Abstract
Whole-genome sequence data enable construction of high-resolution linkage disequilibrium (LD) maps revealing the LD structure of functional elements within genic and subgenic sequences. The Malecot–Morton model defines LD map distances in linkage disequilibrium units (LDUs), analogous to the centimorgan scale of linkage maps. For whole-genome sequence-derived LD maps, we introduce the ratio of corresponding map lengths kilobases/LDU to describe the extent of LD within genome components. The extent of LD is highly variable across the genome ranging from ~38 kb for intergenic sequences to ~858 kb for centromeric regions. LD is ~16% more extensive in genic, compared with intergenic sequences, reflecting relatively increased selection and/or reduced recombination in genes. The LD profile across 18,268 autosomal genes reveals reduced extent of LD, consistent with elevated recombination, in exonic regions near the 5ʹ end of genes but more extensive LD, compared with intronic sequences, across more centrally located exons. Genes classified as essential and genes linked to Mendelian phenotypes show more extensive LD compared with genes associated with complex traits, perhaps reflecting differences in selective pressure. Significant differences between exonic, intronic and intergenic components demonstrate that fine-scale LD structure provides important insights into genome function, which cannot be revealed by LD analysis of much lower resolution array-based genotyping and conventional linkage maps.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Data availability
The LDU maps constructed and described in this study are available at: https://doi.org/10.6084/m9.figshare.7850882.v1.
References
Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, et al. The structure of haplotype blocks in the human genome. Science. 2002;296:2225–9.
Service S, DeYoung J, Karayiorgou M, Roos JL, Pretorious H, Bedoya G, et al. Magnitude and distribution of linkage disequilibrium in population isolates and implications for genome-wide association studies. Nat Genet. 2006;38:556–60.
Jakkula E, Rehnström K, Varilo T, Pietiläinen OPH, Paunio T, Pedersen NL, et al. The genome-wide patterns of variation expose significant substructure in a founder population. Am J Hum Genet. 2008;83:787–94.
Jeffreys AJ, Kauppi L, Neumann R. Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex. Nat Genet. 2001;29:217–22.
Myers S, Freeman C, Auton A, Donnelly P, McVean G. A common sequence motif associated with recombination hot spots and genome instability in humans. Nat Genet. 2008;40:1124–9.
Pengelly RJ, Tapper W, Gibson J, Knut M, Tearle R, Collins A, et al. Whole genome sequences are required to fully resolve the linkage disequilibrium structure of human populations. BMC Genom. 2015;16:666.
Gibson J, Tapper W, Ennis S, Collins A. Exome-based linkage disequilibrium maps of individual genes: functional clustering and relationship to disease. Hum Genet. 2013;132:233–43.
Pengelly RJ, Vergara-Lope A, Alyousfi D, Jabalameli MR, Collins A. Understanding the disease genome: gene essentiality and the interplay of selection, recombination and mutation. Brief Bioinform. 2017;20:267–73. bbx110.
Maniatis N, Collins A, Xu CF, McCarthy LC, Hewett DR, Tapper W, et al. The first linkage disequilibrium (LD) maps: delineation of hot and cold blocks by diplotype analysis. Proc Natl Acad Sci USA. 2002;99:2228–33.
Zhang W, Collins A, Maniatis N, Tapper W, Morton NE. Properties of linkage disequilibrium (LD) maps. Proc Natl Acad Sci USA. 2002;99:17004–7.
Tapper W, Collins A, Gibson J, Maniatis N, Ennis S, Morton NE. A map of the human genome in linkage disequilibrium units. Proc Natl Acad Sci USA. 2005;102:11835–9.
Zhang W, Collins A, Gibson J, Tapper WJ, Hunt S, Deloukas P, et al. Impact of population structure, effective bottleneck time, and allele frequency on linkage disequilibrium maps. Proc Natl Acad Sci USA. 2004;101:18075–80.
Lau W, Kuo TY, Tapper W, Cox S, Collins A. Exploiting large scale computing to construct high resolution linkage disequilibrium maps of the human genome. Bioinformatics. 2006;23:517–9.
McVean GA, Myers SR, Hunt S, Deloukas P, Bentley DR, Donnelly P. The fine-scale structure of recombination rate variation in the human genome. Science. 2004;304:581–4.
Eberle MA, Rieder MJ, Kruglyak L, Nickerson DA. Allele frequency matching between SNPs reveals an excess of linkage disequilibrium in genic regions of the human genome. PLoS Genet. 2006;2:e142.
Kong A, Thorleifsson G, Gudbjartsson DF, Masson G, Sigurdsson A, Jonasdottir A, et al. Fine-scale recombination rate differences between sexes, populations and individuals. Nature. 2010;467:1099–103.
Berger S, Schlather M, de Los Campos G, Weigend S, Preisinger R, Erbe M, et al. A scale-corrected comparison of linkage disequilibrium levels between genic and non-genic regions. PLoS ONE. 2015;10:e0141216.
Erikson GA, Bodian DL, Rueda M, Molparia B, Scott ER, Scott-Van Zeeland AA, et al. Whole-genome sequencing of a healthy aging cohort. Cell. 2016;165:1002–11.
Wigginton JE, Cutler DJ, Abecasis GR. A note on exact tests of Hardy-Weinberg equilibrium. Am J Hum Genet. 2005;76:887–93.
Kong A, Gudbjartsson DF, Sainz J, Jonsdottir GM, Gudjonsson SA, Richardsson B, et al. A high-resolution recombination map of the human genome. Nat Genet. 2002;31:241–7.
Spataro N, Rodríguez JA, Navarro A, Bosch E. Properties of human disease genes and the role of genes linked to Mendelian disorders in complex disease aetiology. Hum Mol Genet. 2017;26:489–500.
Park SG, Hannenhalli S, Choi SS. Conservation in first introns is positively associated with the number of exons within genes and the presence of regulatory epigenetic signals. BMC Genom. 2014;15:526.
Kalari KR, Casavant M, Bair TB, Keen HL, Comeron JM, Casavant TL, et al. First exons and introns–a survey of GC content and gene structure in the human genome. Silico Biol. 2006;6:237–42.
Amit M, Donyo M, Hollander D, Goren A, Kim E, Gelfman S, et al. Differential GC content between exons and introns establishes distinct strategies of splice-site recognition. Cell Rep. 2012;1:543–556.
Fullerton SM, Bernardo Carvalho A, Clark AG. Local rates of recombination are positively correlated with GC content in the human genome. Mol Biol Evol. 2001;18:1139–42.
Payseur BA, Nachman MW. Gene density and human nucleotide polymorphism. Mol Biol Evol. 2002;19:336–40.
Hussin JG, Hodgkinson A, Idaghdour Y, Grenier JC, Goulet JP, Gbeha E, et al. Recombination affects accumulation of damaging and disease-associated mutations in human populations. Nat Genet. 2015;47:400–4.
Khurana E, Fu Y, Colonna V, Mu XJ, Kang HM, Lappalainen T, et al. Integrative annotation of variants from 1092 humans: application to cancer genomics. Science. 2013;342:1235587.
Hellmann I, Ebersberger I, Ptak SE, Pääbo S, Przeworski M. A neutral explanation for the correlation of diversity with recombination rates in humans. Am J Hum Genet. 2003;72:1527–35.
Brick K, Smagulova F, Khil P, Camerini-Otero RD, Petukhova GV. Genetic recombination is directed away from functional genomic elements in mice. Nature. 2012;485:642.
Zhu L, Zhang Y, Zhang W, Yang S, Chen JQ, Tian D. Patterns of exon-intron architecture variation of genes in eukaryotic genomes. BMC Genom. 2009;10:47.
Liebert A, López S, Jones BL, Montalva N, Gerbault P, Lau W, et al. World-wide distributions of lactase persistence alleles and the complex effects of recombination and selection. Hum Genet. 2017;136:1445–53.
ENCODE Project Consortium. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature. 2007;447:799.
Quinn JJ, Chang HY. Unique features of long non-coding RNA biogenesis and function. Nat Rev Genet. 2016;17:47.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Vergara-Lope, A., Ennis, S., Vorechovsky, I. et al. Heterogeneity in the extent of linkage disequilibrium among exonic, intronic, non-coding RNA and intergenic chromosome regions. Eur J Hum Genet 27, 1436–1444 (2019). https://doi.org/10.1038/s41431-019-0419-0
Received:
Revised:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s41431-019-0419-0
This article is cited by
-
X-LDR: an atlas of linkage disequilibrium across species
Genome Biology (2025)
-
Linkage disequilibrium maps for European and African populations constructed from whole genome sequence data
Scientific Data (2019)
