Thromb Haemost 2021; 121(11): 1541-1553
DOI: 10.1055/a-1414-4840
Atherosclerosis and Ischaemic Disease

Somatic Genetic Mosaicism in the Apolipoprotein E-null Mouse Aorta

María del Pilar Valencia-Morales
1  Department of Genetic Engineering, CINVESTAV Irapuato Unit, Irapuato, Mexico
2  Department of Developmental Genetics and Molecular Physiology, “Unidad Universitaria de Secuenciación Masiva y Bioinformática”, Biotechnology Institute, UNAM, Cuernavaca, Mexico
,
Alejandro Sanchez-Flores
3  “Unidad Universitaria de Secuenciación Masiva y Bioinformática”, Biotechnology Institute, UNAM, Cuernavaca, Mexico
,
Dannia Colín-Castelán
4  Department of Medical Sciences, Leon Campus, University of Guanajuato, Leon, Mexico
,
Yolanda Alvarado-Caudillo
4  Department of Medical Sciences, Leon Campus, University of Guanajuato, Leon, Mexico
,
Nicolás Fragoso-Bargas
1  Department of Genetic Engineering, CINVESTAV Irapuato Unit, Irapuato, Mexico
,
Gladys López-González
5  Bachelor’s Degree in Nutrition Programme, Division of Health Sciences, Leon Campus, University of Guanajuato, Leon, Mexico
,
Tania Peña-López
4  Department of Medical Sciences, Leon Campus, University of Guanajuato, Leon, Mexico
,
Magda Ramírez-Nava
5  Bachelor’s Degree in Nutrition Programme, Division of Health Sciences, Leon Campus, University of Guanajuato, Leon, Mexico
,
Carmen de la Rocha
1  Department of Genetic Engineering, CINVESTAV Irapuato Unit, Irapuato, Mexico
,
Dalia Rodríguez-Ríos
1  Department of Genetic Engineering, CINVESTAV Irapuato Unit, Irapuato, Mexico
,
Gertrud Lund
1  Department of Genetic Engineering, CINVESTAV Irapuato Unit, Irapuato, Mexico
,
Silvio Zaina
4  Department of Medical Sciences, Leon Campus, University of Guanajuato, Leon, Mexico
› Author Affiliations
Funding This work was funded by Mexican National Council for Science and Technology (CONACyT) “Atención a Problemas Nacionales” Programme [2015-01-584] and University of Guanajuato Directorate for Research and Postgraduate Programs (DAIP) “2014 Proyectos Interdisciplinarios” [2014/420].

Abstract

In addition to genetic and epigenetic inheritance, somatic variation may contribute to cardiovascular disease (CVD) risk. CVD-associated somatic mutations have been reported in human clonal hematopoiesis, but evidence in the atheroma is lacking. To probe for somatic variation in atherosclerosis, we sought single-nucleotide private variants (PVs) in whole-exome sequencing (WES) data of aorta, liver, and skeletal muscle of two C57BL/6J coisogenic male ApoE null/wild-type (WT) sibling pairs, and RNA-seq data of one of the two pairs. Relative to the C57BL/6 reference genome, we identified 9 and 11 ApoE null aorta- and liver-specific PVs that were shared by all WES and RNA-seq datasets. Corresponding PVs in WT sibling aorta and liver were 1 and 0, respectively, and not overlapping with ApoE null PVs. Pyrosequencing analysis of 4 representative PVs in 17 ApoE null aortas and livers confirmed tissue-specific shifts toward the alternative allele, in addition to significant deviations from mendelian allele ratios. Notably, all aorta and liver PVs were present in the dbSNP database and were predominantly transition mutations within atherosclerosis-related genes. The majority of PVs were in discrete clusters approximately 3 Mb and 65 to 73 Mb away from hypermutable immunoglobin loci in chromosome 6. These features were largely shared with previously reported CVD-associated somatic mutations in human clonal hematopoiesis. The observation that SNPs exhibit tissue-specific somatic DNA mosaicism in ApoE null mice is potentially relevant for genetic association study design. The proximity of PVs to hypermutable loci suggests testable mechanistic hypotheses.



Publication History

Received: 07 December 2020

Accepted: 01 March 2021

Publication Date:
07 March 2021 (online)

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany