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Genetic dissection of the Canq1 locus governing variation in extent of the collateral circulation
Shiliang Wang1, Hua Zhang, Tim Wiltshire
1Department of Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
Insights
Researchers identified genes influencing native collateral formation, crucial for limiting tissue damage in cardiovascular diseases. This study refines a key genetic region, highlighting candidate genes for future research.
Area of Science:
- Cardiovascular Biology
- Genetics
- Vascular Biology
Background:
- Native collaterals are vital endogenous bypass vessels that protect tissues from injury during ischemic events like stroke and heart attack.
- The extent of these collaterals varies significantly between individuals, influenced by genetic factors.
- A previously identified quantitative trait locus, Canq1, on chromosome 7 accounts for substantial heritable variation in collateral extent between mouse strains.
Purpose of the Study:
- To identify specific genes within the Canq1 locus responsible for variations in cerebral pial collateral formation.
- To understand the genetic basis of collateral extent variation in the cerebrovascular system.
Main Methods:
- Utilized recombinant inbred lines and SNP-mapping across multiple mouse strains to narrow down the Canq1 locus.
- Performed genome-wide linkage analysis to confirm the locus's haplotype structure.
- Analyzed gene expression in embryonic cortical pia mater and assessed knockout mouse models for specific vascular genes (IL4ra, Itgal).
Main Results:
- The Canq1 locus was refined through genetic analysis of 21 inbred strains.
- Knockout mice for IL4ra and Itgal showed no significant difference in collateral extent or related outcomes.
- Six out of 116 genes within the Canq1 confidence interval exhibited differential transcript abundance during critical embryonic development periods.
Conclusions:
- The Canq1 locus has been refined, providing a more precise region for genetic investigation.
- Several candidate genes within the refined locus are identified as potentially crucial for native collateral formation and its observed variation.
Background:
Native (pre-existing) collaterals are arteriole-to-arteriole anastomoses that interconnect adjacent arterial trees and serve as endogenous bypass vessels that limit tissue injury in ischemic stroke, myocardial infarction, coronary and peripheral artery disease. Their extent (number and diameter) varies widely among mouse strains and healthy humans. We previously identified a major quantitative trait locus on chromosome 7 (Canq1, LOD = 29) responsible for 37% of the heritable variation in collateral extent between C57BL/6 and BALB/c mice. We sought to identify candidate genes in Canq1 responsible for collateral variation in the cerebral pial circulation, a tissue whose strain-dependent variation is shared by similar variation in other tissues.
Methods And Findings:
Collateral extent was intermediate in a recombinant inbred line that splits Canq1 between the C57BL/6 and BALB/c strains. Phenotyping and SNP-mapping of an expanded panel of twenty-one informative inbred strains narrowed the Canq1 locus, and genome-wide linkage analysis of a SWRxSJL-F2 cross confirmed its haplotype structure. Collateral extent, infarct volume after cerebral artery occlusion, bleeding time, and re-bleeding time did not differ in knockout mice for two vascular-related genes located in Canq1, IL4ra and Itgal. Transcript abundance of 6 out of 116 genes within the 95% confidence interval of Canq1 were differentially expressed >2-fold (p-value<0.05÷150) in the cortical pia mater from C57BL/6 and BALB/c embryos at E14.5, E16.5 and E18.5 time-points that span the period of collateral formation.
Conclusions:
These findings refine the Canq1 locus and identify several genes as high-priority candidates important in specifying native collateral formation and its wide variation.
