Fine-Scale Genetic Structure of the British Population Study Notes

Genetic Structure of the British Population

Introduction

• Fine-scale genetic variation in human populations reflects historical demographic events and has implications for disease studies.
• Analysis of genome-wide SNP data from 2,039 individuals across the UK reveals genetic differentiation patterns corresponding to geography.
• Regional genetic differentiation and shared ancestry with 6,209 Europeans indicate historical demographic events.
• Anglo-Saxon migrations contributed less than half of the genetic material in southeastern England.
• Significant pre-Roman, post-Mesolithic movement into southeastern England from continental Europe is suggested.
• Genetically differentiated subgroups exist in non-Saxon parts of the UK, rather than a general ‘Celtic’ population.

Methods and Data

• PoBI Collection:
  • 2,039 samples from rural UK areas were genotyped.
  • Participants had all four grandparents born within 80 km of each other.
  • Grandparents' average birth year was 1885 (s.d. 18 years).
• Continental European Samples:
  • 6,209 samples from 10 European countries were genotyped.
  • Samples were genotyped in the WTCCC2 study of multiple sclerosis.
  • Approximately 500,000 autosomal SNPs were used for compatibility.

Fine-Scale UK Population Differentiation

• Population structure within the PoBI collection is limited.
  • Average pairwise FST estimates between 30 sample collection districts: 0.0007, maximum: 0.003.
• FineSTRUCTURE Method:
  • A method for detecting fine-scale population structure was applied.
  • It models the correlation between nearby SNPs using multi-marker haplotypes.
  • The algorithm divides samples into genetic clusters hierarchically.

Genetic Clustering and Geography

• Genetic clustering was assessed by plotting individuals on a UK map based on grandparents’ birthplaces.
• Figure 1:
  • Shows a map for 17 clusters and a tree illustrating cluster relationships.
  • Correspondence between genetic clusters and geography is striking.
  • Clusters are highly localized, often occupying non-overlapping regions.
• The approach separates groups in close proximity, such as Cornwall and Devon.
• The hierarchical splitting of individuals into clusters reveals genetic differentiation.
  • Coarsest level: separates Orkney samples from all others.
  • Then Welsh samples separate from non-Orkney samples.
  • Subsequent splits differentiate north and south Wales, north of England, Scotland, and Northern Ireland.
  • Cornwall separates from the large English cluster.
• A large cluster covers most of central and southern England.
• Estimated FST values between clusters are small (average 0.002, maximum 0.007).
• Patterns of ancestry as estimated by fineSTRUCTURE show highly significant differences between clusters (Supplementary Table 3).

Comparison with Other Analysis Tools

• Compared fineSTRUCTURE with principal components and ADMIXTURE.
• Principal components and ADMIXTURE broadly separate samples from Wales and Orkney.
• These methods are unable to distinguish many of the other clusters found by fineSTRUCTURE.
• Analyses confirm that clustering is not an artifact of preferentially selecting related individuals.

UK Clusters in Relation to Europe

• Genetic differences between UK clusters reflect isolation and differing migration patterns from outside the UK.
• Similar fineSTRUCTURE analyses were applied to 6,209 samples from continental Europe.
• The genetic composition of the UK clusters was characterized with respect to the genetic groups in Europe.
• European samples were divided into 51 groups.
• Each UK cluster was estimated for an ancestry profile, characterizing it as a mixture of the ancestry of the 51 European groups.
• The analyses used no geographical information.
• Figure 2:
  • Illustrates estimated ancestry profiles and the sampling locations in Europe.
• Some European groups feature substantially in the ancestry profiles of all UK clusters:
  • GER6 (western Germany).
  • BEL11 (northern Belgium).
  • FRA14 (north-west France).
  • DEN18 (Denmark).
  • SFS31 (southern France and Spain).
• Some European groups feature substantially in some UK clusters but are absent from others:
  • GER3 (northern Germany).
  • FRA12 (France).
  • FRA17 (France).
• Swedish groups (SWE117 and SWE121) feature in the ancestry profiles of the UK clusters.
• Norwegian groups feature substantially in the ancestry profiles of the Orkney clusters, and to a lesser extent clusters involving Scotland and Northern Ireland.

Discussion

• Haplotype-based analysis of genome-wide SNP data reveals fine-scale genetic differentiation within the UK, showing concordance with geography.
• Few of these details have been captured previously.
• The clustering is notable for differentiation over small distances and the stability of some clusters over large distances.
• Genetic differentiation within the UK is not simply related to geographical distance.
• Examples of fine-scale differentiation include:
  • Separation of islands within Orkney.
  • Devon from Cornwall.
  • Welsh/English borders from surrounding areas.
• Edges between clusters follow natural geographical boundaries in some instances.
• Clusters in Northern Ireland span the sea to Scotland.
• Branch lengths of the hierarchical clustering tree indicate the relative differentiation between UK clusters.
• North and south Wales are about as distinct genetically from each other as are central and southern England from northern England and Scotland.

Historical Context

• Figure 3:
  • Gives an overview of major population groups and movements within and into the UK at different times, based on archaeological, historical, and linguistic evidence.
• Samples in Orkney differ genetically from those in the rest of the UK, consistent with historical settlement and long-term control by Norse Vikings.
• Ancestry profiles of the Orkney clusters show substantial contributions from groups in Norway.
• Finding a lack of subtle population structure in central and southern England is informative.
• There must have been sufficient movement of people and DNA since the last major invasions to make the region genetically relatively homogeneous.

Migration and Ancestry

• European ancestry profiles for each of the UK genetic clusters were estimated.
• Modern-day groupings are used as surrogates for the sources and results of major migration events.
• Genetic differences persist through many generations, and there is good concordance with historical evidence.
• European groups (e.g., GER3, FRA12, FRA17) contributing substantially to some, but not all, UK clusters suggests differential input of DNA to different parts of the UK.
• Groups contributing significantly to the ancestry profiles of all UK clusters most probably represent relatively old migration events.
• Groups contributing to only some UK clusters likely represent more recent migration events.
• Briefly, the earliest migrations are best captured by GER6 (western Germany), BEL11 (Belgium), and FRA14 (north-western France).
• A subsequent migration captured by FRA17 (France) contributed a substantial amount of ancestry to the UK outside Wales.
• Known historical migrations and settlements, including the Saxons (GER3, DEN18) and the Norse Vikings (NOR53–NOR90), are seen.

GLOBETROTTER Analysis

• GLOBETROTTER was applied to shed light on two major migration events, in Orkney and central/southern England.
• It tests for recent admixture, identifies contributing groups, and dates the admixture.
• GLOBETROTTER detected strong evidence that the largest Orkney cluster was influenced by a recent admixture event:
  • Contribution of <25\% of the DNA from groups in Norway.
  • Estimated to have occurred 29 generations ago (95% CI: 18–39 generations), corresponding to year 1100 (95% CI: 830–1418).
• For Cent./S England, the method also detected an admixture event:
  • Contribution of <35\% of DNA from GER3.
  • Estimated date of 38 generations (95% CI: 36–40 generations), corresponding to year 858 (95% CI: 802–914).
• GLOBETROTTER analyses detect likely source populations for the known historical migrations (Norse Vikings and Saxons).
• Admixture dates estimated by GLOBETROTTER should provide upper bounds on the dates of the migrations.

Saxon Migrations

• After the Saxon migrations, the language, place names, cereal crops, and pottery styles all changed.
• Two separate analyses (ancestry profiles and GLOBETROTTER) show clear evidence in modern England of the Saxon migration.
• The proportion of Saxon ancestry in Cent./S England is estimated as very likely to be under 50%, and most likely in the range of 10–40%.

Celtic Population

• No evidence of a general ‘Celtic’ population was found in non-Saxon parts of the UK.
• There were many distinct genetic clusters in these regions.
• The ancestry profile of Cornwall is quite different from that of the Welsh clusters, and much closer to that of Devon, and Cent./S England.
• The Welsh clusters represent populations that are more similar to the early post-Ice-Age settlers of Britain than those from elsewhere in the UK.

Conclusion

• The first fine-scale dissection of subtle levels of genetic differentiation within a country has been presented.
• The resulting genetic clusters and ancestry characterization provide novel insights into the peopling of the British Isles.
• Genetic information can augment archaeological, linguistic, and historical approaches to understanding population history.
• The study acts as a proof-of-principle for the power of detailed genetic analyses.