Cargando…

Genetic mapping of novel modifiers for Apc(Min) induced intestinal polyps’ development using the genetic architecture power of the collaborative cross mice

BACKGROUND: Familial adenomatous polyposis is an inherited genetic disease, characterized by colorectal polyps. It is caused by inactivating mutations in the Adenomatous polyposis coli (Apc) gene. Mice carrying a nonsense mutation in the Apc gene at R850, which is designated Apc(Min/+) (Multiple int...

Descripción completa

Detalles Bibliográficos
Autores principales: Dorman, Alexandra, Binenbaum, Ilona, Abu-Toamih Atamni, Hanifa J., Chatziioannou, Aristotelis, Tomlinson, Ian, Mott, Richard, Iraqi, Fuad A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299641/
https://www.ncbi.nlm.nih.gov/pubmed/34294033
http://dx.doi.org/10.1186/s12864-021-07890-x
_version_ 1783726309098127360
author Dorman, Alexandra
Binenbaum, Ilona
Abu-Toamih Atamni, Hanifa J.
Chatziioannou, Aristotelis
Tomlinson, Ian
Mott, Richard
Iraqi, Fuad A.
author_facet Dorman, Alexandra
Binenbaum, Ilona
Abu-Toamih Atamni, Hanifa J.
Chatziioannou, Aristotelis
Tomlinson, Ian
Mott, Richard
Iraqi, Fuad A.
author_sort Dorman, Alexandra
collection PubMed
description BACKGROUND: Familial adenomatous polyposis is an inherited genetic disease, characterized by colorectal polyps. It is caused by inactivating mutations in the Adenomatous polyposis coli (Apc) gene. Mice carrying a nonsense mutation in the Apc gene at R850, which is designated Apc(Min/+) (Multiple intestinal neoplasia), develop intestinal adenomas. Several genetic modifier loci of Min (Mom) were previously mapped, but so far, most of the underlying genes have not been identified. To identify novel modifier loci associated with Apc(Min/+), we performed quantitative trait loci (QTL) analysis for polyp development using 49 F1 crosses between different Collaborative Cross (CC) lines and C57BL/6 J-Apc(Min/+)mice. The CC population is a genetic reference panel of recombinant inbred lines, each line independently descended from eight genetically diverse founder strains. C57BL/6 J-Apc(Min/+) males were mated with females from 49 CC lines. F1 offspring were terminated at 23 weeks and polyp counts from three sub-regions (SB1–3) of small intestinal and colon were recorded. RESULTS: The number of polyps in all these sub-regions and colon varied significantly between the different CC lines. At 95% genome-wide significance, we mapped nine novel QTL for variation in polyp number, with distinct QTL associated with each intestinal sub-region. QTL confidence intervals varied in width between 2.63–17.79 Mb. We extracted all genes in the mapped QTL at 90 and 95% CI levels using the BioInfoMiner online platform to extract, significantly enriched pathways and key linker genes, that act as regulatory and orchestrators of the phenotypic landscape associated with the Apc(Min/+) mutation. CONCLUSIONS: Genomic structure of the CC lines has allowed us to identify novel modifiers and confirmed some of the previously mapped modifiers. Key genes involved mainly in metabolic and immunological processes were identified. Future steps in this analysis will be to identify regulatory elements – and possible epistatic effects – located in the mapped QTL. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12864-021-07890-x.
format Online
Article
Text
id pubmed-8299641
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-82996412021-07-28 Genetic mapping of novel modifiers for Apc(Min) induced intestinal polyps’ development using the genetic architecture power of the collaborative cross mice Dorman, Alexandra Binenbaum, Ilona Abu-Toamih Atamni, Hanifa J. Chatziioannou, Aristotelis Tomlinson, Ian Mott, Richard Iraqi, Fuad A. BMC Genomics Research Article BACKGROUND: Familial adenomatous polyposis is an inherited genetic disease, characterized by colorectal polyps. It is caused by inactivating mutations in the Adenomatous polyposis coli (Apc) gene. Mice carrying a nonsense mutation in the Apc gene at R850, which is designated Apc(Min/+) (Multiple intestinal neoplasia), develop intestinal adenomas. Several genetic modifier loci of Min (Mom) were previously mapped, but so far, most of the underlying genes have not been identified. To identify novel modifier loci associated with Apc(Min/+), we performed quantitative trait loci (QTL) analysis for polyp development using 49 F1 crosses between different Collaborative Cross (CC) lines and C57BL/6 J-Apc(Min/+)mice. The CC population is a genetic reference panel of recombinant inbred lines, each line independently descended from eight genetically diverse founder strains. C57BL/6 J-Apc(Min/+) males were mated with females from 49 CC lines. F1 offspring were terminated at 23 weeks and polyp counts from three sub-regions (SB1–3) of small intestinal and colon were recorded. RESULTS: The number of polyps in all these sub-regions and colon varied significantly between the different CC lines. At 95% genome-wide significance, we mapped nine novel QTL for variation in polyp number, with distinct QTL associated with each intestinal sub-region. QTL confidence intervals varied in width between 2.63–17.79 Mb. We extracted all genes in the mapped QTL at 90 and 95% CI levels using the BioInfoMiner online platform to extract, significantly enriched pathways and key linker genes, that act as regulatory and orchestrators of the phenotypic landscape associated with the Apc(Min/+) mutation. CONCLUSIONS: Genomic structure of the CC lines has allowed us to identify novel modifiers and confirmed some of the previously mapped modifiers. Key genes involved mainly in metabolic and immunological processes were identified. Future steps in this analysis will be to identify regulatory elements – and possible epistatic effects – located in the mapped QTL. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12864-021-07890-x. BioMed Central 2021-07-22 /pmc/articles/PMC8299641/ /pubmed/34294033 http://dx.doi.org/10.1186/s12864-021-07890-x Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research Article
Dorman, Alexandra
Binenbaum, Ilona
Abu-Toamih Atamni, Hanifa J.
Chatziioannou, Aristotelis
Tomlinson, Ian
Mott, Richard
Iraqi, Fuad A.
Genetic mapping of novel modifiers for Apc(Min) induced intestinal polyps’ development using the genetic architecture power of the collaborative cross mice
title Genetic mapping of novel modifiers for Apc(Min) induced intestinal polyps’ development using the genetic architecture power of the collaborative cross mice
title_full Genetic mapping of novel modifiers for Apc(Min) induced intestinal polyps’ development using the genetic architecture power of the collaborative cross mice
title_fullStr Genetic mapping of novel modifiers for Apc(Min) induced intestinal polyps’ development using the genetic architecture power of the collaborative cross mice
title_full_unstemmed Genetic mapping of novel modifiers for Apc(Min) induced intestinal polyps’ development using the genetic architecture power of the collaborative cross mice
title_short Genetic mapping of novel modifiers for Apc(Min) induced intestinal polyps’ development using the genetic architecture power of the collaborative cross mice
title_sort genetic mapping of novel modifiers for apc(min) induced intestinal polyps’ development using the genetic architecture power of the collaborative cross mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299641/
https://www.ncbi.nlm.nih.gov/pubmed/34294033
http://dx.doi.org/10.1186/s12864-021-07890-x
work_keys_str_mv AT dormanalexandra geneticmappingofnovelmodifiersforapcmininducedintestinalpolypsdevelopmentusingthegeneticarchitecturepowerofthecollaborativecrossmice
AT binenbaumilona geneticmappingofnovelmodifiersforapcmininducedintestinalpolypsdevelopmentusingthegeneticarchitecturepowerofthecollaborativecrossmice
AT abutoamihatamnihanifaj geneticmappingofnovelmodifiersforapcmininducedintestinalpolypsdevelopmentusingthegeneticarchitecturepowerofthecollaborativecrossmice
AT chatziioannouaristotelis geneticmappingofnovelmodifiersforapcmininducedintestinalpolypsdevelopmentusingthegeneticarchitecturepowerofthecollaborativecrossmice
AT tomlinsonian geneticmappingofnovelmodifiersforapcmininducedintestinalpolypsdevelopmentusingthegeneticarchitecturepowerofthecollaborativecrossmice
AT mottrichard geneticmappingofnovelmodifiersforapcmininducedintestinalpolypsdevelopmentusingthegeneticarchitecturepowerofthecollaborativecrossmice
AT iraqifuada geneticmappingofnovelmodifiersforapcmininducedintestinalpolypsdevelopmentusingthegeneticarchitecturepowerofthecollaborativecrossmice