Partitioning of genetic variation between regulatory and coding gene segments: the predominance of software variation in genes encoding introvert proteins

Mitchison, Avrion

doi:10.1007/s002510050241

Cited by 25 publications

(15 citation statements)

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“…about is likely to be in selective expression in particular cell types (Daser et al 1996;Mitchison 1997). It is thus interesting that the one Mus MHC class II locus with an invariant promoter, E␣ is the only locus with a variant upstream enhancer (M. Janitz, L. Reiners-Schramm, and R. Lauster, in prep.…”

Section: Mhc Promoter Variability Genome Research 129mentioning

confidence: 99%

“…Coding sequences within the MHC have been shown to be subject to diversifying selection (Hughes and Nei 1988). We suggest that the advantage conferred by this exon diversity is further enhanced by diversity in the associated promoters (Mitchison 1997). Once functional diversity of the protein has been established, the potential exists for differential expression of the proteins to effect immunoregulation.…”

Section: Selective Pressurementioning

confidence: 99%

“…The presumed advantage of heterozygosity lies in the flexibility that it confers on the immune response: The protein under the control of the promoter in one allele is better able to mediate resistance to one type of pathogen, whereas the other allele is better suited to defense against another pathogen. The means by which this is brought about is likely to be in selective expression in particular cell types (Daser et al 1996;Mitchison 1997). It is thus interesting that the one Mus MHC class II locus with an invariant promoter, E␣ is the only locus with a variant upstream enhancer (M. Janitz, L. Reiners-Schramm, and R. Lauster, in prep.…”

Section: Selective Pressurementioning

confidence: 99%

“…These are all genes that encode ''extrovert'' proteins that handle diverse foreign structures such as antigens and parasites, in contrast to the ''introvert'' proteins that handle conserved structures internal to the body (Mitchison 1997); hemoglobin and glucose-6-phosphate dehydrogenase have been included in this list as extrovert proteins, as the high level of polymorphism evident in their structural genes results largely from their interaction with malaria parasites. The genes that encode extrovert proteins often vary in their coding sequences, so as to provide a range of binding sites for these foreign structures, and vary also in their noncoding regions (for reference, see Mitchison 1997). Variation in noncoding gene segments is also evident to a lesser extent among genes encoding introvert proteins, particularly among cytokines (and their receptors and natural antagonists) (Daser et al 1996).…”

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confidence: 99%

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The Distribution of Variation in Regulatory Gene Segments, as Present in MHC Class II Promoters

et al. 1998

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Diversity in the antigen-binding receptors of the immune system has long been a primary interest of biologists. Recently it has been suggested that polymorphism in regulatory (noncoding) gene segments is of substantial importance as well. Here, we survey the level of variation in MHC class II gene promoters in man and mouse using extensive collections of published sequences together with unpublished sequences recently deposited by us in the EMBL gene bank using the Shannon entropy to quantify diversity. For comparison, we also apply our analysis to distantly related MHC class II promoters, as well as to class I promoters and to class II coding regions. We observe a high level of intraspecies variability, which in mouse but not in man is localized to a significant extent near the binding sites of transcription factors-sites that are conserved over longer evolutionary distances. This localization may both indicate and enhance heterozygote advantage, as the presence of two functionally different promoters would be expected to confer flexibility in the immune response.A surge of interest in the variability of regulatory, noncoding gene segments is under way. Collections have been made of promoter sequences for MHC class I and class II genes in man (Louis et al. 1993;Yao et al. 1995) and class II in mouse (Janitz et al. 1997a), which add substantially to the information previously available for promoter sequences in the hemoglobin (Weatherall 1986;Labie and Elion 1996) and glucose-6-phosphate dehydrogenase (Vulliamy et al. 1992) genes. These are all genes that encode ''extrovert'' proteins that handle diverse foreign structures such as antigens and parasites, in contrast to the ''introvert'' proteins that handle conserved structures internal to the body (Mitchison 1997); hemoglobin and glucose-6-phosphate dehydrogenase have been included in this list as extrovert proteins, as the high level of polymorphism evident in their structural genes results largely from their interaction with malaria parasites. The genes that encode extrovert proteins often vary in their coding sequences, so as to provide a range of binding sites for these foreign structures, and vary also in their noncoding regions (for reference, see Mitchison 1997). Variation in noncoding gene segments is also evident to a lesser extent among genes encoding introvert proteins, particularly among cytokines (and their receptors and natural antagonists) (Daser et al. 1996). The functional consequences of this promoter sequence variation is not generally known, but its importance in determining expression level is becoming clearer for the class II MHC genes (Louis et al. 1994;Woolfrey and Nepom 1995), the ACE I gene (Villard et al. 1996), and cytokines genes (Messer et al. 1991;Pociot et al. 1992). For these MHC genes, valuable collections have been made of very distantly related sequences (Benoist and Mathis 1990), which enable comparisons to be made with the level of intraspecific variation. Thus, the basis for systematic study of this form of variation is no...

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Section: Mhc Promoter Variability Genome Research 129mentioning

confidence: 99%

Section: Selective Pressurementioning

confidence: 99%

Section: Selective Pressurementioning

confidence: 99%

mentioning

confidence: 99%

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The Distribution of Variation in Regulatory Gene Segments, as Present in MHC Class II Promoters

et al. 1998

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“…At other times, natural selection will favor a change in protein sequence. By example, when host immunity gene products physically interact with pathogens we expect that protein sequence evolution will occur in response to changes in pathogen populations [12]. However, even in such cases, pathogen attack can sometimes be foiled by specifically altering the regulation of a target protein.…”

Section: Discussionmentioning

confidence: 99%

Tinker where the tinkering's good

Rockman

Stern

2008

Trends in Genetics

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Do general principles govern the genetic causes of phenotypic evolution? One promising idea is that mutations in cis-regulatory regions play a predominant role in phenotypic evolution because they can alter gene activity without causing pleiotropic effects. Recent evidence that revealed the genetic basis of pigmentation pattern evolution in Drosophila santomea supports this notion. Multiple mutations that disrupt an abdominal enhancer of the pleiotropic gene tan partly explain the reduced pigmentation observed in this species. Which mutations underlie phenotypic evolution?Do developmental mechanisms influence genetic evolution? That is, can we predict what types of mutations underlie phenotypic evolution? The simplest model predicts that mutations with the least pleiotropic effects are most likely to contribute to phenotypic variation and divergence. The rationale for this model comes from a synthesis of Fisher's geometrical model of phenotypic evolution [1] with modern developmental biology. Fisher conceived of mutational effects as randomly oriented with respect to phenotypes. Given that phenotypes are complex and multidimensional, he assumed that mutations affect many traits at the same time. Fisher's model thus implies that most mutations generate pleiotropic effects. Such pleiotropic mutations will typically degrade fitness, because it is difficult to improve fitness if each mutation simultaneously affects many aspects of a phenotype. Modern developmental biology has provided an escape from this conundrum by demonstrating that cis-regulatory DNA is often functionally modular: genetically separable elements are responsible for discrete phases and patterns of expression [2][3][4][5]. Thus, although nearly all genes perform pleiotropic roles in development, cis-regulatory regions ensure that not all mutations have pleiotropic effects [3]. Accordingly, evolution is expected to favor mutations that cause fewer pleiotropic effects [6,7], such as mutations in cis-regulatory regions. Is this model correct? The decisive data-the mutations themselves-have been hard to identify. Although mapping natural variation to chromosomal regions is now easy, the final step of identifying the causal genes and mutations remains a massive challenge. Now Jeong et al. [8] have added an important piece to the puzzle by demonstrating that the evolution of Drosophila santomea pigmentation patterning has been driven by mutations at a cis-regulatory element of the pleiotropic enzyme tan, not once, but three separate times (Figure 1). Pale abdomens lack tanDrosophila abdominal pigmentation patterns vary among species. D. santomea, endemic to São Tomé, an island off the west coast of Africa, lost pigmentation in the posterior abdominal segments since divergence from their darkly pigmented sister species D. yakuba. Linkage mapping studies implicated a locus of large effect on the X chromosome as one of four loci contributing to the pigmentation difference between these species [9]. The linkage peak falls

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Identification of four new quantitative trait loci regulating arthritis severity and one new quantitative trait locus regulating autoantibody production in rats with collagen‐induced arthritis

Griffiths

Wang

Joe

et al. 2000

Arthritis & Rheumatism

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Objective. Collagen-induced arthritis (CIA) is a polygenic model of experimentally induced autoimmunity and chronic joint inflammation. This study maps genetic loci that regulate CIA susceptibility in DA/Bkl (DA) and BN/SsNHsd (BN) rats.Methods. Genome scans covering chromosomes 1-20 and interval mapping techniques using 159 simple sequence-length polymorphism markers were used to identify quantitative trait loci (QTLs) that regulate CIA in (DA ؋ BN)F 2 hybrids. Serum antibody titers to type II collagen were determined by enzyme-linked immunosorbent assay.Results. DA rats were high responders to porcine type II collagen (PII) and developed severe CIA (100%). BN rats were low responders to PII and resistant to CIA (0%). BN genes strongly repressed PII-induced CIA. Only 12% of (DA ؋ BN)F 1 rats (7 of 60) and 31% of (DA ؋ BN)F 2 rats (307 of 1,004) developed CIA. Three new QTLs (Cia11, Cia12, and Cia13) with significant logarithm of odds (LOD) scores of 5.6, 4.6, and 4.5, respectively, plus a suggestive QTL (Cia14*, LOD 3.0) regulating arthritis severity were identified on chromosomes 3, 12, 4, and 19. A new QTL, Ciaa3, associating with anticollagen antibody titer (antibody to PII LOD 6.5; antibody to rat type II collagen LOD 5.2) mapped to chromosome 9. Of 10 CIA QTLs previously identified in (DA ؋ F344) and (DA ؋ ACI) rats, only Cia1 in the major histocompatibility complex and a region coincident to Cia5 on chromosome 10 (LOD >8.0) influenced CIA severity in (DA ؋ BN)F 2 rats.Conclusion. Since CIA exhibits many of the pathologic features of rheumatoid arthritis, the data indicate that the variety of genetic elements regulating human autoimmune and rheumatic diseases may be much larger and more varied than originally envisioned.

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Partitioning of genetic variation between regulatory and coding gene segments: the predominance of software variation in genes encoding introvert proteins

Cited by 25 publications

References 42 publications

The Distribution of Variation in Regulatory Gene Segments, as Present in MHC Class II Promoters

The Distribution of Variation in Regulatory Gene Segments, as Present in MHC Class II Promoters

Tinker where the tinkering's good

Identification of four new quantitative trait loci regulating arthritis severity and one new quantitative trait locus regulating autoantibody production in rats with collagen‐induced arthritis

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