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A BALB/c IGHV Reference Set, Defined by Haplotype Analysis of Long-Read VDJ-C Sequences From F1 (BALB/c x C57BL/6) Mice

Jackson, Katherine J.L. ; Kos, Justin T. ; Lees, William ; Gibson, William S. ; Smith, Melissa Laird ; Peres, Ayelet ; Yaari, Gur ; Corcoran, Martin ; Busse, Christian E. and Ohlin, Mats LU orcid , et al. (2022) In Frontiers in Immunology 13.
Abstract

The immunoglobulin genes of inbred mouse strains that are commonly used in models of antibody-mediated human diseases are poorly characterized. This compromises data analysis. To infer the immunoglobulin genes of BALB/c mice, we used long-read SMRT sequencing to amplify VDJ-C sequences from F1 (BALB/c x C57BL/6) hybrid animals. Strain variations were identified in the Ighm and Ighg2b genes, and analysis of VDJ rearrangements led to the inference of 278 germline IGHV alleles. 169 alleles are not present in the C57BL/6 genome reference sequence. To establish a set of expressed BALB/c IGHV germline gene sequences, we computationally retrieved IGHV haplotypes from the IgM dataset. Haplotyping led to the confirmation of 162 BALB/c IGHV gene... (More)

The immunoglobulin genes of inbred mouse strains that are commonly used in models of antibody-mediated human diseases are poorly characterized. This compromises data analysis. To infer the immunoglobulin genes of BALB/c mice, we used long-read SMRT sequencing to amplify VDJ-C sequences from F1 (BALB/c x C57BL/6) hybrid animals. Strain variations were identified in the Ighm and Ighg2b genes, and analysis of VDJ rearrangements led to the inference of 278 germline IGHV alleles. 169 alleles are not present in the C57BL/6 genome reference sequence. To establish a set of expressed BALB/c IGHV germline gene sequences, we computationally retrieved IGHV haplotypes from the IgM dataset. Haplotyping led to the confirmation of 162 BALB/c IGHV gene sequences. A musIGHV398 pseudogene variant also appears to be present in the BALB/cByJ substrain, while a functional musIGHV398 gene is highly expressed in the BALB/cJ substrain. Only four of the BALB/c alleles were also observed in the C57BL/6 haplotype. The full set of inferred BALB/c sequences has been used to establish a BALB/c IGHV reference set, hosted at https://ogrdb.airr-community.org. We assessed whether assemblies from the Mouse Genome Project (MGP) are suitable for the determination of the genes of the IGH loci. Only 37 (43.5%) of the 85 confirmed IMGT-named BALB/c IGHV and 33 (42.9%) of the 77 confirmed non-IMGT IGHV were found in a search of the MGP BALB/cJ genome assembly. This suggests that current MGP assemblies are unsuitable for the comprehensive documentation of germline IGHVs and more efforts will be needed to establish strain-specific reference sets.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
BALB/c, haplotyping, IGHV, SMRT sequencing, substrains
in
Frontiers in Immunology
volume
13
article number
888555
publisher
Frontiers Media S. A.
external identifiers
  • scopus:85132314351
  • pmid:35720344
ISSN
1664-3224
DOI
10.3389/fimmu.2022.888555
language
English
LU publication?
yes
id
e91dd1dd-de9d-4cc9-a07c-974f34f86e7e
date added to LUP
2022-10-06 14:38:50
date last changed
2024-06-13 21:27:41
@article{e91dd1dd-de9d-4cc9-a07c-974f34f86e7e,
  abstract     = {{<p>The immunoglobulin genes of inbred mouse strains that are commonly used in models of antibody-mediated human diseases are poorly characterized. This compromises data analysis. To infer the immunoglobulin genes of BALB/c mice, we used long-read SMRT sequencing to amplify VDJ-C sequences from F1 (BALB/c x C57BL/6) hybrid animals. Strain variations were identified in the Ighm and Ighg2b genes, and analysis of VDJ rearrangements led to the inference of 278 germline IGHV alleles. 169 alleles are not present in the C57BL/6 genome reference sequence. To establish a set of expressed BALB/c IGHV germline gene sequences, we computationally retrieved IGHV haplotypes from the IgM dataset. Haplotyping led to the confirmation of 162 BALB/c IGHV gene sequences. A musIGHV398 pseudogene variant also appears to be present in the BALB/cByJ substrain, while a functional musIGHV398 gene is highly expressed in the BALB/cJ substrain. Only four of the BALB/c alleles were also observed in the C57BL/6 haplotype. The full set of inferred BALB/c sequences has been used to establish a BALB/c IGHV reference set, hosted at https://ogrdb.airr-community.org. We assessed whether assemblies from the Mouse Genome Project (MGP) are suitable for the determination of the genes of the IGH loci. Only 37 (43.5%) of the 85 confirmed IMGT-named BALB/c IGHV and 33 (42.9%) of the 77 confirmed non-IMGT IGHV were found in a search of the MGP BALB/cJ genome assembly. This suggests that current MGP assemblies are unsuitable for the comprehensive documentation of germline IGHVs and more efforts will be needed to establish strain-specific reference sets.</p>}},
  author       = {{Jackson, Katherine J.L. and Kos, Justin T. and Lees, William and Gibson, William S. and Smith, Melissa Laird and Peres, Ayelet and Yaari, Gur and Corcoran, Martin and Busse, Christian E. and Ohlin, Mats and Watson, Corey T. and Collins, Andrew M.}},
  issn         = {{1664-3224}},
  keywords     = {{BALB/c; haplotyping; IGHV; SMRT sequencing; substrains}},
  language     = {{eng}},
  month        = {{06}},
  publisher    = {{Frontiers Media S. A.}},
  series       = {{Frontiers in Immunology}},
  title        = {{A BALB/c IGHV Reference Set, Defined by Haplotype Analysis of Long-Read VDJ-C Sequences From F1 (BALB/c x C57BL/6) Mice}},
  url          = {{http://dx.doi.org/10.3389/fimmu.2022.888555}},
  doi          = {{10.3389/fimmu.2022.888555}},
  volume       = {{13}},
  year         = {{2022}},
}