Table 1.

History of somatic hypermutation (SHM): developments relevant to the reverse transcriptase mechanism.

Year	Author	Main development-discovery-concept	Reference
1957–1959	Burnet	Large repertoire of antibodies each lymphocyte produces one specific antibody	(2)
1959	Lederberg	Somatic mutation explicit in lymphocyte development and Ab diversity	(4)
1962	Fleishman et al.	Amino acid variation in N -terminal regions of V or antigen binding regions	(22)
1966	Brenner and Milstein	Model: V region specific nicking and error prone repair—“SHM”	(23)
1967	Smithies	Somatic “Master-> Slave” Gene Recombination model Ab diversity	(24)
1967	Edeleman and Gally	Somatic recombination between duplicated V genes model Ab diversity	(25)
1968	Cohn	Molecular biology of expectation—rationale for SHM and response to unexpected	(5)
1970	Weigert et al.	Somatic variability in Lambda light chain V region protein sequences	(6)
1970	Wu and Kabat	Hypervariable regions coincide with and define antigen contact regions	(26)
1974	Cunningham	The generation of antibody diversity after antigen	(8)
1974	Cohn	Somatic mutation explanation for Ab diversity clearly laid out	(7)
1976	Tonegawa and Steinberg	DNA V gene counting confirms somatic mutation at molecular level in V lambda	(27)
1977	Tonegawa et al.	DNA V gene counting confirms somatic mutation at molecular level in V lambda	(28)
1981	Gearhart et al.	SHM of the TEPC15 VH rearranged gene in vivo	(29)
1981	Bothwell et al.	SHM to the VH186.2 VH rearranged gene in vivo	(30)
1981	Seising and Storb	SHM of the MOPC167 VK rearranged gene in vivo	(31)
1982	Gearhart	SHM in Rearranged (VDJ) Variable Region Genes In vivo	(32)
1983	Gearhart and Bogenhagen	Somatic mutations occur in the 5′ and 3′ non-coding regions around VDJ genes	(33)
1985	Berek and Milstein	Use of hybridoma technique to sample somatic V[D]J mutant generation in vivo	(34)
1986	Cumano and Rajewsky	Further use hybridoma technique to sample somatic VDJ mutants in vivo	(35)
1987	Steele and Pollard	Model: the reverse transcriptase mechanism of SHM	(12)
1987	Golding et al.	First hint of strand biases in SHM patterns viz. A > G versus T > C	(36)
1990	Both et al.	Defining the 5′ and 3′ boundaries of SHM at VDJ genes	(37)
1990	Lebecque and Gearhart	Defining 5′ and 3′ boundaries of SHM at VDJ genes	(38)
1991–1996	Rogozin et al.	Identification RGYW/WRCY and WA hotspots in SHM data	(39, 40)
1992	Steele et al.	Defining the asymmetrical 5′ to 3′ somatic mutation distribution around V[D]J genes	(41)
1993	Betz et al.	Defining the mutational hot spots across mutated V[D]J transgenes genes	(42)
1995	Yelamos et al.	Any non-lg sequences parked between Promotor and J-C intron somatically mutates	(43)
1996	Peters and Storb	Strong evidence that transcription of VDJ target regions allows somatic mutation	(44)
1995–1998	Blanden et al.	The SHM signature is written into the germline V segment array	(18)
1998	Milstein et al.	Both DNA strands targeted for G:C and A:T mutations in SHM	(45)
1998	Fukita et al.	Strong correlative evidence that transcription of VDJ allows somatic mutation	(46)
1998	Rada et al.	In MSH2-deficient mice mutations are G:C focused suggesting two stages SHM	(47)
1999	Masutani et al.	Discovery of DNA Polymerase -eta and Y family translesion polymerases	(48)
2000	Muramatsu et al.	AID discovered—required to intiate SHM and Ig Class Switch Recombination	(49)
2001–2002	Rogozin et al.; Pavlov et al.	Error-prone DNA Polymerase eta SHM spectrum correlates with WA hotspots	(50, 51)
2001	Zeng et al.	DNA Polymerase eta is the A:T mutator in SHM in humans	(52)
2002–2004	Neuberger et al.	Definitive evidence that AID is a direct DNA C-to-U deaminase of the APOBEC family	(1)
2003	Bransteitter et al.	AID deaminates C > U on ssDNA—targets displaced strand Transcription Bubble	(53)
2003	Chaudhuri et al.	AID deaminates C > U on ssDNA—targets displaced strand Transcription Bubble	(54)
2003	Dickerson et al.	AID deaminates C > U on ssDNA—targets displaced strand Transcription Bubble	(55)
2004	Chaudhuri et al.	AID deaminates C > U on ssDNA—targets displaced strand Transcription Bubble	(56)
2004	Shen and Storb	AID targets both strands at Transcription Bubbles during transcription VDJ	(57)
2004	Rada et al.	MSH2-MSH6 -/-and Uracil DNA Glycosylase -/-define G:C and A:T mutation phases	(58)
2004	Franklin et al.	Human DNA Polymerase eta is an efficient reverse transcriptase, as are kapp, iota	(59)
2004	Steele et al.	First hint that A > G versus T > C strand bias involves an A > l RNA edited intermediate	(60)
2005	Wilson et al.	MSH2-MSH6 stimulates DNA polymerase eta, suggesting a role for A:T mutations	(61)
2006	Steele et al	Evidence WA > WG mutations correlate with the number nascent WA RNA stem loops	(62)
2007	Delbos et al.	Evidence that DNA Polymerase eta is the sole error-prone A:T SHM mutator in vivo	(63)
2009	Steele	SHM data 1984–2008 shows A»T, G»C strand biases explained by RNA/RT-model	(9)
2010–2013	Steele and Lindley; Lindley and Steele	A>>T, G>>T SHM strand biases evident in non-lg genes across all cancer exomes	(10, 13)
2011	Basu et al.	RNA exosome exposes ssDNA for AID on transcribed strand at Transcription Bubbles	(64)
2011	Maul et al.	AID generated Uracils physically located in the DNA of VDJ & Ig class switch regions	(65)
2013	Lindley	Codon-context targeted somatic mutation in cancer exomes	(16)
2016	Steele	Extant evidence supports the RNA/RT-based model and not the DNA-based model	(11)
2017	Zheng et al.	ADAR can directly edit both RNA and DNA A-sites in RNA:DNA hybrids	(15)
2017	Steele and Lindley	ADAR A > l Editing at RNA:DNA Hybrids is strong support for RNA/RT-based model	(14)