Haplotype Structure, LD Blocks, and Uneven Recombination Within the <i>LRP5</i> Gene

Twells, Rebecca C.J.; Mein, Charles A.; Phillips, Michael; Hess, J. Fred; Veijola, Riitta; Gilbey, Matthew; Bright, Matthew; Metzker, Michael L.; Lie, Benedicte A.; Kingsnorth, Amanda; Gregory, E. Crawford; Nakagawa, Yusuke; Snook, Hywel; Wang, William Y.S.; Masters, Jennifer; Johnson, Gillian C.L.; Eaves, Iain A.; Howson, Joanna M.M.; Clayton, David; Cordell, Heather J.; Nutland, Sarah; Rance, Helen E.; Carr, Philippa; Todd, John A.

doi:10.1101/gr.563703

Cited by 58 publications

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“…72 Presently, blocklike patterns have been observed in several human gene loci, for example, in the promoter of the b-globin gene, CYP19, LRP5, CD36, TNFRSF6 and TCRB. 44,[73][74][75][76][77][78] In general, methods for detecting blocks are partly subjective and no single approach definitively establishes block boundaries, especially if there is evidence for possible gene conversion as presented in this analysis of MBL2. It has been assumed that intervening recombination hot spots generate separate haplotype blocks, and in select studies recombination hot spots have been characterized.…”

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Sequence analysis of the mannose-binding lectin (MBL2) gene reveals a high degree of heterozygosity with evidence of selection

et al. 2004

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Human mannose-binding protein (MBL) is a component of innate immunity. To capture the common genetic variants of MBL2, we resequenced a 10.0 kb region that includes MBL2 in 102 individuals representing four major US ethnic groups. In all, 87 polymorphic sites were observed, indicating a high level of heterozygosity (total p ¼ 18.3 Â 10 À4 ). Estimates of linkage disequilibrium across MBL2 indicate that it is divided into two blocks, with a probable recombination hot spot in the 3 0 end. Three non-synonymous SNPs in exon 1 of the encoding MBL2 gene and three upstream SNPs form common 'secretor haplotypes' that can predict circulating levels. Common variants have been associated with increased susceptibility to infection and autoimmune diseases. The high frequencies of B, C and D alleles in certain populations suggest a possible selective advantage for heterozygosity. There is limited diversity of haplotype structure; the 'secretor haplotypes' lie on a restricted number of extended haplotypes, which could include additional linked SNPs, which might also have possible functional implications. There is evidence for gene conversion in the region between the two blocks, in the last exon. Our data should form the basis for conducting MBL2 candidate gene association studies using a locus-wide approach. Keywords: mannose-binding lectin; innate immunity; genetic variation; recombination hot spot; gene conversion IntroductionThe human mannose-binding protein (MBL) is an important component of the innate immune system and provides first-line protection against pathogens as an 'ante-antibody'. 1 MBL is a C-type collectin that functions as a pattern-recognition molecule in the immediate response to invading organisms. Carbohydrate structures on the surfaces of microorganisms (bacteria, fungi and parasites) are recognized by MBL, 2-5 which, in turn, lead to opsonization or activation of the lectin pathway of complement via associated mannosebinding lectin serine proteases (MASP2). [6][7][8] Decreased serum levels of MBL have been correlated with an increased risk for infection in both healthy children and immunocompromised individuals. Circulating levels of MBL and functional activity are partially regulated by genetic variation in the MBL2 gene, which encodes MBL. 9,10 The MBL2 gene is located on chromosome 10q11.2-21 and consists of four exons. 11 Each of the three structural gene polymorphisms in exon 1, known as the B, C and D alleles, interfere with the formation of higher MBL oligomers, leading to alterations in function and circulating levels. [12][13][14][15] Two strongly linked single-nucleotide polymorphisms (SNPs) lie in the proximal promoter (known as L/H and X/Y), as well as an SNP in the 5 0 UTR (known as P/Q); together, these upstream SNPs are linked to the three independent nonsynonymous SNPs (ie, B, C and D) to form the 'secretor haplotypes', which have previously been shown to partially account for alterations in complement activation and decreased circulating levels of MBL. 7,9,10,[16][17][18][19][20] Using ...

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Sequence analysis of the mannose-binding lectin (MBL2) gene reveals a high degree of heterozygosity with evidence of selection

et al. 2004

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“…GWA have revealed relationships between SNPs in LRP5, which encodes a co-receptor of the WNT ligands, and the risk of type 1 diabetes [22,23], as well as obesity [29]. LRP6 mutations are possibly related to the development of bone loss, coronary disease and the metabolic syndrome [24,25].…”

Section: Summary and Perspectivementioning

confidence: 99%

“…Of all the polymorphisms studied to date, TCF7L2 polymorphisms have been demonstrated to have by far the biggest effect on the risk of developing type 2 diabetes [14][15][16][17][18][19][20]. In addition, the human LRP5 gene was mapped to within the IDDM4 region, which is linked to type 1 diabetes on chromosome 11q13 [21][22][23]. Polymorphisms in LRP5 have been shown to be associated with obesity phenotypes, and missense mutations in LRP6 have been shown to be associated with the risk of bone loss, early coronary disease and the metabolic syndrome [24,25].…”

Section: Introduction To the Wnt Signalling Pathwaymentioning

confidence: 99%

“…The co-receptor was shown to be important in transducing WNT signalling and to play critical roles in modulating bone accrual and eye development [37]. The human LRP5 gene maps within the IDDM4 region on chromosome 11q13, which is linked to type 1 diabetes [21][22][23]. A recent GWA study has also shown that polymorphisms in LRP5 are associated with obesity phenotypes [38].…”

Section: Introduction To the Wnt Signalling Pathwaymentioning

confidence: 99%

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The WNT signalling pathway and diabetes mellitus

Jin

2008

Diabetologia

174

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The WNT signalling pathway is involved in many physiological and pathophysiological activities. WNT ligands bind to Frizzled receptors and co-receptors (LDL receptor-related protein 5/6), triggering a cascade of signalling events. The major effector of the canonical WNT signalling pathway is the bipartite transcription factor β-catenin/T cell transcription factor (β-cat/TCF), formed by free β-cat and one of the four TCFs. The WNT pathway is involved in lipid metabolism and glucose homeostasis, and mutations in LRP5 may lead to the development of diabetes and obesity. β-Cat/TCF is also involved in the production of the incretin hormone glucagon-like peptide-1 in the intestinal endocrine L cells. More recently, genome-wide association studies have identified TCF7L2 as a diabetes susceptibility gene, and individuals carrying certain TCF7L2 single nucleotide polymorphisms could be more susceptible to the development of type 2 diabetes. Furthermore, β-cat is able to interact with forkhead box transcription factor subgroup O (FOXO) proteins. Since FOXO and TCF proteins compete for a limited pool of β-cat, enhanced FOXO activity during ageing and oxidative stress may attenuate WNT-mediated activities. These observations shed new light on the pathogenesis of type 2 diabetes as an age-dependent disease.

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“…These blocks are thought to be delineated by recombination hotspots, small areas in which the probability of recombination is far higher than that in the surrounding regions ( Jeffreys et al 2000( Jeffreys et al , 2001Templeton et al 2000;Wang et al 2002;Arnheim et al 2003;Phillips et al 2003;Twells et al 2003). The low probability of recombination inside each block means that the alleles at the SNPs within are passed together from one generation to the next.…”

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Modeling Haplotype Block Variation Using Markov Chains

Greenspan

Geiger

2006

Genetics

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Models of background variation in genomic regions form the basis of linkage disequilibrium mapping methods. In this work we analyze a background model that groups SNPs into haplotype blocks and represents the dependencies between blocks by a Markov chain. We develop an error measure to compare the performance of this model against the common model that assumes that blocks are independent. By examining data from the International Haplotype Mapping project, we show how the Markov model over haplotype blocks is most accurate when representing blocks in strong linkage disequilibrium. This contrasts with the independent model, which is rendered less accurate by linkage disequilibrium. We provide a theoretical explanation for this surprising property of the Markov model and relate its behavior to allele diversity. G ENETIC mapping studies based on linkage disequilibrium (LD) require a model of the background variation in the region being examined. The studies look for markers at which the norms of this model are violated by a set of diseased individuals, inferring that any such markers are likely to be close to a disease-causing allele. While many LD mapping methods do not explicitly refer to such a background model, it exists nonetheless as an underlying assumption. For example, a x 2 -correlation test between disease status and the allele frequencies at individual SNPs assumes that the alleles at each SNP are distributed independently.Recent work on human genomic variation suggests that it is fruitful to group SNP markers together into haplotype blocks (Daly et al. 2001;Goldstein 2001;Patil et al. 2001;Gabriel et al. 2002;Wall and Pritchard 2003). These blocks are thought to be delineated by recombination hotspots, small areas in which the probability of recombination is far higher than that in the surrounding regions ( Jeffreys et al. 2000( Jeffreys et al. , 2001Templeton et al. 2000;Wang et al. 2002;Arnheim et al. 2003;Phillips et al. 2003;Twells et al. 2003). The low probability of recombination inside each block means that the alleles at the SNPs within are passed together from one generation to the next. Therefore, each haplotype block can be considered as a single marker, with the set of alleles at the SNPs in the block constituting its allele (Cardon and Abecasis 2003;Tishkoff and Verrelli 2003). It is hoped that haplotype blocks will enable fewer SNP markers to be genotyped during LD mapping studies, since a small number of haplotypetagging SNPs (htSNPs) can be used to identify the common alleles of each block ( Johnson et al. 2001;Zhang et al. 2002;Sebastiani et al. 2003). The International Haplotype Mapping Project (HapMap) is currently producing a high-density haplotype map of the human genome for several target populations, to enable the efficient selection of htSNPs (International HapMap Consortium 2003).It is not practical or desirable to represent the background variation over SNP or block markers in a large chromosomal region using a full joint distribution. A model must also infer somethin...

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Haplotype Structure, LD Blocks, and Uneven Recombination Within the LRP5 Gene

Cited by 58 publications

References 40 publications

Sequence analysis of the mannose-binding lectin (MBL2) gene reveals a high degree of heterozygosity with evidence of selection

Sequence analysis of the mannose-binding lectin (MBL2) gene reveals a high degree of heterozygosity with evidence of selection

The WNT signalling pathway and diabetes mellitus

Modeling Haplotype Block Variation Using Markov Chains

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