IMGT Locus in Focus

Exp Clin Immunogenet 2001;18:100–116 Received: August 31, 2000

Nomenclature of the Human Immunoglobulin Heavy (IGH) Genes

Marie-Paule Lefranc

Chairperson, IMGT Nomenclature Committee, CNRS, Université Montpellier II, Montpellier, France

Key Words Database GDB and NCBI LocusLink data- Human W IMGT W Immunoglobulin W Heavy bases, in which all the IMGT human IGH chain genes W Orphons genes have been entered. The tables are available at the IMGT Marie-Paule page of IMGT, the international ImMunoGeneTics Abstract database (http://imgt.cines.fr:8104) creat- ‘Nomenclature of the Human Immunoglobu- ed by Marie-Paule Lefranc, Université Mont- lin Heavy (IGH) Genes’, the 16th report of the pellier II, CNRS, France. ‘IMGT Locus in Focus’ section, provides the Copyright © 2001 S. Karger AG, Basel first complete list of all the human IGH genes. The total number of human IGH genes per haploid genome is 170–176 (206–212 genes, Introduction if the orphons and the processed gene are included), of which 77–84 genes are func- ‘Nomenclature of the Human Immuno- tional. IMGT/Human Genome Organization globulin Heavy (IGH) Genes’ is the 16th (HUGO) gene names and definitions of the report of the ‘IMGT Locus in Focus’ section human IGH genes on chromosome 14q32.33, launched in the April 1998 issue of Experi- processed gene on chromosome 9 and IGH mental and Clinical Immunogenetics [1–16]. orphons on chromosomes 15 and 16 are pro- This report comprises two tables and three vided with the gene functionality and the figures entitled, respectively: (1) ‘Complete number of alleles, according to the rules of list of the human IGH genes on chromosome the IMGT Scientific chart, with the accession 14 at 14q32.33’; (2) ‘Human IGH processed numbers of the IMGT reference sequences gene on chromosome 9 and IGH orphons on and with the accession ID of the Genome chromosomes 15 and 16’; (3) ‘Chromosom-

© 2001 S. Karger AG, Basel Prof. Marie-Paule Lefranc, IMGT ABC 0254–9670/01/0182–0100$17.50/0 Laboratoire d’ImmunoGénétique Moléculaire, LIGM, UPR CNRS 1142 Fax + 41 61 306 12 34 IGH, 141 rue de la Cardonille, F–34396 Montpellier Cedex 5 (France) E-Mail [email protected] Accessible online at: Tel. +33 4 99 61 99 65, Fax +33 4 99 61 99 01 www.karger.com www.karger.com/journals/eci E-Mail [email protected], IMGT http://imgt.cines.fr:8104 al localization of the human IGH locus at 14q32.33’; (4) ‘Representation of the human IGH locus at 14q32.33’, and (5) ‘The “CLAS- SIFICATION” concept of the IMGT-ON- TOLOGY exemplified for the IGHV genes’. The tables provide the first complete list of all the human IGH genes. The total number of human IGH genes per haploid genome is 170–176 (206–212 genes, if the orphons and the processed gene are included), of which 77–84 genes are functional. IMGT/Human Genome Organization (HUGO) gene names and definitions of the human IGH genes on chromosome 14q32.33, processed gene on chromosome 9 and IGH orphons on chromo- Fig. 1. Chromosomal localization of the human IGH somes 15 and 16 are provided with the gene locus at 14q32.33. The vertical line indicates the local- functionality and the number of alleles, ac- ization of the IGH locus at 14q32.33. The arrow indi- cording to the rules of the IMGT Scientific cates the orientation 5) → 3) of the locus, and the gene chart, with the accession numbers of the group order in the locus. The arrow is proportional to the size of the locus, indicated in kilobases (kb). The IMGT reference sequences and with the ac- total number of genes in the locus is shown between cession ID of the Genome Database GDB and parentheses. Seven unmapped IGHV genes which NCBI LocusLink databases, in which all the have a provisional designation are not included in this IMGT human IGH genes have been entered. figure. The number of functional genes defines the Detailed references for individual IGHV, potential IGH repertoire, which comprises 76–84 genes (38–46 IGHV, 23 IGHD, 6 IGHJ and, in the IGHD, IGHJ and IGHC genes are avail- most frequent haplotype, 9 IGHC) per haploid ge- able in other reports [5–7, 17]. These ta- nome. bles and figures are available at the IMGT Marie-Paule page of IMGT, the internation- al ImMunoGeneTics database (http://imgt. Fig. 2. Representation of the human IGH locus at cines.fr:8104) created by Marie-Paule Lefranc, 14q32.33. The boxes representing the genes are not to Université Montpellier II, CNRS, Montpel- scale. Exons are not shown. SWITCH sequences are represented by a shaded circle upstream of the IGHC lier, France [18–20]. genes. The 7 unmapped IGHV genes which corre- spond to insertion/deletion polymorphisms but which have not yet been precisely located are not shown. Human IGH Locus at 14q32.33 Pseudogenes which could not be assigned to subgroups with functional genes are designated by a Roman numeral between parentheses, corresponding to the The human IGH locus is located on chro- clans, followed by a hyphen and a number for the local- mosome 14 [21] at band 14q32.33, at the telo- ization from 3) to 5) in the locus. All these pseudogenes meric extremity of the long arm [22, 23] have truncations. Horizontal arrows indicate the ex- (fig. 1). The orientation of the locus has been tent of the allelic IGHC multigene deletions [36, 37, determined by analysis of translocations in- 50–55] or duplications [56–59] described in healthy individuals. I to VI refer to the type of deletion [for a volving the IGH locus in leukemia and lym- review, see ref. 55], duplication or triplication, defined phoma. by the deleted, duplicated or triplicated genes. Exam- ple: deletion I (del G1-EP1-A1-GP-G2-G4).

Human IGH Gene Nomenclature Exp Clin Immunogenet 2001;18:100–116 101 Fig. 2. For legend see p. 101.

102 Exp Clin Immunogenet 2001;18:100–116 Lefranc LocusLink ID Accession (3) in the locus. Seven ) to 5 ) GDB ID accession (3) d by Matsuda et al., 1998. These 1998. al., et Matsuda by d ization from 3 s, corresponding to the clans, followed by a by followed clans, the to corresponding s, a number for the subgroup, followed by a Immunoglobulin heavy constant alpha 1alpha constant heavy Immunoglobulin marker)(A2m 2 alpha constant heavy Immunoglobulin deltaconstant heavy Immunoglobulin epsilonconstant heavy Immunoglobulin P1epsilon constant Immunoglobulinheavy GDB:119333marker)(G1m 1 gamma constant heavy Immunoglobulin 3494 marker)(G2m 2 gamma constant heavy Immunoglobulin GDB:120085marker)(G3m 3 gamma constant heavy Immunoglobulin GDB:119332 GDB:119338marker)(G4m 4 gamma constant 3500 heavy Immunoglobulin 3493 Pgamma constant 3501 heavy Immunoglobulin GDB:119339muconstant heavy Immunoglobulin GDB:120084 GDB:119335 GDB:119340 GDB:119336 3502 1–1diversity Immunoglobulinheavy 3495 3497 3503 3498 1–7diversity heavy Immunoglobulin 1–14diversity heavy Immunoglobulin 1–20diversity heavy Immunoglobulin 1–26diversity heavy Immunoglobulin 2–2diversity GDB:120689Immunoglobulinheavy 2–8diversity heavy Immunoglobulin 3505 GDB:120086 GDB:9953175 3507 GDB:9953261 28510 GDB:9953263 28509 GDB:9953265 28508 GDB:9953266 28507 28506 GDB:9953230 GDB:9953278 28505 28504 IMGT definition gene (2) 2 Number alleles of in the locus. All these pseudogenes have truncations. have pseudogenes these All locus. the in ) to 5 to ) AB006776 IMGT sequence reference numbers accession IMGT func- tionality Complete list of the human IGH genes on chromosome 14 at 14q32.33 at 14 chromosome on genes IGH human the of list Complete IGHG3IGHG4IGHGPIGHM F F ORF F M12958/X03604 X06766 K01316 4 X14939 X14940, 3 1 3 IGHA2IGHDIGHEIGHEP1IGHG1 FIGHG2 F F P J00221 F F K02875-K02882X63693 J00222, J00223 2 J00228 3 AB006775, J00230, 3 3 2 IGHD1–7IGHD1–14IGHD1–20IGHD1–26 FIGHD2–2 ORFIGHD2–8 F F X13972 X13972 F F X97051 X97051 J00232 1 X13972 1 1 1 3 2 IMGT name gene (1) IMGT gene groups Table 1. IGHV gene nomenclature: genes are designated by a number for the subgroup, followed hyphen and local IGHC IGHA1 FM60193 J00220, 1 genes which have been described as insertion/deletion polymorphisms but which have not been precisely located are designated by hyphen and a small letter: IGHV1-c, IGHV1-f, IGHV3-d, IGHV3-g, IGHV3-h, IGHV4-b, IGHV5-a. A putative gene IGHV7-77 was not foun not was IGHV7-77 gene putative A IGHV5-a. IGHV4-b, IGHV3-h, IGHV3-g, IGHV3-d, IGHV1-f, IGHV1-c, letter: small a and hyphen genes are not counted in the potential repertoire [5, 17] and have a provisional designation. provisional a have and 17] [5, repertoire potential the in counted not are genes parenthese between numeral Roman a by designated are genes functional with subgroups to assigned be not could which Pseudogenes 3 from localization the for number a and hyphen respectively: comprise, Clans genes subgroup IGHV7 and IGHV5 IGHV1, I: clan – IGHV(II) pseudogenes and genes, subgroup IGHV6 and IGHV4 IGHV2, II: clan – IGHV(III) pseudogenes and genes, subgroup IGHV3 III: clan – IGHV(IV)-44 pseudogene one IV: clan – concern: which insertion/deletion by polymorphisms allelic indicates (*) asterisk An 45%in Caucasoids observed 4–30–1) 4–30–2, 3–30–3, 4–30–4, (3–30–5, genes 5 of insertion kb 50 a – gene IGHV7–4-1 the – IGHD IGHD1–1 F X97051 1

Human IGH Gene Nomenclature Exp Clin Immunogenet 2001;18:100–116 103 Immunoglobulin heavy variable 1–2variable heavy Immunoglobulin 1–3variable heavy Immunoglobulin 1–8variable heavy Immunoglobulin 1–12variable Immunoglobulinheavy 1–14variable heavy Immunoglobulin 1–17variable heavy Immunoglobulin 1–18variable heavy Immunoglobulin 1–24variable heavy Immunoglobulin 1–45variable heavy Immunoglobulin 1–46variable heavy Immunoglobulin GDB:99316601–58variable heavy Immunoglobulin GDB:9931661 28474 1–67variable heavy Immunoglobulin GDB:9931662 28473 GDB:9931663 28472 GDB:9931664 28471 GDB:9931665 28470 GDB:9931666 28469 GDB:9931667 28468 GDB:9931668 28467 GDB:9931669 28466 GDB:9931670 28465 GDB:9931671 28464 28463 Immunoglobulinheavy diversity 2–15diversity Immunoglobulinheavy 2–21diversity Immunoglobulinheavy 3–3diversity Immunoglobulinheavy 3–9diversity heavy Immunoglobulin 3–10diversity Immunoglobulinheavy 3–16diversity heavy Immunoglobulin 3–22diversity heavy Immunoglobulin 4–4diversity Immunoglobulinheavy 4–11diversity heavy Immunoglobulin 4–17diversity heavy Immunoglobulin GDB:99532924–23diversity heavy Immunoglobulin GDB:9953294 28503 5–5diversity Immunoglobulinheavy 28502 GDB:99532965–12diversity Immunoglobulinheavy GDB:9953298 28501 5–18diversity heavy Immunoglobulin GDB:9953300 28500 5–24diversity heavy GDB:9953302Immunoglobulin 28499 6–6diversity GDB:9953304Immunoglobulinheavy 28498 6–13diversity Immunoglobulinheavy 28497 GDB:99533066–19diversity heavy GDB:9953308Immunoglobulin 28496 6–25diversity heavy GDB:9953310Immunoglobulin 28495 7–27diversity heavy GDB:9953312Immunoglobulin 28494 28493 1joining GDB:9953314heavy Immunoglobulin GDB:99533161Pjoining heavy Immunoglobulin 28492 GDB:9953318 28491 2joining heavy Immunoglobulin GDB:9953320 28490 2Pjoining heavy Immunoglobulin 28489 3joining GDB:9953322heavy Immunoglobulin GDB:99533243Pjoining heavy Immunoglobulin 28488 GDB:9953326 28487 4joining heavy Immunoglobulin GDB:9953328 28486 5joining heavy Immunoglobulin GDB:9953330 28485 6joining heavy Immunoglobulin 28484 GDB:9953332 GDB:9953334 28483 28482 GDB:9953336 GDB:9953338 28481 28480 GDB:9953340 GDB:9953342 28479 28478 GDB:9953344 GDB:9953346 28477 GDB:9953348 28476 28475 IGHV1–3IGHV1–8IGHV1–12IGHV1–14 FIGHV1–17 FIGHV1–18 PIGHV1–24 PIGHV1–45 P X62109IGHV1–46 F M99637 X92210IGHV1–58 F M99639IGHV1–67 F M99640 F M99641 F 2 M99642 P 1 X92209 – – X92343 – M29809 2 X92212 1 3 3 1 – IGHJ1PIGHJ2IGHJ2PIGHJ3IGHJ3P PIGHJ4 FIGHJ5 PIGHJ6 F J00256 P J00256 F J00256 F J00256 F J00256 – J00256 J00256 1 – J00256 2 – 3 2 3 IGHD2–15IGHD2–21IGHD3–3IGHD3–9 FIGHD3–10 FIGHD3–16 FIGHD3–22 F J00234IGHD4–4 F J00235IGHD4–11 FIGHD4–17 F X13972IGHD4–23 X13972 F X13972IGHD5–5 ORF X93614IGHD5–12 F 1 X93616IGHD5–18 ORF 2 X13972IGHD5–24 X13972 2 FIGHD6–6 F 1 X97051 X97051 2 IGHD6–13 F 1 IGHD6–19 ORF 1 IGHD6–25 X13972 F 1 X13972IGHD7–27 F 1 X97051 X97051 F 1 1 F F X13972 X13972 1 X97051 1 1 X97051 1 J00256 1 1 1 1 1 (continued) Table 1 IGHV IGHV1–2 F X07448 4 IGHJ IGHJ1 F J00256 1

104 Exp Clin Immunogenet 2001;18:100–116 Lefranc Immunoglobulin heavy variable 1–68variable heavy Immunoglobulin 1–69variable heavy Immunoglobulin (provisional)1-c variable heavy Immunoglobulin (provisional)1-f variable heavy Immunoglobulin 2–5variable heavy Immunoglobulin 2–10variable Immunoglobulinheavy 2–26variable heavy Immunoglobulin 2–70variable heavy Immunoglobulin GDB:99316743–6variable Immunoglobulinheavy GDB:9931676 28460 3–7variable heavy Immunoglobulin GDB:9931672 28458 3–9variable heavy Immunoglobulin GDB:9931673 28462 3–11variable heavy Immunoglobulin 28461 3–13variable heavy Immunoglobulin 3–15variable heavy Immunoglobulin GDB:99316773–16variable heavy Immunoglobulin GDB:9931678 28457 3–19variable heavy Immunoglobulin GDB:9931679 28456 3–20variable heavy Immunoglobulin GDB:9931680 28455 3–21variable heavy Immunoglobulin 28454 GDB:99316813–22variable heavy Immunoglobulin GDB:99316823–23variable heavy Immunoglobulin 28453 GDB:9931683 28452 3–25variable heavy Immunoglobulin GDB:9931684 28451 3–29variable heavy Immunoglobulin GDB:9931685 28450 3–30variable heavy Immunoglobulin GDB:9931686 28449 3–30–2variable heavy Immunoglobulin GDB:9931687 28448 3–30–3variable heavy Immunoglobulin GDB:9931688 28447 3–30–5variable heavy Immunoglobulin GDB:9931689 28446 3–32variable heavy Immunoglobulin GDB:9931690 28445 3–33variable heavy Immunoglobulin GDB:9931691 28444 3–33–2variable heavy Immunoglobulin GDB:9931692 28443 3–35variable heavy Immunoglobulin GDB:9931693 28442 3–36variable heavy Immunoglobulin GDB:9931694 28441 3–37variable heavy Immunoglobulin GDB:9931735 GDB:9931695 28440 3–38variable heavy Immunoglobulin GDB:9931696 28439 28438 3–41variable heavy Immunoglobulin GDB:9931697 28437 3–42variable heavy Immunoglobulin 28436 3–43variable heavy Immunoglobulin GDB:99316983–47variable heavy Immunoglobulin GDB:9931699 GDB:9931700 28435 3–48variable heavy Immunoglobulin 28434 28433 3–49variable heavy Immunoglobulin GDB:99317013–50variable heavy Immunoglobulin GDB:9931702 28432 3–52variable heavy Immunoglobulin GDB:9931703 28431 3–53variable heavy Immunoglobulin GDB:9931704 28430 3–54variable heavy Immunoglobulin GDB:9931705 28429 3–57variable heavy Immunoglobulin GDB:9931706 28428 GDB:9931707 28427 GDB:9931708 28426 GDB:9931709 28425 GDB:9931710 28424 GDB:9931711 28423 GDB:9931712 28422 GDB:9931713 28421 GDB:9931714 28420 GDB:9931715 28419 28418 IGHV1–68IGHV1–69 IGHV1-cIGHV1-f P FIGHV2–5IGHV2–10 ORFIGHV2–26 AB019437 FIGHV2–70 F L22582 IGHV3–6 P Z18904IGHV3–7 FIGHV3–9 F Z12305IGHV3–11 – X62111 P M99647IGHV3–13 F 7 M99648IGHV3–15 1 F L21969IGHV3–16P F, IGHV3–19 F M99650 2 IGHV3–20 F M99649 9 – M99652IGHV3–21 ORF M99651 1 IGHV3–22 P X92217IGHV3–23 12 F M99655IGHV3–25 X92216 F – IGHV3–29 P 2 3 IGHV3–30 M99656 F 1 IGHV3–30–2 M99657 P(*)IGHV3–30–3 Z14073 2 P 1 (*)IGHV3–30–5 M99659 8 F P FIGHV3–32 M99660 F – M99661IGHV3–33 M99662 1 IGHV3–33–2 M83134IGHV3–35 AB019439 P X92283 2 – IGHV3–36 F (a) P 3 IGHV3–37 – IGHV3–38 ORF – M99664IGHV3–41 P – 19(a) L06618IGHV3–42 AB019439 P 2 M99666IGHV3–43 ORFIGHV3–47 P M99667IGHV3–48 (a) P M99669 – M99668IGHV3–49 F – IGHV3–50 5 P ORF, 1 M99670IGHV3–52 F Z18900 M99671IGHV3–53 F – M99672IGHV3–54 P 2 – IGHV3–57 P M99675 F – M99676 P – 3 M99677 P 2 M99678 M99679 3 M99680 3 M29815 – – 2 – –

Human IGH Gene Nomenclature Exp Clin Immunogenet 2001;18:100–116 105 GDB:9931730 28402 Immunoglobulin heavy variable 4–4variable heavy Immunoglobulin 4–28variable Immunoglobulinheavy 4–30–1variable heavy Immunoglobulin 4–30–2variable heavy Immunoglobulin 4–30–4variable heavy Immunoglobulin 4–31variable heavy Immunoglobulin 4–34variable heavy Immunoglobulin 4–39variable heavy Immunoglobulin 4–55variable heavy Immunoglobulin 4–59variable heavy Immunoglobulin GDB:99317314–61variable heavy Immunoglobulin GDB:9931734 GDB:9931732 28401 4–80variable heavy Immunoglobulin GDB:9953352 28399 28400 (provisional)4-b variable Immunoglobulinheavy GDB:9953354 28398 5–51variable heavy Immunoglobulin 28397 5–78variable heavy Immunoglobulin GDB:9931737(provisional)5-a variable heavy Immunoglobulin GDB:9931738 28396 6–1variable heavy Immunoglobulin GDB:9931739 28395 7–4-1variable heavy Immunoglobulin GDB:9931740 28394 GDB:99317447–27variable heavy Immunoglobulin GDB:9931741 28393 28389 7–34–1variable heavy Immunoglobulin GDB:9931742 28392 7–40variable heavy Immunoglobulin GDB:9931743 GDB:9931747 28391 7–56variable heavy Immunoglobulin 28390 28386 (provisional)7–77 variable heavy Immunoglobulin GDB:99317457–81variable heavy Immunoglobulin GDB:9931746 28388 28387 GDB:9931748 GDB:9931749 GDB:9931753 28385 28384 GDB:9931750 GDB:9931751 28379 28383 28382 GDB:9953358 GDB:9931752 28381 28380 GDB:9931754 28378 Immunoglobulin heavy variable 3–60variable heavy Immunoglobulin 3–62variable heavy Immunoglobulin 3–63variable heavy Immunoglobulin 3–64variable heavy Immunoglobulin 3–65variable heavy Immunoglobulin 3–66variable heavy Immunoglobulin 3–71variable heavy Immunoglobulin 3–72variable heavy Immunoglobulin 3–73variable heavy Immunoglobulin 3–74variable heavy Immunoglobulin GDB:99317163–75variable heavy Immunoglobulin GDB:9931717 28417 3–76variable heavy Immunoglobulin GDB:9931718 28416 3–79variable heavy Immunoglobulin GDB:9931719 28415 (provisional)3-d variable Immunoglobulinheavy GDB:9931720 28414 (provisional)3-g variable heavy Immunoglobulin GDB:9931736 28413 (provisional) 3-h variable heavy Immunoglobulin GDB:9931721 28412 sequence partial GDB:9931722 28411 GDB:9931723 28410 GDB:9931724 28409 GDB:9931729 GDB:9931725 GDB:9931728 28408 28404 GDB:9931726 28407 28403 GDB:9931727 28406 28405 IGHV4–4IGHV4–28 F FIGHV4–31IGHV4–34IGHV4–39 X05713 X05714IGHV4–55 FIGHV4–59 FIGHV4–61 FIGHV4–80 P L10098IGHV4-b F 8 X92278 5 IGHV5–51ORF F, L10094IGHV5–78 P M29811 M99685IGHV5-a F L10088IGHV6–1 F 10(b) P AB019437 13 IGHV7–27P F, IGHV7–34–1 6 Z12367 F 7 – M99686IGHV7–40 X92213IGHV7–56 9 P P X92227IGHV7–77 – IGHV7–81 P X92224/J04097 P 2 5 M99643 AB019739 2 – ORF 4 M99644 M29810 Z27509 – – – – 1 IGHV3–60IGHV3–62IGHV3–63IGHV3–64 PIGHV3–65 PIGHV3–66 PIGHV3–71 F M29813IGHV3–72 P M29814IGHV3–73 F M99681IGHV3–74 P M99682IGHV3–75 F Z27503IGHV3–76 F – X92218IGHV3–79 F – AB019437IGHV3-d P – X92206IGHV3-g P 5 Z27508IGHV3-h P Z12353 – F Z27510 3 – P Z12341 n.d. AB019437 2 1 Z18898 3 Z12336 Z29981 – – – 1 – 1 (continued) Table 1 (*)(*)(*) IGHV4–30–1 IGHV4–30–2 IGHV4–30–4 F F F (b) L10089 Z14238 4 (*) (b) 6 IGHV7–4–1 F L10057 3

106 Exp Clin Immunogenet 2001;18:100–116 Lefranc Immunoglobulin heavy variable (II)-1–1variable heavy Immunoglobulin (II)-15–1variable heavy Immunoglobulin (II)-20–1variable heavy Immunoglobulin (II)-22–1variable heavy Immunoglobulin (II)-26–2variable heavy Immunoglobulin (II)-28–1variable heavy Immunoglobulin (II)-30–1variable heavy Immunoglobulin (II)-31–1variable heavy Immunoglobulin (II)-33–1variable heavy Immunoglobulin GDB:9931755 GDB:9931756(II)-40–1variable heavy Immunoglobulin 28377 GDB:9931757(II)-43–1variable heavy 28376 Immunoglobulin GDB:9931758(II)-44–2variable heavy 28375 Immunoglobulin GDB:9933358(II)-46–1variable heavy 28374 Immunoglobulin GDB:9931759(II)-49–1variable heavy 28373 Immunoglobulin GDB:9931760(II)-51–2variable heavy 28372 Immunoglobulin GDB:9931761(II)-53–1variable heavy 28371 Immunoglobulin GDB:9931762(II)-60–1variable heavy 28370 Immunoglobulin GDB:9953360(II)-62–1variable heavy 28369 Immunoglobulin GDB:9953362(II)-65–1variable heavy 28368 Immunoglobulin GDB:9931763(II)-67–1variable heavy 28367 Immunoglobulin GDB:9931764(II)-74–1variable heavy 28366 Immunoglobulin GDB:9931765(II)-78–1variable heavy 28365 Immunoglobulin GDB:9931766(III)-2–1variable heavy 28364 Immunoglobulin GDB:9931767(III)-5–1variable heavy 28363 Immunoglobulin GDB:9931768(III)-5–2variable heavy 28362 Immunoglobulin GDB:9931769(III)-11–1variable heavy 28361 Immunoglobulin GDB:9931770(III)-13–1variable heavy 28360 Immunoglobulin GDB:9953364(III)-16–1variable heavy 28359 Immunoglobulin GDB:9931771(III)-22–2variable heavy 28358 Immunoglobulin GDB:9931772(III)-25–1variable heavy 28357 Immunoglobulin (III)-26–1variable heavy GDB:9931773 28356 Immunoglobulin (III)-38–1variable heavy GDB:9931774Immunoglobulin 28355 (III)-44variable heavy GDB:9931775Immunoglobulin 28354 GDB:9931776(III)-47–1variable heavy Immunoglobulin 28353 GDB:9931777 28352 (III)-51–1variable heavy Immunoglobulin GDB:9931778 28351 (III)-67–2variable heavy Immunoglobulin GDB:9931779 28350 (III)-67–3variable heavy Immunoglobulin GDB:9931780 28349 (III)-67–4variable heavy Immunoglobulin GDB:9953366 28348 (III)-76–1variable heavy Immunoglobulin GDB:9953368 28347 (III)-82variable heavy Immunoglobulin 28346 (IV)-44–1variable heavy Immunoglobulin GDB:9953370 GDB:9953372 GDB:9953381 28345 28344 GDB:9953382 28343 GDB:9953383 28342 GDB:9953385 28341 GDB:9953386 28340 28339 GDB:9953388 GDB:9953374 28338 28337 IGHV(II)-1–1IGHV(II)-15–1IGHV(II)-20–1 P PIGHV(II)-22–1 PIGHV(II)-26–2 PIGHV(II)-28–1 P AB019441IGHV(II)-30–1 AB019440 PIGHV(II)-31–1 AB019440 PIGHV(II)-33–1 AB019439 PIGHV(II)-40–1 AB019439 PIGHV(II)-43–1 – AB019439 – PIGHV(II)-44–2 AB019439 – PIGHV(II)-46–1 AB019439 – PIGHV(II)-49–1 AB019439 – PIGHV(II)-51–2 AB019438 – PIGHV(II)-53–1 AB019438 – PIGHV(II)-60–1 AB019438 – PIGHV(II)-62–1 AB019438 – PIGHV(II)-65–1 AB019438 – PIGHV(II)-67–1 AB019438 – PIGHV(II)-74–1 AB019438 – PIGHV(II)-78–1 AB019437 – PIGHV(III)-2–1 AB019437 – PIGHV(III)-5–1 AB019437 – PIGHV(III)-5–2 AB019437 – PIGHV(III)-11–1 AB019437 – PIGHV(III)-13–1 P AB019437 – IGHV(III)-16–1 P – AB019441IGHV(III)-22–2 P – AB019440IGHV(III)-25–1 P – AB019440IGHV(III)-26–1 AB019440 P – IGHV(III)-38–1 AB019440 P – IGHV(III)-44 AB019440 P – IGHV(III)-47–1 AB019439 – IGHV(III)-51–1 AB019439 P – PIGHV(III)-67–2 AB019439 – PIGHV(III)-67–3 AB019439 – PIGHV(III)-67–4 – PIGHV(III)-76–1 M99673 AB019438 – PIGHV(III)-82 AB019438 – PIGHV(IV)-44–1 AB019437 – AB019437 P P AB019437 – – AB019437 – – AB019437 AB019438 – – – – –

Human IGH Gene Nomenclature Exp Clin Immunogenet 2001;18:100–116 107 dividual GDB and Locus- and GDB dividual e HUGO symbols, parentheses symbols, HUGO e genes are the following: IGHA1: following: the are genes bb scribed therefore as ‘IGHV4–31’ alleles ‘IGHV4–31’ as therefore scribed scribed therefore as ‘IGHV3–30 alleles’ ‘IGHV3–30 as therefore scribed ly to IGHV3–30–5. to ly ly to IGHV4–30–1. to ly T gene names. Otherwise all the gene names (gene names gene the all Otherwise names. gene T GDB:9992632 OMIM GDB LocusLink HUGO b a IMGT definition IMGT (continued) Entry definitions are identical in IMGT, GDB, LocusLink and HUGO. and LocusLink GDB, IMGT, in identical are definitions Entry There is no entry for the IGHC group in the OMIM and LocusLink databases and in HUGO. The individual OMIM entries for the IGHC the for entries OMIM individual The HUGO. in and databases LocusLink and OMIM the in group IGHC the for entry no is There (2) Gene definitions (full names) are identical (including parentheses) in IMGT and HUGO nomenclatures. HUGO and IMGT in parentheses) (including identical are names) (full definitions Gene (2) HUGO: in and databases, genome LocusLink and GDB, OMIM, the in groups, or locus IGH the concerning entries Other (3) (a) Sequences of the polymorphic IGHV3–30–5 gene cannot be differentiated from those of the IGHV3–30 gene. All sequences are de are sequences All gene. IGHV3–30 the of those from differentiated be cannot gene IGHV3–30–5 polymorphic the of Sequences (a) a b (b) Sequences of the polymorphic IGHV4–30–1 gene cannot be differentiated from those of the IGHV4–31 gene. All sequences are de are sequences All gene. IGHV4–31 the of those from differentiated be cannot gene IGHV4–30–1 polymorphic the of Sequences (b) th in that, Note 1999. in Committee Nomenclature (HUGO) Organization Genome Human the by approved been have names gene IMGT (1) IMGT designation IGHD groupIGHD groupIGHJ groupIGHV groupdiversity heavy Immunoglobulin group joining heavy Immunoglobulin groupvariable heavy Immunoglobulin 146910 147010 147070 GDB:9992625 GDB:120741 GDB:128528 50648 3506 3509 IGHD@ IGHJ@ IGHV@ of the truncated pseudogene names are omitted, and capital letters replace the lowercase letters found in seven provisional IMG provisional seven in found letters lowercase the replace letters capital and omitted, are names pseudogene truncated the of nomenclatures. HUGO and IMGT in identical are symbols) by comparison to the allele *01 of IGHV3–30 (M83134). However, it is not excluded that some of these ‘alleles’ belong exclusive belong ‘alleles’ these of some that excluded not is it However, (M83134). IGHV3–30 of *01 allele the to comparison by exclusive belong ‘alleles’ these of some that excluded not is it However, (L10098). IGHV4–31 of *01 allele the to comparison by 146900, IGHA2: 147000, IGHD: 147170, IGHE: 147180, IGHG1: 147100, IGHG2: 147110, IGHG3: 147120, IGHG4: 147130, IGHM: 147020. In 147020. IGHM: 147130, IGHG4: 147120, IGHG3: 147110, IGHG2: 147100, IGHG1: 147180, IGHE: 147170, IGHD: 147000, IGHA2: 146900, Link entries and HUGO symbols for the IGHC genes are reported in table 1. table in reported are genes IGHC the for symbols HUGO and entries Link Table 1 locusIGH groupIGHC locusheavy Immunoglobulin group constant heavy Immunoglobulin – GDB:118731 3492 IGH@

108 Exp Clin Immunogenet 2001;18:100–116 Lefranc The human IGH locus at 14q32.33 spans they have an open reading frame (ORF). Nine 1,250 kilobases (fig. 2). It consists of 123–129 IGHV orphons and 10 IGHD orphons have IGHV genes [5, 7, 24–29], depending on the been described on chromosome 15 (15q11.2), haplotypes, 27 IGHD genes [6, 30–33] be- and 16 IGHV orphons on chromosome 16 longing to 7 subgroups, 9 IGHJ genes [6, 34] (16p11.2) [5]. In addition, 1 IGHC processed and, in the most frequent haplotype, 11 gene, IGHEP2, is localized on chromosome 9 IGHC genes [35–49] (table 1). Eighty-two to (9p24.2–p24.1) [60]. This is so far the only 88 IGHV genes belong to 7 subgroups, where- processed Ig gene which has been described. as 41 pseudogenes, which are too divergent to be assigned to subgroups, have been assigned to the 4 clans (see header of table 1). Seven IGH Gene Nomenclature and IMGT unmapped IGHV genes have been described Scientific Chart as insertion/deletion polymorphisms but have not yet been precisely located. Most 5) IGHV Gene Names genes occupy a position very close to the chro- Gene names (tables 1, 2) are designated mosome 14q telomere, whereas the IGHC according to the IMGT gene name nomen- genes are in a more centromeric position. The clature for Ig and T cell receptors (TcRs) of potential genomic IGH repertoire is more all vertebrates based on the ‘CLASSIFICA- limited, since it comprises 38–46 functional TION’ concept of the IMGT-ONTOLOGY IGHV genes belonging to 6 or 7 subgroups, [61] (appendix 1) and according to the rules depending on the haplotypes [7], 23 IGHD, 6 of the IMGT Scientific chart [18, 20], avail- IGHJ and, in the most frequent haplotype, 9 able at http://imgt.cines.fr:8104. IMGT gene IGHC genes. Allelic IGHC multigene dele- names and IMGT gene definitions for the tions [36, 37, 50–55], duplications or triplica- human Ig [62] and TcR genes [63] were ap- tions [56–59] have been described in healthy proved by the HUGO Nomenclature Com- individuals. I to VI refer to the type of dele- mittee in 1999. Note that in the HUGO tion [for a review, see ref. 55], duplication or symbols (http://www.gene.ucl.ac.uk/nomen- triplication, defined by the deleted, dupli- clature), slashes and parentheses are omitted cated or triplicated genes (fig. 2). For exam- and capital letters replace the lowercase letters ple, deletion I [36, 37, 50] is designated as found in some provisional IMGT gene names. del G1-EP1-A1-GP-G2-G4. The number of Otherwise, the gene symbols and all the full IGHC genes may vary from 5 in deletion I to names (including slashes and parentheses) are probably up to 19 in triplication III. Dupli- identical in IMGT and HUGO nomencla- cated and triplicated genes have, in all cases tures. but one, not been sequenced. Functionality Criteria of functionality (F = functional; Orphons and Processed Gene P = pseudogene; ORF = open reading frame) (tables 1 and 2) are described in the IMGT Thirty-five IGH genes have been found Scientific chart [1]. The definition of func- outside the main locus in other chromosomal tionality is based on the sequence analysis. As localizations (table 2). These genes, designat- examples, the instances functional (for germ- ed as orphons, cannot contribute to the syn- line V, D, J and for C sequences) mean that thesis of the immunoglobulin chains, even if the coding regions have an ORF without a

Human IGH Gene Nomenclature Exp Clin Immunogenet 2001;18:100–116 109 stop codon, and that there is no described Alleles defect in the splicing sites and/or recombina- The number of alleles of the human IGHV, tion signals and/or regulatory elements. Ac- IGHD, IGHJ and IGHC genes (tables 1 and cording to the gravity of the identified defects, 2) is determined according to ‘Tables of al- the functionality can be defined as ORF, leles’ and ‘Alignments of alleles’, in the IMGT pseudogene or vestigial (for germline V, D, J Repertoire, at http://imgt.cines.fr:8104. A and for C genes) [1]. Complete definitions are dash (–) indicates that allele polymorphism available from the IMGT Scientific chart at of the pseudogenes has not been studied. the IMGT Marie-Paule page. Information on Alignments of all known germline functional gene rearrangement, DNA transcription into and ORF sequences assigned to the different mRNA and RNA translation into a polypep- alleles, by comparison to the allele *01, are tide chain is provided in the IMGT ‘Germline displayed in another source [17]. Human gene tables’ in the IMGT Repertoire (columns IGH entries in this source include 99 genes designated as R, T and Pr, respectively), and and 285 alleles, with a total of 482 sequences has been published in a previous ‘IMGT Lo- [17]. cus in Focus’ report [5]. This information is extracted from the literature and through an Genome Database Accession Numbers IMGT/LIGM-DB sequence database search All IMGT/HUGO human IGH gene sym- [19, 20]. The IMGT/V-QUEST tool, available bols, full names and reference sequence acces- at the IMGT home page at http://imgt. sion numbers have been entered into the Ge- cines.fr:8104, allows the identification of the nome Database GDB, Toronto, Canada germline IGHV, IGHD and IGHJ genes from (http://www.gdb.org), and into LocusLink at IGHV-D-J genomic rearrangements and NCBI (National Center for Biotechnology In- transcripts, and provides translation and two- formation), Bethesda, USA (http://www.ncbi. dimensional representation (Collier de Perles) nlm.nih.gov/LocusLink). Accession ID to of the variable regions [19, 20, 64]. these genome databases are provided in ta- bles 1 and 2. Links to OMIM (Online Men- Reference Sequences delian Inheritance in Man) (http://www.ncbi. For each gene, an IMGT reference se- nlm.nih.gov/Omim) are cited when there are quence accession number is given (tables 1 existing entries in OMIM. Links to the indi- and 2). For the functional or ORF genes, the vidual IMGT, GDB and LocusLink gene en- IMGT reference sequence accession number tries are available from http://imgt.cines. is that corresponding to the allele *01. Note fr:8104 from IMGT Repertoire 1 List of hu- that the number *01 does not necessarily man Ig and TcR genes 1 Immunoglobulins. mean that other alleles are already known, but it signifies that any new polymorphic se- quence will be described by comparison to Correspondences between that allele *01. Although the IMGT accession Nomenclatures and Numberings numbers are the same as those from the EMBL/GenBank/DDBJ generalist databases, Correspondences between nomenclatures the content of the IMGT/LIGM-DB flat files have previously been reported for the human differs in terms of the expert annotations add- IGHV [5] and IGHD genes [6]. ed by IMGT. In order to easily compare sequences of immunoglobulins and TcRs, a unique num-

110 Exp Clin Immunogenet 2001;18:100–116 Lefranc LocusLink ID accession LocusLink ID accession (3) GDB ID accession GDB ID accession (3) IMGT definition gene P2epsilon constant heavy Immunoglobulin GDB:119337 3499 IMGT definition gene (2) 1/OR15–1adiversity heavy Immunoglobulin 1/OR15–1bdiversity heavy Immunoglobulin GDB:99533762/OR15–2adiversity heavy Immunoglobulin GDB:99533782/OR15–2bdiversity heavy Immunoglobulin GDB:9953380 28335 3/OR15–3adiversity heavy Immunoglobulin GDB:9953382 28334 3/OR15–3bdiversity heavy Immunoglobulin GDB:9953384 28333 4/OR15–4adiversity heavy Immunoglobulin GDB:9953386 28332 4/OR15–4bdiversity heavy Immunoglobulin GDB:9953388 28331 5/OR15–5adiversity heavy Immunoglobulin GDB:9953390 28330 5/OR15–5bdiversity heavy Immunoglobulin GDB:9953392 28329 1/OR15–1variable heavy Immunoglobulin GDB:9953394 28328 1/OR15–2variable heavy Immunoglobulin 28327 GDB:99317841/OR15–3variable heavy Immunoglobulin 28326 GDB:99317871/OR15–4variable heavy Immunoglobulin GDB:9953396 28325 1/OR15–5variable heavy Immunoglobulin GDB:9931789 28324 1/OR15–6variable heavy Immunoglobulin GDB:9953398 28323 1/OR15–9variable heavy Immunoglobulin GDB:9931790 28322 3/OR15–7variable heavy Immunoglobulin GDB:9931791 28321 4/OR15–8variable heavy Immunoglobulin GDB:9931792 28320 GDB:9953400 28319 28318 28317 Number alleles of Number alleles of IMGT sequence reference numbers accession IMGT sequence reference numbers accession IMGT func- tionality IMGT func- tionality IMGT name gene IMGT name gene (1) IGHD1/OR15–1bIGHD2/OR15–2a ORFIGHD2/OR15–2b ORFIGHD3/OR15–3a ORFIGHD3/OR15–3b ORFIGHD4/OR15–4a X55576 ORFIGHD4/OR15–4b X55577 ORFIGHD5/OR15–5a X55578 ORFIGHD5/OR15–5b X55579 ORF X55580 ORF X55581IGHV1/OR15–2 – X55582IGHV1/OR15–3 – X55583IGHV1/OR15–4 P – X55584IGHV1/OR15–5ORF P, – IGHV1/OR15–6 P – IGHV1/OR15–9ORF P, Z29595 – IGHV3/OR15–7 P – L25543IGHV4/OR15–8 ORF Z29633 – ORF P, – Z29596 ORF L25542 Z29597 Z29634 – Z29598 – – – – – – – Human IGH processed gene on chromosome 9, and IGH orphons on chromosomes 15 and 16 and 15 chromosomes on orphons IGH and 9, chromosome on gene processed IGH Human On chromosome 9 at 9p24.2–p24.1 at 9 chromosome On 15q11.2 at 15 chromosome On IMGT gene groups IMGT gene groups Table 2. a IGHCb IGHEP2 PIGHD IGHD1/OR15–1a K01241 ORF X55575 – IGHV IGHV1/OR15–1 – ORF Z29631 –

Human IGH Gene Nomenclature Exp Clin Immunogenet 2001;18:100–116 111 LocusLink ID accession (3) GDB ID accession (3) al in IMGT and HUGO nomenclatures. HUGO and IMGT in al IMGT definition gene (2) Number alleles of –––––1/OR16–1variable heavy Immunoglobulin –1/OR16–2variable heavy Immunoglobulin – GDB:99534021/OR16–3variable heavy Immunoglobulin – GDB:99534041/OR16–4variable heavy Immunoglobulin – GDB:9931793 28315 2/OR16–5variable heavy Immunoglobulin – GDB:9931794 28314 3/OR16–6variable heavy Immunoglobulin – GDB:9931795 28313 3/OR16–7variable heavy Immunoglobulin – GDB:9953406 28312 3/OR16–8variable heavy Immunoglobulin – GDB:9931796 28311 3/OR16–9variable heavy Immunoglobulin – GDB:9931797 28310 3/OR16–10variable heavy Immunoglobulin – GDB:9953408 28309 3/OR16–11variable heavy Immunoglobulin – GDB:9953410 28308 3/OR16–12variable heavy Immunoglobulin GDB:9953412 28307 3/OR16–13variable heavy Immunoglobulin GDB:9953414 28306 3/OR16–14variable heavy Immunoglobulin GDB:9953416 28305 3/OR16–15variable heavy Immunoglobulin GDB:9953418 28304 3/OR16–16variable heavy Immunoglobulin GDB:9953420 28303 GDB:9953422 28302 28301 28300 IMGT sequence reference numbers accession IMGT func- tionality IMGT definitionIMGT OMIM GDB LocusLink HUGO IMGT name gene (1) IGHV1/OR16–2IGHV1/OR16–3IGHV1/OR16–4 PIGHV2/OR16–5 PIGHV3/OR16–6 PIGHV3/OR16–7 ORFIGHV3/OR16–8 P Z29600 IGHV3/OR16–9 P Z29639 IGHV3/OR16–10 ORF L25544 Z17397 IGHV3/OR16–11 ORF ORFIGHV3/OR16–12 P L25545 IGHV3/OR16–13 Z29605 ORF Z29604 IGHV3/OR16–14 Z29606 ORFIGHV3/OR16–15 Z29607 PIGHV3/OR16–16 P Z29609 Z29608 P Z29610 Z29611 L25546 Z29613 (continued) On chromosome 16 at 16p11.2 at 16 chromosome On identic are symbols) (gene names gene the Otherwise omitted. are names orphon the of slashes symbols, HUGO the in that Note (1) (2) Gene definitions (full names) are identical (including slashes) in IMGT and HUGO nomenclatures. HUGO and IMGT in slashes) (including identical are names) (full definitions Gene (2) HUGO: in and databases genome LocusLink and GDB, OMIM, the in orphons IGH the concerning entries Other (3) IMGT gene groups IMGT designation Table 2 c IGHV IGHV1/OR16–1 P Z29599 IGHD/OR15IGHV/OR15IGHV/OR1615chromosome on orphons diversity heavy Immunoglobulin 15chromosome on orphons variable heavy Immunoglobulin 16chromosome on orphons variable heavy Immunoglobulin 146990 600949 600949 GDB:119334 GDB:377735 GDB:377743 3496 3510 3511 IGHDOR15@ IGHVOR15@ IGHVOR16@

112 Exp Clin Immunogenet 2001;18:100–116 Lefranc Fig. 3. The ‘CLASSIFICATION’ concept of the IMGT-ONTOLO- GY, exemplified for the IGHV genes.

bering has been defined for the variable re- The unique numbering is used as the output gions [64, 65]. Correspondence between the of the IMGT/V-QUEST alignment tool, and IMGT unique numbering and other number- in the ‘Alignments of alleles’ (IMGT Reper- ings for the human IGHV genes is available toire 1 Proteins and alleles) [17]. from the IMGT Scientific chart and from a Correspondence between the IMGT CH previous report [64]. The IMGT unique num- (immunoglobulin heavy constant exon or do- bering relies on the high conservation of the main) numberings and the protein EU heavy structure of the variable region. This number- chain numbering [69] has been reported else- ing takes into account and combines the defi- where [17]. nition of the framework (FR) and comple- mentarity determining regions (CDR) [66], structural data from X-ray diffraction studies Acknowledgments [67] and the characterization of the hypervari- I thank Gérard Lefranc, Ruth Lovering, Donna able loops [68]. The unique numbering has Maglott, Chris Porter, Sue Povey, Conover Talbot allowed the redefinition of the limits of the and all my immunologist colleagues for their con- FR and CDR [64]. The FR-IMGT and CDR- tribution to the IMGT Nomenclature Committee. I IMGT lengths themselves become crucial in- am grateful to Valérie Contet for the editorial work. formation characterizing the variable regions IMGT is funded by the European Union’s BIOTECH (BIO4CT96-0037) and 5th PCRDT (QLG2-2000- belonging to a group, a subgroup and/or a 01287) programs, the CNRS (Centre National de la gene. For example, for a germline gene of the Recherche Scientifique), the Ministère de la Recherche human IGHV1 subgroup, the lengths of the 3 and the Ministère de l’Education Nationale. Subven- CDR-IMGT, expressed as the number of ami- tions have been received from ARC (Association pour no acids, are designated as [8.8.2] (IMGT la Recherche sur le Cancer) and the Région Langue- doc-Roussillon. Repertoire 1 2D and 3D structures) [7, 64].

Human IGH Gene Nomenclature Exp Clin Immunogenet 2001;18:100–116 113 Appendix 1 share at least 75% identity at the nucleotide level (in the germline configuration for V, D and J). The ‘CLASSIFICATION’ Concept of the ‘gene’: A gene is defined as a DNA sequence that IMGT-ONTOLOGY can be potentially transcribed and/or translated (this The ‘CLASSIFICATION’ concept of the IMGT- definition includes the regulatory elements in 5) and 3), ONTOLOGY (fig. 3) organizes the immunogenetics and the introns, if present). Instances of the ‘gene’ con- knowledge useful for the naming and classification of cept are gene names. By extension, orphons and pseu- the immunoglobulin genes [63]. dogenes are also instances of the ‘gene’ concept. For ‘locus’: A locus is a group of immunoglobulin genes each gene, IMGT has defined a reference sequence that are ordered and are localized in the same chromo- [18]. For the V, D and J genes, the reference sequence somal location in a given species. The ‘locus’ IGH corresponds to a germline entity. The rules for the (14q32.33) is one of the three main immunoglobulin choice of the reference sequences are described at loci in the human genome. Immunoglobulin genes http://imgt.cines.fr:8104 in the IMGT Scientific chart. have also been identified in other chromosomal loca- ‘allele’: An allele is a polymorphic variant of a gene. tions outside the main loci, which represent new Alleles are described, exhaustively and in a standard- instances of the concept locus. However, the genes they ized way, for the four ‘core’ coding regions, that is, the contain, designated as orphons, are not functional. germline V-REGIONs, D-REGIONs and J-REGIONs ‘group’: A group is a set of genes which share the and for the C-REGIONs from immunoglobulin genes. same ‘gene type’ (V, D, J or C) and potentially partici- These alleles refer to sequence polymorphisms, with pate in the synthesis of a polypeptide of the same mutations described at the sequence level [1]. Their ‘chain type’. By extension, a group includes the related sequences are compared to the reference sequence des- pseudogenes and orphons. A 4-letter root designates ignated as *01 (see IMGT Scientific chart at http:// the ‘group’, for example, IGHV, IGHD, IGHJ and imgt.cines.fr:8104 for IMGT description of mutations IGHC for the immunoglobulin heavy genes. and IMGT allele nomenclature for sequence polymor- ‘subgroup’: A subgroup is a set of genes which phisms). belong to the same group, in a given species, and which

References

1 Lefranc MP: IMGT (ImMuno- 5 Pallarès N, Lefebvre S, Contet V, 10 Scaviner D, Lefranc MP: The hu- GeneTics) Locus on Focus. A new Matsuda F, Lefranc MP: The hu- man T cell receptor alpha joining section of Experimental and Clinical man immunoglobulin heavy vari- (TRAJ) genes. Exp Clin Immuno- Immunogenetics. Exp Clin Immu- able genes. Exp Clin Immunogenet genet 2000;17:97–106. nogenet 1998;15:1–7. 1999;16:36–60. 11 Folch G, Lefranc MP: The human T 2 Pallarès N, Frippiat JP, Giudicelli 6 Ruiz M, Pallarès N, Contet V, Bar- cell receptor beta diversity (TRBD) V, Lefranc MP: The human immu- bié V, Lefranc MP: The human and beta joining (TRBJ) genes. Exp noglobulin lambda variable (IGLV) immunoglobulin heavy diversity Clin Immunogenet 2000;17:107– genes and joining (IGLJ) segments. (IGHD) and joining (IGHJ) seg- 114. Exp Clin Immunogenet 1998;15:8– ments. Exp Clin Immunogenet 12 Artero S, Lefranc MP: The Teleostei 18. 1999;16:173–184. immunoglobulin heavy IGH genes. 3 Barbié V, Lefranc MP: The human 7 Scaviner D, Barbié V, Ruiz M, Exp Clin Immunogenet 2000;17: immunoglobulin kappa variable Lefranc MP: Protein displays of 148–161. (IGKV) genes and joining (IGKJ) the human immunoglobulin heavy, 13 Artero S, Lefranc MP: The Teleostei segments. Exp Clin Immunogenet kappa and lambda variable and immunoglobulin light IGL1 and 1998;15:171–183. joining regions. Exp Clin Immuno- IGL2 V, J and C genes. Exp Clin 4 Martinez C, Lefranc MP: The genet 1999;16:234–240. Immunogenet 2000;17:162–172. mouse (Mus musculus) immuno- 8 Folch G, Lefranc MP: The human T 14 Folch G, Scaviner D, Contet V, Le- globulin kappa variable (IGKV) cell receptor beta variable (TRBV) franc MP: Protein displays of the genes and joining (IGKJ) segments. genes. Exp Clin Immunogenet 2000; human T cell receptor alpha, beta, Exp Clin Immunogenet 1998;15: 17:42–54. gamma and delta variable and join- 184–193. 9 Scaviner D, Lefranc MP: The hu- ing regions. Exp Clin Immunogenet man T cell receptor alpha variable 2000;17:205–215. (TRAV) genes. Exp Clin Immuno- genet 2000;17:83–96.

114 Exp Clin Immunogenet 2001;18:100–116 Lefranc 15 Bosc N, Lefranc MP: The mouse 25 Matsuda F, Shin EK, Nagaoka H, 34 Ravetch JV, Siebenlist U, Kors- (Mus musculus) T cell receptor beta Matsumura R, Haino M, Fukita Y, meyer S, Waidmann T, Leder P: variable (TRBV), diversity (TRBD) Taka-ishi S, Imai T, Riley JH, Structure of the human immuno- and joining (TRBJ) genes. Exp Clin Anand R, Soeda E, Honjo T: Struc- globulin Ì locus: Characterization of Immunogenet 2000;17:216–228. ture and physical map of 64 variable embryonic and rearranged J and D 16 Bosc N, Contet V, Lefranc MP: The segments in the 3) 0.8-megabase re- genes. Cell 1981;27:583–591. mouse (Mus musculus) T cell recep- gion of the human immunoglobulin 35 Flanagan JG, Rabbitts TH: Ar- tor delta variable (TRDV), diversity heavy-chain locus. Nat Genet 1993; rangement of human immunoglobu- (TRDD) and joining (TRDJ) genes. 3:88–94. lin heavy chain constant region Exp Clin Immunogenet 2001;18: 26 Cook GP, Tomlinson IM, Walter G, genes implies evolutionary duplica- 51–58. Riethman H, Carter NP, Buluwela tion of a segment containing Á,  and 17 Lefranc MP, Lefranc G: The Immu- L, Winter G, Rabbitts TH: A map · genes. Nature 1982;300:709–713. noglobulin FactsBook. London, Ac- of the human immunoglobulin VH 36 Lefranc MP, Lefranc G, Rabbitts ademic Press, in press. locus completed by analysis of the TH: Inherited deletion of immuno- 18 Lefranc MP, Giudicelli V, Gines- telomeric region of chromosome globulin heavy chain constant re- toux C, Bodmer J, Müller W, Bon- 14q. Nat Genet 1994;7:162–168. gion genes in normal human indi- trop R, Lemaıˆtre M, Malik A, Bar- 27 Matsuda F, Ishii K, Bouvagnet P, viduals. Nature 1982;300:760–762. bié V, Chaume D: IMGT, the inter- Kuma K, Hayashida H, Miyata T, 37 Lefranc MP, Lefranc G, de Lange G, national ImMunoGeneTics data- Honjo T: The complete nucleotide Out TA, van den Broek PJ, van base. Nucleic Acids Res 1999;27: sequence of the human immuno- Nieuwkoop J, Radl J, Helal Chaa- 209–212. globulin heavy chain variable region bani H, van Loghem E, Rabbitts 19 Ruiz M, Giudicelli V, Ginestoux C, locus. J Exp Med 1998;188:2151– TH: Instability of the human immu- Stoehr P, Robinson J, Bödmer J, 2162. noglobulin heavy chain constant re- Marsh S, Bontrop R, Lemaıˆtre M, 28 Matsuda F, Honjo T: The human gion locus indicated by different in- Lefranc G, Chaume D, Lefranc MP: immunoglobulin VH locus. Immu- herited chromosomal deletions. Mol IMGT, the international ImMuno- nologist 1999;7:171–176. Biol Med 1983;1:207–217. GeneTics database. Nucleic Acids 29 Lefranc MP: Locus maps and ge- 38 Rabbitts TH, Forster A, Milstein Res 2000;28:219–221. nomic repertoire of the human Ig CP: Human immunoglobulin heavy 20 Lefranc MP: IMGT ImMuno- genes. Immunologist, in press. chain genes: Evolutionary compari- GeneTics database. Int BIOforum 30 Siebenlist U, Ravetch JV, Kors- sons of CÌ, C‰ and CÁ genes and 2000;4:98–100. meyer S, Waldmann T, Leder P: associated switch sequences. Nucle- 21 Croce CM, Shander M, Martinis J, Human immunoglobulin D seg- ic Acids Res 1981;9:4509–4524. Cicurel L, D’Ancona GG, Dolby ments encoded in tandem multigen- 39 White MB, Shen AL, Word CJ, TW, Koprowski H: Chromosomal ic families. Nature 1981;294:631– Tucker PW, Blattner FR: Human location of the genes for human im- 635. immunoglobulin D: Genomic se- munoglobulin heavy chains. Proc 31 Buluwela L, Albertson DG, Sher- quence of the delta heavy chain. Natl Acad Sci USA 1979;76:3416– rington P, Rabbitts PH, Spurr N, Science 1985;228:733–737. 3419. Rabbitts TH: The use of chromo- 40 Huck S, Fort P, Crawford DH, Le- 22 Kirsch IR, Morton CC, Nakahara somal translocations to study hu- franc MP, Lefranc G: Sequence of a K, Leder P: Human immunoglobu- man immunoglobulin gene organi- human immunoglobulin gamma 3 lin heavy chain genes map to a re- zation: Mapping DH segments with- heavy chain constant region gene: gion of translocations in malignant in 35 kb of the C mu gene and iden- Comparison with the other human B lymphocytes. Science 1982;216: tification of a new DH locus. EMBO C gamma genes. Nucleic Acids Res 301–303. J 1988;7:2003–2010. 1986;14:1779–1789. 23 McBride OW, Battey J, Hollis GF, 32 Ichihara Y, Matsuoka H, Kurosawa 41 Huck S, Lefranc G, Lefranc MP: A Swan DC, Siebenlist U, Leder P: Lo- Y: Organization of human immuno- human immunoglobulin IGHG3 al- calization of human variable and globulin heavy chain diversity gene lele (Gmb0,b1,c3,c5,u) with an constant region immunoglobulin loci. EMBO J 1988;7:4141–4150. IGHG4 converted region and three heavy chain genes on subtelomeric 33 Corbett SJ, Tomlinson IM, Sonn- hinge exons. Immunogenetics 1989; band q32 of chromosome 14. Nucle- hammer ELL, Buck D, Winter G: 30:250–257. ic Acids Res 1982;10:8155–8170. Sequence of the human immuno- 42 Ellison JW, Berson BJ, Hood LE: 24 Shin EK, Matsuda F, Nagaoka H, globulin diversity (D) segment lo- The nucleotide sequence of a human Fukita Y, Imai T, Yokoyama K, cus: A systematic analysis provides immunoglobulin CÁ1 gene. Nucleic Soeda E, Honjo T: Physical map of no evidence for the use of DIR seg- Acids Res 1982;10:4071–4079. the 3) region of the human immuno- ments, inverted D segments, ‘minor’ 43 Max EE, Battey J, Ney R, Kirsch IR, globulin heavy chain locus: Cluster- D segments or D-D recombination. Leder P: Duplication and deletion ing of autoantibody-related variable J Mol Biol 1997;270:587–597. in the human immunoglobulin  segments in one haplotype. EMBO J genes. Cell 1982;29:691–699. 1991;10:3641–3645.

Human IGH Gene Nomenclature Exp Clin Immunogenet 2001;18:100–116 115 44 Bensmana M, Huck S, Lefranc G, 52 Lefranc MP, Lefranc G: Human im- 59 Brusco A, Cariota U, Bottaro A, Lefranc MP: The human immuno- munoglobulin heavy-chain multi- Boccazzi C, Plebani A, Ugazio AG, globulin pseudo-gamma IGHGP gene deletions in healthy individu- Galanello R, van Leeuwen AM, gene shows no major structural de- als. FEBS Lett 1987;213:231–237. DeLange GG, Depelchin S, et al: fect. Nucleic Acids Res 1988;16: 53 Lefranc MP, Hammarstrom L, Structural and immunologic analy- 3108. Smith CI, Lefranc G: Gene dele- sis of gene triplications in the Ig 45 Ellison JW, Hood LE: Linkage and tions in the human immunoglobulin heavy chain constant region locus. J sequence homology of two human heavy chain constant region locus: Immunol 1994;152:129–135. immunoglobulin Á heavy chain con- Molecular and immunological anal- 60 Battey J, Max EE, McBride WO, stant region genes. Proc Natl Acad ysis. Immunodefic Rev 1991;2:265– Swan D, Leder P: A processed hu- Sci USA 1982;79:1984–1988. 281. man immunoglobulin  gene has 46 Ellison JW, Buxbaum J, Hood L: 54 Keyeux G, Lefranc G, Lefranc MP: moved to chromosome 9. Proc Natl Nucleotide sequence of a human A multigene deletion in the human Acad Sci USA 1982;79:5956–5960. immunoglobulin CÁ4 gene. DNA IGH constant region locus involves 61 Giudicelli V, Lefranc MP: On- 1981;1:11–18. highly homologous hot spots of re- tology for immunogenetics: The 47 Flanagan JG, Rabbitts TH: The se- combination. Genomics 1989;5: IMGT-ONTOLOGY. Bioinformat- quence of a human immunoglobulin 431–441. ics 1999;12:1047–1054. epsilon heavy chain constant region 55 Wiebe V, Helal A, Lefranc MP, Le- 62 Lefranc MP: Nomenclature of the gene, and evidence for three non- franc G: Molecular analysis of the human immunoglobulin genes. Curr allelic genes. EMBO J 1982;1:655– T17 immunoglobulin CH multigene Protoc Immunol, in press. 660. deletion (del A1-GP-G2-G4-E). 63 Lefranc MP: Nomenclature of the 48 Flanagan JG, Lefranc MP, Rabbitts Hum Genet 1994;93:520–528. human T cell receptor genes. Curr TH: Mechanisms of divergence and 56 Bottaro A, Cariota U, DeMarchi M, Protoc Immunol, in press. convergence of the human immuno- Carbonara AO: Pulsed-field electro- 64 Lefranc MP: The IMGT unique globulin alpha 1 and alpha 2 con- phoresis screening for immunoglob- numbering for immunoglobulins, T stant region gene sequences. Cell ulin heavy-chain constant-region cell receptors and Ig-like domains. 1984;36:681–688. (IGHC) multigene deletions and du- Immunologist 1999;7:132–136. 49 Bensmana M, Chuchana P, Lefranc plications. Am J Hum Genet 1991; 65 Lefranc MP: Unique database num- G, Lefranc MP: Sequence of the 48:745–756. bering system for immunogenetic CH1 and hinge-CH2 exons of the 57 Bottaro A, Gallina R, Brusco A, Ca- analysis. Immunol Today 1997;8: human immunoglobulin IGHA2 riota U, Boccazzi C, Barilaro MR, 509. A2m(2) allele: Comparison with the Plebani A, Ugazio AG, van Leeu- 66 Kabat EA, et al: Sequences of Pro- nonallelic and allelic IGHA genes. wen AM, DeLange GG, et al: Famil- teins of Immunological Interest. Cytogenet Cell Genet 1991;56:128. ial clustering of IGHC deletions and Washington, Public Health Service, 50 Lefranc G, Chaabani H, Van Log- duplications: Functional and molec- 1987. hem E, Lefranc MP, De Lange G, ular analysis. Immunogenetics 67 Satow Y, Cohen GH, Padlan EA, Helal AN: Simultaneous absence 1993;37:356–363. Davies DR: Phosphocholine bind- of the human IgG1, IgG2, IgG4 58 Brusco A, Cariota U, Bottaro A, ing immunoglobulin Fab McPC603. and IgA1 subclasses: Immunologi- Boccazzi C, Delange G, Van Leeu- An X-ray diffraction study at 2.7 A. cal and immunogenetical considera- wen AM, Galanello R, Plebani A, J Mol Biol 1986;190:593–604. tions. Eur J Immunol 1983;13:240– Ugazio AU, Guerra MG, et al: Dele- 68 Chothia C, Lesk AM: Canonical 244. tions, duplications and triplications structures for the hypervariable re- 51 Migone N, Oliviero S, de Lange G, of the IGHC region in different Ital- gions of immunoglobulins. J Mol Delacroix DL, Boschis D, Altruda F, ian populations. Immunodeficiency Biol 1987;196:901–917. Silengo L, DeMarchi M, Carbonara 1993;4:243–244. 69 Edelman GM, Cunningham BA, AO: Multiple gene deletions within Gall WE, Gottlieb PD, Rutishauser the human immunoglobulin heavy- U, Waxdal MJ: The covalent struc- chain cluster. Proc Natl Acad Sci ture of an entire gammaG immuno- USA 1984;81:5811–5815. globulin molecule. Proc Natl Acad Sci USA 1969;63:78–85.

116 Exp Clin Immunogenet 2001;18:100–116 Lefranc