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Inferring Population Structure and Admixture Proportions in Low-Depth NGS Data

We here present two methods for inferring population structure and admixture proportions in low-depth next-generation sequencing (NGS) data. Inference of population structure is essential in both population genetics and association studies, and is often performed using principal component analysis (PCA) or clustering-based approaches. NGS methods provide large amounts of genetic data but are associated with statistical uncertainty, especially for low-depth sequencing data. Models can account for this uncertainty by working directly on genotype likelihoods of the unobserved genotypes. We propose a method for inferring population structure through PCA in an iterative heuristic approach of estimating individual allele frequencies, where we demonstrate improved accuracy in samples with low and variable sequencing depth for both simulated and real datasets. We also use the estimated individual allele frequencies in a fast non-negative matrix factorization method to estimate admixture proportions. Both methods have been implemented in the PCAngsd framework.

Jonas Meisner and Anders Albrechtsen, Genetics, Volume 210 Issue 2, October 2018

Genomic Analyses from Non-invasive Prenatal Testing Reveal Genetic Associations, Patterns of Viral Infections, and Chinese Population History

Study over genome from >140,000 pregnant women

We analyze whole-genome sequencing data from 141,431 Chinese women generated for non-invasive prenatal testing (NIPT). We use these data to characterize the population genetic structure and to investigate genetic associations with maternal and infectious traits. We show that the present day distribution of alleles is a function of both ancient migration and very recent population movements. We reveal novel phenotype-genotype associations, including several replicated associations with height and BMI, an association between maternal age and EMB, and between twin pregnancy and NRG1. Finally, we identify a unique pattern of circulating viral DNA in plasma with high prevalence of hepatitis B and other clinically relevant maternal infections. A GWAS for viral infections identifies an exceptionally strong association between integrated herpesvirus 6 and MOV10L1, which affects piwi-interacting RNA (piRNA) processing and PIWI protein function. These findings demonstrate the great value and potential of accumulating NIPT data for worldwide medical and genetic analyses.

Siyang Liu et al. Cell, Volume 175, ISSUE 2, P347-359.e14, October 04, 2018

New York Times article

A southern African origin and cryptic structure in the highly mobile plains zebra

Sampling locations for plains zebra

The plains zebra (Equus quagga) is an ecologically important species of the African savannah. It is also one of the most numerous and widely distributed ungulates, and six subspecies have been described based on morphological variation. However, the within-species evolutionary processes have been difficult to resolve due to its high mobility and a lack of consensus regarding the population structure. We obtained genome-wide DNA polymorphism data from more than 167,000 loci for 59 plains zebras from across the species range, encompassing all recognized extant subspecies, as well as three mountain zebras (Equus zebra) and three Grevy’s zebras (Equus grevyi). Surprisingly, the population genetic structure does not mirror the morphology-based subspecies delineation, underlining the dangers of basing management units exclusively on morphological variation. We use demographic modelling to provide insights into the past phylogeography of the species. The results identify a southern African location as the most likely source region from which all extant populations expanded around 370,000 years ago. We show evidence for inclusion of the extinct and phenotypically divergent quagga (Equus quaggaquagga) in the plains zebra variation and reveal that it was less divergent from the other subspecies than the northernmost (Ugandan) extant population.

inter population connection patterns

Casper-Emil T. Pedersen, Anders Albrechtsen, Paul D. Etter, Eric A. Johnson, Ludovic Orlando, Lounes Chikhi, Hans R. Siegismund & Rasmus Heller. A southern African origin and cryptic structure in the highly mobile plains zebra. Nature Ecology & Evolution volume 2, pages 491–498 (2018)

Loss-of-function variants in ADCY3 increase risk of obesity in Greenland


Greenland is like many other countries struggling with overweight and obesity. Both environment and genetics play a role in development of obesity. However, it is not fully known which specific genes that are causing obesity. Researchers from the University of Copenhagen, among others, now appear to have found one of these genes. We found a genetic variation that when carried in two copies causes severe obesity and type 2 diabetes. The gene, ACDY3, losses parts of its function due to the genetic variation which is found in homozygous form in 2% of the Greenland.

Niels Grarup, Ida Moltke, Mette K Andersen, Maria Dalby, Kristoffer Vitting-Seerup, Timo Kern, Yuvaraj Mahendran, Emil Jørsboe, Christina V L Larsen, Inger K Dahl-Petersen, Arthur Gilly, Daniel Suveges, George Dedoussis, Eleftheria Zeggini, Oluf Pedersen, Robin Andersson, Peter Bjerregaard, Marit E Jørgensen, Anders Albrechtsen, Torben Hansen, Loss-of-function variants in ADCY3 increase risk of obesity and type 2 diabetes. Nature Genetics, volume 50, pages172–174 (2018)


Effect of prolonged bottleneck on genetic load

Demographic history for the Greenlandic Inuit

All non-African human populations have experienced bottlenecks following the expansion of modern humans out of Africa some 60,000 years ago. Recently, several studies of human populations have investigated whether smaller population sizes for out-of-Africa populations lead to less efficient purifying selection and thereby higher genetic load. Given that these studies mainly considered large continental human populations we examine these questions using exome data from 18 Greenlandic Inuit. The Greenlandic Inuit population is particularly interesting to study in this context because it has experienced a ~20,000 year long bottleneck during the last ~25,000 years, making it more extreme than most previously studied populations, such as native Americans, in terms of population size. When comparing it to a European population, we do not observe a difference in the overall number of deleterious alleles per individual, implying a similar genetic load assuming an additive model. However, we observe a marked difference in the distribution of this load; the Greenlandic Inuit population has fewer variable sites, and thus on average each variable site has a higher load. Also, each variable site has a higher average derived allele frequency. Consequently, the Greenlandic Inuit carry more homozygous derived genotypes and a higher genetic load assuming a recessive model. Despite the long recent bottleneck, we find that selection has still been acting however, it has acted less efficiently.

SFS for various human populations including Greenlandic Inuit

Our analyses show that the Greenlandic Inuit population has great potential for mapping of disease-causing variants that are rare, and thus difficult to map, in Europeans and other large populations – for both Mendelian and complex diseases. To a certain degree, this characteristic has also been documented for other small populations, yet comparative results for several small populations establish the Greenlandic Inuit as the population with the highest potential for finding novel disease-causing variants.

Pedersen CT, Lohmueller KE, Grarup N, Bjerregaard P, Hansen T, Siegismund HR, Moltke I, Albrechtsen A. The Effect of an Extreme and Prolonged Population Bottleneck on Patterns of Deleterious Variation: Insights from the Greenlandic Inuit. Genetics, 2017

Load comparison between Inuit and Europeans


review on association in isolated populations

Andersen MK, Pedersen CE, Moltke I, Hansen T, Albrechtsen A, Grarup N. Genetics of Type 2 Diabetes: the Power of Isolated Populations. Current diabetes reports, 2016, vol. 16, no. 7, pp. 65

Fatty acid GWAS

Andersen MK, Jørsboe E, Sandholt CH, Grarup N, Jørgensen ME, Færgeman NJ, Bjerregaard P, Pedersen O, Moltke I, Hansen T, Albrechtsen A. Identification of Novel Genetic Determinants of Erythrocyte Membrane Fatty Acid Composition among Greenlanders. PLoS genetics, 2016, vol. 12, no. 6, pp. e1006119

Reveiw on NGS analysis for non-model organisms

da Fonseca RR, Albrechtsen A, Themudo GE, Ramos-Madrigal J, Sibbesen JA, Maretty L, Zepeda-Mendoza ML, Campos PF, Heller R, Pereira RJ. Next-generation biology: Sequencing and data analysis approaches for non-model organisms. Marine genomics, 2016

Method for estimating and using Enrichment of functional categories in association studies

75. Sveinbjornsson G, Albrechtsen A, Zink F, Gudjonsson SA, Oddson A, Másson G, Holm H, Kong A, Thorsteinsdottir U, Sulem P, Gudbjartsson DF, Stefansson K. Weighting sequence variants based on their annotation increases power of whole-genome association studies. Nature genetics, 2016


Selection of Fatty acid genes in the ancestors of Greenlandic inuit

Fumagalli M, Moltke I, Grarup N, Racimo F, Bjerregaard P, Jørgensen ME, Korneliussen TS, Gerbault P, Skotte L, Linneberg A, Christensen C, Brandslund I, Jørgensen T, Huerta-Sánchez E, Schmidt EB, Pedersen O, Hansen T, Albrechtsen A, Nielsen R. Greenlandic Inuit show genetic signatures of diet and climate adaptation. Science, 2015, vol. 349, no. 6254, pp. 1343-1347

Recent genetic history of Native Americans

Raghavan M, Steinrücken M, Harris K, Schiffels S, Rasmussen S, DeGiorgio M, Albrechtsen A, Valdiosera C, Ávila-Arcos MC, Malaspinas AS, Eriksson A, Moltke I, Metspalu M, Homburger JR, Wall J, Cornejo OE, Moreno-Mayar JV, Korneliussen TS, Pierre T, Rasmussen M, Campos PF, Damgaard PB, Allentoft ME, Lindo J, Metspalu E, Rodríguez-Varela R, Mansilla J, Henrickson C, Seguin-Orlando A, Malmström H, Stafford T Jr, Shringarpure SS, Moreno-Estrada A, Karmin M, Tambets K, Bergström A, Xue Y, Warmuth V, Friend AD, Singarayer J, Valdes P, Balloux F, Leboreiro I, Vera JL, Rangel-Villalobos H, Pettener D, Luiselli D, Davis LG, Heyer E, Zollikofer CP, Ponce de León MS, Smith CI, Grimes V, Pike KA, Deal M, Fuller BT, Arriaza B, Standen V, Luz MF, Ricaut F, Guidon N, Osipova L, Voevoda MI, Posukh OL, Balanovsky O, Lavryashina M, Bogunov Y, Khusnutdinova E, Gubina M, Balanovska E, Fedorova S, Litvinov S, Malyarchuk B, Derenko M, Mosher MJ, Archer D, Cybulski J, Petzelt B, Mitchell J, Worl R, Norman PJ, Parham P, Kemp BM, Kivisild T, Tyler-Smith C, Sandhu MS, Crawford M, Villems R, Smith DG, Waters MR, Goebel T, Johnson JR, Malhi RS, Jakobsson M, Meltzer DJ, Manica A, Durbin R, Bustamante CD, Song YS, Nielsen R, Willerslev E. Genomic evidence for the Pleistocene and recent population history of Native Americans. Science, 2015

The ancestry of the famous Kennewick man

Rasmussen M, Sikora M, Albrechtsen A, Korneliussen TS, Moreno-Mayar JV, Poznik GD, Zollikofer CP, Ponce de León MS, Allentoft ME, Moltke I, Jónsson H, Valdiosera C, Malhi RS, Orlando L, Bustamante CD, Stafford TW Jr, Meltzer DJ, Nielsen R, Willerslev E. The ancestry and affiliations of Kennewick Man. Nature, 2015

Review on the genetics of diabetes with a focus on Greenland

68. Grarup N, Moltke I, Albrechtsen A, Hansen T. Diabetes in Population Isolates: Lessons from Greenland. The review of diabetic studies RDS, 2015, vol. 12, no. 3-4, pp. 320-329

Origin and history of domesticated Maize

da Fonseca RR, Smith BD, Wales N, Cappellini E, Skoglund P, Fumagalli M, Samaniego JA, Carøe C, Ávila-Arcos MC, Hufnagel DE, Korneliussen TS, Vieira FG, Jakobsson M, Arriaza B, Willerslev E, Nielsen R, Hufford MB, Albrechtsen A, Ross-Ibarra J, Gilbert MT. The origin and evolution of maize in the Southwestern United States. Nature plants, 2015, vol. 1, pp. 14003, 2015

Uncovering the Genetic History of the Present-Day Greenlandic Population

Uncovering the Genetic History of the Present-Day Greenlandic Population


New research sheds light on the genetic history of the Greenlandic population. Research from Copenhagen University, Steno Diabetes Center and National Institute of Public Health, University of Southern Denmark just published in American Journal of Human Genetics reconstructs the genetic ancestry of present day Greenlanders and provides a genetic map of recent and ancient migrations into the Island.
Within the last 5000 years the world’s largest Island has been colonized many times both by different arctic populations and by European settlers such as the Vikings. Additionally, the Greenlandic population size has increased almost tenfold within the last two hundred years mainly by natural growth but also by migration from Denmark. In this study the researchers study the genetic impact of these migrations and determine which populations have contributed to the genetic composition of modern Greenlanders.

Impact from recent European migration

Based on more than 10% of the adult population and two hundred thousand genetic markers the study finds that 75% of the genetic ancestry is of Inuit origin while the remaining 25% is European. However the amount of European ancestry varies greatly between the different regions in Greenland.
In most locations in Greenland almost everybody has some European ancestry. However, some regions stand out. For example in Tasiilaq and villages in the East most individuals do not have any European ancestry while in cities in West Greenland such as Aasiaat, Maniitsoq and Nuuk all but a few percent have some European ancestry explains post doc Ida Moltke who is the first author of the study. It is not just the amount of European ancestry that varies between regions in Greenland. There are also genetic differences between the individuals from the different regions. Using statistical methods the researchers were able distinguish individuals from North, West and East Greenland.
Due to the historically small size of the population, the settlements in the different regions of the Island diverged a fair amount in a short time. The impact is so pronounced that based on only genetic information it is possible to determine if a person is from Qaanaaq in the North, Tasiilaq in the East or from somewhere in the West. Surprisingly people from Qaanaaq are more genetically distant to people in Tasiilaq than Danish individuals are to people from the southern part of Italy says Associate professor Anders Albrechtsen from the Bioinformatics Centre at the University of Copenhagen.

Ancient migration routes and meeting of cultures

The most recent arctic colonization of Greenland happened around 700 years ago by the Thule culture which is the Inuit ancestors of the current population. However, at the time they were not the only people on the Island. There were still people of the Dorset culture from a previous arctic colonization as well as the Norse – the Viking settlers.

We know from archeological evidence that the cultures met and traded with each other which raises the question of whether the Greenlandic Dorset people or the Vikings settlers interbred with the Thule population. However, we found no evidence that either the Dorset or the Vikings contributed to the gene pool of present day Greenlanders explains Rasmus Nielsen, University of California Berkeley who together with Anders Albrechtsen is a corresponding author of the work.

In addition to investigating previous encounters of cultures the researches were also able to determine the route that was used by the Thule population when colonizing the Island. Many previous studies have suggested that the Thule population reached Tasiilaq in the East using the northern route around the Island. However, the genetic data was not consistent with such a route. Instead the ancestors of the present day individuals living in East Greenland came from the south Based solely on the genetic data we can see each village splitting off one by one starting in the North, then down the west coast all the way to the south tip of the Island and then up again on the East coast. Therefore, the individuals who migrated north on the Island do not appear to have left any genetic trace in the current Tasiilaq population says Anders Albrechtsen.

Small population and genetic risk factors

In addition to describing the genetic history of the Greenlandic population the study also provides a foundation for investigating genetic risk factors for disease. The historically small population size of Greenlanders has had a large impact on the genetic landscape. There are fewer genetic variations in the population compared to large populations such as Chinese or European. However, the variations that exist are more common than in other populations.
The consequence for genetic disease susceptibility is that a lower number of genetic markers will have an impact on disease but the markers that exist will have a higher impact. With the information we have gained from this study we can better understand the genetic risk factors that affect the Greenlandic population. We will use this information in future studies to identify new disease markers with the goal of providing better diagnoses and ultimately treatment of diseases says Ida Moltke


ANGSD: Analysis of Next Generation Sequencing Data

Finally the paper describing the [[1][ANGSD software]] is out. Do you have low or medium depth NGS data. Then this software is for you. No genotype calling only base analysis on genotype likelihoods or read sampling.


ANGSD: Analysis of Next Generation Sequencing Data, Thorfinn Sand Korneliussen, Anders Albrechtsen and Rasmus Nielsen

DivA: Detection of non-homologous and very divergent regions in protein sequence alignments. BMC Research Notes, in press

Rute Fonseca presents her software for detecting and masking problematic regions in protein sequence alignments.

Download DivA

The genetic prehistory of the New World Arctic

We participated in a large project that unraveled the genetic history of the new world arctic populations and showed how all of the paleo-eskimo populations have been completely replaced by the current Inuit cultures.

Raghavan et al. The genetic prehistory of the New World Arctic. Science


A recessive mutation explains more than 10% of all cases of type 2 diabetes in Greenland

In a recent publication we identified a genetic variation that has an extremely large impact on the Greenlandic population. The variation affects a muscle specific isoform of the Gene TBC1D4 which reduces the GLUT4a ctivity which affects postprandial glucose levels.

Moltke et al . A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes. In press. DOI: 10.1038/nature13425


The genome of a Late Pleistocene human from a Clovis burial site in western Montana

Ida Moltke, Thorfinn Korneliusen and Anders Albrechtsen helped analysing the Ancient DNA samples in a study led by Morten Rasmussen and Eske Willeslev. This study shows that the 13000 year old individual was part of the population that where ancestors of most contemporary Native Americans.

Rasmussen M et al. The genome of a Late Pleistocene human from a Clovis burial site in western Montana. Nature, 2014, vol. 506, no. 7487, pp. 225-229

Upper Palaeolithic Siberian genome reveals dual ancestry of Native Americans

Ida Moltke and Anders Albrechtsen helped analyse the data in a large study led Maanasa Raghaven and Eske Willerslev. Here we showed that there was additional geneflow from the Mal'ta population into the Native Americans. This explains the link between Europeans and Native Americans.

Raghavan M, et al. Upper Palaeolithic Siberian genome reveals dual ancestry of Native Americans. Nature, 2014, vol. 505, no. 7481, pp. 87-91


Admixture analysis from low and medium depth sequencing data is now possible.

Line Skotte, Thorfinn Korneliussen and Anders Albrechtsen shows that it is possible in accurately infer admixture proportions even with low depth sequencing data.

Skotte* L, Korneliussen* TS, Albrechtsen A. Estimating individual admixture proportions from next generation sequencing data. Genetics, 2013, vol. 195, no. 3, pp. 693-702


Relatedness estimation is now possible for admixed individuals

Ida Molke and Anders Albrechtsen gives a maximum likelihood solution for estimating pairwise relatedness coefficient for admixed individuals.

[ Moltke I, Albrechtsen A. RelateAdmix: a software tool for estimating relatedness between admixed individuals. Bioinformatics, 2013]


Large scale exome sequencing and genotyping reviels novel loci associated with diabetes and lipid levels

Anders Albrechtsen, Thorfinn Korneliussen and Line Skotte performed the first large scale sequencing based association studies.

Albrechtsen A et a.. Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes. Diabetologia, 2013, vol. 56, no. 2, pp. 298-310



Association for NGS data

Our method that takes genotype uncertainty into accounts

Skotte L, Korneliussen TS, Albrechtsen A. Association testing for next-generation sequencing data using score statistics. Genetic epidemiology, 2012, vol. 36, no. 5, pp. 430-437


Review of NGS data

Our review of NGS data is out

Nielsen R, Paul JS, Albrechtsen A, Song YS, Nature reviews. Genetics, 2011, vol. 12, no. 6, pp. 443-451 Genotype and SNP calling from next-generation sequencing data.