A Fine-Scale Map of Recombination Rates and Hotspots Across the Human Genome

Myers, Simon; Bottolo, Leonardo; Freeman, Colin; McVean, Gil; Donnelly, Peter

doi:10.1126/science.1117196

Cited by 1,038 publications

(1,264 citation statements)

References 28 publications

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“…Long repeats including LINE-1 elements are normally heavily DNA-methylated (Woodcock et al, 1988;Crowther et al, 1991;Woodcock et al, 1997), a feature of heterochromatin. DNA methylation (and heterochromatin in general) has been reported to suppress homologous recombination (Pàldi et al, 1995;Maloisel and Rossignol, 1998;Schnable et al, 1998;Fu et al, 2002;Yao et al, 2002;Yamada et al, 2004;Myers et al, 2005) as well as transposition (Yoder et al, 1997;Walsh et al, 1998;Hirochika et al, 2000;Robertson, 2001;Bird, 2002;Kato et al, 2003). Accordingly, reports of deletions caused by homologous recombination between LINE-1 elements are rare (Segal et al, 1999) except in cancers (Florl and Schulz, 2003) where LINE-1 elements are frequently hypomethylated (Santourlidis et al, 1999;Takai et al, 2000;Ehrlich, 2002;Carnell and Goodman, 2003;Florl et al, 2004;Roman-Gomez et al, 2005).…”

Section: Non-random Repeat Distributions Via Natural Selectionmentioning

confidence: 99%

Repetitive sequence environment distinguishes housekeeping genes

Eller¹,

Regelson²,

Merriman³

et al. 2007

Gene

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Housekeeping genes are expressed across a wide variety of tissues. Since repetitive sequences have been reported to influence the expression of individual genes, we employed a novel approach to determine whether housekeeping genes can be distinguished from tissue-specific genes their repetitive sequence context. We show that Alu elements are more highly concentrated around housekeeping genes while various longer (>400-bp) repetitive sequences ("repeats"), including Long Interspersed Nuclear Element 1 (LINE-1) elements, are excluded from these regions. We further show that isochore membership does not distinguish housekeeping genes from tissue-specific genes and that repetitive sequence environment distinguishes housekeeping genes from tissue-specific genes in every isochore. The distinct repetitive sequence environment, in combination with other previously published sequence properties of housekeeping genes, were used to develop a method of predicting housekeeping genes on the basis of DNA sequence alone. Using expression across tissue types as a measure of success, we demonstrate that repetitive sequence environment is by far the most important sequence feature identified to date for distinguishing housekeeping genes.

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Section: Non-random Repeat Distributions Via Natural Selectionmentioning

confidence: 99%

Repetitive sequence environment distinguishes housekeeping genes

Eller¹,

Regelson²,

Merriman³

et al. 2007

Gene

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“…The dotted line shows the evaluation of Equation 6 under the neutral model. The probability of escape for the distal locus is given by p y ¼ 1 À e ÀRy tM=2 with t M ¼ 0:1. average recombination rate is R ¼ 0:4=kb in European populations (Myers et al 2005), so that a polymorphism 5 kb from the selected site will have only a 50% probability of being older than the selected mutation. Figure 4 shows that inclusion of recent mutations has a marked effect on s 2 d .…”

Section: Incorporating Neutral Mutations Younger Than the Selected Mumentioning

confidence: 99%

The Structure of Linkage Disequilibrium Around a Selective Sweep

2007

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The fixation of advantageous mutations by natural selection has a profound impact on patterns of linked neutral variation. While it has long been appreciated that such selective sweeps influence the frequency spectrum of nearby polymorphism, it has only recently become clear that they also have dramatic effects on local linkage disequilibrium. By extending previous results on the relationship between genealogical structure and linkage disequilibrium, I obtain simple expressions for the influence of a selective sweep on patterns of allelic association. I show that sweeps can increase, decrease, or even eliminate linkage disequilibrium (LD) entirely depending on the relative position of the selected and neutral loci. I also show the importance of the age of the neutral mutations in predicting their degree of association and describe the consequences of such results for the interpretation of empirical data. In particular, I demonstrate that while selective sweeps can eliminate LD, they generate patterns of genetic variation very different from those expected from recombination hotspots.

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“…That analysis included 80 SNPs across the MHC locus but did not include any of the eight SNPs typed in this study. Fourth, estimated recombination rates from HapMap data indicate regions of high recombination on both sides of the C2/BF locus 24 (M.D. and B.G., unpublished data).…”

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Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration

et al. 2006

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Age-related macular degeneration (AMD) is the most common form of irreversible blindness in developed countries 1,2 . Variants in the factor H gene (CFH, also known as HF1), which encodes a major inhibitor of the alternative complement pathway, are associated with the risk for developing AMD [3][4][5][6][7][8] . Here we test the hypothesis that variation in genes encoding other regulatory proteins of the same pathway is associated with AMD. We screened factor B (BF) and complement component 2 (C2) genes, located in the major histo-compatibility complex class III region, for genetic variation in two independent cohorts comprising ~900 individuals with AMD and ~400 matched controls. Haplotype analyses identify a statistically significant common risk haplotype (H1) and two protective haplotypes. The L9H variant of BF and the E318D variant of C2 (H10), as well as a variant in intron 10 of C2 and the R32Q variant of BF (H7), confer a significantly reduced risk of AMD (odds ratio = 0. 45 and 0.36, respectively). Combined analysis of the C2 and BF haplotypes and CFH variants shows that variation in the two loci can predict the clinical outcome in 74% of the affected individuals and 56% of the controls. These data expand and refine our understanding of the genetic risk for AMD.Correspondence should be addressed to R.A. (rla22@columbia.edu) or M.D. (dean@ncifcrf.gov). Note: Supplementary information is available on the Nature Genetics website. AUTHOR CONTRIBUTION STATEMENTThe AMD Genetics Clinical Study Group includes Stanley Chang, Lawrence A. Yannuzzi, John C. Merriam and Irene Barbazetto (Department of Ophthalmology, Columbia University, New York); Leonid E. Lerner (F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania School of Medicine, Philadelphia) and Stephen Russell, Jamal Hoballah, Jill Hageman and Heather Stockman (Department of Ophthalmology and Visual Sciences, Center for Macular Degeneration, University of Iowa, Iowa City, Iowa, USA). COMPETING INTERESTS STATEMENTThe authors declare competing financial interests (see the Nature Genetics website for details).Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions/ NIH Public Access Inflammation has a central role in the pathobiology of AMD 9-14 . Dysfunction of the complement pathway is proposed to induce significant damage to macular cells, leading to atrophy, degeneration and the elaboration of choroidal neovascular membranes 3,[15][16][17] . Activation of the alternative pathway is initiated by cleavage of C3b-bound factor B (BF), resulting in the formation of the C3Bb complex (C3 convertase). This complex is stabilized by properdin, whereas its dissociation is accelerated by regulatory proteins, including complement factor H (CFH), the major inhibitor of the alternative complement pathway. As CFH haplotypes are associated with AMD 3 , we hypothesized that the same may be true for activators of the same pathway, such as complement factor B (BF). BF and compl...

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A Fine-Scale Map of Recombination Rates and Hotspots Across the Human Genome

Cited by 1,038 publications

References 28 publications

Repetitive sequence environment distinguishes housekeeping genes

Repetitive sequence environment distinguishes housekeeping genes

The Structure of Linkage Disequilibrium Around a Selective Sweep

Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration

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