Inter-individual genomic heterogeneity within European population isolates

Autoři: Paolo Anagnostou aff001;  Valentina Dominici aff001;  Cinzia Battaggia aff001;  Alessandro Lisi aff001;  Stefania Sarno aff003;  Alessio Boattini aff003;  Carla Calò aff004;  Paolo Francalacci aff004;  Giuseppe Vona aff004;  Sergio Tofanelli aff005;  Miguel G. Vilar aff006;  Vincenza Colonna aff007;  Luca Pagani aff008;  Giovanni Destro Bisol aff001
Působiště autorů: Dipartimento di Biologia Ambientale, Università di Roma “La Sapienza”, Rome, Italy aff001;  Istituto Italiano di Antropologia, Rome, Italy aff002;  Dipartimento di Scienze Biologiche, Geologiche ed Ambientali, Università di Bologna, Bologna, Italy aff003;  Dipartimento di Scienze della Vita e dell’Ambiente, Università di Cagliari, Monserrato, Cagliari, Italy aff004;  Dipartimento di Biologia, Università di Pisa, Pisa, Italy aff005;  National Geographic Society, Washington DC, United States of America aff006;  Institute of Genetics and Biophysics “A. Buzzati-Traverso”, National Research Council (CNR), Naples, Italy aff007;  APE Lab, Department of Biology, University of Padova, Padova, Italy aff008;  Estonian Biocentre, Institute of Genomics, University of Tartu, Tartu, Estonia aff009
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0214564


A number of studies carried out since the early ‘70s has investigated the effects of isolation on genetic variation within and among human populations in diverse geographical contexts. However, no extensive analysis has been carried out on the heterogeneity among genomes within isolated populations. This issue is worth exploring since events of recent admixture and/or subdivision could potentially disrupt the genetic homogeneity which is to be expected when isolation is prolonged and constant over time. Here, we analyze literature data relative to 87,815 autosomal single-nucleotide polymorphisms, which were obtained from a total of 28 European populations. Our results challenge the traditional paradigm of population isolates as structured as genetically (and genomically) uniform entities. In fact, focusing on the distribution of variance of intra-population diversity measures across individuals, we show that the inter-individual heterogeneity of isolated populations is at least comparable to the open ones. More in particular, three small and highly inbred isolates (Sappada, Sauris and Timau in Northeastern Italy) were found to be characterized by levels of inter-individual heterogeneity largely exceeding that of all other populations, possibly due to relatively recent events of genetic introgression. Finally, we propose a way to monitor the effects of inter-individual heterogeneity in disease-gene association studies.

Klíčová slova:

Europe – Haplotypes – Inbreeding – Italy – Molecular genetics – Population genetics – Species diversity – Genomic imprinting


1. Ward RH, Neel JV. Gene frequencies and microdifferentiation among the Makiritare Indians. IV. A comparison of a genetic network with ethnohistory and migration matrices; a new index of genetic isolation. Am J Hum Genet. 1970;22: 538–561. 5516237

2. Arcos-Burgos M, Muenke M. Genetics of population isolates. Clin Genet. 2002;61: 233–247. doi: 10.1034/j.1399-0004.2002.610401.x 12030885

3. Colonna V, Nutile T, Astore M, Guardiola O, Antoniol G, Ciullo M, et al. Campora: a young genetic isolate in South Italy. Hum Hered. 2007;64: 123–135. doi: 10.1159/000101964 17476112

4. Charlesworth B. Fundamental concepts in genetics: effective population size and patterns of molecular evolution and variation. Nat Rev Genet. 2009;10: 195–205. 19204717

5. Palin K, Campbell H, Wright AF, Wilson JF, Durbin R. Identity-by-descent-based phasing and imputation in founder populations using graphical models. Genet Epidemiol. 2011;35: 853–860. doi: 10.1002/gepi.20635 22006673

6. de la Chapelle A, Wright FA. Linkage disequilibrium mapping in isolated populations: the example of Finland revisited. Proc Natl Acad Sci U S A. 1998;95: 12416–12423. doi: 10.1073/pnas.95.21.12416 9770501

7. Jorde LB, Watkins WS, Kere J, Nyman D, Eriksson AW. Gene mapping in isolated populations: new roles for old friends? Hum Hered. 2000;50: 57–65. doi: 10.1159/000022891 10545758

8. Varilo T, Laan M, Hovatta I, Wiebe V, Terwilliger JD, Peltonen L. Linkage disequilibrium in isolated populations: Finland and a young sub-population of Kuusamo. Eur J Hum Genet. 2000;8: 604–612. doi: 10.1038/sj.ejhg.5200482 10951523

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: 556–560. doi: 10.1038/ng1770 16582909

10. Kristiansson K, Naukkarinen J, Peltonen L. Isolated populations and complex disease gene identification. Genome Biol. 2008;9: 109. doi: 10.1186/gb-2008-9-8-109 18771588

11. Colonna V, Pistis G, Bomba L, Mona S, Matullo G, Boano R, et al. Small effective population size and genetic homogeneity in the Val Borbera isolate. Eur J Hum Genet. 2013;21: 89–94. doi: 10.1038/ejhg.2012.113 22713810

12. Hatzikotoulas K, Gilly A, Zeggini E. Using population isolates in genetic association studies. Brief Funct Genomics. 2014;13: 371–377. doi: 10.1093/bfgp/elu022 25009120

13. Panoutsopoulou K, Hatzikotoulas K, Xifara DK, Colonna V, Farmaki A-E, Ritchie GRS, et al. Genetic characterization of Greek population isolates reveals strong genetic drift at missense and trait-associated variants. Nat Commun. 2014;5: 5345. doi: 10.1038/ncomms6345 25373335

14. Xue Y, Mezzavilla M, Haber M, McCarthy S, Chen Y, Narasimhan V, et al. Enrichment of low-frequency functional variants revealed by whole-genome sequencing of multiple isolated European populations. Nat Commun. 2017;8: 15927. doi: 10.1038/ncomms15927 28643794

15. Anagnostou P, Dominici V, Battaggia C, Pagani L, Vilar M, Wells RS, et al. Overcoming the dichotomy between open and isolated populations using genomic data from a large European dataset. Sci Rep. 2017;7: 41614. doi: 10.1038/srep41614 28145502

16. Capocasa M, Anagnostou P, Bachis V, Battaggia C, Bertoncini S, Biondi G, et al. Linguistic, geographic and genetic isolation: a collaborative study of Italian populations. J Anthropol Sci. 2014;92: 201–231. 24607994

17. Anagnostou P, Capocasa M, Dominici V, Montinaro F, Coia V, Destro-Bisol G. Evaluating mtDNA patterns of genetic isolation using a re-sampling procedure: A case study on Italian populations. Ann Hum Biol. 2017;44: 140–148. doi: 10.1080/03014460.2016.1181784 27109644

18. Human Genome Diversity Project (HGDP). Encyclopedia of Genetics, Genomics, Proteomics and Informatics. 2008. pp. 923–923.

19. Sarno S, Boattini A, Pagani L, Sazzini M, De Fanti S, Quagliariello A, et al. Ancient and recent admixture layers in Sicily and Southern Italy trace multiple migration routes along the Mediterranean. Sci Rep. 2017;7: 1984. doi: 10.1038/s41598-017-01802-4 28512355

20. Behar DM, Yunusbayev B, Metspalu M, Metspalu E, Rosset S, Parik J, et al. The genome-wide structure of the Jewish people. Nature. 2010;466: 238–242. doi: 10.1038/nature09103 20531471

21. Hellenthal G, Busby GBJ, Band G, Wilson JF, Capelli C, Falush D, et al. A genetic atlas of human admixture history. Science. 2014;343: 747–751. doi: 10.1126/science.1243518 24531965

22. Yunusbayev B, Metspalu M, Järve M, Kutuev I, Rootsi S, Metspalu E, et al. The Caucasus as an asymmetric semipermeable barrier to ancient human migrations. Mol Biol Evol. 2012;29: 359–365. doi: 10.1093/molbev/msr221 21917723

23. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81: 559–575. doi: 10.1086/519795 17701901

24. O’Connell J, Gurdasani D, Delaneau O, Pirastu N, Ulivi S, Cocca M, et al. A general approach for haplotype phasing across the full spectrum of relatedness. PLoS Genet. 2014;10: e1004234. doi: 10.1371/journal.pgen.1004234 24743097

25. Lawson DJ, Hellenthal G, Myers S, Falush D. Inference of population structure using dense haplotype data. PLoS Genet. 2012;8: e1002453. doi: 10.1371/journal.pgen.1002453 22291602

26. Haasl RJ, Payseur BA. Multi-locus inference of population structure: a comparison between single nucleotide polymorphisms and microsatellites. Heredity. 2011;106: 158–171. doi: 10.1038/hdy.2010.21 20332809

27. Rosenberg NA, Li LM, Ward R, Pritchard JK. Informativeness of genetic markers for inference of ancestry. Am J Hum Genet. 2003;73: 1402–1422. doi: 10.1086/380416 14631557

28. Johnson NA, Coram MA, Shriver MD, Romieu I, Barsh GS, London SJ, et al. Ancestral Components of Admixed Genomes in a Mexican Cohort. PLoS Genet. 2011;7: e1002410. doi: 10.1371/journal.pgen.1002410 22194699

29. Maples BK, Gravel S, Kenny EE, Bustamante CD. RFMix: a discriminative modeling approach for rapid and robust local-ancestry inference. Am J Hum Genet. 2013;93: 278–288. doi: 10.1016/j.ajhg.2013.06.020 23910464

30. Vogel F. Break-up of isolates. In: Roberts DF, Fujiki N, Torizuka K, Roberts DF, Fujiki N, Torizuka K, editors. Isolation, Migration and Health. Cambridge: Cambridge University Press; 1992. pp. 41–54.

31. Viazzo PP. Transizioni alla modernità in area alpina. Dicotomie, paradossi, questioni aperte. Histoire des Alpes—Storia delle Alpi—Geschichte der Alpen 2007;12: 13–28.

32. Elhaik E, Greenspan E, Staats S, Krahn T, Tyler-Smith C, Xue Y, et al. The GenoChip: a new tool for genetic anthropology. Genome Biol Evol. 2013;5: 1021–1031. doi: 10.1093/gbe/evt066 23666864

33. Novembre J, Johnson T, Bryc K, Kutalik Z, Boyko AR, Auton A, et al. Genes mirror geography within Europe. Nature. 2008;456: 98–101. doi: 10.1038/nature07331 18758442

34. Lao O, Lu TT, Nothnagel M, Junge O, Freitag-Wolf S, Caliebe A, et al. Correlation between genetic and geographic structure in Europe. Curr Biol. 2008;18: 1241–1248. doi: 10.1016/j.cub.2008.07.049 18691889

35. Bittles AH. Population stratification and genetic association studies in South Asia. J Mol Genet Med. 2005;1: 43–48. 19565013

36. Esko T, Mezzavilla M, Nelis M, Borel C, Debniak T, Jakkula E, et al. Genetic characterization of northeastern Italian population isolates in the context of broader European genetic diversity. Eur J Hum Genet. 2013;21: 659–665. doi: 10.1038/ejhg.2012.229 23249956

37. Karafet TM, Bulayeva KB, Bulayev OA, Gurgenova F, Omarova J, Yepiskoposyan L, et al. Extensive genome-wide autozygosity in the population isolates of Daghestan. Eur J Hum Genet. 2015;23: 1405–1412. doi: 10.1038/ejhg.2014.299 25604856

38. Colonna V, Nutile T, Ferrucci RR, Fardella G, Aversano M, Barbujani G, et al. Comparing population structure as inferred from genealogical versus genetic information. Eur J Hum Genet. 2009;17: 1635–1641. doi: 10.1038/ejhg.2009.97 19550436

39. Heutink P, Oostra BA. Gene finding in genetically isolated populations. Hum Mol Genet. 2002;11: 2507–2515. doi: 10.1093/hmg/11.20.2507 12351587

40. Marchini J, Cardon LR, Phillips MS, Donnelly P. The effects of human population structure on large genetic association studies. Nat Genet. 2004;36: 512–517. doi: 10.1038/ng1337 15052271

41. Rosenberg NA, Pritchard JK, Weber JL, Cann HM, Kidd KK, Zhivotovsky LA, et al. Genetic structure of human populations. Science. 2002;298: 2381–2385. doi: 10.1126/science.1078311 12493913

Článek vyšel v časopise


2019 Číslo 10