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Chromosomal Substitution Strategies to Localize Genomic Regions Related to Complex Traits

Allen W. Cowley, Melinda R. Dwinell

10.1002/cphy.c180029

Source: Volume 10, Issue 2, April 2020

Published online: March 2020

Full Article on Wiley Online Library



Abstract

Chromosomal substitution strategies provide a powerful tool to anonymously reveal the relationship between DNA sequence variants and a normal or disease phenotype of interest. Even in this age of CRISPR‐Cas9 genome engineering, the knockdown or overexpression of a gene provides relevant information to our understanding of complex disease only when a close association of an allelic variant with the phenotype has first been established. Limitations of genetic linkage approaches led to the development of more efficient breeding strategies to substitute chromosomal segments from one animal strain into the genetic background of a different strain, enabling a direct comparison of the phenotypes of the strains with variant(s) that differ only at a defined locus. This substitution can be a whole chromosome (consomic), a part of a chromosome (congenic), or as small as only a single or several alleles (subcongenics). In contrast to complete knockout of a specific candidate gene of interest, which simply studies the effects of complete elimination of the gene, the substitution of naturally occurring variants can provide special insights into the functional actions of wild‐type alleles. Strategies for production of these inbred strains are reviewed, and a number of examples are used to illustrate the utility of these model systems. Consomic/congenic strains provide a number of experimental advantages in the study of functions of genes and their variants, which are emphasized in this article, such as replication of experimental studies; determination of temporal relationships throughout a life; rigorously controlled experiments in which relations between genotype and phenotype can be tested with the confounding effects of heterogeneous genetic backgrounds, both targeted and multilayered; and “omic” studies performed at many levels of functionality, from molecules to organelles, cells to organs, and organs to organismal behavior across the life span. The application of chromosomal substitution strategies and development of consomic/congenic rat and mouse strains have greatly expanded our knowledge of genomic variants and their phenotypic relationship to physiological functions and to complex diseases such as hypertension and cancer. © 2020 American Physiological Society. Compr Physiol 10:365‐388, 2020.

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Figure 1. Figure 1. (A) Schematic representation of the derivation of a consomic strain in which parental strains are intercrossed to generate the Fl population (40%–50% heterozygosity; half blue, half red alleles). These rats are then backcrossed with the parental SS strain. The N2 rats that are determined by genotyping to be heterozygous along the target chromosome are then backcrossed for ∼4 to 8 generations [e.g., marker assister selection for rats with most SS (blue) alleles]. This yields offspring with an isogenic SS background for all but the target chromosome as shown in (B). Selected male and female rats are then mated resulting in approximately 25% of the offspring being homozygous for the chromosome of interest. These rats are then inbred to produce a stable inbred consomic strain with the substitution of one entire chromosome from the BN strain into the background of the SS strain. Reprinted, with permission, from Cowley AW, et al., 2004 17.
Figure 2. Figure 2. Example of reduced blood pressure salt sensitivity resulting from substitution of chromosome 13 from the BN into the SS/Mcwi strain (SS‐13BN consomic rat). Shown is the mean arterial pressure (MAP) in conscious SS (n = 18), SS‐13BN (n = 15), and BN (n = 16) rats exposed to a high‐salt (4.0% NaCl) diet for 4 weeks. P < 0.05 comparing SS versus SS; and SS‐13BN versus BN 20.
Figure 3. Figure 3. Example of impact of genomic background on mean arterial pressure (MAP) responses to a high‐salt diet. Substitution of chromosome 18 from the BN to the SS strain (SS‐18BN) greatly reduced salt‐induced hypertension (8.0% diet; 3 weeks). Conversely, substitution of chromosome 18 from SS to the BN strain (BN‐18SS) resulted in a relatively small increase in MAP in response to the high‐salt diet.
Figure 4. Figure 4. Consomic rat panel in which each of the 20 autosomes and the X and Y chromosomes from the BN strain were transferred onto the SS genetic background. Shown are the mean arterial pressure (MAP) in male (A) and female (B) SS, BN, and consomic rat strains (indicated by the substituted chromosome) fed a high‐sodium diet (8.0% NaCl diet; 3 weeks) 89. Consomics with P < 0.05 versus SS of the same sex (*); consomic females differing (P < 0.05) from males are designated by #.
Figure 5. Figure 5. Consomic rat panel in which each of the 20 autosomes and the X and Y chromosomes from the BN strain were transferred onto the fawn‐hooded hypertensive (FHH) genetic background. Comparison of the sensitivity to phenylepinephrine (PE) of the aortic rings of consomic male rats to those of the parental salt‐sensitive rats (SS, black fill) after the rats were fed (A) a low‐salt (LS) diet (0.4% NaCl, A) or (B) a high‐salt (HS) diet (4.0% NaCl; 3 weeks). The numbers within each bar represent the n of that group. Y‐axis, −log EC50. *P < 0.05, significantly different from the SS parental strain; ∝ P < 0.05, significantly different from the same strain on an LS diet 62.
Figure 6. Figure 6. Generation of chromosome Y (chrY) consomic rats. A male individual from the donor strain is first crossed to a female from the host strain. Resulting F1 males are then backcrossed to a female from the host strain to generate the N2 generation. Males from the latter are backcrossed again to females from the host strain, the procedure being repeated (n) times. The genome of the final consomic strain is the same as that of the host strain, with the exception of the MSY from the donor strain. Redrawn, with permission, from Prokop JW and Deschepper CF, 2015 111.
Figure 7. Figure 7. Overview of the consomic xenograph model (CXM) 31. (A) Reduced susceptibility to DMBA‐induced mammary tumors in SS.BN2 consomic rats (n = 14) compared with SS (n = 40), as reported by Adamovic et al. 1. (B) Schematic representation of the SS and SS.BN3 genomes that were modified by TALEN‐mediated editing of the IL2Rγ gene. The number bars represent chromosomes that were derived from SS (white) or BN (black). (C) The transgenically labeled human 231Luc+ breast cancer cells were orthotopically implanted in the MFP (see dashed lines) of SSIL2Rγ and SS.BN3IL2Rγ rats. Tumor progression (e.g., growth, vasculogenesis, and metastasis) was tracked over the duration of the experiment. (D) Since the 231Luc+ tumor cells were the same between strains (gray), any differences in tumor progression can be attributed to differences in the SSIL2Rγ (green) and SS.BN3IL2Rγ (blue) microenvironments 31,33. Reprinted, with permission, from Flister MJ, et al., 2014 31.
Figure 8. Figure 8. Schematic representation of the generation of a congenic strain from congenic strains. (A) With the availability of the consomic SS‐13BN strain, the consomic strain is backcrossed to the homozygous parent strain (SS) to make an F1 generation where the offspring is homozygote for all alleles, except the single heterozygous target chromosome of interest (chr 13 in this case). Brother‐sister mating of the F1 rats results in many recombinations within the target chromosome. (B) Each rat is genotyped, and rats selected for heterozygosity at a particular locus with the goal of selecting a similar recombination in a male and female rat. These rats will be intercrossed yielding homozygosity in about 25% of the offspring, which will then be brother‐sister mated to create the inbred congenic line. To obtain a rat that is homozygous within a single 1‐cM interval, it can be estimated that in a population of 1000 F2 rats, there would be, on average, animals that are congenic at a 10 to 20 cM resolution.
Figure 9. Figure 9. (A) Representation of the overlapping congenic strains developed in which segments of various lengths of chromosome 13 from the Brown‐Norway rat (black bars) were introgressed in the genetic background of the SS rat, by marker‐assisted breeding. Delimitation of the congenic regions is defined by the first outward SS marker allele. Thin bars represent chromosome crossover regions. The table to the right of the graph summarizes the mean arterial pressure (MAP) + SEM on day 14 of high‐salt (HS) diet for each of the congenic strains. Significant differences from the SS strain on day 14 HS (P < 0.05) are also shown. Redrawn, with permission, from Moreno C, et al., 2007 93. (B) Candidate region of chr13 (55.13 BN26) was reduced from 13.4 to 1.37 Mb (position by RN5 genome assembly). The SS regions are indicated in white, while the alleles derived from the Brown‐Norway (BN) rats are indicated in black. The narrowed region (1.37 Mb) is shaded in gray. Mean arterial pressure (MAP) on day 14 of high‐salt (HS) diet for the 13 overlapping strains and the salt‐sensitive (SS) and congenic SS.13BN26 strains is summarized for each of the congenic substrains to the right of the graph. Significant differences from the SS strain on day 14 HS (P < 0.05) are also shown. Redrawn, with permission, from Cowley AW, et al., 2014 18. (C) Representation of a 3.62‐Mb region of chromosome (chr) 13 (26‐N) spanned by six overlapping congenic strains. Various lengths of chr 13 from the Brown‐Norway rat (indicated by black bars) were introgressed into the genetic background of the SS rat (white bar). Mean arterial pressure (MAP) measured on day 14 of high‐NaCl diet is shown in the attached table of each congenic substrain. Significant differences from the SS strain on day 14 HS (P < 0.05) are also shown. The narrowed region (0.71 Mb) is shown within the blue‐boxed area in which reside three candidate genes (AstN1, Pappa2, and MiR488p). Redrawn, with permission, from Cowley AW, et al., 2014 21.
Figure 10. Figure 10. Illustration of the convergence of classic and modern genomic approaches to identify allelic variants associated with hypertension in human and animal model systems. Bidirectional approaches can now be applied to reveal the functional relevance of allelic variants (SNPs) discovered in human populations by GWAS or in rat or mouse models by linkage, congenics, on hybrid diversity panels. Homology mapping using dense genomic sequencing data enables variants discovered in humans to be mapped to mouse and rat where function can be studied in great depth using in vitro and in vivo approaches and validated by gene‐editing techniques. Conversely, variants discovered in animal models can direct searches for homologous variants and studies in human subpopulations containing homologous variants. Reprinted, with permission, from Cowley AW, 2018 16.


Figure 1. (A) Schematic representation of the derivation of a consomic strain in which parental strains are intercrossed to generate the Fl population (40%–50% heterozygosity; half blue, half red alleles). These rats are then backcrossed with the parental SS strain. The N2 rats that are determined by genotyping to be heterozygous along the target chromosome are then backcrossed for ∼4 to 8 generations [e.g., marker assister selection for rats with most SS (blue) alleles]. This yields offspring with an isogenic SS background for all but the target chromosome as shown in (B). Selected male and female rats are then mated resulting in approximately 25% of the offspring being homozygous for the chromosome of interest. These rats are then inbred to produce a stable inbred consomic strain with the substitution of one entire chromosome from the BN strain into the background of the SS strain. Reprinted, with permission, from Cowley AW, et al., 2004 17.


Figure 2. Example of reduced blood pressure salt sensitivity resulting from substitution of chromosome 13 from the BN into the SS/Mcwi strain (SS‐13BN consomic rat). Shown is the mean arterial pressure (MAP) in conscious SS (n = 18), SS‐13BN (n = 15), and BN (n = 16) rats exposed to a high‐salt (4.0% NaCl) diet for 4 weeks. P < 0.05 comparing SS versus SS; and SS‐13BN versus BN 20.


Figure 3. Example of impact of genomic background on mean arterial pressure (MAP) responses to a high‐salt diet. Substitution of chromosome 18 from the BN to the SS strain (SS‐18BN) greatly reduced salt‐induced hypertension (8.0% diet; 3 weeks). Conversely, substitution of chromosome 18 from SS to the BN strain (BN‐18SS) resulted in a relatively small increase in MAP in response to the high‐salt diet.


Figure 4. Consomic rat panel in which each of the 20 autosomes and the X and Y chromosomes from the BN strain were transferred onto the SS genetic background. Shown are the mean arterial pressure (MAP) in male (A) and female (B) SS, BN, and consomic rat strains (indicated by the substituted chromosome) fed a high‐sodium diet (8.0% NaCl diet; 3 weeks) 89. Consomics with P < 0.05 versus SS of the same sex (*); consomic females differing (P < 0.05) from males are designated by #.


Figure 5. Consomic rat panel in which each of the 20 autosomes and the X and Y chromosomes from the BN strain were transferred onto the fawn‐hooded hypertensive (FHH) genetic background. Comparison of the sensitivity to phenylepinephrine (PE) of the aortic rings of consomic male rats to those of the parental salt‐sensitive rats (SS, black fill) after the rats were fed (A) a low‐salt (LS) diet (0.4% NaCl, A) or (B) a high‐salt (HS) diet (4.0% NaCl; 3 weeks). The numbers within each bar represent the n of that group. Y‐axis, −log EC50. *P < 0.05, significantly different from the SS parental strain; ∝ P < 0.05, significantly different from the same strain on an LS diet 62.


Figure 6. Generation of chromosome Y (chrY) consomic rats. A male individual from the donor strain is first crossed to a female from the host strain. Resulting F1 males are then backcrossed to a female from the host strain to generate the N2 generation. Males from the latter are backcrossed again to females from the host strain, the procedure being repeated (n) times. The genome of the final consomic strain is the same as that of the host strain, with the exception of the MSY from the donor strain. Redrawn, with permission, from Prokop JW and Deschepper CF, 2015 111.


Figure 7. Overview of the consomic xenograph model (CXM) 31. (A) Reduced susceptibility to DMBA‐induced mammary tumors in SS.BN2 consomic rats (n = 14) compared with SS (n = 40), as reported by Adamovic et al. 1. (B) Schematic representation of the SS and SS.BN3 genomes that were modified by TALEN‐mediated editing of the IL2Rγ gene. The number bars represent chromosomes that were derived from SS (white) or BN (black). (C) The transgenically labeled human 231Luc+ breast cancer cells were orthotopically implanted in the MFP (see dashed lines) of SSIL2Rγ and SS.BN3IL2Rγ rats. Tumor progression (e.g., growth, vasculogenesis, and metastasis) was tracked over the duration of the experiment. (D) Since the 231Luc+ tumor cells were the same between strains (gray), any differences in tumor progression can be attributed to differences in the SSIL2Rγ (green) and SS.BN3IL2Rγ (blue) microenvironments 31,33. Reprinted, with permission, from Flister MJ, et al., 2014 31.


Figure 8. Schematic representation of the generation of a congenic strain from congenic strains. (A) With the availability of the consomic SS‐13BN strain, the consomic strain is backcrossed to the homozygous parent strain (SS) to make an F1 generation where the offspring is homozygote for all alleles, except the single heterozygous target chromosome of interest (chr 13 in this case). Brother‐sister mating of the F1 rats results in many recombinations within the target chromosome. (B) Each rat is genotyped, and rats selected for heterozygosity at a particular locus with the goal of selecting a similar recombination in a male and female rat. These rats will be intercrossed yielding homozygosity in about 25% of the offspring, which will then be brother‐sister mated to create the inbred congenic line. To obtain a rat that is homozygous within a single 1‐cM interval, it can be estimated that in a population of 1000 F2 rats, there would be, on average, animals that are congenic at a 10 to 20 cM resolution.


Figure 9. (A) Representation of the overlapping congenic strains developed in which segments of various lengths of chromosome 13 from the Brown‐Norway rat (black bars) were introgressed in the genetic background of the SS rat, by marker‐assisted breeding. Delimitation of the congenic regions is defined by the first outward SS marker allele. Thin bars represent chromosome crossover regions. The table to the right of the graph summarizes the mean arterial pressure (MAP) + SEM on day 14 of high‐salt (HS) diet for each of the congenic strains. Significant differences from the SS strain on day 14 HS (P < 0.05) are also shown. Redrawn, with permission, from Moreno C, et al., 2007 93. (B) Candidate region of chr13 (55.13 BN26) was reduced from 13.4 to 1.37 Mb (position by RN5 genome assembly). The SS regions are indicated in white, while the alleles derived from the Brown‐Norway (BN) rats are indicated in black. The narrowed region (1.37 Mb) is shaded in gray. Mean arterial pressure (MAP) on day 14 of high‐salt (HS) diet for the 13 overlapping strains and the salt‐sensitive (SS) and congenic SS.13BN26 strains is summarized for each of the congenic substrains to the right of the graph. Significant differences from the SS strain on day 14 HS (P < 0.05) are also shown. Redrawn, with permission, from Cowley AW, et al., 2014 18. (C) Representation of a 3.62‐Mb region of chromosome (chr) 13 (26‐N) spanned by six overlapping congenic strains. Various lengths of chr 13 from the Brown‐Norway rat (indicated by black bars) were introgressed into the genetic background of the SS rat (white bar). Mean arterial pressure (MAP) measured on day 14 of high‐NaCl diet is shown in the attached table of each congenic substrain. Significant differences from the SS strain on day 14 HS (P < 0.05) are also shown. The narrowed region (0.71 Mb) is shown within the blue‐boxed area in which reside three candidate genes (AstN1, Pappa2, and MiR488p). Redrawn, with permission, from Cowley AW, et al., 2014 21.


Figure 10. Illustration of the convergence of classic and modern genomic approaches to identify allelic variants associated with hypertension in human and animal model systems. Bidirectional approaches can now be applied to reveal the functional relevance of allelic variants (SNPs) discovered in human populations by GWAS or in rat or mouse models by linkage, congenics, on hybrid diversity panels. Homology mapping using dense genomic sequencing data enables variants discovered in humans to be mapped to mouse and rat where function can be studied in great depth using in vitro and in vivo approaches and validated by gene‐editing techniques. Conversely, variants discovered in animal models can direct searches for homologous variants and studies in human subpopulations containing homologous variants. Reprinted, with permission, from Cowley AW, 2018 16.
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Teaching Material

Allen W. Cowley Jr. and Melinda R. Dwinell. Chromosomal Substitution Strategies to Localize Genomic Regions Related to Complex Traits. Compr Physiol 10 : 2020, 365-388.

Didactic Synopsis

Major teaching points

• Complex physiological traits are influenced not only by genomic variation, but also environmental and lifestyle factors. The combination of these factors contributes to disease risk, onset and progression.

• Genetic linkage studies have been successfully used to identify quantitative trait loci (QTL) for many complex traits across the genome. In some cases, these QTL map to different chromosomal regions in males and females.

• Consomic rat panels are generated through a breeding strategy to substitute a chromosome from one inbred strain into the genetic background of a different inbred strain. Phenotypic differences between these strains are a consequence of the substituted alleles.

• Further breeding can be used to narrow the region introgressed from a full chromosome to a narrow region of a chromosome to produce a "congenic strain". Congenic strains contain fewer genes within the narrowed chromosomal regions, therefore reducing the number of candidate genes and genetic variants influencing a trait.

• Advances in gene editing techniques provide opportunities to study the function of candidate genes in physiological processes.

Didactic Legends

The following legends to the figures that appear throughout the article are written to be useful for teaching.

Figure 1. Teaching points. The development of a consomic strain through a well defined breeding strategy provides a model to map biology onto the genome. In the case of a consomic strain, one chromosome from a parental strain is introgressed onto the background of a different parental strain. The result is a stable inbred consomic strain with the substitution of a single chromosome from one inbred strain into the background of a second inbred strain.

Figure 2. Teaching points. The utility of a consomic strains can be seen through this example in which chromosome 13 from the normotensive Brown Norway (BN) strain was substituted into the Dahl Salt-Sensitive strain. The introgression of chromosome 13 from the BN significantly reduced the blood pressure in response to a high salt challenge. A region or regions on chromosome 13 are contributing to the salt-sensitivity.

Figure 3. Teaching points. Comparison of the impact of background strain can also be studied using consomic strains. In this example, chromosome 18 was introgressed first from the BN strain into the SS background and subsequently from the SS strain into the BN background. Substitution from the BN to the SS strain resulted in an attenuated blood pressure response to a high salt challenge. The reverse, substitution from the SS to the BN, had only a small effect on the salt-sensitivity.

Figure 4. Teaching points. An even broader and more valuable approach to studying the impact of a chromosomal substitution on a complex trait is through the use of an entire consomic panel. The development of a consomic strain for each autosome and the X and Y chromosomes allows for the detection of multiple chromosomes containing regions with candidate genes involved in a phenotype or disease mechanism. In addition, differences between male and female rats for the same trait are easily identified.

Figure 5. Teaching points. In some cases, having consomic strains developed with the same chromosome (e.g chromosome 13 from the BN strain) introgressed into the background of two different inbred strains (e.g. Salt-sensitive or the Fawn Hooded Hypertensive) refines the chromosomes containing key regions involved in the trait. In other cases, the effect of a different background strain (Salt-sensitive or Fawn Hooded Hypertensive) with substitution from the same inbred strain (BN) points to the interaction of multiple genes involved in the trait.

Figure 6. Teaching points. The importance of the sex chromosomes specific phenotypic diversity. The development of a MSY consomic strain through careful breeding identified key sex-specific differences between the two parental strains. This approach has been used to identify genomic differences between male and female rats and translated to human.

Figure 7. Teaching points. Another fascinating extension of the consomic approach to study complex disease was accomplished through genomic modification of the IL2Rγ gene on a consomic strain. This model can be used to implant human cancer cells and study tumor progression in different microenvironments.

Figure 8. Teaching points. One approach used successfully by many groups to narrow a genomic region mapped to a trait has been to develop congenic strains. Congenic strains contain a small region of the introgressed chromosome, thus narrowing the list of potential genes of interest involved in the development of the phenotype. Through careful breeding, regions can be narrowed to within a 1 cM interval.

Figure 9. Teaching points. The development of overlapping congenic strains covering segments across a chromosome allows for the identification of one or several genomic regions mapping to a trait. These small congenic regions sometimes contain only a handful of genes, making the identification of key genes involved in a disease mechanism manageable. Congenic strains, like consomic strains, are inbred strains and provide a renewable resource for repeated studies and experimental groups.

 

Figure 10. Teaching points. Over the years, different approaches have been used to identify allelic variants associated with a complex disease such as hypertension. The approaches include human population studies, linkage analysis, and a variety of animal models. Approaches using human data to inform animal model studies and variants identified in animal models and subsequently identified in human populations have led to better understanding of the disease mechanism and to treatment approaches. 


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Article Title: Chromosomal Substitution Strategies to Localize Genomic Regions Related to Complex Traits
 

How to Cite

Allen W. Cowley, Melinda R. Dwinell. Chromosomal Substitution Strategies to Localize Genomic Regions Related to Complex Traits. Compr Physiol 2020, 10: 365-388. doi: 10.1002/cphy.c180029