -0.14
0.03 0.17 -0.06 0.25 0.25 -0.08
0.01 0.05 -0.02 0.10 0.07 -0.02
Z
a) El2 B1 B2 B3 B4 MO 2
0.17 0.65 0 0.91 0.78 0
0 0 0.5 0 0 0.5
Total
1.97
0.00
1.74
1.50
1.02
0.56
0.19
b) Ell 3 4 5 6 DeJ II
0.34 0 0 0.03 0.30 0.08
0 0.5 0.5 0.41 0.25 0.25
0.30 -0.23 -0.13 -0.54 - 0.45 -0.71
0.26 -0.20 -0.10 -0.30 0.00 -0.24
0.21 -0.15 -0.05 -0.10 0.27 0.06
0.15 -0.10 -0.02 -0.01 0.28 0.07
0.08 -0.05 -0.01 0.03 0.17 -0.01
Total
0.37
0.28
- 1.76
- 0.58
0.24
0.37
0.21
0 0 0 0.30 0 0.15
0.5 0.5 0.5 0.21 0.5 0.39
Ell/Rh 5.11 2.07 3.48 0.27 7.58 2.36
0 0.08 0.04 0 0.05 0
a The references to the pedigrees are as follows: B1, B2, B3, B4, Bannerman and Renwick (1962); MO, De J, Geerdink et al. (1967); 2, Chalmers and Lawler (1953); 3, Goodall et al. (1953); 4, Goodall et al. (1954); 5, 6, LaMer and Sandier (1954); II, Lovric et al. (1965)
suggests t h a t these two loci m a y be linked. A test o f heterogeneity ( M o r t o n , 1956) b e t w e e n the Fy/E12 a n d F y / E l l linkages yielded Z~ = 4.95, which is significant ( P < 0.02). T h e i n f o r m a t i o n on the R h / E l l linkage for pedigree 6 is very sparse, so its classification as Ell is uncertain. O m i t t i n g it, however, still gives significant h e t e r o g e n e i t y b e t w e e n the Fy/E12 a n d F y / E l l linkages (Z12 = 4 . 4 1 ; P < 0.03). T a b l e 2 gives the l o d scores for males a n d females separately. T h e r e is no certain r e c o m b i n a n t for either sex. A s s u m i n g t h a t the p r i o r p r o b a b i l i t y o f linkage in m a n is 0.054, the reliability o f the linkage test ( R a o et al., 1978) at Z = 1.97 is 0.84, indicating that the m a j o r i t y o f pairs o f loci with a l o d score o f at least 1.97 are expected to be true. R a o et al. (1979) c o n s t r u c t e d a m a x i m u m l i k e l i h o o d m a p o f c h r o m o s o m e 1 giving m a p l o c a t i o n s for 13 m a r k e r s . F o r El2 to be on this m a p , it is necessary t h a t the r e c o m b i n a t i o n values between E12 a n d the 13 m a r k e r s be consistet with the m a p . T h e o b s e r v e d values for E12 are 0m = 0 r = 0 with Fy, a n d 0m = 0 f = 0 . 5 with Rh, a n d the t o t a l o f the m a x i m u m o b s e r v e d l o d scores is 2.07. W h e n the p o s i t i o n o f E12 is estimated, c o n s t r a i n i n g it to lie o n the m a p with 13 fixed locations, the m a x i m u m p r e d i c t e d ( m a p - c o n s t r a i n e d ) l o d score is 2.06, which is suggestive o f El2 being on c h r o m o s o m e 1, b u t does n o t reach the c o n v e n t i o n a l level o f 3.
229
Another Elliptocytosis Locus on Chromosome 1? Table 2. Lod scores for Duffy and Elz (sexes separate) Pedigree
Z
0
0.05
0.1
0.2
0.3
0.4
Male B1 B2 B3 B4 MO 2
0.08 0.21 0 0.28 0.85 .
0 0 0.5 0 0
0.06 0.18 -0.15 0.24 0.78 .
0.05 0.14 -0.12 0.21 0.71 .
0.03 0.08 -0.07 0.15 0.56 .
0.01 0.04 -0.03 0.09 0.39
0.00 0.01 -0.01 0.04 0.20
Total
1.23
0.00
1.11
0.99
0.75
0.50
0.24
Female B1 B2 B3 B4 MO 2
0.08 0.21 0.00 0.78 0.18 0
0 0 0.47 0 0 0.5
0.06 0.18 -0.20 0.69 0.17 -0.17
0.05 0.14 -0.16 0.61 0.16 -0.17
0.03 0.08 -0.09 0.44 0.13 -0.14
0.01 0.04 -0.03 0.28 0.09 -0.08
0.00 0.01 -0.01 0.13 0.04 -0.02
Total
0.84
0.00
0.73
0.63
0.45
0.31
0.15
.
.
.
Other elliptocytosis pedigrees reported in the literature include one by C h a g a n t i et al. (1975), for which there is very little i n f o r m a t i o n o n linkage with Rh: two n o n r e c o m b i n a n t s a n d one r e c o m b i n a n t . This elliptocytosis, however, shows no evidence of linkage to the centromeric h e t e r o m o r p h i s m (01q12) of c h r o m o s o m e 1. If it is El2, this result would not be compatible with close linkage of El2 to Fy, a n d the m a p - c o n s t r a i n e d lod score would be reduced to 0.4. If linkage between Fy a n d El2 is confirmed, then each a r m of c h r o m o s o m e 1 will have been shown to carry a n elliptocytosis locus. This a r r a n g e m e n t is also f o u n d on the X c h r o m o s o m e for two loci for mental r e t a r d a t i o n (Lubs et al., 1968; Fried a n d Sanger, 1973), a n d family data suggest that the loci for the two hemophilias a n d also the two types of muscular dystrophy (Becker a n d D u c h e n n e ) m a y be o n different arms of the X c h r o m o s o m e , suggesting insertional duplication.
Acknowledgments. This work was supported by grants GM 23021 from the U.S. National Institutes of Health and 1-475 from the National Foundation. This publication is PGL paper no. 204.
References Bannerman, R. M., Renwick, J. H.: The hereditary elliptocytoses: clinical and linkage data. Ann. Hum. Genet. 26, 23--38 (1962) Chaganti, R. S. K., Weitkamp, L. R., Fleming, J., Miller, G., German, J.: Polymorphic chromosomes and gene assignment in man. Rotterdam Conference (1974): Second International
230
B.J.B. Keats
Workshop on Human Gene Mapping. Birth Defects: Original Article Series, XI (3), 93--98, 1975. The National Foundation, New York Chalmers, J. N. M:, Lawler, S. D.: Data on linkage in man: elliptocytosis and blood groups. I. Families 1 and 2. Ann. Eugen. 17, 267--271 (1953) Fried, K., Sauger, R.: Possible linkage between Xg and the locus for a gene causing mental retardation with or without hydrocephalus. J. Med. Genet. 10, 172-18 (1973) Geerdink, R. A., Nijenhuis, L. E., Huizinga, J.: Hereditary eUiptocytosis: linkage data in man. Ann. Hum. Genet. 30, 363--378 (1967) Goodall, H. B., Hendry, D. W. W,, Lawler, S. D., Stephen, S. A.: Data on linkage in man: elliptocytosis and blood groups. II. Family 3. Ann. Eugen. 17, 272--278 (1953) Goodall, H. B., Hendry, D. W. W., Lawler, S. D., Stephen, S. A.: Data on linkage in man: elliptocytosis and blood groups. III. Family 4. Ann. Eugen. 18, 325--327 (1954) Keats, B. J. B., Morton, N. E., Rao, D. C., Williams, W. R.: A source book for linkage in man. Baltimore: Johns Hopkins University Press 1979 Lawler, S. D., Sandler, M.: Data on linkage in man: elliptocytosis and blood groups. IV. Families 5, 6 and 7. Ann. Eugen. 18, 328--334 (1954) Lovric, V. A., Walsh, R. J., Bradley, M. A.: Hereditary elliptocytosis: genetic linkage with the Rh chromosome. Aust. Ann. Med. 14, 162--166 (1965) Lubs, H. A.: A marker X chromosome. Am. J. Hum. Genet. 21, 231--244 (1969) Morton, N. E.: The detection and estimation of linkage between the genes for elliptocytosis and the Rh blood type. Am. J. Hum. Genet. 8, 80--96 (1956) Morton, N. E.: Analysis of crossingover in man. In: Winnipeg Conference (i977): Fourth International Workshop on Human Gene Mapping. Birth Defects: Original Article Series 1979. The National Foundation, New York Ott, J.: Estimation of the recombination fraction in human pedigrees: efficient computation of the likelihood for human linkage studies. Am. J. Hum. Genet. 26, 588--597 (1974) Rao, D. C., Keats, B. J. B., Laloud, J. M., Morton, N. E., Ye% S,: A maximum likelihood map of chromosome 1. Am.J. Hum. Genet. 31 (in press, 1979) Rao, D. C., Keats, B. J. B., Morton, N. E., Yee, S., Lew, R.: Variability of human linkage data. Am. J. Hum. Genet. 30, 516--529 (1978)
Received January 19 / Revised March 15, 1979
