Chromosome-wide distribution of haplotype blocks and the role of recombination hot spots

Phillips, Michael; Lawrence, Robert; Sachidanandam, Ravi; Morris, Andrew P.; Balding, David J.; Donaldson, M. A.; Studebaker, J. F.; Ankener, Wendy; Alfisi, S.V.; Kuo, Fengshen; Camisa, A.L.; Pazorov, V.; Scott, Kathryn; Carey, Benjamin J.; Faith, Janet; Katari, G.; Bhatti, H.A.; Cyr, Justin M; Derohannessian, V.; Elosua, Carolina; Forman, Angela M; Grecco, N.M.; Hock, Cricket R; Kuebler, Jennifer; Lathrop, Jessica A; Mockler, M.A.; Nachtman, Eric P; Restine, Stephanie; Varde, Shobha; Hozza, M.J.; Gelfand, Craig A.; Broxholme, John; Abecasis, Gonçalo R.; Boyce-Jacino, Michael T.; Cardon, Lon R.

doi:10.1038/ng1100

Cited by 268 publications

(227 citation statements)

References 25 publications

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“…Five LD blocks from the Finnish sample were observed although only 41 SNPs were used in this study, suggesting that the SNPs selected were sufficient to represent the 'true' LD structure in this region and that the block structure was not an artifact of either low marker density or marker selection. 23 To compare haplotype configuration and frequency between CEU and the Finnish samples, we constructed haplotypes using shared SNPs between those used in the HapMap project and this study (26 markers, Table 2). In our analyses, we only considered those haplotypes with a frequency 40.03.…”

Section: Discussionmentioning

confidence: 99%

“…When we initiated this study, HapMap data for the NTRK2 region was not available, but such cross-comparisons are essential for designing association studies. 23 It is the long-term remodeling of neuronal circuitry that is thought to underlie development of addictive behaviors, including AD. 24 BDNF is well known to be essential for neuronal survival, protection and activity-dependent synaptic remodeling.…”

Section: Discussionmentioning

confidence: 99%

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Nucleotide sequence variation within the human tyrosine kinase B neurotrophin receptor gene: association with antisocial alcohol dependence

Anderson

Neyer

et al. 2007

Pharmacogenomics J

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To identify sequence variants in genes that may have roles in neuronal responses to alcohol, we resequenced the 5 0 region of tyrosine kinase B neurotrophin receptor gene (NTRK2) and determined linkage disequilibrium (LD) values, haplotype structure, and performed association analyses using 43 single nucleotide polymorphisms (SNPs) covering the entire NTRK2 region in a Finnish Caucasian sample of 229 alcohol-dependent subjects with antisocial personality disorder (ASPD) and 287 healthy controls. Individually, three SNPs were associated with alcohol dependence and alcohol abuse (AD) (P-value from 0.0019 to 0.0059, significance level was set at Pp0.01 corrected for multiple testing), whereas a common 18 locus haplotype within the largest LD block of NTRK2, a 119-kb region containing the 5 0 flanking region and exons 1-15, was marginally overrepresented in control subjects compared to AD individuals (global P ¼ 0.057). Taken together, these results support a role for the NTRK2 gene in addiction in a Caucasian population with AD and a subtype of ASPD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Nucleotide sequence variation within the human tyrosine kinase B neurotrophin receptor gene: association with antisocial alcohol dependence

Anderson

Neyer

et al. 2007

Pharmacogenomics J

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“…42,54,55,57,67,68 Most of these studies report LD data for markers spanning large genomic regions, and used pre-ascertained SNPs from public databases with limited marker density. 56,[69][70][71] The identification of smaller blocks within candidate genes is probably beyond the resolution of these studies because of inadequate marker density for detection of LD patterns. 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.…”

Section: Discussionmentioning

confidence: 99%

“…Still, the block boundaries are open to interpretation, as per the results of alternative simulation programs for boundaries, which do not always define hot spots. 71,72 In addition, we used the Dynamic Programming Algorithms (DPA) for haplotype block partitioning to estimate the block pattern. 70,83 Although it has been shown that this approach identified fewer and larger haplotype blocks than a LD method, 84 it separated a 3 0 block of identical size based on the observed haplotypes in our data set.…”

Section: Discussionmentioning

confidence: 99%

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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“…[33][34][35][36][37][38][39] The general pattern found in the regions examined so far is a series of discrete tracts of low recombination, high LD and therefore with a reduced number of haplotypes, the so-called 'haplotype blocks' bounded by recombination hotspots. Haplotype block structure has been found to vary according to genomic region (due to genomic factors affecting its pattern) and also between different global populations (due to demographic factors), 33,36,[38][39][40][41][42][43][44] see Bertranpetit et al 45 for a review. In fact, the goal of the International HapMap Project (http://www.hapmap.org) is to develop a haplotype map of the human genome, the HapMap, which will describe the common patterns of human DNA sequence variation in four distinct human populations.…”

Section: Introductionmentioning

confidence: 99%

Extreme population differences across Neuregulin 1 gene, with implications for association studies

et al. 2005

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Neuregulin 1 (NRG1) is one of the most exciting candidate genes for schizophrenia in recent years since its first association with the disease in an Icelandic population. Since then, many association studies have analysed allele and haplotype frequencies in distinct populations yielding varying results: some have replicated the association, although with different alleles or haplotypes being associated, whereas others have failed to replicate the association. These contradictory results might be attributed to population differences in allele and haplotype frequencies. In order to approach this issue, we have typed 13 SNPs across this large 1.4 Mb gene, including two of the SNPs originally found associated with schizophrenia in the Icelandic population, the objective being to discover if the underlying cause of the association discrepancies to date may be due to population-specific genetic variation. The analyses have been performed in a total of 1088 individuals from 39 populations, covering most of the genetic diversity in the human species. Most of the SNPs analysed displayed differing frequencies according to geographical region. These allele differences are especially relevant in two SNPs located in a large intron of the gene, as shown by the extreme F ST values, which reveal genetic stratification correlated to broad continental areas. This finding may be indicative of the influence of some local selective forces on this gene. Furthermore, haplotype analysis reveals a clear clustering according to geographical areas. In summary, our findings suggest that NRG1 presents extreme population differences in allele and haplotype frequencies. We have given recommendations for taking this into account in future association studies since this diversity could give rise to erroneous results.

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Chromosome-wide distribution of haplotype blocks and the role of recombination hot spots

Cited by 268 publications

References 25 publications

Nucleotide sequence variation within the human tyrosine kinase B neurotrophin receptor gene: association with antisocial alcohol dependence

Nucleotide sequence variation within the human tyrosine kinase B neurotrophin receptor gene: association with antisocial alcohol dependence

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

Extreme population differences across Neuregulin 1 gene, with implications for association studies

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