Sequence features in regions of weak and strong linkage disequilibrium

Smith, Albert V.; Thomas, Daniel; Munro, Heather M.; Abecasis, Gonçalo R.

doi:10.1101/gr.4421405

Cited by 87 publications

(104 citation statements)

References 54 publications

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“…However, in the human genome, high LD in coding regions has been reported to be associated with sequence conservation in mouse sequences (Kato et al, 2006). Some repeats were also associated with regions of high LD (LINE repeats) or weak LD (SINE repeats, Alu sequences) (Smith et al, 2005). In this study, no relationship was found between LD and nucleotide diversity, an indicator of sequence conservation.…”

Section: Ld Patternscontrasting

confidence: 39%

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The heterogeneous levels of linkage disequilibrium in white spruce genes and comparative analysis with other conifers

Pavy

Gagnon

et al. 2011

Heredity

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In plants, knowledge about linkage disequilibrium (LD) is relevant for the design of efficient single-nucleotide polymorphism arrays in relation to their use in population and association genomics studies. Previous studies of conifer genes have shown LD to decay rapidly within gene limits, but exceptions have been reported. To evaluate the extent of heterogeneity of LD among conifer genes and its potential causes, we examined LD in 105 genes of white spruce (Picea glauca) by sequencing a panel of 48 haploid megagametophytes from natural populations and further compared it with LD in other conifer species. The average pairwise r 2 value was 0.19 (s.d.¼0.19), and LD dropped quickly with a half-decay being reached at a distance of 65 nucleotides between sites. However, LD was significantly heterogeneous among genes. A first group of 29 genes had stronger LD (mean r 2 ¼0.28), and a second group of 38 genes had weaker LD (mean r 2 ¼0.12). While a strong relationship was found with the recombination rate, there was no obvious relationship between LD and functional classification. The level of nucleotide diversity, which was highly heterogeneous across genes, was also not significantly correlated with LD. A search for selection signatures highlighted significant deviations from the standard neutral model, which could be mostly attributed to recent demographic changes. Little evidence was seen for hitchhiking and clear relationships with LD. When compared among conifer species, on average, levels of LD were similar in genes from white spruce, Norway spruce and Scots pine, whereas loblolly pine and Douglas fir genes exhibited a significantly higher LD.

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Section: Ld Patternscontrasting

confidence: 39%

“…LD can also be highly variable between chromosomes and between different regions within chromosomes (Yan et al, 2009). Highly heterogeneous levels of LD were also described along the human genome, which could be partially correlated with sequence features (Smith et al, 2005).…”

Section: Ld Patternsmentioning

confidence: 98%

The heterogeneous levels of linkage disequilibrium in white spruce genes and comparative analysis with other conifers

Pavy

Gagnon

et al. 2011

Heredity

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show abstract

“…Although the majority of gene classes are equally divided between these two extreme quartiles of the genome, some classes of genes show a marked skew in their distribution 64,84,85 . Genes involved in immune responses and neurophysiological processes are more often located in regions of low LD, whereas genes involved in DNA and RNA metabolism, response to DNA damage and the cell cycle are preferentially located in regions of strong linkage disequilibrium.…”

Section: Insights Into Recombination and Natural Selectionmentioning

confidence: 99%

A haplotype map of the human genome

Belmont¹,

Boudreau²,

Leal³

et al. 2005

Nature

5,224

1,633

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A haplotype map of the human genomeThe International HapMap Consortium* Inherited genetic variation has a critical but as yet largely uncharacterized role in human disease. Here we report a public database of common variation in the human genome: more than one million single nucleotide polymorphisms (SNPs) for which accurate and complete genotypes have been obtained in 269 DNA samples from four populations, including ten 500-kilobase regions in which essentially all information about common DNA variation has been extracted. These data document the generality of recombination hotspots, a block-like structure of linkage disequilibrium and low haplotype diversity, leading to substantial correlations of SNPs with many of their neighbours. We show how the HapMap resource can guide the design and analysis of genetic association studies, shed light on structural variation and recombination, and identify loci that may have been subject to natural selection during human evolution.

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“…9 -12 The recently published HapMap dataset allowed for the first time the identification of functional categories of genes that are preferentially located within regions of weak LD (immune response and sensory perception) and strong LD (DNA and RNA metabolism and cell cycle). 13,14 In addition, several functional categories related to neurotransmission showed reduced LD. 13 These LD patterns result from the joint influence of drift and different modes of selection on multiple sites under a complex population history.…”

Section: Introductionmentioning

confidence: 99%

“…13,14 In addition, several functional categories related to neurotransmission showed reduced LD. 13 These LD patterns result from the joint influence of drift and different modes of selection on multiple sites under a complex population history. Nevertheless, the biased LD patterns gave rise to the hypothesis that it could be advantageous for certain types of genes to be located in regions of increased recombination.…”

Section: Introductionmentioning

confidence: 99%

Enrichment of HapMap recombination hotspot predictions around human nervous system genes: evidence for positive selection ?

Freudenberg

Ptáček

2007

Eur J Hum Genet

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Channels and developmental genes belong to the molecular key players in the human central nervous system (CNS). Mutations in these genes often cause monogenic neurological disease and interspecies comparisons had shown reduced divergence. On the other hand, accelerated evolution of genes with roles in neurotransmission and development had indicated widespread positive selection in hominids. In the present study, we hypothesized that recombination hotspots could be enriched at genes with particularly important role in the CNS, because at those loci beneficial mutations may occur on a highly constrained background and consequently increased recombination could promote their fixation. To test this hypothesis, we retrieved CNS genes based on keyword search, expression data and expert knowledge. Consistent with our hypothesis, we find an enrichment of hotspot predictions around genes that are retrieved by all three strategies. Moreover, when comparing human genes based on their Gene Ontology annotations, we find hotspot predictions preferentially located around channels and neurodevelopmental genes. Taken together with the distinct sequence evolution that was reported by comparative genomic studies, this finding indicates continued positive selection at many CNS gene loci. In support of this interpretation, we also find an enrichment of recombination hotspot predictions around conserved noncoding regions that were reported to display a signature of accelerated evolution in the human lineage. Widespread positive selection acting on CNS gene loci could relate to the high prevalence of human nervous system disorders with genetically complex inheritance, potentially under an ancestral susceptibility allele model.

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Sequence features in regions of weak and strong linkage disequilibrium

Cited by 87 publications

References 54 publications

The heterogeneous levels of linkage disequilibrium in white spruce genes and comparative analysis with other conifers

The heterogeneous levels of linkage disequilibrium in white spruce genes and comparative analysis with other conifers

A haplotype map of the human genome

Enrichment of HapMap recombination hotspot predictions around human nervous system genes: evidence for positive selection ?

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