The HLA-A:HLA-B crossovers and their contribution in analysing possible haplotype-specific recombination rates

Hum Genet (1982) 61 : 127-134

© Springer-Verlag 1982

The HLA-A:HLA-B Crossovers and Their Contribution in Analysing Possible Haplotype-Specific Recombination Rates

K. Bender*

Institut ftir Humangenetik und Anthropologie der Universitfit Freiburg, Albertstr. 11, D-7800 Freiburg, Bundesrepublik Deutschland

Summary. The 266 haplotypes associated with 133 reported HLA-A:HLA-B crossovers in Whites were distributed in a manner representative for European populations. F rom this observation it follows that differentia1 recombination rates (haplotype-controlled crossover reduction or enhancement mechanisms) do not operate in the human histocompatibility complex.

Introduction

A most striking feature of the H L A system besides its many closely linked, functionally related, and highly polymorphic genes is the significant over- and underrepresentation of certain allelic combinations, called linkage disequilibrium. Especially the haplotype HLA-A1,B8 (in most cases also associated with HLA-Cw7, HLA-D/DR3, C f , C4 AOB1, B f s) is outstanding in the

European populat ion with its frequency of 6%-7% and its delta value of 0.06, followed by HLA-A3,B7 (Cw7, D/DR2, C f , B f s ) and HLA-A29, Bw44 (Cw ~, D/DRZ C21, C4 A3~1, B f F) (Baur and Danilovs 1980). Even if these combinations represent founder haplotypes, there has been ample time for their possible break- down through crossing-over (Bodmer 1973). The fact of the still existing linkage disequilibrium was therefore explained mainly by

selective advantage for carriers with these "optimally composed" constellations. But also other conservation mechanisms must be taken into consideration: (1) fertilization distortion, favoring gametes with the HLA-A1,B8 haplotype, and (2) crossover reduction or suppression by (a) a situation analogous to that of the T-complex of the mouse (Hammerberg and Klein 1975), (b) a short interstitial deletion bringing the A1 and B8 genes closer together, and (c) a short inversion between the two genes.

Selective fertility could be ruled out by Albert et al. (1973), who observed no deviations from the expected Mendelian segregation ratios. Possible crossing-over reduction mechanisms have not yet been analyzed. A simple approach would be to look at whether the overrepresented haplotypes are involved in crossing-over events less often than expected by their frequency of occurrence. I have therefore collected all available HLA-A, HLA-B recombinats in Caucasians from the literature. Non- European cases were excluded in order to reach comparable allele and haplotype parameters. Care was taken not to count an event twice.

Results and Discussion

The 133 European HLA-A, HLA-B crossing-overs recorded are listed in Table 1 in the order of their detection. They represent

Table 1. List of HLA-A :HLAB crossovers from the literature in the order of their detection a

No. Family Sex b Haplotypes involved Authors ° designation in recombination

1. HN-RH M A2,B40 (CPH 39) A3,B7

2. 114 P A9,B7 A3,B18

3. BIN M A28,B15,Cw3,Bf t Aw19(Aw32),B12, Cw5,Bf s

4. CPH 41 P ALB7 A2,B27

5. CPH 112 P A1,B8 A28,B40

6. Sa 22 P A2,B12 AlO, B15

7. L-4 M A3,B14 A28,B40

8. T 152 M A2,B7 Awlg, Bw21

* Supported by the Deutsche Forschungsgemeinschaft

Kissmeyer-Nielsen et al. (1969) d,~

Bodmer et al. (1970) ~

Dausset et al. (1970) e,f,

Svejgaard et al. (1971) e,g,h

Svejgaard et al. (1971) e



Svejgaard et al. (1971) e,~

0340-6717/82/0061/0127/$01.60

128

Table 1 (continued)

No. Family Sex b Haplotypes involved Authors c designation in recombinat ion

9. U F44 M All, Bw35 Aw19,B27

10. AKH-N-21 M A9,B12 AwI9,B" O"

11. AKH-N-45 M ALB8,Bf s A2,B27,Bf s

12. AKH-N-51 P ALB15_ Aw19(Aw32),B8

13. AKH-R-143 M A2,B5 All, B12

14. - P ALB5 A3,B7

15. 037a P A3,B27 A9,B12

16. 085 M ALB40 A3,B7

17. 0189 M Aw19(Aw32),B15 A3,Bwl6

18. CAN P A3,B7 A2,B12

19. Le P A2,B27 Awl9,B7

20. Bo M ALB8 A2,B12

21. KA P A2,B8 A1LBw35

22. MEL P A3,Bw35 A28,B5

23. HOP P A2,B8,DR4,Bf s (ROO 07) A9(Aw24),B5(Bw51),Bf s

24. HA M A2,B12,Bf s (v. d. HA) All, Bw35, Cw4,Bf F

25. STE P A1LB5,Cw3 A9,B8

26. PA P ALB8 A2,B12

27. Fu P A28,B27 A2,B12

28. de Lu M A2,B27,Cwl (Del) Aw19(A29),B12

29. BLO M ALB5 A3,B13

30. 1934 M A2,B40 A9(Aw24),B15

31. Hea M A3,B7 A2,B12

32. - M A9,B15,Cw3" A2,B27, Cwl

33. 2205a P A9,B15(Bw63),Cw3 (EV) AZB13

34. 2205b M A2,B15(Bw62) (EV) ALB40, Cw3

35. HOW P A9, (Aw24),B27, Cw2,DR4 (JAW 02) A2,B12(Bw44), Cw5,DR5

36. Jones M A3,B7 Aw19(Aw32),B18

37. 31 P AIO, B5 A9,Bw35

38. SEB 3 M A2,B17,Bf s Aw19(Aw32),BS, Bf s

Svejgaard et al. (1971) ~


Svejgaard et al. (1971) e,h,i

Svejgaard et al. (1971) *,h


Gatti et al. (1971) e

Mayr (1971) ~,j

Mayr (1971) e

Yunis et al. (1971) e,k

Seignalet (1971) ~

Lebrun et al. (1971) e

Soulier and Prou-Wartelle (1972) e

Eijsvoogel et al. (1972) 5,1

Eijsvoogel et al. (1972a) e

Eijsvoogel et al. (1972a) ~,m

Eijsvoogel et al. (1972a) ~,n

Eijsvoogel et al. (1972a) e,n

Klouda and Lawler (1972) ~

Sachs et al. (1972) e

Payne et al. (1972) ~,°,p,q

Seidl and Spielmann (1973)

Speiser et al. (1973)

Yunis et al. (1974) ~

L6w et al. (1974)

Richiardi et al. (1974) n

Richiardi et al. (1974) n

Kostyu et al. (1974) m

Cross et al. (1975)

v a n d e r D o e s et al. (1975)

Teisberg et al. (1975)

Table 1 (continued)

No. Family Sex u Haplotypes involved Authors c designation in recombinat ion

39. EB 25a ? A2,B15,Bf F Awl9,B"O",Bf s

40. EB 25b M A9,B1S, Bf F ALBw35,Bf F

41. Endelave M A9(Aw24),Bw22,Cw1 A2,B27,Cw2

42. 365 AQ M ALB5 A2,B13

43. 371 BE P ALB18 AlO(A26),B8

44. 383 DV P ALB8 A9,Bwl6

45. GOM M Aw19(Aw33),Bw35 A2,Bwl6

46. - P A9,B12 A3,B18

47. Hoe P Aw19(Aw32),B40,Cw3 A3,B7

48. v.N. M A9,B15(Bw63),Cw3 A1,B37

49. v.V. M A3,B40, Cw3 A9,B7

50. Seh. M A9,B40,Cw2,Bf s AILB5, Cw4,Bf F

51. Fam. 1 M A3,Bw35,Cw4 (Ma, Me) AIO, B8

52. Faro. 2 M Aw19,B13,Bf s (O'S,DH) AILB5,Bf s

53. Faro. 3 M Aw19(Aw31),B8,Bf s (Or) A28,Bw35,Bf s

54. P M ALB17 A2,B12

55. - M ALB8,Bf s AILB40, Cw3,Bf s

56. - M ALB17, Cw3,Bf j" A2,Bw16(Bw39),Bf s

57. 4 M AIO, B40,Cw3 A9,B7

58. DeV P ALB8 Aw19(A29),B12

59. KOU M A2,BT, Cw3,Bf s (ROO 09) AlO(A25),B13,Cw6,DRT, Bf s

60. v. Ro. M A2,B12 AILB5

61. Ares M AZB7 Awl9 (Aw30),B5, Cwl

62. Ros M A3,Bw3&Cw4 A2,B15, Cw4

63. Bak M A2,B13 AIO(A2S),BI7

64. Ah P A2,B40,Cw3,BfS A2,B14,Bf s

65. To M A9(Aw24),B40,Cw3,Bf s A2,B12,D2,Bf F

66. Bw M ALB17,DR3 AIO, Bwl6

67. Ki P Awl9(Aw30),B,,O,,,BfFI AIO, B18,Bf F

68. H2 P A2,Bw2LDRLBfSl A28,Bw16(Bw38),DR2,Bf s



Hansen et al. 1975

Belvedere et al. (1975)



Howell and Perkins (1975)

Olaisen et al. (1976)

Bijnen et al. (1976)




Suciu-Foca et al. (1976) n,~,t

Suciu-Foca et al. (1976) n,s

Suciu-Foca et al. (1976) n

i

Albert et al. (1977a) .. . . c

Barnard et al. (1977)

Cann et al. (1977)

Waltz and Rose (1977)

van Rood et al. (1977)

vanRood et al. (1977) m





Suciu-Foca and Rubinstein (1977b)

Suciu-Foca and Rubinstein (1977b) TM

Suciu-Foca and Rubinstein (1977b) ~,~

Suciu-Foca and Rubinstein (1977b) y


129

130

Table 1 (continued)

No. Family Sex b Haplotypes involved Authors ° designation in recombinat ion

69. Hy M A9(Aw24),B27,Cw3,Bf s A28,B15, Cwl, Bf F

70. BER P A2,B12 A9(Aw24),B15, Cw3,Dw4

71. SL M ALB37 A2,B15, Cw3,Dw4

72. 87 M A10(A26),BS, DR3,C2~,Bf s (DAU 06) A2,B5(BwSl),DR7, C2~,Bf s

73. 74 M A9(Aw24),BT, C21Bf s Aw19(A29),B12,DR 7, C2~,Bf F

74. 68 P AlO(A26),B5(Bw52),DR2,C2~,Bf s All, B40, Cw2,D R5, C21,Bf s

75. 58 M A28,B15,Cw3,DRw6,C2J, Bf F Aw19(Aw32),B12, Cw5,DR5, C21,BfS

76. WIEL M ALB17,Cw6,DR7,C21Bf s (Wi;RIT 02) A2,B37,Cw6,DRS, C2~,Bf F

77. 001 M Aw19(Aw30),B12(Bw44),DR7 AlO(A26),Bw16(Bw38),DRw4x7

78. K M A2,B12,DR4 ALB8,DR3

79. K M A2,B12,DR4 ALB8,DR3

80. Li M A3,B7 A9(Aw24),B15

81. Tu. P A2,B8,DR3 AlO(A25),Bw16,DR7

82. Si M ALBw41,Dw4 A2,B8,Dw3

83. St P A2,B15,Dwl A9(Aw23),Bw21,Dw3

84. - M A9(Aw24),BS, DR3 All, B5, Cw4,DR1

85. BAT 23 M A2,B12(Bw44),CwS, DR2,C2J, Bf s A 3, B40 (Bw60), Cw3, DR2, C21, Bf s

86. BET 01 P ALB17(Bw57),Cw6,DRw6 A2,B8, Cw2,DR2

87. BLA 07 M A9(Aw24),B40(Bw60),Cw3 A2,Bw35, Cw4,DR1

88. BRN 04 P A1,Bw22 (Bw55), Cw2,DR2, C21,Bf r AlO(A25),B18,DR5, C2~,Bf s

89. BRN 05 M A2,B14,Cw3,DR7,C21,Bf s AlO(A25),B18,DR4, C21Bf s

90. CRB 24 P A2,B5(Bw53),Cw4 AlO(A26),Bw16(Bw38),DR4

91. ENT 02 P A3,B5(Bw51),CwLDRLC2~,Bf s A2,B12 (Bw4 5), Cw6,D Rw6, C21,Bf F

92. FER 04 M AlO(A26),B40(Bw60),Cw2,DR4 A1LB5(Bw51)

93. FES 09 M A1,B8,DR3,C2~,Bf s All, B12 (Bw44), Cw5,DR4, C2~,Bf s

94. FES 98 P Aw19(A29),B12(Bw44),DR5,C2~,Bf p AlO(A2 6),B27, Cw2,DR3, C2~,Bf s

95. FES 99 M ALB8,DR3,C2~,Bf s Aw19(A29),B12(Bw45), Cw6,DR4, C2~,Bf s

96. HAN 09 M Aw19(Aw31),Bw35, Cw4, C21,Bf s A9(Aw24),B40(Bw60), Cw3,DR4, C2~,Bf s

97. KAS 64 P A3,B17,Cw3,DR7,C2~,Bf s A1,B8,DR3, C2~,Bf s

98. KIS 09 P A3,B8,DR3,C2~,Bf F A28,Bw35,Cw4, C21,Bf s


Dupont et al. (1977)

Dupont et al. '(i977)

Dausset et al. (1978) m,z

Dausset et al. (1978) z



Baur and Rittner (1978) m .. . .

Hartzman et al. (1978)

Park et al. (1978)

Park et al. (1978)

Suciu-Foca et aL (1979)

Suciu-Foca et al. (1979)

Suciu-Foca et al, (1979)

Suciu-Foca et al. (1979)

Walford and Hodge (1980)

Hawkins et al. (1980)














131

Table 1 (continued)

No. Family Sex b Haplotypes involved Authors ° designation in recombination

99. LAW 22 P A9(Aw24),B15(Bw62),Cw4,DR9,C2~,Bf s A28,B" 0" (Bu),DR4, C2~,Bf s

100. RIT 03 P A2,B27,Cw2,DRLC21,Bf s A9(Aw2 4),B40(Bw60), Cw3,DR4, C2~,Bf s

101. ROO 06 P A2,B40(Bw60), Cw3,DR4, C2~,Bf s ALB8,DR3, C2~,Bf s

102. ROO 10 P Aw19(Aw31),B27,Cw2,DRS, C21,Bf s ALB8,DR1, C2~,Bf s

103. STA 19 M A2,B7,DR2,C2~,Bf s A3,Bw35, Cw4,DR1, C2~,Bf F

104. VIV 04 M Aw19(A29),B12(Bw44),DR7 A2,Aw21(Bw50), Cw6,DR7

105. VIV 05 P A28,Bw35, Cw4, C21,Bf F A2,B15(Bw62), Cw3,DR2, C21,Bf s

106. VIV 10 M A2,Bw16(Bw39),DRw6,C21,Bf s ALB2 7, Cw2,DRw9, C2J, Bf s

107. WER 02 M A9(Aw23),B12(Bw44),DR7 A3,Bw35, Cw4,DR1

108. YUN 04 M A3,B8,DR3,C2~,Bf s All, B15 (Bw62 ), Cw 3,D R 4, C2~,Bf s

109. BAT 24 P A3,B7,DR2,C2~,Bf s A w19 (A29), B12 (Bw44), DR4, C2 ~, Bf s

110. BRA 23 M A9(Aw24),B12(Bw45),Cw6,DR4 A2,Bw21(Bw50),DR7

111. BRN 07 P A2,B12(Bw44),DR3,C21,Bf F ALB18,DR3, C21,Bf vI

112. BRN 07 M A3,B12(Bw44),DR3,C2~,Bf s A2,B7,DR2, C2~,Bf s

113. BRT 01 M ALB40(Bw48) ,DR7 AlO(A26),Bw16(Bw38),DR2

114. CRB 23 M A3,B40(Bw61),DR5,Bf s A9(Aw23),Bw21(Bw49),DRS, Bf s

115. DOS 01 M A9(Aw24),B5(Bw51),C2~,Bf s Awl9(Aw30),B13, Cw6,DR7, C2~,Bf s

116. FUL 08 P Awl9(Aw30),B5(Bw51),DR1, C21,Bf s ALB12 (Bw44),DR9, C21,Bf s

117. JAW 05 M ALB8,DR3 A3,B7,DR1

118. JAW 08 M Aw19(Aw32),B8 A1,B7

119. KAS 42 P ALB37,C2~,Bf s A2,B12 (Bw44 ),D R2, C2~,Bf s

120. MUE 09 M A28,B8,DR3 A3,B7,DR2

121. MYE 10 M A2,B40(Bw61),Cw3,DR1,BfS Aw19(Aw32),BI5(Bw62),DR6,Bf s

122. RUB 06 P All, B7,DR2,BfS A3,Bw35,DR4,Bf s

123. SUF 06 M A9(Aw23),B7,DR7 A2,Bw35, Cw3,DR8

124. SVE 20 M A1,Bw16(Bw39),DR8,C2~,BfS A3,B12 (Bw4 5), Cw6,D R 4, C2~,Bf s

125. TER 03 M ALB8,DR3 A2,B12 (Bw44),D R 4

126. TSB 06 P A2,B12(Bw44),Cw5,BfF AlO(A25),BlS, DR2,Bf s

127. BET 54 P Aw19(Aw32),BS(Bw53), Cw4,DR4 ALB27,DR5

128. KAS 34 P A2,B17,Cw3,C21BfS All, Bw21(Bw49),DR5, C2I BUg



Hawkins et al. (1980) b'



















Hawkins et al. (t980)









132

Table 1 (continued)

No. Family Sex b Haplotypes involved Authors c designation in recombination

129. JEA 02 P

130. AB4 M

131. F14 M

132. F62 M

133. F62 M

A2,B27,Cw2 Awlg(Aw32),B12(Bw44),DR4

A28,B15, Cw 3,Dw6, C21, B f F, C4 x3~1 AlO(A25),B18, Dw2, (22 Q°,BfS, C4 A4B2

A2,B15, Cw3,Bf s A"O",BS, B f s

A1,B40(Bw61),DRI, C2~,Bf s, C4 A~e~ A9(Aw23),B15(Bw63), C21,Bf r, C4 A3'BI

ALB40(Bw61),ORL C21,Bf s C4 A3B1 A9 (A w23), B15(Bw63), C21,BfF,, C4 A~el


Raum et al. (1981)

Own unpublished result



Apparently non-caucasoid are omitted b M, maternal; P, paternal c Further reports given in footnotes d Svejgaard et al. (1971) e Weitkamp et al. (1973) f Legrand and Dausset (1977) g Dupont et al. (1971) h Lamm et al. (1972) i Lamm et al. (1978) J Mayr and Mickerts (1971)

k Ward and Seigler (1973) i Eijsvoogel et al. (1972b) m Hawkins et al. (1980) n Bijnen et al. (1976) o Payne et al. (1975) P Payne et al. (1977) q Sasazuki et ai. (1975) r Suciu-Foca and Rubenstein (1977b) s Suciu-Foca et al. (1975) t Suciu-Foca et al. (1979)

u Albert et al. (1977b) v Albert et al. (1975) w Fotino et al. (1977) × Suciu-Foca et al. (1977) Y Suciu-Foca and Rubenstein (1977a) z France (1977) a' Rittner et al. (1980) b' Schreuder et al. (1980) °' Albert et al. (1977c)

Table 2. HLA-A and HLA-B allele frequencies from Table 1 data

Allele Frequency Allele Frequency

A 1 O. 17 B13 0.03

A2 0.26 B14 0.01

A3 0. I2 B15 0.10

A9 0.14 Bwl6 0.05

AIO 0.08 B17 0.04

A l l 0.06 B18 0.04

A28 0.05 Bw21 0.03

Awl9 0.12 Bw22 0.01

A"O" 0.003 B27 0.06

Total 1.00 Bw35 0.07 B37 0.015

B5 0.08 B40 0.09

B7 0.09 Bw41 0.003

B8 0.12 B"O" 0.015

B12 0.15 Total 1.00

266 haplotypes which were given in their most complete state, i.e., with all available in format ion on the associated H L A - C , H L A - D / D R , and complement componen t alleles (C2, C4, BJ). But only the H L A - A and HLA-B data were considered. Most crossing-overs were singular events. In families EV (nos. 33 and 34) and BRN 07 (nos. 111 and 112), however, one recombina t ion occurred in the mothe r and one in the father, and in families K (nos. 78 and 79) and F62 (nos. 132 and 133) there were even two recombinants , among 9 and 10 children respectively. Of the 133 crossing-overs 81 occurred in females, conf i rming the obser- vat ion of Svejgaard et al. (1971) of a 1.6 times higher materna l than paternal H L A - A , B recombina t ion frequency.

Interestingly, the H L A - A and HLA-B allele and haplotype frequencies (Tables 2 and 3) f rom the 266 haplotypes correspond

Table 3. HLA-A, HLA-B haplotype frequencies from Table 1 data

A1 A2 A3 A9 AIO A l l A28 Awl9 A"O" Z

B5 3 3 1 2 2 6 1 4 22

B7 2 5 11 5 1 1 25

B8 16 5 2 2 3 1 3 1 33

BI2 1 20 2 5 2 11 41

B13 3 1 1 2 7

B14 2 1 3

B15 1 7 10 1 1 4 2 26

Bw16 1 3 l 1 5 1 12

B17 5 2 1 1 9

B18 2 2 5 1 10

Bw21 3 2 1 1 7

Bw22 1 1 2

B27 2 8 1 2 1 1 2 17

Bw35 1 2 6 1 3 3 2 18

B37 3 1 4

B40 5 5 3 5 2 2 2 1 25

Bw41 1 1

B"O'" 1 3 4

Z 44 69 32 36 21 16 14 33 1 266

well to those known for the European popula t ions (Baur and Dani lovs 1980). Especially the haplotype A 1,B8 is represented in crossing-over events exactly as expected (16 in 266 = 6%), as is also t rue for all the other haplotypes. Thus, nei ther a mechanism result ing in a haplotype-specific reduced nor in an enhanced recombina t ion rate can be demonst ra ted . Since fertil ization distort ions were ruled out earlier (Albert et al. 1973), the only plausible explanat ion left for the still existing linkage disequi- l ibr ium seems to be selective advantage [as p roposed by Bodmer (1973)], at least in the past.

133

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Received March 23, 1982

Documents

The HLA-A:HLA-B crossovers and their contribution in analysing possible haplotype-specific recombination rates