Regionally enriched rare deleterious exonic variants in the UK and Ireland.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
02 Oct 2024
02 Oct 2024
Historique:
received:
27
09
2022
accepted:
13
08
2024
medline:
3
10
2024
pubmed:
3
10
2024
entrez:
2
10
2024
Statut:
epublish
Résumé
It is unclear how patterns of regional genetic differentiation in the UK and Ireland might impact the protein-coding fraction of the genome. We exploit UK Biobank (UKB) and Viking Genes whole exome sequencing data to study regional genetic differentiation across the UK and Ireland in protein coding genes, encompassing 44,696 unrelated individuals from 20 regions of origin. We demonstrate substantial exonic differentiation among Shetlanders, Orcadians, individuals with full or partial Ashkenazi Jewish ancestry and in several mainland regions (particularly north and south Wales, southeast Scotland and Ireland). With stringent filtering criteria, we find 67 regionally enriched (≥5-fold) variants likely to have adverse biomedical consequences in homozygous individuals. Here, we show that regional genetic variation across the UK and Ireland should be considered in the design of genetic studies and may inform effective genetic screening and counselling.
Identifiants
pubmed: 39358353
doi: 10.1038/s41467-024-51604-2
pii: 10.1038/s41467-024-51604-2
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
8454Informations de copyright
© 2024. The Author(s).
Références
Cann, R. L., Stoneking, M. & Wilson, A. C. Mitochondrial DNA and human evolution. Nature 325, 31–36 (1987).
pubmed: 3025745
doi: 10.1038/325031a0
Casanova, M. et al. A human Y-linked DNA polymorphism and its potential for estimating genetic and evolutionary distance. Science 230, 1403–1406 (1985).
pubmed: 2999986
doi: 10.1126/science.2999986
Y Chromosome Consortium. A nomenclature system for the tree of human Y-chromosomal binary haplogroups. Genome Res. 12, 339–348 (2002).
doi: 10.1101/gr.217602
The 1000 Genomes Project Consortium. et al. A global reference for human genetic variation. Nature 526, 68–74 (2015).
doi: 10.1038/nature15393
Leslie, S. et al. The fine-scale genetic structure of the British population. Nature 519, 309–314 (2015).
pubmed: 25788095
pmcid: 4632200
doi: 10.1038/nature14230
Gilbert, E. et al. The genetic landscape of Scotland and the Isles. Proc. Natl Acad. Sci. USA 116, 19064–19070 (2019).
pubmed: 31481615
pmcid: 6754546
doi: 10.1073/pnas.1904761116
Bray, S. M. et al. Signatures of founder effects, admixture, and selection in the Ashkenazi Jewish population. Proc. Natl Acad. Sci. USA 107, 16222–16227 (2010).
pubmed: 20798349
pmcid: 2941333
doi: 10.1073/pnas.1004381107
Halachev, M. et al. Increased ultra-rare variant load in an isolated Scottish population impacts exonic and regulatory regions. PLoS Genet 15, e1008480 (2019).
pubmed: 31765389
pmcid: 6901239
doi: 10.1371/journal.pgen.1008480
Kerr, S. M. et al. An actionable KCNH2 Long QT syndrome variant detected by sequence and haplotype analysis in a population research cohort. Sci. Rep. 9, 10964 (2019).
pubmed: 31358886
pmcid: 6662790
doi: 10.1038/s41598-019-47436-6
Chheda, H. et al. Whole-genome view of the consequences of a population bottleneck using 2926 genome sequences from Finland and United Kingdom. Eur. J. Hum. Genet. 25, 477–484 (2017).
pubmed: 28145424
pmcid: 5346294
doi: 10.1038/ejhg.2016.205
Gilly, A. et al. Cohort-wide deep whole genome sequencing and the allelic architecture of complex traits. Nat. Commun. 9, 4674 (2018).
pubmed: 30405126
pmcid: 6220258
doi: 10.1038/s41467-018-07070-8
Kaiser, V. B. et al. Homozygous loss-of-function variants in European cosmopolitan and isolate populations. Hum. Mol. Genet. 24, 5464–5474 (2015).
pubmed: 26173456
pmcid: 4572071
doi: 10.1093/hmg/ddv272
Kerr, S. M. et al. Clinical case study meets population cohort: identification of a BRCA1 pathogenic founder variant in Orcadians. Eur. J. Hum. Genet. 31, 588–595 (2023).
Davies N. The Isles: A History, Vol. 1120 (Papermac, 1999).
Pooley, C. & Turnbull, J. Migration And Mobility In Britain Since The Eighteenth Century 1st edn, Vol. 440 (Routledge, 2005).
Wilson, J. F. et al. Genetic evidence for different male and female roles during cultural transitions in the British Isles. Proc. Natl Acad. Sci. USA 98, 5078–5083 (2001).
pubmed: 11287634
pmcid: 33166
doi: 10.1073/pnas.071036898
Sudlow, C. et al. UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 12, e1001779 (2015).
pubmed: 25826379
pmcid: 4380465
doi: 10.1371/journal.pmed.1001779
Diaz-Papkovich, A., Anderson-Trocmé, L., Ben-Eghan, C. & Gravel, S. UMAP reveals cryptic population structure and phenotype heterogeneity in large genomic cohorts. PLoS Genet 15, e1008432 (2019).
pubmed: 31675358
pmcid: 6853336
doi: 10.1371/journal.pgen.1008432
Bycroft, C. et al. The UK Biobank resource with deep phenotyping and genomic data. Nature 562, 203–209 (2018).
pubmed: 30305743
pmcid: 6786975
doi: 10.1038/s41586-018-0579-z
Canela-Xandri, O., Rawlik, K. & Tenesa, A. An atlas of genetic associations in UK biobank. Nat. Genet. 50, 1593–1599 (2018).
pubmed: 30349118
pmcid: 6707814
doi: 10.1038/s41588-018-0248-z
Sinnott-Armstrong, N. et al. Genetics of 35 blood and urine biomarkers in the UK biobank. Nat. Genet. 53, 185–194 (2021).
pubmed: 33462484
doi: 10.1038/s41588-020-00757-z
Cirulli, E. T. et al. Genome-wide rare variant analysis for thousands of phenotypes in over 70,000 exomes from two cohorts. Nat. Commun. 11, 542 (2020).
pubmed: 31992710
pmcid: 6987107
doi: 10.1038/s41467-020-14288-y
Wang, Q. et al. Rare variant contribution to human disease in 281,104 UK biobank exomes. Nature 597, 527–532 (2021).
pubmed: 34375979
pmcid: 8458098
doi: 10.1038/s41586-021-03855-y
Szustakowski, J. D. et al. Advancing human genetics research and drug discovery through exome sequencing of the UK biobank. Nat. Genet. 53, 942–948 (2021).
pubmed: 34183854
doi: 10.1038/s41588-021-00885-0
McQuillan, R. et al. Runs of homozygosity in European populations. Am. J. Hum. Genet 83, 359–372 (2008).
pubmed: 18760389
pmcid: 2556426
doi: 10.1016/j.ajhg.2008.08.007
Naseri, A. et al. Personalized genealogical history of UK individuals inferred from biobank-scale IBD segments. BMC Biol. 19, 32 (2021).
pubmed: 33593342
pmcid: 7888130
doi: 10.1186/s12915-021-00964-y
Gilbert, E., Shanmugam, A. & Cavalleri, G. L. Revealing the recent demographic history of Europe via haplotype sharing in the UK Biobank. Proc. Natl Acad. Sci. USA 119, e2119281119 (2022).
pubmed: 35696575
pmcid: 9233301
doi: 10.1073/pnas.2119281119
Ceballos, F. C., Joshi, P. K., Clark, D. W., Ramsay, M. & Wilson, J. F. Runs of homozygosity: windows into population history and trait architecture. Nat. Rev. Genet. 19, 220–234 (2018).
pubmed: 29335644
doi: 10.1038/nrg.2017.109
Ziff, M. & Harris, J. A collaborative genetic carrier screening model for the British Ashkenazi Jewish community. J. Community Genet. 13, 133–135 (2022).
pubmed: 34841494
doi: 10.1007/s12687-021-00568-7
Karczewski, K. J. et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581, 434–443 (2020).
pubmed: 32461654
pmcid: 7334197
doi: 10.1038/s41586-020-2308-7
Landrum, M. J. et al. ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res. 46, D1062–D1067 (2018).
pubmed: 29165669
doi: 10.1093/nar/gkx1153
Jewish Genetic Disease Consortium. “Jewish” Genetic Diseases and Non-Jewish Carriers. https://www.jewishgeneticdiseases.org/jewish-genetic-diseases/ (2013).
Centres for Disease Control and Prevention. Jewish Women and BRCA Gene Mutations https://www.cdc.gov/cancer/breast/young_women/bringyourbrave/hereditary_breast_cancer/jewish_women_brca.htm (2024).
Hanson, D. et al. The primordial growth disorder 3-M syndrome connects ubiquitination to the cytoskeletal adaptor OBSL1. Am. J. Hum. Genet. 84, 801–806 (2009).
pubmed: 19481195
pmcid: 2694976
doi: 10.1016/j.ajhg.2009.04.021
Clayton, P. E. et al. Exploring the spectrum of 3-M syndrome, a primordial short stature disorder of disrupted ubiquitination. Clin. Endocrinol. (Oxf.) 77, 335–342 (2012).
pubmed: 22624670
doi: 10.1111/j.1365-2265.2012.04428.x
Pardo, L. M., MacKay, I., Oostra, B., van Duijn, C. M. & Aulchenko, Y. S. The effect of genetic drift in a young genetically isolated population. Ann. Hum. Genet. 69, 288–295 (2005).
pubmed: 15845033
doi: 10.1046/J.1469-1809.2005.00162.x
Dudley, J. T. et al. Human genomic disease variants: a neutral evolutionary explanation. Genome Res 22, 1383–1394 (2012).
pubmed: 22665443
pmcid: 3409252
doi: 10.1101/gr.133702.111
Carmi, S. et al. Sequencing an Ashkenazi reference panel supports population-targeted personal genomics and illuminates Jewish and European origins. Nat. Commun. 5, 4835 (2014).
pubmed: 25203624
doi: 10.1038/ncomms5835
Xue, Y. et al. Enrichment of low-frequency functional variants revealed by whole-genome sequencing of multiple isolated European populations. Nat. Commun. 8, 15927 (2017).
pubmed: 28643794
pmcid: 5490002
doi: 10.1038/ncomms15927
Capelli, C. et al. A Y chromosome census of the British Isles. Curr. Biol. CB 13, 979–984 (2003).
pubmed: 12781138
doi: 10.1016/S0960-9822(03)00373-7
Goodacre, S. et al. Genetic evidence for a family-based Scandinavian settlement of Shetland and Orkney during the Viking periods. Heredity 95, 129–135 (2005).
pubmed: 15815712
doi: 10.1038/sj.hdy.6800661
Epskamp, S., Cramer, A. O. J., Waldorp, L. J., Schmittmann, V. D. & Borsboom, D. qgraph: Network visualizations of relationships in psychometric data. J. Stat. Softw. 48, 1–18 (2012).
Fruchterman, T. M. J. & Reingold, E. M. Graph drawing by force-directed placement. Softw. Pract. Exp. 21, 1129–1164 (1991).
doi: 10.1002/spe.4380211102
Dikilitas, O. et al. Familial hypercholesterolemia in the electronic medical records and genomics network: prevalence, penetrance, cardiovascular risk, and outcomes after return of results. Circ. Genomic Precis. Med. 16, e003816 (2023).
Shao, Y., Liu, S. & Grinzaid, K. Evaluation of two-year Jewish genetic disease screening program in Atlanta: insight into community genetic screening approaches. J. Community Genet. 6, 137–145 (2015).
pubmed: 25564014
pmcid: 4356671
doi: 10.1007/s12687-014-0208-y
Zlotogora, J. The Israeli national population program of genetic carrier screening for reproductive purposes. How should it be continued? Isr. J. Health Policy Res. 8, 73 (2019).
pubmed: 31839005
pmcid: 6912952
doi: 10.1186/s13584-019-0345-1
Crowgey, E. L., Washburn, M. C., Kolb, E. A. & Puffenberger, E. G. Development of a novel next-generation sequencing assay for carrier screening in old order Amish and Mennonite populations of Pennsylvania. J. Mol. Diagn. 21, 687–694 (2019).
pubmed: 31028937
pmcid: 7338886
doi: 10.1016/j.jmoldx.2019.03.004
Haworth, S. et al. Apparent latent structure within the UK Biobank sample has implications for epidemiological analysis. Nat. Commun. 10, 333 (2019).
pubmed: 30659178
pmcid: 6338768
doi: 10.1038/s41467-018-08219-1
Cook, J. P., Mahajan, A. & Morris, A. P. Fine-scale population structure in the UK biobank: implications for genome-wide association studies. Hum. Mol. Genet. 29, 2803–2811 (2020).
pubmed: 32691046
doi: 10.1093/hmg/ddaa157
Fry, A. et al. Comparison of sociodemographic and health-related characteristics of UK biobank participants with those of the general population. Am. J. Epidemiol. 186, 1026–1034 (2017).
pubmed: 28641372
pmcid: 5860371
doi: 10.1093/aje/kwx246
Chang, C. C. et al. Second-generation PLINK: rising to the challenge of larger and richer datasets. GigaScience 4, 7 (2015).
pubmed: 25722852
pmcid: 4342193
doi: 10.1186/s13742-015-0047-8
Staples, J. et al. PRIMUS: Rapid reconstruction of pedigrees from genome-wide estimates of identity by descent. Am. J. Hum. Genet. 95, 553–564 (2014).
pubmed: 25439724
pmcid: 4225580
doi: 10.1016/j.ajhg.2014.10.005
Li, H. Low-Complexity Regions Identified With Sdust. https://github.com/lh3/sdust (2024).
McLaren, W. et al. The Ensembl variant effect predictor. Genome Biol. 17, 122 (2016).
pubmed: 27268795
pmcid: 4893825
doi: 10.1186/s13059-016-0974-4
Anderson, C. A. et al. Data quality control in genetic case-control association studies. Nat. Protoc. 5, 1564–1573 (2010).
pubmed: 21085122
pmcid: 3025522
doi: 10.1038/nprot.2010.116
Centre For Statistical Genetics. Regions of Linkage Disequilibrium (LD). https://genome.sph.umich.edu/wiki/Regions_of_high_linkage_disequilibrium_(LD) (2021).
UMAP. Python Script. https://github.com/diazale/gt-dimred/blob/master/scripts/general_umap_script.py (2024).
Weir, B. S. & Cockerham, C. C. Estimating F-statistics for the analysis of population structure. Evolution 38, 1358 (1984).
pubmed: 28563791
Wright, S. The interpretation of population structure by F-statistics with special regard to systems of mating. Evolution 19, 395 (1965).
doi: 10.2307/2406450
Danecek, P. et al. The variant call format and VCF tools. Bioinformatics 27, 2156–2158 (2011).
pubmed: 21653522
pmcid: 3137218
doi: 10.1093/bioinformatics/btr330
Felsenstein, J. PHYLIP (Phylogeny Inference Package) Version 3.6. Distributed by Author. Department of Genome Sciences, University of Washington, Seattle. http://evolution.genetics.washington.edu/phylip.html (2005).
Letunic, I. & Bork, P. Interactive tree Of life (iTOL) v4: recent updates and new developments. Nucleic Acids Res. 47, W256–W259 (2019).
pubmed: 30931475
pmcid: 6602468
doi: 10.1093/nar/gkz239