Rheumatology Advance Access originally published online on June 12, 2006
Rheumatology 2006 45(9):1062-1067; doi:10.1093/rheumatology/kel088
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Mice, humans and haplotypes—the hunt for disease genes in SLE
Rheumatology Section, Imperial College, Faculty of Medicine, Hammersmith Hospital, London W12 0NN, UK.
Correspondence to: T. J. Vyse. E-mail: t.vyse{at}imperial.ac.uk
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Abstract |
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Defining the polymorphisms that contribute to the development of complex genetic disease traits is a challenging, although increasingly tractable problem. Historically, the technical difficulties in conducting association studies across the entire human genome are such that murine models have been used to generate candidate genes for analysis in human complex diseases, such as SLE. In this article we discuss the advantages and disadvantages of this approach and specifically address some assumptions made in the transition from studying one species to another, using lupus as an example. These issues include differences in genetic structure and genetic organisation which are a reflection on the population history. Clearly there are major differences in the histories of the human population and inbred laboratory strains of mice. Both human and murine genomes do exhibit structure at the genetic level. That is to say, they comprise haplotypes which are genomic regions that carry runs of polymorphisms that are not independently inherited. Haplotypes therefore reduce the number of combinations of the polymorphisms in the DNA in that region and facilitate the identification of disease susceptibility genes in both mice and humans. There are now novel means of generating candidate genes in SLE using mutagenesis (with ENU) in mice and identifying mice that generate antinuclear autoimmunity. In addition, murine models still provide a valuable means of exploring the functional consequences of genetic variation. However, advances in technology are such that human geneticists can now screen large fractions of the human genome for disease associations using microchip technologies that provide information on upwards of 100,000 different polymorphisms. These approaches are aimed at identifying haplotypes that carry disease susceptibility mutations and rely less on the generation of candidate genes.
KEY WORDS: Genetic polymorphism, Association Haplotype, SLE.
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Introduction |
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Many of the rheumatic diseases that are encountered in the clinic, both degenerative and inflammatory, behave as complex genetic traits. The term complex in this context is meaningful, reflecting the multiple genetic, environmental and stochastic factors that combine to result in the disease state. As inflammatory rheumatic diseases affect a minority of the population, one may infer that the genes involved in disease predisposition exert a relatively weak effect. One hypothesis is that a large number of common gene variants, or polymorphisms, are required. As these variants are common in the general population, they must, individually, have a weak individual effect: this is usually described as the ‘common disease common variant’ hypothesis [1]. The heterogeneity of the human population is such that much rarer but more penetrant alleles also contribute to complex disease; such alleles are more likely to be population-specific since there is a greater chance that they will have arisen more recently in human ancestry. The combination of relatively weak individual gene effects and multiple genes being involved in disease presents a significant challenge for geneticists intent on uncovering disease susceptibility in complex traits.
One possible experimental approach in disease genetics is to use animal models. In systemic lupus erythematosus (SLE), there are several murine models that spontaneously develop a lupus-like disease whose pathological features overlap completely with the human disease, and these strains can be used to identify candidate disease genes that may be involved in human SLE. In this review, we consider how the organization of the genomes of the two species may help or hinder this inter-species extrapolation.
Murine models of SLE
The use of mouse models genetically prone to disease can be of considerable value, not only in generating candidate genes but also in investigating the functional consequences of genetic variation. The commonly used inbred strains of mice, that is mice bred to carry identical genomes and be homozygous at every locus, were derived from wild mice at the beginning of the last century. These mice were originally bred for the ‘medical curiosity market’, being selected for unusual coat colour, neurological features and other ‘collectable’ traits. Such ‘fancy strains’ predominantly originated by selected breeding of wild mice such as Mus musculus, Mus domesticus and Mus spretus [2]. The observation that some of these traits appeared to mimic human disease states contributed to the rationale for developing inbred mouse strains to study human disease, a field of study that began with experiments into the genetic basis of transplanted tumour acceptance or rejection [3]. There are several murine models of SLE. The best characterized are members of the New Zealand (NZ) disease model, namely the New Zealand Black (NZB), New Zealand White (NZW) and the progeny of the NZB and NZW mice (NZBxNZW F1, or BWF1) (reviewed in [4, 5]). These mice develop a spontaneous disease, with varying degrees of severity, which is phenotypically very similar to human SLE. In particular, the BWF1 mice develop a severe disease, with a proliferative and sclerosing diffuse glomerulonephritis. Mirroring the human disease, female NZ mice, all develop a more severe disease with an earlier onset [4]. One straightforward question to ask of the SLE murine models is: if we identify lupus susceptibility genes in the mouse, what is the likelihood that these genes, or structurally and functionally related ones, will contribute to human SLE?
Local differences in genomic structure and function
Much of our current understanding of the immune system has been gleaned from the mouse, and there is ample evidence to support a close relation between human and murine immunology. It is this closeness that underpins the utility of murine models in the study of human auto-immune disease. However, this relation is not exact—there might appear to be equivalent, identically named genes in the two species, but with considerable differences in gene expression and function. The differences between the murine and human immune systems have been comprehensively reviewed by Mestas and Hughes [6]. There is some evidence that the same genetic lesion may contribute to SLE in different species. The hereditary deficiency of complement component C1q is a rare cause of human SLE [7], and mice carrying the C1qa targeted deletion develop systemic auto-immunity [8]. However, this is a very rare contributor to human disease and complete loss of gene function is unlikely to be a frequent component of genetic susceptibility in most cases of SLE. When considering the relation between the genetic contribution to lupus in humans and mice, it is extremely unlikely that the two species carry an identical polymorphism in the same disease susceptibility gene. A much more likely situation is that a gene that is relevant to disease will carry non-identical polymorphisms in mice and humans, but those polymorphisms will have a similar effect, for example on the gene expression or function of the gene product.
When one is comparing possible disease-associated genes between a murine disease model and the human condition (or vice versa) it is important to consider just how comparable genes or gene families are in the two species. Do all human genes have equivalents (called orthologues) in mice? In broad terms there is considerable parity between the genes in the two species—it is estimated that 99% of mouse genes have a homologue in the human genome, with 80% believed to have been derived from the same ancestral gene [9]. Differences are often subtle and can be illustrated by examples of the organization of genes with immunological function encoded on human chromosome 1q23, which is by coincidence mirrored by genes encoded on distal mouse chromosome 1. Genes in this area of the genome have been implicated in SLE as a result of linkage analyses, in both NZ mice [10, 11] and humans [12]. Figure 1 illustrates two situations that one can encounter when comparing genomic organization in two species. In some cases the organization of genes can seem to be highly related, as in the nine-gene signalling lymphocyte activation molecule (SLAM) locus. The SLAM genes are expressed on T, NK, B and dendritic cells and their self-ligation contribute to cell–cell interactions between these various cell types. Conversely, some loci seem to be considerably different, such as the interferon-inducible (Ifi/HIN200) and immunoglobulin Fc gamma receptor (FCGR) loci. In such instances, it is very difficult to determine the human–mouse orthologues for a given gene, even when one examines the actual sequence. Therefore, one can only infer orthology on a gene–gene family basis, rather than on a gene–gene basis.
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R gene families, which show considerable diversity in both gene number and gene position. These latter gene families highlight the considerable difficulty in directly comparing candidate genes between humans and murine disease models. Genes and gene positions of the Ifi gene family from [The genetic architecture of the inbred laboratory mouse
In the preceding section, we briefly discussed the genetic organization of murine and human genomes at a local level, and the problems that can be encountered when attempting to identify equivalent genes in the two species. As well as structural organization, the genome also possesses a genetic organization. This is the relationship between genetic variants in the genome. In any species, this genetic structure is, not surprisingly, influenced by the history of population expansion and breeding. How much variation exists within a given species at disease susceptibility loci is referred to as genetic architecture. The pattern of genetic variation in mice and man will be briefly summarized, and this will be related to the recent population history of each species.
By definition, inbred mouse strains have been bred to be genetically ‘identical’, achieved by brother–sister mating, or intercrossing, over many generations. The breeding of many of these mouse strains has been insufficiently documented to evaluate their precise genealogy (see [13] for a genealogy chart of laboratory mice). However, recent developments in both genetics and informatics have allowed the relatedness and pattern of variation in inbred mouse strains to be defined at the level of DNA structure. The sequencing of the mouse genome [9], and the definition and subsequent variation of common sequence variants throughout the genome of numerous mouse strains [14] has provided a new resource that circumvents, to some extent, the problems with determining gene–gene orthology.
Observing the pattern of variation between different inbred strains, it was apparent that the degree of variation was not constant throughout the genome [15]. Moreover, when the pattern of variations in individual inbred strains was compared there was limited heterogeneity. For a string of 10 single nucleotide polymorphisms (SNPs) encoded in tandem in the genome, there would be a theoretical total number of 210 possible polymorphism combinations. However, the observed number of possibilities is dramatically less than this possible total [14]. Indeed for some regions of the genome, only two main strings, or haplotypes of variants are present in a number of different strains. A good example of this phenomenon is the previously discussed SLAM locus, which exhibits two basic divergent haplotypes in 34 inbred strains [16] (Fig. 2). This restricted diversity reflects the origin of multiple inbred mouse strains from a common precursor, as described above.
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Influence of genetic architecture on disease genes
Given that the majority of inbred strains were derived from a limited number of founder wild mice, the restricted variation in the genome of inbred strains is not unexpected. This limited degree of genetic variation will restrict the amount of disease genes that can be identified using spontaneous murine models of disease.
Is there any experimental evidence to substantiate this assertion? The model of limited genetic diversity would predict that linkage studies in a given disease might identify similar genomic regions in different mouse strains. Turning again to the NZ murine model of SLE, overlapping regions linked to disease phenotypes have indeed been identified. An example of this phenomenon is observed on the distal end of mouse chromosome 1. This region of genome contains the NZW-derived Sle1a–d locus [11] and the NZB-derived Nba2 [10]. The existence of shared haplotypes in laboratory mice leads to the prediction that disease susceptibility genes are not necessarily unique to disease susceptibility strains, and there is good evidence to support this claim. The distal chromosome 1 SLE-susceptibility locus (Fig. 1) has been implicated in other mouse genetic studies in SLE. Individually, the 129/Sv and C57BL/6 mice do not develop any auto-immune disease. However, when these strains are intercrossed the resulting progeny develop a lupus-like disease, with genetic contributions from the genomes of both strains [17]. Interestingly, a 129/Sv-derived disease susceptibility locus in this cross co-localized with the NZ-derived Nba2/Sle1a–d locus on distal chromosome 1, and NZB, NZW and 129/Sv have all been shown to have a common haplotype across the Slam locus [16].
The likelihood of there being some common auto-immune disease variants contributed by multiple strains is high. Circumstantial evidence in support of the limited genetic heterogeneity in murine lupus is corroborated by the relatively frequent observation of antinuclear antibody (ANA) production in artificially mutagenized mice (http://www.apf.edu.au/resources/wt/data.shtml). Using the chemical mutagen N-ethyl-N-nitrosourea (ENU), numerous research groups have embarked on extensive phenotyping of mice that carry heritable traits as a consequence of genomic mutations. One such mutant, the sanroque mouse, has been shown to result from a mutation in the novel gene Roquin, which encodes a RING-type ubiquitin ligase [18]. However, as multiple other strains have been found to produce ANA it is highly likely that there are many genetic routes to antinuclear auto-immunity.
Human genetic architecture
The above arguments indicate that susceptibility to murine lupus may arise from genetic polymorphisms that are not unique to particular strains. That is they arise from variations that are common in inbred and may originate in wild-type mice. Needless to say, recent human population history differs somewhat from that of inbred laboratory mice. However, what the two species have in common is that ‘recent’ events have had a major impact on the architecture of their respective genomes. Population expansion in human populations has the potential to influence the frequency and complexity of alleles that predispose to disease in human complex genetic disease traits [19]. The current global population is in excess of 6 billion. This population has arisen from a relatively small founder cohort. The precise details of this dramatic expansion in numbers can be estimated, albeit imprecisely, from population genetics. The human founder cohort can be estimated to be in the order of 25 000 individuals and the major human population expansion has occurred over the preceding 700–6000 generations; that is in the range of 18–150 millennia [19]. This impressive demonstration of fecundity has had a major impact on the genetic architecture of the modern human population. The dramatic increase in population size would be expected to increase the numerical representation of disease alleles, even rarer ones, in modern humans. The relative preservation of alleles present in the original human population has been used as an argument to support the ‘common disease common variant’ hypothesis [1]. The descriptive title conveys the main idea that complex disease traits may be influenced by relatively common alleles that are present in the population, including, by definition, many individuals who do not exhibit the disease trait. Thus, there exists an analogous state between human and murine genomes, in that alleles or extended strings of alleles in a haplotype may contribute to complex disease traits without necessarily inducing disease in all carriers. The existence of haplotypes in the human genome contributes to the chance of success in identifying disease susceptibility genes [20]. For example, when asking whether a polymorphism is associated with disease it is not essential for that variant to be the actual causal allele for the association to be positive. Provided that the actual causal allele and marker allele being screened bear a sufficiently strong correlation (being on the same or closely linked haplotypes) then the association test will give a signal. A limited number of haplotypes in the genome can also impede progress in disease gene identification. The presence of extended associated haplotypes in the MHC in SLE has delayed the identification of the causal genes within the MHC that operate in SLE (a situation reflected in a number of other auto-immune diseases) [21]. However, with very dense maps of genetic variation that are now available in the human genome, the challenge of breaking down haplotypes is becoming more tractable. Examining genetic association in different populations may be particularly fruitful in providing different patterns of recombination in the genome that may be informative. The greater complexity of the genetic architecture of the human genome compared with the inbred mouse genome may mean that once a genetic locus is identified, then tracking down the likely causal alleles within it will be easier in humans than in the mouse.
Identification of SLE disease genes
Over the last few years, there has been considerable progress in identifying disease susceptibility alleles in human SLE; progress is being made at an exponential rate. One of the first regions of the genome to be studied in relation to auto-immune disease was the MHC. In SLE, the actual causal MHC genes remain to be identified with associations identified with various class II alleles and polymorphisms in the class II region that encode multiple genes with diverse immunological function [21]. As mentioned in the preceding section, attempts to identify causal disease genes have been hampered by extended haplotypes. Although it is important to realize that overall the pattern of recombination across the human MHC does not differ significantly from that seen in the genome on average [22]. The mouse MHC, designated H2, is represented by a limited number of haplotypes in inbred mouse strains. The consistent and strong linkage with this region in murine models and the influences of the H2 region appear diverse, that is enhancing in some circumstances and inhibitory in others [23]. It is likely that multiple genes contribute from the H2 to disease in mice, a situation that is likely to exist in human SLE, although mapping is of an insufficient resolution in both to determine whether any of the genetic MHC effects are equivalent in the two species.
Outside the MHC, genes with substantiated evidence for association include genes in the innate immune system, such as C-reactive protein (CRP) [24] and mannose-binding lectin (MBL) [25], multiple variants in the immunoglobulin Fc receptor genes [26, 32], co-stimulatory genes such as PDCD1 [27], as well as genes in the interferon signalling pathway [28]. The contribution of murine genetics to these studies was largely functional, in that the immunological function of the genes gained through murine studies implicated the potential role of these genes in auto-immunity. Several genes, or gene clusters have been directly identified through the analysis of the NZ model of SLE such as the Slam genes [16] or the Ifi genes [29, 30]. The equivalent human genes (Fig. 1) are the subject of intense scrutiny in human SLE, however, at present it remains to be clearly established whether genes in these families will play a role in human disease. Clear examples of the direct genetic extrapolation from spontaneous mouse model to man are therefore currently lacking. Interestingly, a recent study has implicated the human FCGR3B gene in lupus nephritis, a genetic lesion at Fcgr3 having initially been established in a rat model of nephrotoxic nephritis [33]. Single gene defects in murine models are known to act as disease accelerators: well-known examples are the lympho-proliferation (lpr) and generalized lymphadenopathy (gld) mutations [34]. The molecular characterization of these defects [35] indicated that the mutations compromised the function of FASL and FAS, respectively, and that these derangements impeded efficient apoptosis. The role of apoptosis in auto-immunity has been a fruitful field of investigation in SLE. Although mutations that severely abrogate the function of these molecules in humans have been described, these rare patients present with lymphadenopathy and haematological auto-immunity rather than typical SLE [36]. Mice remain an invaluable tool for exploring the molecular basis by which genetic variation influences the function of gene products. Such functional experiments are a vital step in moving from genetic variation to elucidating disease mechanism.
In summary, we have discussed the factors that may influence the success of utilizing the genetics of murine lupus to identify human disease susceptibility genes. Given the similarities between the human and murine immune systems and the occurrence of spontaneous genetic lupus-like disease in some strains of mice, the value of murine genetics would appear to be self-evident. This potential value has recently been increased by the availability of ENU mutants that develop antinuclear auto-immunity. However, the actuality of cross-species comparison is somewhat more complex. The details of how local genomic structure may differ between the two species have been discussed and how this would impact on the choice of candidate genes. We have also considered the question of genetic organization of the genomes in inbred mice and humans. It would appear that relatively common alleles or haplotypes contribute to disease susceptibility in both species and that these haplotypes will not be unique to those with disease. The identification of disease susceptibility genes in human SLE is beginning to yield valuable results; whether it will be possible to extrapolate from genes identified in murine models to human disease directly will be known soon.
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Glossary |
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Single nucleotide polymorphisms are common variations in DNA sequence. A SNP arises when there is a change in a single nucleotide (A, C, G or T) in a sequence of DNA. For example, in sequence variant 1 ATGCACTCA, the fourth nucleotide is C, in sequence variant 2 ATGTACTCA, the fourth nucleotide C is replaced with T. The variation is called an SNP if it affects more than 1% of the population.
An allele is an alternate form of the same gene at the same position on the same chromosome.
A haplotype describes a combination of alleles that are close together in the genome and inherited together as a consequence of minimal genetic recombination (Fig. 2).
Genetic association occurs when an allele is more commonly inherited in those with a particular phenotype such as a disease. The allele itself may be causal, or it may segregate with the actual causal polymorphism.
Linkage occurs when individuals with a particular disease or phenotype share genetic markers at a locus more frequently than those individuals without disease.
An orthologue refers to a gene or genomic region in two (or more) species that are derived from a common ancestral gene. Function is generally conserved between orthologous genes.
The signalling lymphocyte activation molecule (SLAM) gene cluster contains nine genes, located on chromosome 1q22-23 in man and distal chromosome 1 in mice. The locus forms part of the immunoglobulin gene superfamily and encodes proteins involved in T-cell stimulation.
The haematopoietic interferon-inducible nuclear proteins with 200 amino acid repeat (HIN200 locus) gene cluster is located on chromosome 1q23 in man and contains four genes that encode interferon-inducible nuclear proteins that appear to act as transcription factors.
The Ifi genes are encoded in the murine interferon-inducible gene cluster located on distal mouse chromosome 1, which is orthologous to the human HIN200 locus.
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Acknowledgments |
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As part of the ongoing studies into the genetics of SLE in the Vyse laboratory, the authors would like to acknowledge the contribution from patients and families with SLE. The donation of blood from these study participants is an essential contribution to genetic studies. We are also grateful to the primary care staff who have helped us collect blood samples and our clinical colleagues in rheumatology and nephrology who have provided us with patients with SLE. The authors acknowledge support from the Wellcome Trust (T.J.V. and R.J.R.) and the Arthritis Research Campaign (MMAF). We thank Marina Botto for her critical reading of the manuscript.
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