**10. References**

132 Gene Duplication

encoding proteins with only indirect roles in immunity. The -barrel encoded by genes of the IGSF has obviously been a successful structural motif which can explain its conservation during evolution and diversification into many variants. While IGSF polygeny is widespread, the degree of polygeny is especially pronounced among those that encode the variable heavy and light chain genes of antibodies and the T cell receptor (TCR). Early estimates suggested there were as many as 1000 variable heavy (VH) genes in mice and hundreds in humans. While subsequently studies, including genome projects, have lowered the number of VH genes to ~100-150 in these species, this is still a very large number of homologous genes to occupy a single locus. Similar duplication is seen among genes encoding the variable light chain genes, i.e. V and V. However, there are large variations in the numbers and features of

This article surveys the duplicated Ig genes in a number of species and uses examples indicating that Ig polygeny resulted from a combination of duplication and genomic gene conversion. Since understanding the evolutionary forces at work in this process requires some understanding of the role played by these duplicated genes in humoral immunity, we review the processes involved in the generation of the antibody repertoire such as Ig gene segment recombination, junctional diversity, somatic hypermutation (SHM) and somatic gene conversion (SGC). We review these processes in various vertebrates but focus on data obtained using the neonatal and newborn piglet model to suggest that evolutionary improvements in somatic processes have reduced the need for the Ig polygeny that evolved among lower vertebrates. We also describe the more recent duplication of the Cgenes of mammals that indicates the process was similar. C genes encode the subclasses of mammalian IgG, the "flagship mammalian antibody" that is unique to this vertebrate class. Since this duplication event occurred more recently, we thought it could provide insight

We propose that the extensive polygeny of VH, Vand Vgenes among vertebrates gave adaptive advantage to the earliest vertebrates for generating a diverse repertoire of antibody specificities much as the more recent evolutionary diversification of C genes resulted in IgG subclass antibodies with different effector functions. We suggest that the evolutionary appearance of mechanisms to somatically alter V-region genes reduced the importance of polygeny in V-region loci for certain mammals and birds. In higher mammals these mechanisms make it possible for a complete functional repertoire to be generated using just one or a few VH genes. This hypothesis can explain why so many of the V-region genes of higher mammals are seldom used, and why deletions of VH genes and C genes have no effect. We propose that these genes remain as evolutionary vestiges or redundant back-ups in the genome in a manner that parallels the retention of IgD in most mammals. An alternative hypothesis is that the extensive somatic recombination which characterizes the variable region loci (Section 4) creates instability that promotes duplication and genomic gene conversion. In any case, these hypotheses challenge the existing paradigm that random VH, DH and JH recombination among the many gene segments is necessary for survival (presented in immunology textbooks) by placing Ig polygeny into evolutionary perspective.

The authors acknowledge the Molecular Cell Biology Program of the National Science Foundation (USA) and Biological Mimetics of Fredrick, Md for their support of the studies

duplicated VH and VL genes among mammals and other vertebrates.

into the advantages conferred by gene duplication.

**9. Acknowledgement** 

described.


Immunoglobulin Polygeny: An Evolutionary Perspective 135

Currier, S. J., Gallara, J. L. & Knight K. L. (1998). Partial genetic map of the rabbit VH

Davies, J. & Riechmannn, L. (1995). Antibody VH domains as small recognitions units.

Dawichki, W. & Marshall, J.S. (2007). New and emerging roles for mast cells in host defense.

De Genst, E., Saerens,D., Muyldermans, S. & Conrath, K. (2006). Antibody repertoire

deWildt, R. M., Hoet, R. M., van Venrooig, W. J., Tomlinson, I. M. & Winter, G. (1999).

Diaz, M., Stanfield, R.L., Greenberg, S. & Flajnik, M. F. (2002). Structural analysis, selection

Dooley, H., Flajnik, M.F. & Porter, J. (2003). Selection and characterization of naturally–

Dooley, H. & Flajnik, M.F. (2006). Antibody repertoire development in cartilagenous fish.

Du Pasquier, L., Robert, J., Courtet, M., & Mussmann, R. (2000). B cell development in the

Edholm, E-S, Bengton, E., Staffor, J. L., Sahoo, M., Taylor, E. R. , Miller, N. W. & Wilson, M.

Eguchi-Ogawa, T, Sun, X-Z., Wertz, N., Uenishi, H., Puimi, F., Chardon, P., Wells, K., Tobin,

Flanagan, J.G. & Rabbitts, T. H. (1982) Arrangement of human immunoglobulin heavy

Foster, S. J., Brezinschek, H. P., Brezinschek, R. I. & Lipsky, P. E. (1997). Molecular

Gay, D., Saunders, T., Camper, S. & Weigert, M. (1993). Receptor editing: an approach by autoreactive B cells to escape tolerance. *J. Exp. Med.* 177 pp. 999-1008. Glas, A. M., van Monfort, E. H. N. & Milner, E. C. B. (2000). The human antibody repertoire:

Gu, H., Tarlinton, D., Muller, W., Rajewsky, K. & Forster, I. (1991). Most peripheral B cells in

Analysis of heavy and light chain pairing indicates that receptor editing shapes the

and ontogeny of the shark new antigen receptor (IgNAR): identification of a new locus preferentially expressed in early development. *Immunogenetics* 54: 501-512. Dildrop, R, Krawinkel, U., Winter, E. & Rajewsky, K. (1985). VH gene expression in murine

lipopolysaccharide blasts distribute over the nine known VH-groups and may be

occurring single domain (IgNAR) antibody fragments from immunized sharks by

(2010). Identification of two IgD+ B cell populations in channel catfish, Ictalurus

G. J. & Butler, J. E. (2010). Antibody repertoire development in fetal and neonatal piglets. XI. The relationship of VDJ usage and the genomic organization of the

chain constant region genes implies evolutionary duplication of a segment

mechansism and selective influences that shape the kappa gene repertoire of IgM+

Old notions, current realities and VH gene-dependent biases. In: *The antibodies,* (Zanetti, M. &Capra, J.D., eds). Vol 6 , pp 63-79. Harwood Academic Publishers ,

development in camelids. *Dev. Comp. Immunol.* 30 pp. 187-198.

human antibody repertoire. *J. Mol. Bio*. 285 pp. 895-901.

random. *Eur. J. Immunology* 15 pp. 1154-1156.

phage display. *Mol. Immunol.* 40 pp. 25-33.

punctatus. *J. Immunol.* 185 pp. 4082-4094.

B cells. *J. Clin. Invest.* 99 pp. 1614-1627.

Amsterdam.

amphibian Xenopus. *Immunol. Rev.* 175 pp. 201-213.

variable heavy chain locus. *J. Immunol.* 184 pp. 3734-3742.

containing , and genes. *Nature* 300 pp. 709-713.

mice are ligand restricted. *J. Exp. Med.* 173 pp. 1357-1371

*Devel. Comp. Immunol.* 30 pp. 43-56.

chromosomal region. *J. Immunol.* 140 pp. 1651-1659.

*Biotechnol.* 13 pp. 475-479.

*Curr. Opin. Immunol.* 19 pp. 31-18.


Butler, J. E., (1974). Immunoglobulins of the mammary secretions. In: *Lactation, a* 

Butler, J. E., & Kehrle Jr., M. E. (2005). Immunocytes and immunoglobulins in milk. In:

and J. Bienenstock, eds.), 3rd Edition, Academic Press, NY. pp. 1763-1793. Butler, J. E., Francis, D., Freeling, J., Weber, P., Sun, J. & Krieg, A. M. (2005). Antibody

Butler, J. E., Sun, J. & Navarro, P. (1996). The swine immunoglobulin heavy chain locus has a single JH and no identifiable IgD. *International Immunology* 8 pp. 1897-1904. Butler, J. E., Weber, P., Sinkora, M., Baker, D., Schoenherr, A., Mayer, B. & Francis, D.

Butler, J. E., Sun, X-Z , Wertz, N., Lager, K. M., Urban Jr., J. , Nara, P. & Tobin, G. (2011b).

Butler, J. E., Zhao, Y., Sinkora, M., Wertz, N. & Kacskovics, I. (2009a). Immunoglobulins, antibody repertoire and B cell developmen*t. Devel. Comp. Immunol.* 33 pp. 321-333 Butler, J. E., Lager, K. M., Splichal, I., Francis, D., Kacskovics, I., Sinkora, M., Wertz, N., Sun,

Butler, J. E., Wertz, N., Zhao, Y., Kunz, T. H., Bratsch, S., Whitaker, J. & Schountz, T. (2010).

Butler, J. E., Weber, P. & Wertz, N. (2006). Antibody repertoire development in fetal and

Cerato, E., Birkle, S., Portoukalian, J., Mezazigh, A., Chatal, J.F. & Aubry, J. (1997). Variable

(GD2, GD3) and their O-acetylated derivatives. *Hybridoma* 16 pp. 307-316. Chen, K., Xu, W., Wilson, M., He, B., Miller, N. W., Begnten, E., Edholm, E-S, Santini, P.A.,

255. Academic Press, New York.

*Immunol.* 175 pp. 6772-6785.

of adaptive immunity. *Immunol. Res.* 39 pp. 33-51.

Development. *Vet. Immunol. Immunopath.* 128 pp. 147-170.

mammals. *Devel. Com. Immunol.* 35 pp. 272-284.

exposed to environmental antigen.

*Immunol*.177 pp. 5459-5470.

pp. 889-898.

*Comprehensive Treatise*, (Larson, B. L. & Smith, V., eds.), Vol. III, Chapter V, pp. 217-

*Mucosal Immunology*, (J. Mestecky, M. E. Lamm, W. Strober, J. R. McGhee, L. Mayer

repertoire development in fetal and neonatal piglets. IX. Three PAMPs act synergistically to allow germfree piglets to respond to TI-2 and TD antigens. *J.* 

(2002). Antibody repertoire development in fetal and neonatal piglets. VIII. Colonization is required for newborn piglets to make serum antibodies to Tdependent and type 2 T-independent antigens. *J. Immunol.* 169 pp. 6822-6830. Butler, J. E., Weber, P., Sinkora, M., Sun, J., Ford, S. J. & Christenson, R. (2000). Antibody

repertoire development in fetal and neonatal piglets. II. Characterization of heavy chain CDR3 diversity in the developing fetus*. J. Immunol.* 165 pp. 6999-7011. Butler, J. E. & Sinkora, M. (2007). The isolator piglet: A model for studying the development

Antibody repertoire development in fetal and neonatal piglets. XXI. VH usage remains constant during development in fetal piglets and postnatally in pigs

J., Zhao, Y., Brown, W. R., DeWald, R., Dierks, S., Muyldermanns, S., Lunney, J.K., McCray, P. B., Rogers, C. S., Welsh, M. J., Navarro, P., Klobasa, F., Habe, F. & Ramsoondar, J. (2009b). The Piglet as a Model for B cell and Immune System

Two suborders of bats have the canonical isotypes repertoire of other eutherian

neonatal pigs. XIII. "Hybrid VH genes" and the pre-immune repertoire revisited*. J.* 

region gene segments of nine monoclonal antibodies specific to disialgangliosides

Rath, R., Chiu, A., Cattalinei, M., Litzman, J., Busseel, J., Huang, B., Meini, A., Riesbaeck, K., Cunningham-Rudles, C., Plebani, A. & Cerutti, A. (2009). Immunoglobulin D enhances immune surveillance by activating antimicrobioal, proinflammatory and B cell-stimulating programs in basophils. *Nat. Immunol.* 10


Immunoglobulin Polygeny: An Evolutionary Perspective 137

Lefranc, M. P., Lefranc, G. & Rabbitts, T. H. (1982). Inherited deletion of immunoglobulin heavy chain constant region genes in normal individuals. *Nature* 300 pp. 760-762.

Liu, Y.J., de Bouteiller, O., Arpin, C., Briere, F., Gailbert, L., Ho, S. , Martinez-Valdez, H.,

Lutz, C., Ledermann, B., Kosco-Vilbois, M. H., Ochsenbein, A. F., Zingernagel, R. M., Kohler,

Mageed, R. A., Marmer, I. J. , Wynn, S. L., Moyes, S. P, Maziak, B. B., Bruggemann, M. &

Maki, R., Roeder W., Trawnecker, A., Sidman, C., Wabl, M., Raschke, W. & Tonegawa, S.

Malynn, B. A., Berman, J. E., Yancopous, G. D., Bona. C. A. & Alt, F. W. (1987). Expression of

Marchalonis, J. J., Schluter, S. F., Bernstein, R. M. & Edmundson, A. B. (1998). Phylogenetic

Marr, S., Morales, H., Bottaro, A., Cooper, M., Flajnik, M. & Robert, J. (2007). Localization

Matsuda, F., Shin, E. K., Nagaoka, H., Matsumura, R., Haino, M., Fukita, Y., Taka-ishi, S.,

Matsuda, F., Ishii, K., Bourvagnet, P., Kuma, K., Hayashida, H., Miyata, T. & Honjo, T.

Matsuda, F., Sin, E. K., Hirabayashi, Y., Nagaoka, H., Yoshida, M. C., Zong, S. Q. & Honjo, T.

Migone, N., Oliviero, S., de Lange, G., Delacroix, D. L., Boschis, D., Altruda, F., Silengo, L.,

human heavy-chain cluste*r. Proc. Nat'l Acad. Sci*. USA 81 pp. 5811-5815.

translocation of variable region segments. *EMBO J*. 9: pp. 2501-2506. Meselson, M. S. & Radding, C. M. (1975). A general model for genetic recombination. *Proc.* 

immunoglobulin heavy-chain locus. *Nature Genet.* 3 pp. 88-94.

chain region locus *J. Expt. Med*. 188 pp. 2151-2161.

*Nat'l Acad. Sci.* USA 72 pp. 358-361.

Lewin, B., (2004). *Genes VIII*. Pearson-Prentice Hall, Upper Saddle River, N.J. p. 87.

pp. 240-244.

4 pp. 603-613.

cells. *Nature* 393 pp. 797-801.

*Immunol*. pp. 135: 75-94.

*Immunol.* 179 pp. 6783-6789.

70 pp. 417-506.

variable region. *Clin. Exp. Immunol.* 123 pp. 1-8.

expression of immunoglobulin delta. *Cell*. 24 pp. 353-365

subclasses: immunological and immunogenetical considerations*. Eur. J. Immunol* 13

Banchereau, J. & Lebecque, S. (1990). Normal IgD+IgM- germinal center B cells can express up to 80 mutations in the variable region of their IgD transcripts. *Immunity*

G. & Brombacher, F. (1998). IgD can largely substitute for loss of IgM function in B

MacKworth-Young, C. G. (2001). Rearrangement of the human heavy chain variable region gene V3-23 in transgenic mice generates antibodies reactive with a range of antigens on the basis of VHCDR3 and residues intrinsic to the heavy chain

(1981). The role of DNA rearrangement and alternative RNA processing in the

the immunoglobulin heavy-chain variable gene repertoire. *Curr. Top. Microbiol.* 

emergence and molecular evolution of the immunoglobulin family. *Adv. Immunol*.

and differential expression of activation-induced cytidine deaminase in the amphibian Xenopus upon antigen stimulation and during early development. *J.* 

Imai, T., Riley, J. H., Amand, R., Soeda, E. & Honjo, T. (1993). Structure and physical map of 64 variable segments in 3' 0.8-megabase region of the human

(1998). The complete nucleotide sequence of the human immunoglobulin heavy

(1990). Organization of variable region segments of the human immunoglobulin heavy chain: duplication of the D5 cluster within the locus and interchromosomal

Demarchi, M., & Carbonaro, A. O. (1984). Multiple gene deletions within the


Hamers-Casterman, C., Atarhouch, T., Muylermans, S., Robinson, G., Hamers, C., Songa, E.

Hammarstrom L., Lefranc G., Lefranc M-P, Persson, M.A.A. & Smith, C.I.E. (1986). *Monogr.* 

Herrin, B. R. & Cooper, M. D. (2010). Alternative adaptive immunity in jawless vertebrates.

Hordvik, I., Thevarajan, J., Sandal, I., Bastani, N. & Krossoy, B. (1999). Molecular cloning

Ichiyoshi, Y. & Casali, P. (1994). Analysis of the structural correlates for antibody

Janeway, C.A., Travers, P., Walport, M., & Shlomchik, M.J. (2005). Immunobiology, 6th

Janssens, R., Dekker, S., Hendriks, R. W., Panayotou, G., van Remoortere, A., San, J. K.,

Johnston, C. M., Wood, A. L., Bolland, D. J. & Corcoran, A. E. (2006). Complete sequence

Karasuyama, H., Mukai, K., Tsujimura, Y., & Obata, K. (2009). Newly discovered roles for

Keyeux, G, Lefranc, G. & Lefranc, M. P. (1989). A multigene deletion in the human IGH

Klobasa, F., Werhahn, E., & Butler, J.E. (1981). Regulation of humoral immunity in the piglet by immunoglobulins of maternal origin. *Res. Vet. Sci*. 31 pp. 195-206. Knight, K. L. (1992). Restricted VH usage and generation of antibody diversity in rabbit.

Koelsch, K., Zheng, N. Y., Zhang, Q., Duty, A., Helms, C., Mathias, M. D., Jared, M., Smith,

Lavoie, T. B., Mohan, S., Lipschults, C. A., Grivel, J-C., Li, Y. l., Mainhart, C. R., Kam-

Lefranc, M. P., Lefranc, G., de Lange, G., Out ,T. A., van den Broek, P. J., van Nieuwkoop, J.,

Lefranc, G., Chaabani, H., van Loghem, E., Lefranc, M. P., de Lange, G. & Helal, A. N.

autoreactive in healthy individuals. *J. Clin Invest.* 117 pp. 1558-1565. Kranz, D. M. & Voss, Jr., E. W. (1981). Restricted reassociation of heavy and light chains

heavy and light chain V segments *J. Exp. Med*. 180 pp. 885-895.

mice. *Proc. Nat'l. Acad. Sc*i. USA 103 pp. 15130-15135.

light chains. *Nature* 363 pp. 446-448.

Edition, Garland Science, New York.

*J. Immunol.* 185 pp. 1367-1374.

*J. Immunol*. 50 pp. 202-210.

*Immunol.* 176 pp. 4221-4234.

*Genomics* 5 pp. 432-441.

*Ann. Rev. Immunol.* 10 pp. 593-616.

*Mol. Immunol.* 36 pp. 1189-1205.

217.

*Allergy* 20 pp. 18-25.

B., Bendahman, N. & Hammers, R. (1993). Naturally occurring antibodies devoid of

and phylogenetics analysis of the Atlantic salmon immunoglobulin D gene. *Scand.* 

polyreactivity by multiple reassortments of chimeric human immunoglobulin

Groveld, F. & Drabek, D. (2006). Generation of heavy-chain-only antibodies in

assembly and characterization of the C57BL/6 mouse heavy chain V region. *J.* 

basophils : a neglected minority gains new respect. *Nature Rev. Immunol.* 9 pp. 9-13.

constant region locus involves highly homologous hot spots of recombination.

K., Capra, J. D., & Wilson, P. C. (2007). Mature B cells class switch to IgD are

from hapten-specific monoclonal antibodies. *Proc. Nat'l Acad. Sci*. 78 pp. 5807-5811.

Morgan, L. N. W., Drohan, W. N. & Smith-Gill, S. J. (1999). Structural differences among monoclonal antibodies with distinct fine specificities and kinetic properties.

Radl, J., Hela, A. N., Chaabani, H., van Loghem, E. & Rabbitts, T. H. (1983a) Instability of the human immunoglobulin heavy chain constant region locus indicated by different inherited chromosomal deletions. *Mol. Biol Med*. 1 pp. 207-

(1983b). Simultaneous absence of the human IgG1, IgG2, IgG4 and IgA1

subclasses: immunological and immunogenetical considerations*. Eur. J. Immunol* 13 pp. 240-244.


Immunoglobulin Polygeny: An Evolutionary Perspective 139

Reynaud, C.A., Anquez, V., Daher,A. & Weill, J. (1987). A hyperconversion mechanism generates the chichen pre-immune light chain repertoire. *Cell.* 48 pp. 379-388. Rodkey, L. S. & Adler, F. L. (1983). Regulation of natural anti- allotypic antibody responses

Roes, J. & Rajewsky, K. (1993). Immunoglobulin D (IgD)-deficient mice reveal an auxiliary

Rowe, D. S. & Fahey, J. L. (1965). A new class of human immunoglobulins. *J. Expt. Med.* 121

Rumfelt, L. L., McKinney, E. C., Taylor, E. & Flajnik, M. F. 2002). The development of

formation during ontogeny of the spleen. *Scand. J. Immunol.* 56 pp. 130-148. Schiaffella, E., Sehgal, D., Anderson, A. O. & Mage,R. G. (1999). Gene conversion and

Schroeder, H. W. Jr., Hillson, H. L. & Perlmutter, R. M. (1987). Early restriction of human

Schroeder. H.W. Jr, Hillson, H.L. & Perlmutter, R.M*.* (1990). Structure and evolution of

Sheehan, K. M., Mainville, C. A., Willert, S. & Brodeur, P. H. (1993). The utilization of

Solem, S.T. & Stenvik, J. (2006). Antibody repertoire development in teleosts--a review with

Spieker-Polet, H., Yam, P-C., & Knight K. L. (1993). Differential espression of 13 IgA-heavy chain genes in rabbit lymphoid tissues. *J. Immunol.* 150 pp. 5457-5465. Srisapoome, P., Ohira, T., Hirona, I. & Aoki, T. (2004). Genes of the constant regions of

Stenvik, J. & Jorgensen, T. O. (2000). Immunoglobulin D (IgD) of Atlantic cod has a unique

Sun, J., Hayward, C., Shinde, R., Christenson, R., Ford, S.P. & Butler, J.E. (1998). Antibody

80% of VH usage during 84 days of fetal life. *J. Immunol*. 161 pp. 5070-5078 Sun, J., Kacskovics, I., Brown, W. R. & Butler, J. E. (1994). Expressed swine VH genes belong to a small VH gene family homologous to human VH III. *J. Immunol.* 153 pp. 5618-5627. Szostak, J. W., Orr-Weaver, T. L. & Rothstein, R. J. (1983). The double-strand break repair

Thomson, C. A., Little, K. Q., Reason, D. C. &Schrader, J. W. (2011). Somatic diversity in

Tiegs, S. L., Russell, D. M. & Nemazee, D. (1993). Receptor editing in self-reactive bone

centers of immunized rabbits. *J. Immunol.* 162 pp. 3984-3995.

antibody repertoire. *Science* 238 pp. 791-793.

structure. *Immunogenetics* 51 pp. 452-461.

model for recombination. *Cell.* 33 pp. 25-35.

marrow B cells. *J. Exp. Med*. 177 pp. 1009-1020.

multiple pathogens. *J. Immumnol.* 186: pp. 2291-2298.

mammalian VH families. *Int'l Immunol* 2 pp. 41-45.

*Med.* 152 pp. 1024-1035.

177 pp. 45-55.

pp. 171-199.

151 pp. 5363-5375.

56 pp. 292-300.

76.

by network induced auto-anti-idiotypic responsiveness of their offspring. *J. Exp.* 

receptor function for IgD in antigen-mediated recruitment of B cells. *J. Exp. Med.*

primary and secondary lymphoid tissues In the nurse shark *Ginglymostoma cirratum.* B cell zones precede dendritic cell immigration and T cell cell zones

hypermutation during diversification of VH sequences in developing germinal

individual VH exons in the primary repertoire of adult BALB/c mice. *J. Immunol.* 

emphasis on salmonids and *Gadus morrhua* L. *Develop. Comp. Immunology* 30 pp. 57-

functional heavy chain of Japanese flounder. *Parealichthys olivaceus*. *Immunogenetics*

repertoire development in fetal and neonatal piglets. I. Four VH genes account for

CDR3 loops allows single V-genes to encode innate immunological memories for


Miller, M. A., & Steele, R.E. (2000). Lemon encodes an unusual receptor protein-tyrosine kinase expressed during gametogenesis in Hydra. *Dev. Biol*. 224:286-298. Mo, J.A., & Holmdahl, R. (1996). The B cell response to autologous type II collagen: biased V gene repertoire with V gene sharing and epitope shift. *J. Immunol.* 157 pp. 2440-2448. Monroe, J. G., Havran, W. L., & Cambier, J. C. (1983). B lymphocyte activation entry into

Muyldermans, S., Ghassabeh, G.H., & Saerens D. (2009)*.* Single-domain antibodies. In :

Navarro, P., Christenson, R. Ekhardt, G, Lunney, J.K., Rothschild,M., Bosworth, B, Lemke, J.

porcine IgA is breed dependent. *Vet. Immunol. Immunopath*. 73 pp. 287-295. Nguyen, V., Su, C., Muyldermans, S. van der Loo, W. (2002). Heavy chain antibodies in Camelidea; a case of evolutionary innovation. *Immunogenetics* 54 pp. 39-47. Nitschke, L., Kosco, M. L., Kohler, G., & Lamers, M. C. (1993). Immunoglobulin D deficient

Notarangelo, L. D., Fischer, A.,Geha, R.S., Casanova, J-L., Chapel, H, Conley, M.E.,

immunodeficiencies: 2009 update. *J. Allergy Clin. Immunol*. 124: 1161-1178. Ogawa, K., Wakayama, A., Kunsisada, T., Oril, H., Watanabe, K. & Agata, K. (1998).

Ohta, Y. & Flajnik, M. (2006). IgD, like IgM , is a primordial immunoglobulin class

Olsson, P.G., Rabbani, H., Hammarstromn, L. & Smith, C.I.E. (1993). Novel human

Ratcliffe, M. J. H. (2006). Antibodies, immunoglobulin genes and the bursa of Fabricius in

Reiter, Y., Schuck, P., Boyd, L. F. & Plaksin, D. (1999). An antibody single –domain phage

variable region of the mouse strain 129S1. *J. Immunol.* 179 pp. 2419-2427.

chicken. B cell development. *Devel. Comp. Immunol.* 30 pp. 101-118.

Padlan, E. A. (1994). Anatomy of the antibody molecule. *Mol. Immunol.* 31 pp. 169-217. Plaut, A.G., Wustar, R. Jr. & Capra, J.D. (1974). Differential susceptibility of human IgA immunoglobulins to streptococal IgA proteases. *J. Clin. Invest.* 54 pp. 1295-1300. Rabbani, H., Kondo, N., Smith, C.I., Hammarstrom, L. (1995). The influence of gene deletion

dependent antigens. *Proc. Nat'l Acad Sci.* USA 90 pp.1887-1891.

planarians. *Biochem. Biophys Res. Commun*. 248 pp. 204-209.

*Clin. Immunl. Immunopathol.* 76:S pp. 214-218.

*Immunol*. 13 pp. 208-213.

10728.

Press. Chapter 16, pp. 216-230.

cell cycle is accompanied by decrease expression of IgD but not IgM. *Eur. J.* 

*Recombinant antibodies for immunotherapy*, Little, M. (ed.), Cambridge University

& Butler, J.E. (2000). Genetic differences in the frequency of the hinge variants of

mice can mount normal immune responses to thymus –independent and –

Cunningham-Rundles, C., Etzioni, A., Hammarstrom, L., Nonoyama, S., Ochs, H.D., Puck, J., Roifman, C., Seger, R., & Wedgwood, J. (2009). Primary

Identification of a receptor tyrosine kinase involved in germ cell differentiation in

perpetuated in most jawed vertebrates. *Proc. Nat'l. Acad. Sci.* USA 103 pp. 10723-

immunoglobulin heavy chain constant region gene deletion haplotypes characterized by pulsed -field electrophoresis. *Clin. Exp. Immunol.* 94: pp. 84-90.

and duplication within the IGHC locus on serum immunoglobulin subclass levels.

display library of a native heavy chain variable region: Isolation of functional single-domain VH molecules with a unique interface. *J. Mol. Bio.* 290 pp. 685-698. Retter, I., Chevillard, C., Scharfe, M., Conrad, A., Hafner, M., Im, T-H , Ludewig, M.,

Nordsied,G., Severitt, S., Thies, S., Mauhar, A., Bloecker, H., Mueller, W. & Riblet, R. (2007). Sequence and characterization of the Ig heavy chain constant and partial


**8** 

*Republic of Korea* 

**Gene Duplication in Insecticide Resistance** 

*Department of Agricultural Biotechnology, Seoul National University, Seoul* 

Gene duplication is a widely observed phenomenon in all three kingdoms of life and is considered to be a major driving force in the evolution of genomes and organisms. Gene duplication refers to any duplication event of a region of DNA that contains genes, eventually giving rise to gene families. In a classical sense, gene duplication is considered to predate functional diversification. When a duplicated copy is generated, the surplus copy is released from the selective pressure that is posed by random mutations, which allows the rapid accumulation of mutations without deleterious consequences to the organism (Zhang, 2003). The accumulated mutations can increase the fitness of the organism or create a novel function, thereby playing a major role in evolution through functional divergence (Ohno, 1970; Taylor and Raes, 2004). Paralogous gene family members that share a common ancestor gene are generated from a duplication event, which is distinguished from the orthologous genes in different genomes that share a common ancestor as a result of a speciation event (Hurles, 2004). In another theory, instead one copy retains the original function after gene duplication, both of the two copies become to undergo complementary functional diversification, allowing the evolution of an organism over generations (Force et al., 1999). Whole genome duplication events are also common particularly in plant species having polyploidy genomes. Whole genome duplication has influenced the evolutionary

One example of extensive gene duplication is the gene amplification. Contrary to gene duplication, which is a doubling mechanism of one gene, gene amplification refers to the process by which the copy number of a particular gene is specifically increased to a greater extent compared to those of other genes, resulting in a dramatic increase in gene dosage. Gene amplification generally results from the repeated replication of a stretch of DNA in a specific region of a genome. Because gene amplification increases the copy number of a gene relatively quickly, it is commonly involved in gene expression control during the development of an organism. Increased copy numbers of a particular gene enables rapid

The most common mechanism of gene duplication is homologous recombination by unequal crossing-over between short repeated sequences on homologous segments of chromosomes during meiosis. The replication slippage is also responsible for the duplication of small contiguous repeats of DNA. The possibility and frequency of gene duplication depend on the degree of repetitive sequence distribution between two homologous chromosomes. Detailed information on gene duplication mechanisms can be

production of a large amount of protein within a short period.

**1. Introduction** 

path in many species.

found elsewhere in this book.

Si Hyeock Lee and Deok Ho Kwon

