Genetic characterization of Greek population isolates reveals strong genetic drift at missense and trait-associated variants

Panoutsopoulou, Kalliope; Hatzikotoulas, Konstantinos; Xifara, Dionysia K.; Colonna, Vincenza; Farmaki, Aliki‐Eleni; Ritchie, Graham R. S.; Southam, Lorraine; Gilly, Arthur; Tachmazidou, Ioanna; Fatumo, Segun; Matchan, Angela; Rayner, Nigel W.; Ντάλλα, Ιωάννα; Mezzavilla, Massimo; Chen, Yuan; Kiagiadaki, Chrysoula; Zengini, Eleni; Mamakou, Vasiliki; Athanasiadis, Antonis; Γιαννακοπούλου, Μαργαρίτα; Kariakli, Vassiliki-Eirini; Nsubuga, Rebecca N.; Karabarinde, Alex; Sandhu, Manjinder S.; McVean, Gil; Tyler‐Smith, Chris; Tsafantakis, Emmanouil; Karaleftheri, Maria; Xue, Yali; Dedoussis, George; Zeggini, Eleftheria

doi:10.1038/ncomms6345

Cited by 63 publications

(65 citation statements)

References 60 publications

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“…Figure 2 shows the median amount of coverage obtainable by IBS tiling as a function of comparison sample size, imposing various restrictions on the minimum segment length in cM. (For similar results, see Figure 2b of Carmi et al (2014) and Figure 2 of Panoutsopoulou et al (2014).) Approximately 2.8 Giga base-pairs (Gbp) were covered by IBS segments anywhere in the genome among any pair of chromosomes from distinct people; we take this to be approximately the maximum possible genomic length recoverable by IBS with our SNP set.…”

Section: Resultsmentioning

confidence: 79%

Attacks on genetic privacy via uploads to genealogical databases

Edge

Coop

2019

Preprint

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7Direct-to-consumer (DTC) genetics services are increasingly popular for genetic genealogy, with 8 tens of millions of customers as of 2019. Several DTC genealogy services allow users to upload 9 their own genetic datasets in order to search for genetic relatives. A user and a target person in 10 the database are identified as genetic relatives if the user's uploaded genome shares one or more 11 sufficiently long segments in common with that of the target person-that is, if the two genomes 12 share one or more long regions identical by state (IBS). IBS matches reveal some information 13 about the genotypes of the target person, particularly if the chromosomal locations of IBS matches 14 are shared with the uploader. Here, we describe several methods by which an adversary who 15 wants to learn the genotypes of people in the database can do so by uploading multiple datasets. 16Depending on the methods used for IBS matching and the information about IBS segments 17 returned to the user, substantial information about users' genotypes can be revealed with a few 18 hundred uploaded datasets. For example, using a method we call IBS tiling, we estimate that an 19 adversary who uploads approximately 900 publicly available genomes could recover at least one 20 allele at SNP sites across up to 82% of the genome of a median person of European ancestries. 21In databases that detect IBS segments using unphased genotypes, approximately 100 uploads of 22 falsified datasets can reveal enough genetic information to allow accurate genome-wide imputation 23 of every person in the database. We provide simple-to-implement suggestions that will prevent the 24 exploits we describe and discuss our results in light of recent trends in genetic privacy, including 25 the recent use of uploads to DTC genetic genealogy services by law enforcement. 26(Regalado, 2019). One of the major applications of DTC genetics has been genetic genealogy. 31Customers of companies such as 23andMe and Ancestry, once they are genotyped, can view a list 32 of other customers who are likely to be genetic relatives. These putative relatives' full names are 33 often given, and sometimes contact details are given as well. Such genealogical matching services 34 are of interest to people who want to find distant genetic relatives to extend their family tree, and 35 can be particularly useful to people who otherwise may not have information about their genetic 36 relatives, such as adoptees or the biological children of sperm donors. Several genetic genealogy 37 services-including GEDmatch, MyHeritage, FamilyTreeDNA, and LivingDNA (Table 1)-allow 38 users to upload their own genetic data if they have been genotyped by another company. These 39 entities generally offer some subset of their services at no charge to uploaders, which helps to 40 grow their databases. Upload services have also been used by law enforcement, with the goal of 41 identifying relatives of the source of a crime-scene sample (Erlich et al., 2018; Edge and Coop, 42 2019), prompting discussion abo...

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Section: Resultsmentioning

confidence: 79%

Attacks on genetic privacy via uploads to genealogical databases

Edge

Coop

2019

Preprint

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“…35 This type of inference has provided regional insights into how African American migration routes, which differ markedly from those of European Americans, have changed since the dawn of slavery in the US. 36,37 High levels of haplotype sharing have been observed in a number of other founder populations, including the Druze; 38 Ashkenazi and other Jews; [39][40][41] Indians; 42 French Canadians; 43 Hispanic/Latino and Native Americans; [44][45][46] European isolates; [47][48][49][50][51] and other European populations. 30,[52][53][54] However, few studies have investigated recent demographic history in depth with pairwise haplotype sharing in Finns, who are among the best-studied population isolates.…”

Section: Introductionmentioning

confidence: 99%

Haplotype Sharing Provides Insights into Fine-Scale Population History and Disease in Finland

Martin

Karczewski

Kerminen

et al. 2018

The American Journal of Human Genetics

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Finland provides unique opportunities to investigate population and medical genomics because of its adoption of unified national electronic health records, detailed historical and birth records, and serial population bottlenecks. We assembled a comprehensive view of recent population history (≤100 generations), the timespan during which most rare-disease-causing alleles arose, by comparing pairwise haplotype sharing from 43,254 Finns to that of 16,060 Swedes, Estonians, Russians, and Hungarians from geographically and linguistically adjacent countries with different population histories. We find much more extensive sharing in Finns, with at least one ≥ 5 cM tract on average between pairs of unrelated individuals. By coupling haplotype sharing with fine-scale birth records from more than 25,000 individuals, we find that although haplotype sharing broadly decays with geographical distance, there are pockets of excess haplotype sharing; individuals from northeast Finland typically share several-fold more of their genome in identity-by-descent segments than individuals from southwest regions. We estimate recent effective population-size changes through time across regions of Finland, and we find that there was more continuous gene flow as Finns migrated from southwest to northeast between the early- and late-settlement regions than was dichotomously described previously. Lastly, we show that haplotype sharing is locally enriched by an order of magnitude among pairs of individuals sharing rare alleles and especially among pairs sharing rare disease-causing variants. Our work provides a general framework for using haplotype sharing to reconstruct an integrative view of recent population history and gain insight into the evolutionary origins of rare variants contributing to disease.

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“…The Mylopotamos villages, which include Anogia, Zoniana, Livadia and Gonies (estimated population size of 6000 in total), have remained geographically isolated for an estimated 1000 years. The genetic isolatedness and demographic history of this population has been established previously (20). …”

Section: Methodsmentioning

confidence: 93%

Very low-depth sequencing in a founder population identifies a cardioprotectiveAPOC3signal missed by genome-wide imputation

et al. 2016

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Cohort-wide very low-depth whole-genome sequencing (WGS) can comprehensively capture low-frequency sequence variation for the cost of a dense genome-wide genotyping array. Here, we analyse 1x sequence data across the APOC3 gene in a founder population from the island of Crete in Greece (n = 1239) and find significant evidence for association with blood triglyceride levels with the previously reported R19X cardioprotective null mutation (β = −1.09,σ = 0.163, P = 8.2 × 10−11) and a second loss of function mutation, rs138326449 (β = −1.17,σ = 0.188, P = 1.14 × 10−9). The signal cannot be recapitulated by imputing genome-wide genotype data on a large reference panel of 5122 individuals including 249 with 4x WGS data from the same population. Gene-level meta-analysis with other studies reporting burden signals at APOC3 provides robust evidence for a replicable cardioprotective rare variant aggregation (P = 3.2 × 10−31, n = 13 480).

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Genetic characterization of Greek population isolates reveals strong genetic drift at missense and trait-associated variants

Cited by 63 publications

References 60 publications

Attacks on genetic privacy via uploads to genealogical databases

Attacks on genetic privacy via uploads to genealogical databases

Haplotype Sharing Provides Insights into Fine-Scale Population History and Disease in Finland

Very low-depth sequencing in a founder population identifies a cardioprotectiveAPOC3signal missed by genome-wide imputation

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