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Identity-by-descent detection across 487,409 British samples reveals fine-scale population structure, evolutionary history, and trait associations

Juba Nait Saada, Georgios Kalantzis, Derek Shyr, Martin Robinson, Alexander Gusev, Pier Francesco Palamara
doi: https://doi.org/10.1101/2020.04.20.029819
Juba Nait Saada
1Department of Statistics, University of Oxford, Oxford, UK
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  • For correspondence: juba.naitsaada@stats.ox.ac.uk palamara@stats.ox.ac.uk
Georgios Kalantzis
1Department of Statistics, University of Oxford, Oxford, UK
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Derek Shyr
2Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
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Martin Robinson
3Department of Computer Science, University of Oxford, Oxford, UK
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Alexander Gusev
4Brigham & Women’s Hospital, Division of Genetics, Boston, MA 02215, USA
5Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
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Pier Francesco Palamara
1Department of Statistics, University of Oxford, Oxford, UK
6Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
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  • For correspondence: juba.naitsaada@stats.ox.ac.uk palamara@stats.ox.ac.uk
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Abstract

Detection of Identical-By-Descent (IBD) segments provides a fundamental measure of genetic relatedness and plays a key role in a wide range of genomic analyses. We developed a new method, called FastSMC, that enables accurate biobank-scale detection of IBD segments transmitted by common ancestors living up to several hundreds of generations in the past. FastSMC combines a fast heuristic search for IBD segments with accurate coalescent-based likelihood calculations and enables estimating the age of common ancestors transmitting IBD regions. We applied FastSMC to 487,409 phased samples from the UK Biobank and detected the presence of ∼214 billion IBD segments transmitted by shared ancestors within the past 1,500 years. We quantified time-dependent shared ancestry within and across 120 postcodes, obtaining a fine-grained picture of genetic relatedness within the past two millennia in the UK. Sharing of common ancestors strongly correlates with geographic distance, enabling the localization of a sample’s birth coordinates from genomic data. We sought evidence of recent positive selection by identifying loci with unusually strong shared ancestry within recent millennia and we detected 12 genome-wide significant signals, including 7 novel loci. We found IBD sharing to be highly predictive of the sharing of ultra-rare variants in exome sequencing samples from the UK Biobank. Focusing on loss-of-function variation discovered using exome sequencing, we devised an IBD-based association test and detected 29 associations with 7 blood-related traits, 20 of which were not detected in the exome sequencing study. These results underscore the importance of modelling distant relatedness to reveal subtle population structure, recent evolutionary history, and rare pathogenic variation.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵* Co-supervised this work.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted April 21, 2020.
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Identity-by-descent detection across 487,409 British samples reveals fine-scale population structure, evolutionary history, and trait associations
Juba Nait Saada, Georgios Kalantzis, Derek Shyr, Martin Robinson, Alexander Gusev, Pier Francesco Palamara
bioRxiv 2020.04.20.029819; doi: https://doi.org/10.1101/2020.04.20.029819
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Identity-by-descent detection across 487,409 British samples reveals fine-scale population structure, evolutionary history, and trait associations
Juba Nait Saada, Georgios Kalantzis, Derek Shyr, Martin Robinson, Alexander Gusev, Pier Francesco Palamara
bioRxiv 2020.04.20.029819; doi: https://doi.org/10.1101/2020.04.20.029819

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