Population Structure, Stratification, and Introgression of Human Structural Variation

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2020 Jun 13

PMID 32531199

Citations 41

Authors

Mohamed A Almarri

Anders Bergstrom

Javier Prado-Martinez

Fengtang Yang

Beiyuan Fu

Alistair S Dunham

Yuan Chen

Matthew E Hurles

Chris Tyler-Smith

Yali Xue

Affiliations

Soon will be listed here.

Abstract

Structural variants contribute substantially to genetic diversity and are important evolutionarily and medically, but they are still understudied. Here we present a comprehensive analysis of structural variation in the Human Genome Diversity panel, a high-coverage dataset of 911 samples from 54 diverse worldwide populations. We identify, in total, 126,018 variants, 78% of which were not identified in previous global sequencing projects. Some reach high frequency and are private to continental groups or even individual populations, including regionally restricted runaway duplications and putatively introgressed variants from archaic hominins. By de novo assembly of 25 genomes using linked-read sequencing, we discover 1,643 breakpoint-resolved unique insertions, in aggregate accounting for 1.9 Mb of sequence absent from the GRCh38 reference. Our results illustrate the limitation of a single human reference and the need for high-quality genomes from diverse populations to fully discover and understand human genetic variation.

Citing Articles

Long-read sequencing of 945 Han individuals identifies structural variants associated with phenotypic diversity and disease susceptibility.

Gong J, Sun H, Wang K, Zhao Y, Huang Y, Chen Q Nat Commun. 2025; 16(1):1494.

PMID: 39929826 PMC: 11811171. DOI: 10.1038/s41467-025-56661-9.

Diversity and consequences of structural variation in the human genome.

Collins R, Talkowski M Nat Rev Genet. 2025; .

PMID: 39838028 DOI: 10.1038/s41576-024-00808-9.

Somatic Recombination Between an Ancient and a Recent Gene Variant Is Associated with the NOTCH2 Gain-of-Function Phenotype in Chronic Lymphocytic Leukemia.

Hubmann R, Hilgarth M, Lowenstern T, Lienhard A, Sima F, Reisinger M Int J Mol Sci. 2024; 25(23).

PMID: 39684291 PMC: 11641350. DOI: 10.3390/ijms252312581.

A Catalogue of Structural Variation across Ancestrally Diverse Asian Genomes.

Juan Tan J, Li Z, Porta M, Rajaby R, Lim W, Tan Y Nat Commun. 2024; 15(1):9507.

PMID: 39496583 PMC: 11535549. DOI: 10.1038/s41467-024-53620-8.

Comprehensive evaluation and guidance of structural variation detection tools in chicken whole genome sequence data.

Ma C, Shi X, Li X, Zhang Y, Peng M BMC Genomics. 2024; 25(1):970.

PMID: 39415108 PMC: 11481438. DOI: 10.1186/s12864-024-10875-1.

References

Handsaker R, Van Doren V, Berman J, Genovese G, Kashin S, Boettger L . Large multiallelic copy number variations in humans. Nat Genet. 2015; 47(3):296-303. PMC: 4405206. DOI: 10.1038/ng.3200. View

Marks P, Garcia S, Martinez Barrio A, Belhocine K, Bernate J, Bharadwaj R . Resolving the full spectrum of human genome variation using Linked-Reads. Genome Res. 2019; 29(4):635-645. PMC: 6442396. DOI: 10.1101/gr.234443.118. View

McLaren W, Gil L, Hunt S, Riat H, Ritchie G, Thormann A . The Ensembl Variant Effect Predictor. Genome Biol. 2016; 17(1):122. PMC: 4893825. DOI: 10.1186/s13059-016-0974-4. View

Akay A, Di Domenico T, Suen K, Nabih A, Parada G, Larance M . The Helicase Aquarius/EMB-4 Is Required to Overcome Intronic Barriers to Allow Nuclear RNAi Pathways to Heritably Silence Transcription. Dev Cell. 2017; 42(3):241-255.e6. PMC: 5554785. DOI: 10.1016/j.devcel.2017.07.002. View

Bergstrom A, McCarthy S, Hui R, Almarri M, Ayub Q, Danecek P . Insights into human genetic variation and population history from 929 diverse genomes. Science. 2020; 367(6484). PMC: 7115999. DOI: 10.1126/science.aay5012. View

Yamanaka M, Kato Y, Angata T, Narimatsu H . Deletion polymorphism of SIGLEC14 and its functional implications. Glycobiology. 2009; 19(8):841-6. DOI: 10.1093/glycob/cwp052. View

Schneider V, Graves-Lindsay T, Howe K, Bouk N, Chen H, Kitts P . Evaluation of GRCh38 and de novo haploid genome assemblies demonstrates the enduring quality of the reference assembly. Genome Res. 2017; 27(5):849-864. PMC: 5411779. DOI: 10.1101/gr.213611.116. View

Ceballos F, Joshi P, Clark D, Ramsay M, Wilson J . Runs of homozygosity: windows into population history and trait architecture. Nat Rev Genet. 2018; 19(4):220-234. DOI: 10.1038/nrg.2017.109. View

Prufer K, de Filippo C, Grote S, Mafessoni F, Korlevic P, Hajdinjak M . A high-coverage Neandertal genome from Vindija Cave in Croatia. Science. 2017; 358(6363):655-658. PMC: 6185897. DOI: 10.1126/science.aao1887. View

10.

Kosugi S, Momozawa Y, Liu X, Terao C, Kubo M, Kamatani Y . Comprehensive evaluation of structural variation detection algorithms for whole genome sequencing. Genome Biol. 2019; 20(1):117. PMC: 6547561. DOI: 10.1186/s13059-019-1720-5. View

11.

Redon R, Ishikawa S, Fitch K, Feuk L, Perry G, Andrews T . Global variation in copy number in the human genome. Nature. 2006; 444(7118):444-54. PMC: 2669898. DOI: 10.1038/nature05329. View

12.

Hebbring S, Moyer A, Weinshilboum R . Sulfotransferase gene copy number variation: pharmacogenetics and function. Cytogenet Genome Res. 2009; 123(1-4):205-10. PMC: 2920188. DOI: 10.1159/000184710. View

13.

Huerta-Sanchez E, Jin X, Asan , Bianba Z, Peter B, Vinckenbosch N . Altitude adaptation in Tibetans caused by introgression of Denisovan-like DNA. Nature. 2014; 512(7513):194-7. PMC: 4134395. DOI: 10.1038/nature13408. View

14.

Li H, Durbin R . Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009; 25(14):1754-60. PMC: 2705234. DOI: 10.1093/bioinformatics/btp324. View

15.

Browning S, Browning B, Zhou Y, Tucci S, Akey J . Analysis of Human Sequence Data Reveals Two Pulses of Archaic Denisovan Admixture. Cell. 2018; 173(1):53-61.e9. PMC: 5866234. DOI: 10.1016/j.cell.2018.02.031. View

16.

Hsieh P, Vollger M, Dang V, Porubsky D, Baker C, Cantsilieris S . Adaptive archaic introgression of copy number variants and the discovery of previously unknown human genes. Science. 2019; 366(6463). PMC: 6860971. DOI: 10.1126/science.aax2083. View

17.

Smith A, Esko J, Hajduk S . Killing of trypanosomes by the human haptoglobin-related protein. Science. 1995; 268(5208):284-6. DOI: 10.1126/science.7716520. View

18.

Gordon D, Huddleston J, Chaisson M, Hill C, Kronenberg Z, Munson K . Long-read sequence assembly of the gorilla genome. Science. 2016; 352(6281):aae0344. PMC: 4920363. DOI: 10.1126/science.aae0344. View

19.

Weisenfeld N, Kumar V, Shah P, Church D, Jaffe D . Direct determination of diploid genome sequences. Genome Res. 2017; 27(5):757-767. PMC: 5411770. DOI: 10.1101/gr.214874.116. View

20.

Sudmant P, Rausch T, Gardner E, Handsaker R, Abyzov A, Huddleston J . An integrated map of structural variation in 2,504 human genomes. Nature. 2015; 526(7571):75-81. PMC: 4617611. DOI: 10.1038/nature15394. View