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Dissecting Epistatic QTL for Blood Pressure in Rats: Congenic Strains versus Heterogeneous Stocks, a Reality Check

John P. Rapp, Bina Joe

10.1002/cphy.c180038

Source: Volume 9, Issue 4, October 2019

Published online: September 2019

Full Article on Wiley Online Library



Abstract

Advances in molecular genetics have provided well‐defined physical genetic maps and large numbers of genetic markers for both model organisms and humans. It is now possible to gain a fundamental understanding of the genetic architecture underlying quantitative traits, of which blood pressure (BP) is an important example. This review emphasizes analytical techniques and results obtained using the Dahl salt‐sensitive (S) rat as a model of hypertension by presenting results in detail for three specific chromosomal regions harboring genetic elements of increasing complexity controlling BP. These results highlight the critical importance of genetic interactions (epistasis) on BP at all levels of structure, intragenic, intergenic, intrachromosomal, interchromosomal, and across whole genomes. In two of the three examples presented, specific DNA structural variations leading to biochemical, physiological, and pathological mechanisms are well defined. This proves the usefulness of the techniques involving interval mapping followed by substitution mapping using congenic strains. These classic techniques are compared to newer approaches using sophisticated statistical analysis on various segregating or outbred model‐organism populations, which in some cases are uniquely useful in demonstrating the existence of higher‐order interactions. It is speculated that hypertension as an outlier quantitative phenotype is dependent on higher‐order genetic interactions. The obstacle to the identification of genetic elements and the biochemical/physiological mechanisms involved in higher‐order interactions is not theoretical or technical but the lack of future resources to finish the job of identifying the individual genetic elements underlying the quantitative trait loci for BP and ascertaining their molecular functions. © 2019 American Physiological Society. Compr Physiol 9:1305‐1337, 2019.

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Figure 1. Figure 1. Deoxy‐corticosterone (DOC) is hydroxylated at either the 18 or the 11β position by the enzyme Cyp11b1 to produce 18OH‐DOC or corticosterone (a.k.a. Kendall's compound B) as shown. The length of the green arrows is proportional to the probability of the reactions in Dahl R rats (salt resistant) and the lengths of the red arrows is proportional to the probability of the reactions in Dahl S rats (salt sensitive).
Figure 2. Figure 2. Scatter diagram demonstrating Mendelian inheritance for the steroid ratio 18OH‐DOC/(18OH‐DOC + B) determined for adrenals incubated in vitro with excess DOC substrate. Data are shown for R and S rats, their F1 hybrids, and the backcross populations F1xR (BR) and F1xS (BS). Note that the steroid ratio segregated in a 1:1 ratio in the backcross populations. The steroid ratio segregated in a 1:2:1 ratio in an F2 population (data not shown). Reused, with permission, from Rapp JP and Dahl LK, 1972 99.
Figure 3. Figure 3. Interval mapping and congenic strain for RNO7. (A) RNO7 map in cM for an F1(SxR)xS backcross population of 150 rats. The black portion of the bar to the left of the map shows the congenic segment of R introgressed into the S background, which includes the Cyp11b1 gene (labeled Cyp11b in the figure). The hatched portions of the bar are the regions where recombination occurred. The map was constructed in 1997 when few markers were available. (B) LOD plots for BP and heart weight adjusted for differences in body weight (HW.Adj). The dotted line at an LOD of 1.9 and the solid line at an LOD of 3.3 represent, respectively, the thresholds for suggestive and significant linkage to the phenotype. Note that the LOD peak for BP is at the marker for Cyp11b1. Reused, with permission, from Cicila GT, et al., 1997 23.
Figure 4. Figure 4. Congenic strains for the BP QTL on RNO7. (A) Second iteration of congenic strains developed from the initial congenic strain in Figure 3. The first iteration of congenic substrains is reported in Ref. 24, which provided the congenic strain S.R (11Bx4) in this figure. The black portion of the bars to the left of the map shows the congenic segment of R introgressed into the S background. The Cyp11b1 gene is labeled D7Mco7 (Cyp11b) in the figure. The open portions of the bars are the regions where crossover events occurred. Map intervals are in cM. Note that the recombination defining the lower end of the congenic interval occurred within the Cyp11b1 gene creating a chimeric gene that did retain the amino acid changes in exon 7 causing the BP difference (see text). (B) Bar graph showing the effect of each congenic strain on BP (black bars) and heart weight (open bars). The effect is the value for the congenic strain minus the value of S rats so that a negative value indicates that the congenic strain had a lower value than the S rats. *Indicates significance of at least p < 0.001. Reused, with permission, from Garrett MR and Rapp JP, 2003 41.
Figure 5. Figure 5. Comprehensive illustration of interval mapping and substitution mapping with congenic strains for RNO10. The LOD plot is from an F2(SxLEW) population 42. The bars below the LOD plot represent 21 congenic strains where the introgressed interval is from LEW rats on the S rat background. The markers and their physical locations defining the ends of the congenic strains are given. The green bars represent congenic strains that had a BP effect, and the black bars those strains with no BP effect. The bottom of the figure shows a detailed enlargement of the 1.34 Mb region for congenic strain S.LEW x12x2x3x8. The BP effects of Regions 1, 2, and 3 are given in Figure 6. Reused, with permission, from Saad Y, et al., 2007 112.
Figure 6. Figure 6. Congenic strains and their phenotypic effects for the region of interest from Figure 5 on RNO10. The physical map is on the left and the congenic intervals (LEW introgressed into S) are shown on the right as bars where the open ends represent the interval in which recombination occurred, the green bars are strains with a significant phenotypic effect, and the black bars are the strains without an effect. Phenotypic effects for BP and heart weight are at the bottom where green bars represent a significant effect on BP and black bars represent no effect on BP. The hatched bars represent a significant effect on heart weight and the open bars indicate no effect on heart weight. The phenotypic effect is the value for the congenic strain minus the value for S rats so that a negative value indicates that the congenic strain had a lower value than the S rats and a positive value indicates that the congenic strain had a higher value than S rats. Region 1 is defined by data in Ref. 111. Reused, with permission, from Saad Y, et al., 2007 112.
Figure 7. Figure 7. Representative ECG recordings from individual S and congenic strain S.LEWx12x2x3x5 rats. The congenic region is shown in Figure 6. Note the shorter QT interval in the congenic rats, which was still significant after correcting for differences in heart rate. Reused, with permission, from Gopalakrishnan K, et al., 2011 46.
Figure 8. Figure 8. LOD plot for RNO5 from an F2 population derived by crossing S and Lewis (LEW) rats. The black bar at the bottom of the plot shows the extent of the initial congenic strain made by introgressing a part of LEW chromosome 5 into the S background. This congenic strain significantly reduced BP relative to S. The blue box to the left of the LOD peak is the region subsequently shown to contain two mutually interdependent QTL such that the BP lowering effect of the LEW allele at one QTL was completely dependent on the presence of the LEW allele at the other QTL and vice versa. Reused, with permission, from Garrett MR, et al., 1998 42.
Figure 9. Figure 9. Monocongenic and bicongenic strains and their phenotypic effects for strains derived from the boxed region from Figure 8 on RNO5. The physical map is on the left and the congenic intervals are shown on the right. The black parts of the bars represent LEW DNA and the open ends represent the interval in which recombination occurred. For the bicongenic strains, the open region between the introgressed LEW DNA represents S DNA. The BP effect and its significance for each strain are shown in the lower part of the diagram. The BP effect is the value for the congenic strain minus the value for S rats so that a negative value indicates that the congenic strain had a lower BP than the S rats and a positive value indicates that the congenic strain had a higher BP than the S rats. Only the bicongenic strain constructed in Group 4 had a significant effect on BP. The orange bars at the right for QTL1 and QTL2 are from Ref. 40. Reused, with permission, from Pillai R, et al., 2013 93.
Figure 10. Figure 10. Schematic representation of a new iteration of bicongenic substrains developed from the bicongenic strain S.LEW(5)x6Bx9x5 shown in Figure 9, which in this figure is the strain at the left and now labeled S.LEW(5) strain1. The general format of the diagram is identical to Figure 9. **indicates a significance level of p < 0.01 for the BP difference between the bicongenic strain and S rats. Note the dramatic changes in BP as the lower LEW segment in the S.LEW(5) strain 8 is progressively shortened stepwise. The newly defined congenic intervals are shown at the far right in green where the LEW allele decreases BP relative to S and in light orange where the LEW allele increases BP relative to S. Reused, with permission, from Waghulde H, et al., 2018 126.
Figure 11. Figure 11. BP for populations produced by repeated backcrossing of LEW to S rats. The red dots are the average population BP and the vertical black bars are ±2 SEM. Note that the LEW BP phenotype is completely dominant to S and that on repeated backcrossing to S the BP only increases between backcross 2 (BC2) and backcross 3 (BC3). The figure is drawn using the data given in the legend of Supplemental Figure 3 in Crespo K, et al. Circ Cardiovasc Genet 8:610‐617, 2015 27.
Figure 12. Figure 12. Congenic strains on RNO13 demonstrating a potential “hypotensive suppressor” (a.k.a. “hypertensive enhancer”). The general format of the diagram is similar to Figure 9, but here the introgressed DNA (black) is from the Brown Norway (BN) strain on the S background. S DNA is represented by open bars and the small gray regions are the interval in which crossover events occurred. Note that the addition of the BN DNA segment in strain 26S (which by itself has no BP effect) to the BN DNA segment in 26R causes an increase in BP from 144 mmHg in 26R to 163 mmHg in 26Q. The figure is redrawn from Figure 1 of Cowley AW et al. Physiol Genomics 48: 62‐72, 2016 with permission 26.
Figure 13. Figure 13. Capacitating epistatic effect of QTL Growth9 in the chicken AIL at F8 derived from the high weight selected (HWS) and low weight selected (LWS) lines. The vertical axis is the body weight in grams of chickens at 56 days of age. The horizontal axis gives the number of loci that are homozygous (HH) for the HWS line allele increasing weight at any of the four growth QTL Growth2, Growth4, Growth6, and Growth 12. The lower (black) line is for animals homozygous (LL) for the LWS line allele decreasing weight at QTL Growth9. Note that the progressive addition of HH alleles at other loci has no effect on body weight when Growth9 is LL. The upper (red) line is for animals HH at QTL Growth9. Note that the progressive addition of HH alleles at other loci markedly increased body weight when Growth9 is HH. Reused, with permission, from Pettersson M, et al., 2011 91.
Figure 14. Figure 14. Histogram of QTL resolution for rat heterogeneous stocks (HS) and congenic strains. The inset expands the scale for the size of the QTL region from 0 to 3 Mb. The data for HS (black bars) are calculated from Supplementary Table 3 in Ref. 108 (average 5.14 Mb, median 4.45 Mb) and the congenic strain data (red bars) are from Supplementary Table S1 of this article (average 0.670 Mb, median 0.495 Mb).
Figure 15. Figure 15. (A) Genome scan for the phenotype retroperitoneal fat pad weight (RetroFat) using rat HS. The horizontal axis is the position of each SNP on all the chromosomes, and the vertical axis is the significance level (−log10 of the probability) associating RetroFat with each SNP marker. Each dot represents one SNP marker. Note that SNPs on RNO1 and RNO6 equal or exceed the significance threshold at 4.7. (B) Enlargement of the genome scan for RetroFat on RNO6 from (A). The horizontal axis is in megabase. The shaded region represents a QTL localization to a 6.14 Mb disequilibrium support interval containing 130 genes with the support level of −log10 P = 4.73. Further analysis (not shown) reduced this region to 1.46 Mb containing 30 genes including the candidate gene Adcy3. The gray scale in the upper right corner is for r 2, which is a measure of linkage disequilibrium. (C) Heterogeneous stocks (HS) founder‐strain haplotype effects on the RNO6 RetroFat QTL. Note that the C/T variants in Adcy3 are designated next to each strain. The phenotypic effects of haplotypes are scaled to have a mean of zero and a standard deviation of 1. The important point is that the haplotype effect of WKY is well below that of the other strains and WKY is the only strain carrying C at the SNP in Adcy3. Reused, with permission, from Keele GR, et al., 2018 60.
Figure 16. Figure 16. (A) Schematic illustration of the mosaic structure of haplotype blocks in the genome of individual rats from a population of heterogeneous stock (HS) rats. Ten rats each with 20 autosomal pairs of chromosomes are shown. The region on chromosome 5 indicated by the red symbol represents the region in which an SNP polymorphism associated with a specific phenotype is located. The SNP in each rat can be either homozygous for one SNP allele, heterozygous, or homozygous for the alternate SNP allele. (B) Schematic illustration of the genomic structure of 20 autosomal pairs of chromosomes in 5 rats from a congenic strain and 5 rats from the control (recipient) strain on which the congenic strain is developed. Purple represents DNA of the recipient strain. The red region in the congenic rats represents a minimal congenic interval of donor DNA, which is causing a specific phenotypic effect. The yellow spots represent an SNP allele in the congenic interval, which is a candidate for causing the phenotypic effect. The red region in the control rats is the homologous region containing only recipient rat DNA. The SNP is homozygous for one SNP allele in all congenic rats and homozygous for the alternate SNP allele in all control rats.
Figure 17. Figure 17. The diagram shows possible outcomes of cosegregation analysis between blood pressure and a marker locus linked to a quantitative trait locus (QTL) that actually influences blood pressure. Four different chromosomal arrangements (haplotypes) of two marker alleles and two QTL alleles are shown, and each haplotype is assumed to be carried in the homozygous state in a different inbred strain. Strains are crossed pairwise (shown by brackets at the right), and F2 populations are produced from the cross. The diagram indicates in which pairwise combinations the marker is informative and will allow a cosegregation test between the marker and blood pressure and in which pairwise combinations the marker is not informative, preventing such analyses. In the four crosses in which the marker is informative, two will yield positive cosegregation of the marker with blood pressure and two will not, depending on whether different QTL alleles are present in the cross. Reused, with permission, from Rapp JP and Deng AY, 1995 103.
Figure 18. Figure 18. The diagram shows the breeding scheme for production of a congenic strain from two inbred strains. The M1 allele of the donor strain replaces the M2 allele of the recipient strain at locus M. In reality, one selects for more than one genetic marker in a region to ensure that a large region of donor chromosome is introgressed into the initial congenic strain. The genetic background of the donor strain is represented by a clear symbol; the genetic background of the recipient strain by a black symbol. Increasing shades of gray represent the progressive increase in genetic background attributable to the recipient strain. BC indicates backcross. In the present context, the recipient strain is always the inbred S rat (SS/Jr) and the donor strain can be any other inbred strain. Reused, with permission, from Rapp JP and Deng AY, 1995 103.
Figure 19. Figure 19. The diagram shows substitution mapping of a quantitative trait locus (QTL) for blood pressure with the use of a set of nested congenic substrains derived from the original congenic strain 1. A map of informative markers (A to H) is assumed to be known along a chromosomal region thought to contain a blood pressure QTL. Strain 1 is a congenic strain in which the entire chromosomal region (A to H) has been substituted into the recipient SS/Jr strain from the donor strain by the technique shown in Figure A2. The thick line represents chromosome from the donor normotensive strain, and the thin line represents chromosome from the recipient hypertensive strain (assumed to be Dahl salt‐sensitive SS/Jr rat). Note that the original congenic strain 1 has a lower BP than SS/Jr indicating that the strain 1 has captured a BP‐altering allele(s). The substrains 2 to 7 are obtained by crossing strain 1 back to SS/Jr to duplicate the original congenic region and to create the heterozygous state. Heterozygotes are intercrossed to obtain recombinant chromosomes in the resulting F2 population, which is screened using appropriate markers A to H. Each new useful recombinant chromosome is duplicated by crossing the individual rat carrying it to SS/Jr and then selectively breeding each new recombinant to homozygosity producing substrains 2‐7. In the example, the QTL is located between markers D and E as indicated by the arrow. This substituted region contains a minus QTL allele different from the plus QTL allele present in the recipient SS/Jr strain, and thus the substitution lowers blood pressure of strain 1 relative to SS/Jr. Strains 2 through 7 are congenic substrains carrying various donor fragments as indicated. If the donor fragment contains the minus QTL allele, then the congenic substrain carrying it will have its blood pressure lowered relative to SS/Jr. If the minus QTL allele is absent in the donor fragment, the congenic strain will have the same blood pressure level as the parental recipient SS/Jr strain. This information on the presence or absence of a blood pressure effect, combined with the location of the substituted chromosomal fragment, can be used to map the blood pressure QTL to a smaller region, in this case the differential segment between strains 4 and 5. In practice, it is often useful to make nested congenic strains from both ends of the initial congenic strain 1. Further localization of the QTL could be pursued by making a second iteration of congenic substrains starting with strain 4 and paying special attention to substrains derived from the right end of strain 4. This is exactly the procedure carried out in text Figure 4. Reused, with permission, from Rapp JP and Deng AY, 1995 103.


Figure 1. Deoxy‐corticosterone (DOC) is hydroxylated at either the 18 or the 11β position by the enzyme Cyp11b1 to produce 18OH‐DOC or corticosterone (a.k.a. Kendall's compound B) as shown. The length of the green arrows is proportional to the probability of the reactions in Dahl R rats (salt resistant) and the lengths of the red arrows is proportional to the probability of the reactions in Dahl S rats (salt sensitive).


Figure 2. Scatter diagram demonstrating Mendelian inheritance for the steroid ratio 18OH‐DOC/(18OH‐DOC + B) determined for adrenals incubated in vitro with excess DOC substrate. Data are shown for R and S rats, their F1 hybrids, and the backcross populations F1xR (BR) and F1xS (BS). Note that the steroid ratio segregated in a 1:1 ratio in the backcross populations. The steroid ratio segregated in a 1:2:1 ratio in an F2 population (data not shown). Reused, with permission, from Rapp JP and Dahl LK, 1972 99.


Figure 3. Interval mapping and congenic strain for RNO7. (A) RNO7 map in cM for an F1(SxR)xS backcross population of 150 rats. The black portion of the bar to the left of the map shows the congenic segment of R introgressed into the S background, which includes the Cyp11b1 gene (labeled Cyp11b in the figure). The hatched portions of the bar are the regions where recombination occurred. The map was constructed in 1997 when few markers were available. (B) LOD plots for BP and heart weight adjusted for differences in body weight (HW.Adj). The dotted line at an LOD of 1.9 and the solid line at an LOD of 3.3 represent, respectively, the thresholds for suggestive and significant linkage to the phenotype. Note that the LOD peak for BP is at the marker for Cyp11b1. Reused, with permission, from Cicila GT, et al., 1997 23.


Figure 4. Congenic strains for the BP QTL on RNO7. (A) Second iteration of congenic strains developed from the initial congenic strain in Figure 3. The first iteration of congenic substrains is reported in Ref. 24, which provided the congenic strain S.R (11Bx4) in this figure. The black portion of the bars to the left of the map shows the congenic segment of R introgressed into the S background. The Cyp11b1 gene is labeled D7Mco7 (Cyp11b) in the figure. The open portions of the bars are the regions where crossover events occurred. Map intervals are in cM. Note that the recombination defining the lower end of the congenic interval occurred within the Cyp11b1 gene creating a chimeric gene that did retain the amino acid changes in exon 7 causing the BP difference (see text). (B) Bar graph showing the effect of each congenic strain on BP (black bars) and heart weight (open bars). The effect is the value for the congenic strain minus the value of S rats so that a negative value indicates that the congenic strain had a lower value than the S rats. *Indicates significance of at least p < 0.001. Reused, with permission, from Garrett MR and Rapp JP, 2003 41.


Figure 5. Comprehensive illustration of interval mapping and substitution mapping with congenic strains for RNO10. The LOD plot is from an F2(SxLEW) population 42. The bars below the LOD plot represent 21 congenic strains where the introgressed interval is from LEW rats on the S rat background. The markers and their physical locations defining the ends of the congenic strains are given. The green bars represent congenic strains that had a BP effect, and the black bars those strains with no BP effect. The bottom of the figure shows a detailed enlargement of the 1.34 Mb region for congenic strain S.LEW x12x2x3x8. The BP effects of Regions 1, 2, and 3 are given in Figure 6. Reused, with permission, from Saad Y, et al., 2007 112.


Figure 6. Congenic strains and their phenotypic effects for the region of interest from Figure 5 on RNO10. The physical map is on the left and the congenic intervals (LEW introgressed into S) are shown on the right as bars where the open ends represent the interval in which recombination occurred, the green bars are strains with a significant phenotypic effect, and the black bars are the strains without an effect. Phenotypic effects for BP and heart weight are at the bottom where green bars represent a significant effect on BP and black bars represent no effect on BP. The hatched bars represent a significant effect on heart weight and the open bars indicate no effect on heart weight. The phenotypic effect is the value for the congenic strain minus the value for S rats so that a negative value indicates that the congenic strain had a lower value than the S rats and a positive value indicates that the congenic strain had a higher value than S rats. Region 1 is defined by data in Ref. 111. Reused, with permission, from Saad Y, et al., 2007 112.


Figure 7. Representative ECG recordings from individual S and congenic strain S.LEWx12x2x3x5 rats. The congenic region is shown in Figure 6. Note the shorter QT interval in the congenic rats, which was still significant after correcting for differences in heart rate. Reused, with permission, from Gopalakrishnan K, et al., 2011 46.


Figure 8. LOD plot for RNO5 from an F2 population derived by crossing S and Lewis (LEW) rats. The black bar at the bottom of the plot shows the extent of the initial congenic strain made by introgressing a part of LEW chromosome 5 into the S background. This congenic strain significantly reduced BP relative to S. The blue box to the left of the LOD peak is the region subsequently shown to contain two mutually interdependent QTL such that the BP lowering effect of the LEW allele at one QTL was completely dependent on the presence of the LEW allele at the other QTL and vice versa. Reused, with permission, from Garrett MR, et al., 1998 42.


Figure 9. Monocongenic and bicongenic strains and their phenotypic effects for strains derived from the boxed region from Figure 8 on RNO5. The physical map is on the left and the congenic intervals are shown on the right. The black parts of the bars represent LEW DNA and the open ends represent the interval in which recombination occurred. For the bicongenic strains, the open region between the introgressed LEW DNA represents S DNA. The BP effect and its significance for each strain are shown in the lower part of the diagram. The BP effect is the value for the congenic strain minus the value for S rats so that a negative value indicates that the congenic strain had a lower BP than the S rats and a positive value indicates that the congenic strain had a higher BP than the S rats. Only the bicongenic strain constructed in Group 4 had a significant effect on BP. The orange bars at the right for QTL1 and QTL2 are from Ref. 40. Reused, with permission, from Pillai R, et al., 2013 93.


Figure 10. Schematic representation of a new iteration of bicongenic substrains developed from the bicongenic strain S.LEW(5)x6Bx9x5 shown in Figure 9, which in this figure is the strain at the left and now labeled S.LEW(5) strain1. The general format of the diagram is identical to Figure 9. **indicates a significance level of p < 0.01 for the BP difference between the bicongenic strain and S rats. Note the dramatic changes in BP as the lower LEW segment in the S.LEW(5) strain 8 is progressively shortened stepwise. The newly defined congenic intervals are shown at the far right in green where the LEW allele decreases BP relative to S and in light orange where the LEW allele increases BP relative to S. Reused, with permission, from Waghulde H, et al., 2018 126.


Figure 11. BP for populations produced by repeated backcrossing of LEW to S rats. The red dots are the average population BP and the vertical black bars are ±2 SEM. Note that the LEW BP phenotype is completely dominant to S and that on repeated backcrossing to S the BP only increases between backcross 2 (BC2) and backcross 3 (BC3). The figure is drawn using the data given in the legend of Supplemental Figure 3 in Crespo K, et al. Circ Cardiovasc Genet 8:610‐617, 2015 27.


Figure 12. Congenic strains on RNO13 demonstrating a potential “hypotensive suppressor” (a.k.a. “hypertensive enhancer”). The general format of the diagram is similar to Figure 9, but here the introgressed DNA (black) is from the Brown Norway (BN) strain on the S background. S DNA is represented by open bars and the small gray regions are the interval in which crossover events occurred. Note that the addition of the BN DNA segment in strain 26S (which by itself has no BP effect) to the BN DNA segment in 26R causes an increase in BP from 144 mmHg in 26R to 163 mmHg in 26Q. The figure is redrawn from Figure 1 of Cowley AW et al. Physiol Genomics 48: 62‐72, 2016 with permission 26.


Figure 13. Capacitating epistatic effect of QTL Growth9 in the chicken AIL at F8 derived from the high weight selected (HWS) and low weight selected (LWS) lines. The vertical axis is the body weight in grams of chickens at 56 days of age. The horizontal axis gives the number of loci that are homozygous (HH) for the HWS line allele increasing weight at any of the four growth QTL Growth2, Growth4, Growth6, and Growth 12. The lower (black) line is for animals homozygous (LL) for the LWS line allele decreasing weight at QTL Growth9. Note that the progressive addition of HH alleles at other loci has no effect on body weight when Growth9 is LL. The upper (red) line is for animals HH at QTL Growth9. Note that the progressive addition of HH alleles at other loci markedly increased body weight when Growth9 is HH. Reused, with permission, from Pettersson M, et al., 2011 91.


Figure 14. Histogram of QTL resolution for rat heterogeneous stocks (HS) and congenic strains. The inset expands the scale for the size of the QTL region from 0 to 3 Mb. The data for HS (black bars) are calculated from Supplementary Table 3 in Ref. 108 (average 5.14 Mb, median 4.45 Mb) and the congenic strain data (red bars) are from Supplementary Table S1 of this article (average 0.670 Mb, median 0.495 Mb).


Figure 15. (A) Genome scan for the phenotype retroperitoneal fat pad weight (RetroFat) using rat HS. The horizontal axis is the position of each SNP on all the chromosomes, and the vertical axis is the significance level (−log10 of the probability) associating RetroFat with each SNP marker. Each dot represents one SNP marker. Note that SNPs on RNO1 and RNO6 equal or exceed the significance threshold at 4.7. (B) Enlargement of the genome scan for RetroFat on RNO6 from (A). The horizontal axis is in megabase. The shaded region represents a QTL localization to a 6.14 Mb disequilibrium support interval containing 130 genes with the support level of −log10 P = 4.73. Further analysis (not shown) reduced this region to 1.46 Mb containing 30 genes including the candidate gene Adcy3. The gray scale in the upper right corner is for r 2, which is a measure of linkage disequilibrium. (C) Heterogeneous stocks (HS) founder‐strain haplotype effects on the RNO6 RetroFat QTL. Note that the C/T variants in Adcy3 are designated next to each strain. The phenotypic effects of haplotypes are scaled to have a mean of zero and a standard deviation of 1. The important point is that the haplotype effect of WKY is well below that of the other strains and WKY is the only strain carrying C at the SNP in Adcy3. Reused, with permission, from Keele GR, et al., 2018 60.


Figure 16. (A) Schematic illustration of the mosaic structure of haplotype blocks in the genome of individual rats from a population of heterogeneous stock (HS) rats. Ten rats each with 20 autosomal pairs of chromosomes are shown. The region on chromosome 5 indicated by the red symbol represents the region in which an SNP polymorphism associated with a specific phenotype is located. The SNP in each rat can be either homozygous for one SNP allele, heterozygous, or homozygous for the alternate SNP allele. (B) Schematic illustration of the genomic structure of 20 autosomal pairs of chromosomes in 5 rats from a congenic strain and 5 rats from the control (recipient) strain on which the congenic strain is developed. Purple represents DNA of the recipient strain. The red region in the congenic rats represents a minimal congenic interval of donor DNA, which is causing a specific phenotypic effect. The yellow spots represent an SNP allele in the congenic interval, which is a candidate for causing the phenotypic effect. The red region in the control rats is the homologous region containing only recipient rat DNA. The SNP is homozygous for one SNP allele in all congenic rats and homozygous for the alternate SNP allele in all control rats.


Figure 17. The diagram shows possible outcomes of cosegregation analysis between blood pressure and a marker locus linked to a quantitative trait locus (QTL) that actually influences blood pressure. Four different chromosomal arrangements (haplotypes) of two marker alleles and two QTL alleles are shown, and each haplotype is assumed to be carried in the homozygous state in a different inbred strain. Strains are crossed pairwise (shown by brackets at the right), and F2 populations are produced from the cross. The diagram indicates in which pairwise combinations the marker is informative and will allow a cosegregation test between the marker and blood pressure and in which pairwise combinations the marker is not informative, preventing such analyses. In the four crosses in which the marker is informative, two will yield positive cosegregation of the marker with blood pressure and two will not, depending on whether different QTL alleles are present in the cross. Reused, with permission, from Rapp JP and Deng AY, 1995 103.


Figure 18. The diagram shows the breeding scheme for production of a congenic strain from two inbred strains. The M1 allele of the donor strain replaces the M2 allele of the recipient strain at locus M. In reality, one selects for more than one genetic marker in a region to ensure that a large region of donor chromosome is introgressed into the initial congenic strain. The genetic background of the donor strain is represented by a clear symbol; the genetic background of the recipient strain by a black symbol. Increasing shades of gray represent the progressive increase in genetic background attributable to the recipient strain. BC indicates backcross. In the present context, the recipient strain is always the inbred S rat (SS/Jr) and the donor strain can be any other inbred strain. Reused, with permission, from Rapp JP and Deng AY, 1995 103.


Figure 19. The diagram shows substitution mapping of a quantitative trait locus (QTL) for blood pressure with the use of a set of nested congenic substrains derived from the original congenic strain 1. A map of informative markers (A to H) is assumed to be known along a chromosomal region thought to contain a blood pressure QTL. Strain 1 is a congenic strain in which the entire chromosomal region (A to H) has been substituted into the recipient SS/Jr strain from the donor strain by the technique shown in Figure A2. The thick line represents chromosome from the donor normotensive strain, and the thin line represents chromosome from the recipient hypertensive strain (assumed to be Dahl salt‐sensitive SS/Jr rat). Note that the original congenic strain 1 has a lower BP than SS/Jr indicating that the strain 1 has captured a BP‐altering allele(s). The substrains 2 to 7 are obtained by crossing strain 1 back to SS/Jr to duplicate the original congenic region and to create the heterozygous state. Heterozygotes are intercrossed to obtain recombinant chromosomes in the resulting F2 population, which is screened using appropriate markers A to H. Each new useful recombinant chromosome is duplicated by crossing the individual rat carrying it to SS/Jr and then selectively breeding each new recombinant to homozygosity producing substrains 2‐7. In the example, the QTL is located between markers D and E as indicated by the arrow. This substituted region contains a minus QTL allele different from the plus QTL allele present in the recipient SS/Jr strain, and thus the substitution lowers blood pressure of strain 1 relative to SS/Jr. Strains 2 through 7 are congenic substrains carrying various donor fragments as indicated. If the donor fragment contains the minus QTL allele, then the congenic substrain carrying it will have its blood pressure lowered relative to SS/Jr. If the minus QTL allele is absent in the donor fragment, the congenic strain will have the same blood pressure level as the parental recipient SS/Jr strain. This information on the presence or absence of a blood pressure effect, combined with the location of the substituted chromosomal fragment, can be used to map the blood pressure QTL to a smaller region, in this case the differential segment between strains 4 and 5. In practice, it is often useful to make nested congenic strains from both ends of the initial congenic strain 1. Further localization of the QTL could be pursued by making a second iteration of congenic substrains starting with strain 4 and paying special attention to substrains derived from the right end of strain 4. This is exactly the procedure carried out in text Figure 4. Reused, with permission, from Rapp JP and Deng AY, 1995 103.
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Supplemental Material: Table S1 and References for Table S1

J. P. Rapp, B. Joe. Dissecting Epistatic QTL for Blood Pressure in Rats: Congenic Strains Versus Heterogeneous Stocks, a Reality Check. Compr Physiol 9: 2019, 1305-1337.

SUPPLEMENTAL TABLE S1. Information for the insert in text Figure 14


Congenic Interval in kb

Designation of
Congenic Strain (cs) or
Differential Segment (dif)



Reference

 

 

 

723

cs (26P)

Figure 1 in Cowley AW et al. Physiol Genomics 48:62-72, 2016

1084

cs (26R)

Figure 1 in Cowley AW et al. Physiol Genomics 48:62-72, 2016

1140

cs (26S)

Figure 1 in Cowley AW et al. Physiol Genomics 48:62-72, 2016

177

cs (S.R118x4x4)

Figure 1 in Garrett MR et al. Mammalian Genome 14:268-273, 2003

42.5

dif (Rffl)

Figure 1 in Cheng X et al. PLOS Genetics 13(8):el006961

401

dif (Region 1)

Figure 7 in Saad Y et al. Hypertension 50:891-898, 2007

409

dif (Region 3)

Figure 7 in Saad Y et al. Hypertension 50:891-898, 2007

375

cs (S.LEWx12x2x3x5)

Figure 7 in Saad Y et al. Hypertension 50:891-898, 2007

307

cs (S.LEWx12x2x3x1)

Figure 7 in Saad Y et al. Hypertension 50:891-898, 2007

2260

cs (lower segment S.LEW(5) strain 4)

Figure 1 in Waghulde H et al. J Hypertension 36: in press 2018

1310

dif (QTL3)

Figure 1 in Waghulde H et al. J Hypertension 36: in press 2018

175

dif (QTL4)

Figure 1 in Waghulde H et al. J Hypertension 36: in press 2018

117

dif (not named)

Figure 6 in Garrett MR et al. Hypertension 45:451-459, 2005

805

cs (D1Mco4x1x3Bx1)

Figure 2 in Joe B et al. Human Molecular Genetics 209:2825-2838, 2009

160

cs (C10S.L28)

Figure 1 in Chauvet C et al. J Hypertension 26:893-901, 2008

1200

cs (C10S.L29)

Figure 1 in Chauvet C et al. J Hypertension 26:893-901, 2008

580

cs (C10S.L30)

Figure 1 in Chauvet C et al. J Hypertension 26:893-901, 2008

788

dif S.SHR(9) BP QTL

Figure 1A in Nie Y et al. Physiol Genomics 48:409-419

Median 494.5

 

 

Average 669.6

 

 

 

References for Supplemental Table S1

Chauvet C, Charron S, Menard A, Xiao C, Roy J, Deng AY. Submegabase resolution of epistatically interacting quantitative trait loci for blood pressure applicable for essential hypertension. J Hypertension 26:893-901, 2008

Cheng X, Waghulde H, Mell B, Morgan EE, Pruett-Miller SM, Joe B. Positional cloning of quantitative trait nucleotides for blood pressure and cardiac QT-interval by targeted CRISPR/Cas9 editing of a novel long non-coding RNA. PLoS Genet 13(8):e1006961, 2017

Cowley AW, Jr., Yang C, Kumar V, Lazar J, Jacob H, Geurts AM, Liu P, Dayton A, Kurth T, Liang M. Pappa2 is linked to salt-sensitive hypertension in Dahl S rats. Physiol Genomics 48: 62-72, 2016 doi: 10.1152/physiolgenomics.00097.2015

Garrett MR, Rapp JP. Defining the blood pressure QTL on chromosome 7 in Dahl rats by a 177-kb congenic segment containing Cyp11b1. Mammalian Genome 14: 268-273, 2003

Garrett MR, Meng H, Rapp JP, Joe B. Locating a blood pressure quantitative trait locus within 117 kb on the rat genome. Substitution mapping and renal expression analysis. Hypertension 45:451-459, 2005 

Joe B, Saad Y, Dhindaw S, Lee NH, Frank BC, Achinike OH, Luu TV, Gopalakrishnan K, Toland EJ, Farms P, Yerga-Woolwine S, Manickavasagam E, Rapp JP, Garrett MR, Coe D, Apte SS, Rankinen T, Pérusse L, Ehret GB, Ganesh SK, Cooper RS, O'Connor A, Rice T, Weder AB, Chakravarti A, Rao DC, Bouchard C. Positional identification of variants of Adamts16 linked to inherited hypertension. Hum Mol Genet 18:2825-2838, 2009 doi: 10.1093/hmg/ddp218

Nie Y, Kumarasamy S, Waghulde H, Cheng X, Mell B, Czernik PJ, Lecka-Czernik B, Joe B. High-resolution mapping of a novel rat blood pressure locus on chromosome 9 to a region containing the Spp2 gene and colocalization of a QTL for bone mass. Physiol Genomics 48:409-419, 2016 doi:10.1152/physiolgenomics.00004.2016

Saad Y, Yerga-Woolwine S, Saikumar J, Farms P, Manickavasagam E, Toland EJ, Joe B. Congenic interval mapping of RNO10 reveals a compex cluster of closely-linked genetic determinants of blood pressure. Hypertension 50:891-898, 2007

Waghulde H, Pillai R, Cheng X, Nie Y, Mell B, Joe B. Fine mapping of epistatic genetic determinants of blood pressure on rat chromosome 5. J Hypertens 36: 1486-1491, 2018 doi: 10.1097/HJH.0000000000001732

 

 

Teaching Material

J. P. Rapp, B. Joe. Dissecting Epistatic QTL for Blood Pressure in Rats: Congenic Strains Versus Heterogeneous Stocks, a Reality Check. Compr Physiol 9: 2019, 1305-1337.

Didactic Synopsis

Major Teaching Points:

  • Quantitative traits are genetically defined by the combined effects of multiple so-called quantitative trait loci (QTL). QTL can be localized on chromosomes by two techniques:

-By linkage analysis in genetically segregating populations derived from crosses of inbred strains followed by substitution mapping using congenic strains.

-By genome scans of outbred populations.

-Each of the above techniques has advantages and disadvantages depending on the phenotype studied and the model-organism resources historically available.

  • Demonstrating the existence of QTL is not the same as understanding the mechanisms by which they work, which includes defining the following:

-Genetic interaction (epistasis) between and among QTL, which is almost universal.

-QTL are usually compound, meaning that the chromosomal region identified as a QTL often contains multiple interacting genetic elements impacting the quantitative phenotype.

-Causative genetic elements within a QTL are not limited to variants in protein coding gene structure but include regulatory elements and noncoding RNA.

-Ultimately QTL causative genetic elements have to be connected to biochemical and physiological mechanisms they control, which in turn explain the changes in the quantitative phenotype.

 


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Article Title: Dissecting Epistatic QTL for Blood Pressure in Rats: Congenic Strains versus Heterogeneous Stocks, a Reality Check
 

How to Cite

John P. Rapp, Bina Joe. Dissecting Epistatic QTL for Blood Pressure in Rats: Congenic Strains versus Heterogeneous Stocks, a Reality Check. Compr Physiol 2019, 9: 1305-1337. doi: 10.1002/cphy.c180038