Patterns of Somatic Mutations in Immunoglobulin Variable Genes

ABSTRACT The mechanism responsible for somatic mutation in the variable genes of antibodies is unknown and may differ from previously described mechanisms that produce mutation in DNA. We have analyzed 421 somatic mutations from the rearranged immunoglobulin variable genes of mice to determine (1) if the nucleotide substitutions differ from those generated during meiosis and (2) if the presence of nearby direct and inverted repeated sequences could template mutations around the variable gene. The results reveal a difference in the pattern of substitutions obtained from somatic mutations vs. meiotic mutations. An increased frequency of T:A to C:G transitions and a decreased frequency of mutations involving a G in the somatic mutants compared to the meiotic mutants is indicated. This suggests that the mutational processes responsible for somatic mutation in antibody genes differs from that responsible for mutation during meiosis. An analysis of the local DNA sequences revealed many direct repeats and palindromic sequences that were capable of templating some of the known mutations. Although additional factors may be involved in targeting mutations to the variable gene, mistemplating by nearby repeats may provide a mechanism for the enhancement of somatic mutation.

Download Full-text

Somatic mutations of immunoglobulin variable genes are restricted to the rearranged V gene

Science ◽

10.1126/science.6857243 ◽

1983 ◽

Vol 220 (4602) ◽

pp. 1179-1181 ◽

Cited By ~ 35

Author(s):

J Gorski ◽

P Rollini ◽

B Mach

Keyword(s):

Somatic Mutations ◽

Immunoglobulin Variable Genes ◽

V Gene ◽

Variable Genes

Download Full-text

A unifying hypothesis for the molecular mechanism of somatic mutation and gene conversion in rearranged immunoglobulin variable genes

Immunology and Cell Biology ◽

10.1046/j.1440-1711.1998.00738.x ◽

1998 ◽

Vol 76 (3) ◽

pp. 288-293 ◽

Cited By ~ 11

Author(s):

Robert V Blanden ◽

Edward J Steele

Keyword(s):

Gene Conversion ◽

Molecular Mechanism ◽

Somatic Mutation ◽

Immunoglobulin Variable Genes ◽

Variable Genes

Download Full-text

Process-specific somatic mutation distributions vary with three-dimensional genome structure

10.1101/426080 ◽

2018 ◽

Author(s):

Kadir C. Akdemir ◽

Victoria T. Le ◽

Sarah Killcoyne ◽

Devin A. King ◽

Ya-Ping Li ◽

...

Keyword(s):

Somatic Mutation ◽

X Chromosome ◽

Genome Organization ◽

Somatic Mutations ◽

Light Exposure ◽

Human Cancer ◽

Three Dimensional ◽

Cancer Evolution ◽

Cancer Types ◽

Mutational Processes

AbstractSomatic mutations arise during the life history of a cell. Mutations occurring in cancer driver genes may ultimately lead to the development of clinically detectable disease. Nascent cancer lineages continue to acquire somatic mutations throughout the neoplastic process and during cancer evolution (Martincorena and Campbell, 2015). Extrinsic and endogenous mutagenic factors contribute to the accumulation of these somatic mutations (Zhang and Pellman, 2015). Understanding the underlying factors generating somatic mutations is crucial for developing potential preventive, therapeutic and clinical decisions. Earlier studies have revealed that DNA replication timing (Stamatoyannopoulos et al., 2009) and chromatin modifications (Schuster-Böckler and Lehner, 2012) are associated with variations in mutational density. What is unclear from these early studies, however, is whether all extrinsic and exogenous factors that drive somatic mutational processes share a similar relationship with chromatin state and structure. In order to understand the interplay between spatial genome organization and specific individual mutational processes, we report here a study of 3000 tumor-normal pair whole genome datasets from more than 40 different human cancer types. Our analyses revealed that different mutational processes lead to distinct somatic mutation distributions between chromatin folding domains. APOBEC- or MSI-related mutations are enriched in transcriptionally-active domains while mutations occurring due to tobacco-smoke, ultraviolet (UV) light exposure or a signature of unknown aetiology (signature 17) enrich predominantly in transcriptionally-inactive domains. Active mutational processes dictate the mutation distributions in cancer genomes, and we show that mutational distributions shift during cancer evolution upon mutational processes switch. Moreover, a dramatic instance of extreme chromatin structure in humans, that of the unique folding pattern of the inactive X-chromosome leads to distinct somatic mutation distribution on X chromosome in females compared to males in various cancer types. Overall, the interplay between three-dimensional genome organization and active mutational processes has a substantial influence on the large-scale mutation rate variations observed in human cancer.

Download Full-text

Mapping the Germline and Somatic Mutation Interaction Landscape in Indolent and Aggressive Prostate Cancers

Journal of Oncology ◽

10.1155/2019/4168784 ◽

2019 ◽

Vol 2019 ◽

pp. 1-15 ◽

Cited By ~ 2

Author(s):

Tarun Karthik Kumar Mamidi ◽

Jiande Wu ◽

Chindo Hicks

Keyword(s):

Signaling Pathways ◽

Somatic Mutation ◽

Regulatory Networks ◽

Molecular Mechanisms ◽

Somatic Mutations ◽

Multiple Gene ◽

Gene Regulatory ◽

Aggressive Tumors ◽

Prostate Cancers ◽

Mutation Information

Background. A majority of prostate cancers (PCas) are indolent and cause no harm even without treatment. However, a significant proportion of patients with PCa have aggressive tumors that progress rapidly to metastatic disease and are often lethal. PCa develops through somatic mutagenesis, but emerging evidence suggests that germline genetic variation can markedly contribute to tumorigenesis. However, the causal association between genetic susceptibility and tumorigenesis has not been well characterized. The objective of this study was to map the germline and somatic mutation interaction landscape in indolent and aggressive tumors and to discover signatures of mutated genes associated with each type and distinguishing the two types of PCa. Materials and Methods. We integrated germline mutation information from genome-wide association studies (GWAS) with somatic mutation information from The Cancer Genome Atlas (TCGA) using gene expression data from TCGA on indolent and aggressive PCas as the intermediate phenotypes. Germline and somatic mutated genes associated with each type of PCa were functionally characterized using network and pathway analysis. Results. We discovered gene signatures containing germline and somatic mutations associated with each type and distinguishing the two types of PCa. We discovered multiple gene regulatory networks and signaling pathways enriched with germline and somatic mutations including axon guidance, RAR, WINT, MSP-RON, STAT3, PI3K, TR/RxR, and molecular mechanisms of cancer, NF-kB, prostate cancer, GP6, androgen, and VEGF signaling pathways for indolent PCa and MSP-RON, axon guidance, RAR, adipogenesis, and molecular mechanisms of cancer and NF-kB signaling pathways for aggressive PCa. Conclusion. The investigation revealed germline and somatic mutated genes associated with indolent and aggressive PCas and distinguishing the two types of PCa. The study revealed multiple gene regulatory networks and signaling pathways dysregulated by germline and somatic alterations. Integrative analysis combining germline and somatic mutations is a powerful approach to mapping germline and somatic mutation interaction landscape.

Download Full-text

Molecular evolution of homologous gene sequences in germline-limited and somatic chromosomes of Acricotopus

Genome ◽

10.1139/g04-026 ◽

2004 ◽

Vol 47 (4) ◽

pp. 732-741 ◽

Cited By ~ 2

Author(s):

Wolfgang Staiber

Keyword(s):

Molecular Evolution ◽

Dna Sequences ◽

Sequence Data ◽

Structural Evolution ◽

5S Rdna ◽

Oligonucleotide Primer ◽

Homologous Gene ◽

Gene Sequences ◽

Nucleotide Substitutions ◽

Degenerate Oligonucleotide

The origin of germline-limited chromosomes (Ks) as descendants of somatic chromosomes (Ss) and their structural evolution was recently elucidated in the chironomid Acricotopus. The Ks consist of large S-homologous sections and of heterochromatic segments containing germline-specific, highly repetitive DNA sequences. Less is known about the molecular evolution and features of the sequences in the S-homologous K sections. More information about this was received by comparing homologous gene sequences of Ks and Ss. Genes for 5.8S, 18S, 28S, and 5S ribosomal RNA were choosen for the comparison and therefore isolated first by PCR from somatic DNA of Acricotopus and sequenced. Specific K DNA was collected by microdissection of monopolar moving K complements from differential gonial mitoses and was then amplified by degenerate oligonucleotide primer (DOP)-PCR. With the sequence data of the somatic rDNAs, the homologous 5.8S and 5S rDNA sequences were isolated by PCR from the DOP-PCR sequence pool of the Ks. In addition, a number of K DOP-PCR sequences were directly cloned and analysed. One K clone contained a section of a putative N-acetyltransferase gene. Compared with its homolog from the Ss, the sequence exhibited few nucleotide substitutions (99.2% sequence identity). The same was true for the 5.8S and 5S sequences from Ss and Ks (97.5%100% identity). This supports the idea that the S-homologous K sequences may be conserved and do not evolve independently from their somatic homologs. Possible mechanisms effecting such conservation of S-derived sequences in the Ks are discussed.Key words: microdissection, DOP-PCR, germline-limited chromosomes, molecular evolution.

Download Full-text

Molecular analysis of immunoglobulin variable genes in human immunodeficiency virus-related non-Hodgkin's lymphoma reveals implications for disease pathogenesis and histogenesis

Haematologica ◽

10.3324/haematol.12705 ◽

2008 ◽

Vol 93 (8) ◽

pp. 1178-1185 ◽

Cited By ~ 18

Author(s):

D. Capello ◽

M. Martini ◽

A. Gloghini ◽

M. Cerri ◽

S. Rasi ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Molecular Analysis ◽

Hodgkin’S Lymphoma ◽

Hodgkin's Lymphoma ◽

Disease Pathogenesis ◽

Non Hodgkin’S Lymphoma ◽

Non Hodgkin's Lymphoma ◽

Immunodeficiency Virus ◽

Immunoglobulin Variable Genes ◽

Variable Genes

Download Full-text

Integrating Genetic and Transcriptomic Data to Reveal Pathogenesis and Prognostic Markers of Pancreatic Adenocarcinoma

Frontiers in Genetics ◽

10.3389/fgene.2021.747270 ◽

2021 ◽

Vol 12 ◽

Author(s):

Kaisong Bai ◽

Tong Zhao ◽

Yilong Li ◽

Xinjian Li ◽

Zhantian Zhang ◽

...

Keyword(s):

Gene Expression ◽

Pancreatic Adenocarcinoma ◽

Somatic Mutation ◽

Somatic Mutations ◽

Prognostic Markers ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Genomic Variation ◽

The Cancer Genome Atlas ◽

Driver Genes

Pancreatic adenocarcinoma (PAAD) is one of the deadliest malignancies and mortality for PAAD have remained increasing under the conditions of substantial improvements in mortality for other major cancers. Although multiple of studies exists on PAAD, few studies have dissected the oncogenic mechanisms of PAAD based on genomic variation. In this study, we integrated somatic mutation data and gene expression profiles obtained by high-throughput sequencing to characterize the pathogenesis of PAAD. The mutation profile containing 182 samples with 25,470 somatic mutations was obtained from The Cancer Genome Atlas (TCGA). The mutation landscape was generated and somatic mutations in PAAD were found to have preference for mutation location. The combination of mutation matrix and gene expression profiles identified 31 driver genes that were closely associated with tumor cell invasion and apoptosis. Co-expression networks were constructed based on 461 genes significantly associated with driver genes and the hub gene FAM133A in the network was identified to be associated with tumor metastasis. Further, the cascade relationship of somatic mutation-Long non-coding RNA (lncRNA)-microRNA (miRNA) was constructed to reveal a new mechanism for the involvement of mutations in post-transcriptional regulation. We have also identified prognostic markers that are significantly associated with overall survival (OS) of PAAD patients and constructed a risk score model to identify patients’ survival risk. In summary, our study revealed the pathogenic mechanisms and prognostic markers of PAAD providing theoretical support for the development of precision medicine.

Download Full-text

Dissecting Human Antibody Responses: Useful, Basic, and Surprising Findings

Blood ◽

10.1182/blood.v130.suppl_1.sci-49.sci-49 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. SCI-49-SCI-49

Author(s):

Antonio Lanzavecchia

Keyword(s):

B Cell ◽

Dna Sequences ◽

Neutralizing Antibodies ◽

Influenza A ◽

Somatic Mutations ◽

Vaccine Design ◽

Human Memory ◽

Affinity Maturation ◽

Effective Vaccine ◽

Human Antibody

Abstract We use cell culture-based high-throughput methods to interrogate human memory B cell and plasma cell repertoires and to isolate antibodies selected on the basis of their neutralizing potency and breadth. Relevant examples are antibodies that neutralize all influenza A viruses or even four paramyxoviruses. By targeting conserved structures, these broadly neutralizing antibodies are less prone to select escape mutants and are promising candidates for prophylaxis and therapy of infections, as well as tools for vaccine design. The value of a target-agnostic approach to vaccine design is illustrated by our discovery of extremely potent antibodies that neutralize human cytomegalovirus, which led to the identification of their viral ligand, a pentameric complex that was then produced and tested as an effective vaccine. By reconstructing the genealogy trees of specific B cell clones, we investigate the role of somatic mutations in affinity maturation and in generation of antibody variants with broader or different specificity. Somatic mutations can also generate autoantibodies, as found in patients with pemphigus and autoimmune pulmonary alveolar proteinosis. Recently, while searching for antibodies that broadly react with malaria variant antigens, we discovered a new mechanism of antibody diversification, which relies on templated insertions of genomic DNA sequences into immunoglobulin genes, followed by somatic mutations. Disclosures Lanzavecchia: Humabs SA: Equity Ownership, Research Funding.

Download Full-text

Molecular analysis of the hot spot region related to length mutations in wheat chloroplast DNAs. I. Nucleotide divergence of genes and intergenic spacer regions located in the hot spot region.

Genetics ◽

10.1093/genetics/129.3.873 ◽

1991 ◽

Vol 129 (3) ◽

pp. 873-884 ◽

Cited By ~ 1

Author(s):

Y Ogihara ◽

T Terachi ◽

T Sasakuma

Keyword(s):

Dna Sequences ◽

Gene Evolution ◽

Hot Spot ◽

Intergenic Spacer ◽

Open Reading Frames ◽

Coding Region ◽

Nucleotide Substitutions ◽

Plant Groups ◽

Nucleotide Divergence ◽

Chloroplast Dnas

Abstract The nucleotide divergence of chloroplast DNAs around the hot spot region related to length mutation in Triticum (wheat) and Aegilops was analyzed. DNA sequences (ca. 4.5 kbp) of three chloroplast genome types of wheat complex were compared with one another and with the corresponding region of other grasses. The sequences region contained rbcL and psaI, two open reading frames, and a pseudogene, rpl23' (pseudogene for ribosomal protein L23) disrupted by AT-rich intergic spacer regions. The evolution of these genes in the closely related wheat complex is characterized by nonbiased nucleotide substitutions in terms of being synonymous/nonsynonymous, having A-T pressure transitions over transversions, and frequent changes at the third codon position, in contrast with the gene evolution among more distant plant groups where biased nucleotide substitutions have frequently occurred. The sequences of these genes had diverged almost in proportion to taxonomic distance. The sequence of the pseudogene rpl23' changed approximately two times faster than that of the coding region. Sequence comparison between the pseudogene and its protein-coding counterpart revealed different degrees of nucleotide homology in wheat, rice and maize, suggesting that the transposition timing of the pseudogene differed and/or that different rates of gene conversion operated on the pseudogene in the cpDNA of the three plant groups in Gramineae. The intergenic spacer regions diverged approximately ten times faster than the genes. The divergence of wheat from barley, and that from rice are estimated based on the nucleotide similarity to be 1.5, 10 and 40 million years, respectively.

Download Full-text