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1. Complexity of avian evolution revealed by family-level genomes

Author

Stiller, Josefin, Feng, Shaohong, Chowdhury, Al-Aabid, Rivas-González, Iker, Duchêne, David A., Fang, Qi, Deng, Yuan, Kozlov, Alexey, Stamatakis, Alexandros, Claramunt, Santiago, Nguyen, Jacqueline M. T., Ho, Simon Y. W., Faircloth, Brant C., Haag, Julia, Houde, Peter, Cracraft, Joel, Balaban, Metin, Mai, Uyen, Chen, Guangji, Gao, Rongsheng, Zhou, Chengran, Xie, Yulong, Huang, Zijian, Cao, Zhen, Yan, Zhi, Ogilvie, Huw A., Nakhleh, Luay, Lindow, Bent, Morel, Benoit, Fjeldså, Jon, Hosner, Peter A., da Fonseca, Rute R., Petersen, Bent, Tobias, Joseph A., Székely, Tamás, Kennedy, Jonathan David, Reeve, Andrew Hart, Liker, Andras, Stervander, Martin, Antunes, Agostinho, Tietze, Dieter Thomas, Bertelsen, Mads F., Lei, Fumin, Rahbek, Carsten, Graves, Gary R., Schierup, Mikkel H., Warnow, Tandy, Braun, Edward L., Gilbert, M. Thomas P., Jarvis, Erich D., Mirarab, Siavash, and Zhang, Guojie

Published
2024
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5. Orthologous genes identified by transcriptome sequencing in the spider genus Stegodyphus

Author

Mattila Tiina M, Bechsgaard Jesper S, Hansen Troels T, Schierup Mikkel H, and Bilde Trine

Subjects
Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background The evolution of sociality in spiders involves a transition from an outcrossing to a highly inbreeding mating system, a shift to a female biased sex ratio, and an increase in the reproductive skew among individuals. Taken together, these features are expected to result in a strong reduction in the effective population size. Such a decline in effective population size is expected to affect population genetic and molecular evolutionary processes, resulting in reduced genetic diversity and relaxed selective constraint across the genome. In the genus Stegodyphus, permanent sociality and regular inbreeding has evolved independently three times from periodic-social (outcrossing) ancestors. This genus is therefore an ideal model for comparative studies of the molecular evolutionary and population genetic consequences of the transition to a regularly inbreeding mating system. However, no genetic resources are available for this genus. Results We present the analysis of high throughput transcriptome sequencing of three Stegodyphus species. Two of these are periodic-social (Stegodyphus lineatus and S.tentoriicola) and one is permanently social (S. mimosarum). From non-normalized cDNA libraries, we obtained on average 7,000 putative uni-genes for each species. Three-way orthology, as predicted from reciprocal BLAST, identified 1,792 genes that could be used for cross-species comparison. Open reading frames (ORFs) could be deduced from 1,345 of the three-way alignments. Preliminary molecular analyses suggest a five- to ten-fold reduction in heterozygosity in the social S. mimosarum compared with the periodic-social species. Furthermore, an increased ratio of non-synonymous to synonymous polymorphisms in the social species indicated relaxed efficiency of selection. However, there was no sign of relaxed selection on the phylogenetic branch leading to S. mimosarum. Conclusions The 1,792 three-way ortholog genes identified in this study provide a unique resource for comparative studies of the eco-genomics, population genetics and molecular evolution of repeated evolution of inbreeding sociality within the Stegodyphus genus. Preliminary analyses support theoretical expectations of depleted heterozygosity and relaxed selection in the social inbreeding species. Relaxed selection could not be detected in the S. mimosarum lineage, suggesting that there has been a recent transition to sociality in this species.

Published
2012
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6. Haplotype frequencies in a sub-region of chromosome 19q13.3, related to risk and prognosis of cancer, differ dramatically between ethnic groups

Author

Wang Jun, Li Heng, Mailund Thomas, Schierup Mikkel H, Tjønneland Anne, Vogel Ulla, Bolund Lars, and Nexø Bjørn A

Subjects
Internal medicine, RC31-1245, Genetics, QH426-470
Abstract

Abstract Background A small region of about 70 kb on human chromosome 19q13.3 encompasses 4 genes of which 3, ERCC1, ERCC2, and PPP1R13L (aka RAI) are related to DNA repair and cell survival, and one, CD3EAP, aka ASE1, may be related to cell proliferation. The whole region seems related to the cellular response to external damaging agents and markers in it are associated with risk of several cancers. Methods We downloaded the genotypes of all markers typed in the 19q13.3 region in the HapMap populations of European, Asian and African descent and inferred haplotypes. We combined the European HapMap individuals with a Danish breast cancer case-control data set and inferred the association between HapMap haplotypes and disease risk. Results We found that the susceptibility haplotype in our European sample had increased from 2 to 50 percent very recently in the European population, and to almost the same extent in the Asian population. The cause of this increase is unknown. The maximal proportion of overall genetic variation due to differences between groups for Europeans versus Africans and Europeans versus Asians (the Fst value) closely matched the putative location of the susceptibility variant as judged from haplotype-based association mapping. Conclusion The combined observation that a common haplotype causing an increased risk of cancer in Europeans and a high differentiation between human populations is highly unusual and suggests a causal relationship with a recent increase in Europeans caused either by genetic drift overruling selection against the susceptibility variant or a positive selection for the same haplotype. The data does not allow us to distinguish between these two scenarios. The analysis suggests that the region is not involved in cancer risk in Africans and that the susceptibility variants may be more finely mapped in Asian populations.

Published
2009
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8. Whole genome association mapping by incompatibilities and local perfect phylogenies

Author

Besenbacher Søren, Mailund Thomas, and Schierup Mikkel H

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Abstract

Abstract Background With current technology, vast amounts of data can be cheaply and efficiently produced in association studies, and to prevent data analysis to become the bottleneck of studies, fast and efficient analysis methods that scale to such data set sizes must be developed. Results We present a fast method for accurate localisation of disease causing variants in high density case-control association mapping experiments with large numbers of cases and controls. The method searches for significant clustering of case chromosomes in the "perfect" phylogenetic tree defined by the largest region around each marker that is compatible with a single phylogenetic tree. This perfect phylogenetic tree is treated as a decision tree for determining disease status, and scored by its accuracy as a decision tree. The rationale for this is that the perfect phylogeny near a disease affecting mutation should provide more information about the affected/unaffected classification than random trees. If regions of compatibility contain few markers, due to e.g. large marker spacing, the algorithm can allow the inclusion of incompatibility markers in order to enlarge the regions prior to estimating their phylogeny. Haplotype data and phased genotype data can be analysed. The power and efficiency of the method is investigated on 1) simulated genotype data under different models of disease determination 2) artificial data sets created from the HapMap ressource, and 3) data sets used for testing of other methods in order to compare with these. Our method has the same accuracy as single marker association (SMA) in the simplest case of a single disease causing mutation and a constant recombination rate. However, when it comes to more complex scenarios of mutation heterogeneity and more complex haplotype structure such as found in the HapMap data our method outperforms SMA as well as other fast, data mining approaches such as HapMiner and Haplotype Pattern Mining (HPM) despite being significantly faster. For unphased genotype data, an initial step of estimating the phase only slightly decreases the power of the method. The method was also found to accurately localise the known susceptibility variants in an empirical data set – the ΔF508 mutation for cystic fibrosis – where the susceptibility variant is already known – and to find significant signals for association between the CYP2D6 gene and poor drug metabolism, although for this dataset the highest association score is about 60 kb from the CYP2D6 gene. Conclusion Our method has been implemented in the Blossoc (BLOck aSSOCiation) software. Using Blossoc, genome wide chip-based surveys of 3 million SNPs in 1000 cases and 1000 controls can be analysed in less than two CPU hours.

Published
2006
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9. Evidence of recombination among early-vaccination era measles virus strains

Author

Muller Claude P, Mordhorst Carl H, Schierup Mikkel H, and Christensen Laurids S

Subjects
Evolution, QH359-425
Abstract

Abstract Background The advent of live-attenuated vaccines against measles virus during the 1960'ies changed the circulation dynamics of the virus. Earlier the virus was indigenous to countries worldwide, but now it is mediated by a limited number of evolutionary lineages causing sporadic outbreaks/epidemics of measles or circulating in geographically restricted endemic areas of Africa, Asia and Europe. We expect that the evolutionary dynamics of measles virus has changed from a situation where a variety of genomic variants co-circulates in an epidemic with relatively high probabilities of co-infection of the individual to a situation where a co-infection with strains from evolutionary different lineages is unlikely. Results We performed an analysis of the partial sequences of the hemagglutinin gene of 18 measles virus strains collected in Denmark between 1965 and 1983 where vaccination was first initiated in 1987. The results were compared with those obtained with strains collected from other parts of the world after the initiation of vaccination in the given place. Intergenomic recombination among pre-/early-vaccination strains is suggested by 1) estimations of linkage disequilibrium between informative sites, 2) the decay of linkage disequilibrium with distance between informative sites and 3) a comparison of the expected number of homoplasies to the number of apparent homoplasies in the most parsimonious tree. No significant evidence of recombination could be demonstrated among strains circulating at present. Conclusion We provide evidence that recombination can occur in measles virus and that it has had a detectable impact on sequence evolution of pre-vaccination samples. We were not able to detect recombination from present-day sequence surveys. We believe that the decreased rate of visible recombination may be explained by changed dynamics, since divergent strains do not meet very often in current epidemics that are often spawned by a single sequence type. Signs of pre-vaccination recombination events in the present-day sequences are not strong enough to be detectable.

Published
2005
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10. CoaSim: A flexible environment for simulating genetic data under coalescent models

Author

Pedersen Christian NS, Schierup Mikkel H, Mailund Thomas, Mechlenborg Peter JM, Madsen Jesper N, and Schauser Leif

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Abstract

Abstract Background Coalescent simulations are playing a large role in interpreting large scale intra-specific sequence or polymorphism surveys and for planning and evaluating association studies. Coalescent simulations of data sets under different models can be compared to the actual data to test the importance of different evolutionary factors and thus get insight into these. Results We have created the CoaSim application as a flexible environment for Monte Carlo simulation of various types of genetic data under equilibrium and non-equilibrium coalescent processes for a variety of applications. Interaction with the tool is through the Guile version of the Scheme scripting language. Scheme scripts for many standard and advanced applications are provided and these can easily be modified by the user for a much wider range of applications. A graphical user interface with less functionality and flexibility is also included. It is primarily intended as an exploratory and educational tool Conclusion CoaSim is a powerful tool because of its flexibility and ease of use. This is illustrated through very varied uses of the application, e.g. evaluation of association mapping methods, parametric bootstrapping, and design and choice of markers for specific questions

Published
2005
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11. Pigs in sequence space: A 0.66X coverage pig genome survey based on shotgun sequencing

Author

Li Wei, Dong Wei, Hu Songnian, Liu Bin, Wang Jun, Klein Ami, Hornshøj Henrik, Mailund Thomas, Christensen Ole F, Stærfeldt Hans-Henrik, Panitz Frank, Gorodkin Jan, Jørgensen Frank G, Schierup Mikkel H, Wernersson Rasmus, Wong Gane KS, Yu Jun, Wang Jian, Bendixen Christian, Fredholm Merete, Brunak Søren, Yang Huanming, and Bolund Lars

Subjects
Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background Comparative whole genome analysis of Mammalia can benefit from the addition of more species. The pig is an obvious choice due to its economic and medical importance as well as its evolutionary position in the artiodactyls. Results We have generated ~3.84 million shotgun sequences (0.66X coverage) from the pig genome. The data are hereby released (NCBI Trace repository with center name "SDJVP", and project name "Sino-Danish Pig Genome Project") together with an initial evolutionary analysis. The non-repetitive fraction of the sequences was aligned to the UCSC human-mouse alignment and the resulting three-species alignments were annotated using the human genome annotation. Ultra-conserved elements and miRNAs were identified. The results show that for each of these types of orthologous data, pig is much closer to human than mouse is. Purifying selection has been more efficient in pig compared to human, but not as efficient as in mouse, and pig seems to have an isochore structure most similar to the structure in human. Conclusion The addition of the pig to the set of species sequenced at low coverage adds to the understanding of selective pressures that have acted on the human genome by bisecting the evolutionary branch between human and mouse with the mouse branch being approximately 3 times as long as the human branch. Additionally, the joint alignment of the shot-gun sequences to the human-mouse alignment offers the investigator a rapid way to defining specific regions for analysis and resequencing.

Published
2005
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12. A region of suppressed recombination misleads neoavian phylogenomics

Author

Mirarab, Siavash, primary, Rivas-González, Iker, additional, Feng, Shaohong, additional, Stiller, Josefin, additional, Fang, Qi, additional, Mai, Uyen, additional, Hickey, Glenn, additional, Chen, Guangji, additional, Brajuka, Nadolina, additional, Fedrigo, Olivier, additional, Formenti, Giulio, additional, Wolf, Jochen B. W., additional, Howe, Kerstin, additional, Antunes, Agostinho, additional, Schierup, Mikkel H., additional, Paten, Benedict, additional, Jarvis, Erich D., additional, Zhang, Guojie, additional, and Braun, Edward L., additional

Published
2024
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13. A region of suppressed recombination misleads neoavian phylogenomics

Author

Mirarab, Siavash, Rivas-González, Iker, Feng, Shaohong, Stiller, Josefin, Fang, Qi, Mai, Uyen, Hickey, Glenn, Chen, Guangji, Brajuka, Nadolina, Fedrigo, Olivier, Formenti, Giulio, Wolf, Jochen B. W., Howe, Kerstin, Antunes, Agostinho, Schierup, Mikkel H., Paten, Benedict, Jarvis, Erich D., Zhang, Guojie, Braun, Edward L., Mirarab, Siavash, Rivas-González, Iker, Feng, Shaohong, Stiller, Josefin, Fang, Qi, Mai, Uyen, Hickey, Glenn, Chen, Guangji, Brajuka, Nadolina, Fedrigo, Olivier, Formenti, Giulio, Wolf, Jochen B. W., Howe, Kerstin, Antunes, Agostinho, Schierup, Mikkel H., Paten, Benedict, Jarvis, Erich D., Zhang, Guojie, and Braun, Edward L.

Abstract

Genomes are typically mosaics of regions with different evolutionary histories. When speciation events are closely spaced in time, recombination makes the regions sharing the same history small, and the evolutionary history changes rapidly as we move along the genome. When examining rapid radiations such as the early diversification of Neoaves 66 Mya, typically no consistent history is observed across segments exceeding kilobases of the genome. Here, we report an exception. We found that a 21-Mb region in avian genomes, mapped to chicken chromosome 4, shows an extremely strong and discordance-free signal for a history different from that of the inferred species tree. Such a strong discordance-free signal, indicative of suppressed recombination across many millions of base pairs, is not observed elsewhere in the genome for any deep avian relationships. Although long regions with suppressed recombination have been documented in recently diverged species, our results pertain to relationships dating circa 65 Mya. We provide evidence that this strong signal may be due to an ancient rearrangement that blocked recombination and remained polymorphic for several million years prior to fixation. We show that the presence of this region has misled previous phylogenomic efforts with lower taxon sampling, showing the interplay between taxon and locus sampling. We predict that similar ancient rearrangements may confound phylogenetic analyses in other clades, pointing to a need for new analytical models that incorporate the possibility of such events.

Published
2024

16. A genomic history of Aboriginal Australia

Author

Malaspinas, Anna-Sapfo, Westaway, Michael C, Muller, Craig, Sousa, Vitor C, Lao, Oscar, Alves, Isabel, Bergström, Anders, Athanasiadis, Georgios, Cheng, Jade Y, Crawford, Jacob E, Heupink, Tim H, Macholdt, Enrico, Peischl, Stephan, Rasmussen, Simon, Schiffels, Stephan, Subramanian, Sankar, Wright, Joanne L, Albrechtsen, Anders, Barbieri, Chiara, Dupanloup, Isabelle, Eriksson, Anders, Margaryan, Ashot, Moltke, Ida, Pugach, Irina, Korneliussen, Thorfinn S, Levkivskyi, Ivan P, Moreno-Mayar, J Víctor, Ni, Shengyu, Racimo, Fernando, Sikora, Martin, Xue, Yali, Aghakhanian, Farhang A, Brucato, Nicolas, Brunak, Søren, Campos, Paula F, Clark, Warren, Ellingvåg, Sturla, Fourmile, Gudjugudju, Gerbault, Pascale, Injie, Darren, Koki, George, Leavesley, Matthew, Logan, Betty, Lynch, Aubrey, Matisoo-Smith, Elizabeth A, McAllister, Peter J, Mentzer, Alexander J, Metspalu, Mait, Migliano, Andrea B, Murgha, Les, Phipps, Maude E, Pomat, William, Reynolds, Doc, Ricaut, Francois-Xavier, Siba, Peter, Thomas, Mark G, Wales, Thomas, Wall, Colleen Ma’run, Oppenheimer, Stephen J, Tyler-Smith, Chris, Durbin, Richard, Dortch, Joe, Manica, Andrea, Schierup, Mikkel H, Foley, Robert A, Lahr, Marta Mirazón, Bowern, Claire, Wall, Jeffrey D, Mailund, Thomas, Stoneking, Mark, Nielsen, Rasmus, Sandhu, Manjinder S, Excoffier, Laurent, Lambert, David M, and Willerslev, Eske

Subjects
Africa, Australia, Datasets as Topic, Desert Climate, Gene Flow, Genetics, Population, Genome, Human, Genomics, History, Ancient, Human Migration, Humans, Language, Native Hawaiian or Other Pacific Islander, New Guinea, Phylogeny, Population Dynamics, Racial Groups, Tasmania, General Science & Technology
Abstract

The population history of Aboriginal Australians remains largely uncharacterized. Here we generate high-coverage genomes for 83 Aboriginal Australians (speakers of Pama-Nyungan languages) and 25 Papuans from the New Guinea Highlands. We find that Papuan and Aboriginal Australian ancestors diversified 25-40 thousand years ago (kya), suggesting pre-Holocene population structure in the ancient continent of Sahul (Australia, New Guinea and Tasmania). However, all of the studied Aboriginal Australians descend from a single founding population that differentiated ~10-32 kya. We infer a population expansion in northeast Australia during the Holocene epoch (past 10,000 years) associated with limited gene flow from this region to the rest of Australia, consistent with the spread of the Pama-Nyungan languages. We estimate that Aboriginal Australians and Papuans diverged from Eurasians 51-72 kya, following a single out-of-Africa dispersal, and subsequently admixed with archaic populations. Finally, we report evidence of selection in Aboriginal Australians potentially associated with living in the desert.

Published
2016

17. Strong selective sweeps associated with ampliconic regions in great ape X chromosomes

Author

Nam, Kiwoong, Munch, Kasper, Hobolth, Asger, Dutheil, Julien Y., Veeramah, Krishna, Woerner, August, Hammer, Michael F., Project, Great Ape Genome Diversity, Mailund, Thomas, and Schierup, Mikkel H.

Subjects
Quantitative Biology - Populations and Evolution
Abstract

The unique inheritance pattern of X chromosomes makes them preferential targets of adaptive evolution. We here investigate natural selection on the X chromosome in all species of great apes. We find that diversity is more strongly reduced around genes on the X compared with autosomes, and that a higher proportion of substitutions results from positive selection. Strikingly, the X exhibits several megabase long regions where diversity is reduced more than five fold. These regions overlap significantly among species, and have a higher singleton proportion, population differentiation, and nonsynonymous to synonymous substitution ratio. We rule out background selection and soft selective sweeps as explanations for these observations, and conclude that several strong selective sweeps have occurred independently in similar regions in several species. Since these regions are strongly associated with ampliconic sequences we propose that intra-genomic conflict between the X and the Y chromosomes is a major driver of X chromosome evolution., Comment: This the resubmitted version, with supplementary

Published
2014

18. Extreme selective sweeps independently targeted the X chromosomes of the great apes

Author

Nam, Kiwoong, Munch, Kasper, Hobolth, Asger, Dutheil, Julien Yann, Veeramah, Krishna R, Woerner, August E, Hammer, Michael F, Mailund, Thomas, Schierup, Mikkel Heide, Prado-Martinez, Javier, Sudmant, Peter H, Kidd, Jeffrey M, Li, Heng, Kelley, Joanna L, Lorente-Galdos, Belen, O’Connor, Timothy D, Santpere, Gabriel, Cagan, Alexander, Theunert, Christoph, Casals, Ferran, Laayouni, Hafid, Halager, Anders E, Malig, Maika, Hernandez-Rodriguez, Jessica, Hernando-Herraez, Irene, Prüfer, Kay, Pybus, Marc, Johnstone, Laurel, Lachmann, Michael, Alkan, Can, Twigg, Dorina, Petit, Natalia, Baker, Carl, Hormozdiari, Fereydoun, Fernandez-Callejo, Marcos, Dabad, Marc, Wilson, Michael L, Stevison, Laurie, Camprubí, Cristina, Carvalho, Tiago, Ruiz-Herrera, Aurora, Vives, Laura, Mele, Marta, Abello, Teresa, Kondova, Ivanela, Bontrop, Ronald E, Pusey, Anne, Lankester, Felix, Kiyang, John A, Bergl, Richard A, Lonsdorf, Elizabeth, Myers, Simon, Ventura, Mario, Gagneux, Pascal, Comas, David, Siegismund, Hans, Blanc, Julie, Agueda-Calpena, Lidia, Gut, Marta, Fulton, Lucinda, Tishkoff, Sarah A, Mullikin, James C, Wilson, Richard K, Gut, Ivo G, Gonder, Mary Katherine, Ryder, Oliver A, Hahn, Beatrice H, Navarro, Arcadi, Akey, Joshua M, Bertranpetit, Jaume, Reich, David, Schierup, Mikkel H, Hvilsom, Christina, Andrés, Aida M, Wall, Jeffrey D, Bustamante, Carlos D, Eichler, Evan E, and Marques-Bonet, Tomas

Subjects
Human Genome, Genetics, Animals, Computational Biology, Databases, Genetic, Genetic Variation, Genetics, Population, Hominidae, Models, Genetic, Polymorphism, Genetic, Selection, Genetic, Species Specificity, X Chromosome, Great Ape Genome Diversity Project, X-chromosome evolution, ampliconic genes, great apes, meiotic drive, selective sweeps
Abstract

The unique inheritance pattern of the X chromosome exposes it to natural selection in a way that is different from that of the autosomes, potentially resulting in accelerated evolution. We perform a comparative analysis of X chromosome polymorphism in 10 great ape species, including humans. In most species, we identify striking megabase-wide regions, where nucleotide diversity is less than 20% of the chromosomal average. Such regions are found exclusively on the X chromosome. The regions overlap partially among species, suggesting that the underlying targets are partly shared among species. The regions have higher proportions of singleton SNPs, higher levels of population differentiation, and a higher nonsynonymous-to-synonymous substitution ratio than the rest of the X chromosome. We show that the extent to which diversity is reduced is incompatible with direct selection or the action of background selection and soft selective sweeps alone, and therefore, we suggest that very strong selective sweeps have independently targeted these specific regions in several species. The only genomic feature that we can identify as strongly associated with loss of diversity is the location of testis-expressed ampliconic genes, which also have reduced diversity around them. We hypothesize that these genes may be responsible for selective sweeps in the form of meiotic drive caused by an intragenomic conflict in male meiosis.

Published
2015

19. Inference of Purifying and Positive Selection in Three Subspecies of Chimpanzees (Pan troglodytes) from Exome Sequencing

Author

Bataillon, Thomas, Duan, Jinjie, Hvilsom, Christina, Jin, Xin, Li, Yingrui, Skov, Laurits, Glemin, Sylvain, Munch, Kasper, Jiang, Tao, Qian, Yu, Hobolth, Asger, Wang, Jun, Mailund, Thomas, Siegismund, Hans R, and Schierup, Mikkel H

Subjects
Genetics, Human Genome, Underpinning research, 1.1 Normal biological development and functioning, Animals, Demography, Exome, Exons, Genetic Fitness, Genomics, Humans, INDEL Mutation, Pan troglodytes, Polymorphism, Single Nucleotide, Selection, Genetic, Sequence Analysis, DNA, effective size, fitness effect, mutation, selection, Biochemistry and Cell Biology, Evolutionary Biology, Developmental Biology
Abstract

We study genome-wide nucleotide diversity in three subspecies of extant chimpanzees using exome capture. After strict filtering, Single Nucleotide Polymorphisms and indels were called and genotyped for greater than 50% of exons at a mean coverage of 35× per individual. Central chimpanzees (Pan troglodytes troglodytes) are the most polymorphic (nucleotide diversity, θw = 0.0023 per site) followed by Eastern (P. t. schweinfurthii) chimpanzees (θw = 0.0016) and Western (P. t. verus) chimpanzees (θw = 0.0008). A demographic scenario of divergence without gene flow fits the patterns of autosomal synonymous nucleotide diversity well except for a signal of recent gene flow from Western into Eastern chimpanzees. The striking contrast in X-linked versus autosomal polymorphism and divergence previously reported in Central chimpanzees is also found in Eastern and Western chimpanzees. We show that the direction of selection statistic exhibits a strong nonmonotonic relationship with the strength of purifying selection S, making it inappropriate for estimating S. We instead use counts in synonymous versus nonsynonymous frequency classes to infer the distribution of S coefficients acting on nonsynonymous mutations in each subspecies. The strength of purifying selection we infer is congruent with the differences in effective sizes of each subspecies: Central chimpanzees are undergoing the strongest purifying selection followed by Eastern and Western chimpanzees. Coding indels show stronger selection against indels changing the reading frame than observed in human populations.

Published
2015

20. Author Correction: Comparative and demographic analysis of orang-utan genomes

Author

Locke, Devin P., Hillier, LaDeana W., Warren, Wesley C., Worley, Kim C., Nazareth, Lynne V., Muzny, Donna M., Yang, Shiaw-Pyng, Wang, Zhengyuan, Chinwalla, Asif T., Minx, Pat, Mitreva, Makedonka, Cook, Lisa, Delehaunty, Kim D., Fronick, Catrina, Schmidt, Heather, Fulton, Lucinda A., Fulton, Robert S., Nelson, Joanne O., Magrini, Vincent, Pohl, Craig, Graves, Tina A., Markovic, Chris, Cree, Andy, Dinh, Huyen H., Hume, Jennifer, Kovar, Christie L., Fowler, Gerald R., Lunter, Gerton, Meader, Stephen, Heger, Andreas, Ponting, Chris P., Marques-Bonet, Tomas, Alkan, Can, Chen, Lin, Cheng, Ze, Kidd, Jeffrey M., Eichler, Evan E., White, Simon, Searle, Stephen, Vilella, Albert J., Chen, Yuan, Flicek, Paul, Ma, Jian, Raney, Brian, Suh, Bernard, Burhans, Richard, Herrero, Javier, Haussler, David, Faria, Rui, Fernando, Olga, Darré, Fleur, Farré, Domènec, Gazave, Elodie, Oliva, Meritxell, Navarro, Arcadi, Roberto, Roberta, Capozzi, Oronzo, Archidiacono, Nicoletta, Della Valle, Giuliano, Purgato, Stefania, Rocchi, Mariano, Konkel, Miriam K., Walker, Jerilyn A., Ullmer, Brygg, Batzer, Mark A., Smit, Arian F. A., Hubley, Robert, Casola, Claudio, Schrider, Daniel R., Hahn, Matthew W., Quesada, Victor, Puente, Xose S., Ordoñez, Gonzalo R., López-Otín, Carlos, Vinar, Tomas, Brejova, Brona, Ratan, Aakrosh, Harris, Robert S., Miller, Webb, Kosiol, Carolin, Lawson, Heather A., Taliwal, Vikas, Martins, André L., Siepel, Adam, RoyChoudhury, Arindam, Ma, Xin, Degenhardt, Jeremiah, Bustamante, Carlos D., Gutenkunst, Ryan N., Mailund, Thomas, Dutheil, Julien Y., Hobolth, Asger, Schierup, Mikkel H., Ryder, Oliver A., Yoshinaga, Yuko, de Jong, Pieter J., Weinstock, George M., Rogers, Jeffrey, Mardis, Elaine R., Gibbs, Richard A., and Wilson, Richard K.

Published
2022
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21. Variation and association to diabetes in 2000 full mtDNA sequences mined from an exome study in a Danish population

Author

Li, Shengting, Besenbacher, Soren, Li, Yingrui, Kristiansen, Karsten, Grarup, Niels, Albrechtsen, Anders, Sparsø, Thomas, Korneliussen, Thorfinn, Hansen, Torben, Wang, Jun, Nielsen, Rasmus, Pedersen, Oluf, Bolund, Lars, and Schierup, Mikkel H

Subjects
Biological Sciences, Genetics, Human Genome, Diabetes, 2.1 Biological and endogenous factors, Aetiology, Metabolic and endocrine, Case-Control Studies, DNA, Mitochondrial, Denmark, Diabetes Mellitus, Exome, Gene Frequency, Genetic Association Studies, Genetic Variation, Genetics, Population, Genotype, Humans, Phylogeny, Polymorphism, Genetic, Quantitative Trait, Heritable, White People, diabetes, mtDNA, population history, Clinical Sciences, Genetics & Heredity, Clinical sciences
Abstract

In this paper, we mine full mtDNA sequences from an exome capture data set of 2000 Danes, showing that it is possible to get high-quality full-genome sequences of the mitochondrion from this resource. The sample includes 1000 individuals with type 2 diabetes and 1000 controls. We characterise the variation found in the mtDNA sequence in Danes and relate the variation to diabetes risk as well as to several blood phenotypes of the controls but find no significant associations. We report 2025 polymorphisms, of which 393 have not been reported previously. These 393 mutations are both very rare and estimated to be caused by very recent mutations but individuals with type 2 diabetes do not possess more of these variants. Population genetics analysis using Bayesian skyline plot shows a recent history of rapid population growth in the Danish population in accordance with the fact that >40% of variable sites are observed as singletons.

Published
2014

22. Great ape genetic diversity and population history.

Author

Prado-Martinez, Javier, Sudmant, Peter H, Kidd, Jeffrey M, Li, Heng, Kelley, Joanna L, Lorente-Galdos, Belen, Veeramah, Krishna R, Woerner, August E, O'Connor, Timothy D, Santpere, Gabriel, Cagan, Alexander, Theunert, Christoph, Casals, Ferran, Laayouni, Hafid, Munch, Kasper, Hobolth, Asger, Halager, Anders E, Malig, Maika, Hernandez-Rodriguez, Jessica, Hernando-Herraez, Irene, Prüfer, Kay, Pybus, Marc, Johnstone, Laurel, Lachmann, Michael, Alkan, Can, Twigg, Dorina, Petit, Natalia, Baker, Carl, Hormozdiari, Fereydoun, Fernandez-Callejo, Marcos, Dabad, Marc, Wilson, Michael L, Stevison, Laurie, Camprubí, Cristina, Carvalho, Tiago, Ruiz-Herrera, Aurora, Vives, Laura, Mele, Marta, Abello, Teresa, Kondova, Ivanela, Bontrop, Ronald E, Pusey, Anne, Lankester, Felix, Kiyang, John A, Bergl, Richard A, Lonsdorf, Elizabeth, Myers, Simon, Ventura, Mario, Gagneux, Pascal, Comas, David, Siegismund, Hans, Blanc, Julie, Agueda-Calpena, Lidia, Gut, Marta, Fulton, Lucinda, Tishkoff, Sarah A, Mullikin, James C, Wilson, Richard K, Gut, Ivo G, Gonder, Mary Katherine, Ryder, Oliver A, Hahn, Beatrice H, Navarro, Arcadi, Akey, Joshua M, Bertranpetit, Jaume, Reich, David, Mailund, Thomas, Schierup, Mikkel H, Hvilsom, Christina, Andrés, Aida M, Wall, Jeffrey D, Bustamante, Carlos D, Hammer, Michael F, Eichler, Evan E, and Marques-Bonet, Tomas

Subjects
Animals, Animals, Wild, Animals, Zoo, Hominidae, Gorilla gorilla, Humans, Pan paniscus, Pan troglodytes, Inbreeding, Genetics, Population, Population Density, Evolution, Molecular, Phylogeny, Polymorphism, Single Nucleotide, Genome, Africa, Asia, Southeastern, Gene Flow, Genetic Variation, General Science & Technology
Abstract

Most great ape genetic variation remains uncharacterized; however, its study is critical for understanding population history, recombination, selection and susceptibility to disease. Here we sequence to high coverage a total of 79 wild- and captive-born individuals representing all six great ape species and seven subspecies and report 88.8 million single nucleotide polymorphisms. Our analysis provides support for genetically distinct populations within each species, signals of gene flow, and the split of common chimpanzees into two distinct groups: Nigeria-Cameroon/western and central/eastern populations. We find extensive inbreeding in almost all wild populations, with eastern gorillas being the most extreme. Inferred effective population sizes have varied radically over time in different lineages and this appears to have a profound effect on the genetic diversity at, or close to, genes in almost all species. We discover and assign 1,982 loss-of-function variants throughout the human and great ape lineages, determining that the rate of gene loss has not been different in the human branch compared to other internal branches in the great ape phylogeny. This comprehensive catalogue of great ape genome diversity provides a framework for understanding evolution and a resource for more effective management of wild and captive great ape populations.

Published
2013

23. A high-coverage Neandertal genome from Vindija Cave in Croatia

Author

Prüfer, Kay, de Filippo, Cesare, Grote, Steffi, Mafessoni, Fabrizio, Korlević, Petra, Hajdinjak, Mateja, Vernot, Benjamin, Skov, Laurits, Hsieh, Pinghsun, Peyrégne, Stéphane, Reher, David, Hopfe, Charlotte, Nagel, Sarah, Maricic, Tomislav, Fu, Qiaomei, Theunert, Christoph, Rogers, Rebekah, Skoglund, Pontus, Chintalapati, Manjusha, Dannemann, Michael, Nelson, Bradley J., Key, Felix M., Rudan, Pavao, Kućan, Željko, Gušić, Ivan, Golovanova, Liubov V., Doronichev, Vladimir B., Patterson, Nick, Reich, David, Eichler, Evan E., Slatkin, Montgomery, Schierup, Mikkel H., Andrés, Aida M., Kelso, Janet, Meyer, Matthias, and Pääbo, Svante

Published
2017

27. Genome-wide coancestry reveals details of ancient and recent male-driven reticulation in baboons

Author

Sørensen, Erik F., primary, Harris, R. Alan, additional, Zhang, Liye, additional, Raveendran, Muthuswamy, additional, Kuderna, Lukas F. K., additional, Walker, Jerilyn A., additional, Storer, Jessica M., additional, Kuhlwilm, Martin, additional, Fontsere, Claudia, additional, Seshadri, Lakshmi, additional, Bergey, Christina M., additional, Burrell, Andrew S., additional, Bergman, Juraj, additional, Phillips-Conroy, Jane E., additional, Shiferaw, Fekadu, additional, Chiou, Kenneth L., additional, Chuma, Idrissa S., additional, Keyyu, Julius D., additional, Fischer, Julia, additional, Gingras, Marie-Claude, additional, Salvi, Sejal, additional, Doddapaneni, Harshavardhan, additional, Schierup, Mikkel H., additional, Batzer, Mark A., additional, Jolly, Clifford J., additional, Knauf, Sascha, additional, Zinner, Dietmar, additional, Farh, Kyle K.-H., additional, Marques-Bonet, Tomas, additional, Munch, Kasper, additional, Roos, Christian, additional, and Rogers, Jeffrey, additional

Published
2023
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28. Pervasive incomplete lineage sorting illuminates speciation and selection in primates

Author

Rivas-González, Iker, Rousselle, Marjolaine, Li, Fang, Zhou, Long, Dutheil, Julien Y., Munch, Kasper, Shao, Yong, Wu, Dongdong, Schierup, Mikkel H., Zhang, Guojie, Rivas-González, Iker, Rousselle, Marjolaine, Li, Fang, Zhou, Long, Dutheil, Julien Y., Munch, Kasper, Shao, Yong, Wu, Dongdong, Schierup, Mikkel H., and Zhang, Guojie

Abstract

INTRODUCTION Incomplete lineage sorting generates gene trees that are incongruent with the species tree. Incomplete lineage sorting has been described in many phylogenetic clades, including birds, marsupials, and primates. For example, the level of incomplete lineage sorting in the human-chimp-gorilla branch adds up to ~30%, which means that, even though our closest primate relatives are chimps, 15% of our genome resembles more the gorilla than the chimp genome, and another 15% groups the chimp with the gorilla first. RATIONALE Although incomplete lineage sorting is usually regarded as an obstacle for phylogenetic reconstruction, it holds valuable information about the evolutionary history of the species because its extent depends on the ancestral effective population sizes and the time between speciation events. Additionally, recurrent ancestral selective processes are expected to influence how the proportion of incongruent trees varies along the genome, which makes incomplete lineage sorting a useful tool to study ancient evolutionary events. In this study, we estimate the incomplete lineage sorting landscape by running a coalescent hidden Markov model in species trios along a 50-way primate genome alignment. We then leverage the signal of incomplete lineage sorting to reconstruct ancestral effective population parameters and to analyze the genomic determinants that influence the sorting of lineages. RESULTS We find widespread incomplete lineage sorting across the primate tree in 29 nodes, some reaching as much as 64% of the genome. Combining CoalHMM with a machine learning pipeline, we reconstruct the speciation times of the primate phylogeny without the need for fossil calibrations. Our speciation time estimates are more recent than divergence times, and they are in agreement with previous estimates based on fossil evidence. Our reconstructed ancestral effective population sizes show that they increase toward the past. We additionally det, Incomplete lineage sorting (ILS) causes the phylogeny of some parts of the genome to differ from the species tree. In this work, we investigate the frequencies and determinants of ILS in 29 major ancestral nodes across the entire primate phylogeny. We find up to 64% of the genome affected by ILS at individual nodes. We exploit ILS to reconstruct speciation times and ancestral population sizes. Estimated speciation times are much more recent than genomic divergence times and are in good agreement with the fossil record. We show extensive variation of ILS along the genome, mainly driven by recombination but also by the distance to genes, highlighting a major impact of selection on variation along the genome. In many nodes, ILS is reduced more on the X chromosome compared with autosomes than expected under neutrality, which suggests higher impacts of natural selection on the X chromosome. Finally, we show an excess of ILS in genes with immune functions and a deficit of ILS in housekeeping genes. The extensive ILS in primates discovered in this study provides insights into the speciation times, ancestral population sizes, and patterns of natural selection that shape primate evolution.

Published
2023

29. Genome-wide coancestry reveals details of ancient and recent male-driven reticulation in baboons

Author

Sørensen, Erik F., Harris, R. Alan, Zhang, Liye, Raveendran, Muthuswamy, Kuderna, Lukas F.K., Walker, Jerilyn A., Storer, Jessica M., Kuhlwilm, Martin, Fontsere, Claudia, Seshadri, Lakshmi, Bergey, Christina M., Burrell, Andrew S., Bergman, Juraj, Phillips-Conroy, Jane E., Shiferaw, Fekadu, Chiou, Kenneth L., Chuma, Idrissa S., Keyyu, Julius D., Fischer, Julia, Gingras, Marie Claude, Salvi, Sejal, Doddapaneni, Harshavardhan, Schierup, Mikkel H., Batzer, Mark A., Jolly, Clifford J., Knauf, Sascha, Zinner, Dietmar, Farh, Kyle K.H., Marques-Bonet, Tomas, Munch, Kasper, Roos, Christian, and Rogers, Jeffrey

Subjects
Article
Abstract

Baboons (genusPapio) are a morphologically and behaviorally diverse clade of catarrhine monkeys that have experienced hybridization between phenotypically and genetically distinct phylogenetic species. We used high coverage whole genome sequences from 225 wild baboons representing 19 geographic localities to investigate population genomics and inter-species gene flow. Our analyses provide an expanded picture of evolutionary reticulation among species and reveal novel patterns of population structure within and among species, including differential admixture among conspecific populations. We describe the first example of a baboon population with a genetic composition that is derived from three distinct lineages. The results reveal processes, both ancient and recent, that produced the observed mismatch between phylogenetic relationships based on matrilineal, patrilineal, and biparental inheritance. We also identified several candidate genes that may contribute to species-specific phenotypes.One-Sentence SummaryGenomic data for 225 baboons reveal novel sites of inter-species gene flow and local effects due to differences in admixture.

Published
2023
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30. Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores

Author

Ripke, Stephan, Neale, Benjamin M., Corvin, Aiden, Walters, James T.R., Farh, Kai-How, Holmans, Peter A., Lee, Phil, Bulik-Sullivan, Brendan, Collier, David A., Huang, Hailiang, Pers, Tune H., Agartz, Ingrid, Agerbo, Esben, Albus, Margot, Alexander, Madeline, Amin, Farooq, Bacanu, Silviu A., Begemann, Martin, Belliveau, Richard A., Jr., Bene, Judit, Bergen, Sarah E., Bevilacqua, Elizabeth, Bigdeli, Tim B., Black, Donald W., Bruggeman, Richard, Buccola, Nancy G., Buckner, Randy L., Byerley, William, Cahn, Wiepke, Cai, Guiqing, Campion, Dominique, Cantor, Rita M., Carr, Vaughan J., Carrera, Noa, Catts, Stanley V., Chambert, Kimberly D., Chan, Raymond C.K., Chen, Ronald Y.L., Chen, Eric Y.H., Cheng, Wei, Cheung, Eric F.C., Chong, Siow Ann, Cloninger, C. Robert, Cohen, David, Cohen, Nadine, Cormican, Paul, Craddock, Nick, Crowley, James J., Curtis, David, Davidson, Michael, Davis, Kenneth L., Degenhardt, Franziska, Del Favero, Jurgen, DeLisi, Lynn E., Demontis, Ditte, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Dudbridge, Frank, Durmishi, Naser, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Essioux, Laurent, Fanous, Ayman H., Farrell, Martilias S., Frank, Josef, Franke, Lude, Freedman, Robert, Freimer, Nelson B., Friedl, Marion, Friedman, Joseph I., Fromer, Menachem, Genovese, Giulio, Georgieva, Lyudmila, Gershon, Elliot S., Giegling, Ina, Giusti-Rodrguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I., Golimbet, Vera, Gopal, Srihari, Gratten, Jacob, Grove, Jakob, de Haan, Lieuwe, Hammer, Christian, Hamshere, Marian L., Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Hartmann, Annette M., Henskens, Frans A., Herms, Stefan, Hirschhorn, Joel N., Hoffmann, Per, Hofman, Andrea, Hollegaard, Mads V., Hougaard, David M., Ikeda, Masashi, Joa, Inge, Julia, Antonio, Kahn, Rene S., Kalaydjieva, Luba, Karachanak-Yankova, Sena, Karjalainen, Juha, Kavanagh, David, Keller, Matthew C., Kelly, Brian J., Kennedy, James L., Khrunin, Andrey, Kim, Yunjung, Klovins, Janis, Knowles, James A., Konte, Bettina, Kucinskas, Vaidutis, Kucinskiene, Zita Ausrele, Kuzelova-Ptackova, Hana, Kahler, Anna K., Laurent, Claudine, Keong, Jimmy Lee Chee, Lee, S. Hong, Legge, Sophie E., Lerer, Bernard, Li, Miaoxin, Li, Tao, Liang, Kung-Yee, Lieberman, Jeffrey, Limborska, Svetlana, Loughland, Carmel M., Lubinski, Jan, Lnnqvist, Jouko, Macek, Milan, Jr., Magnusson, Patrik K.E., Maher, Brion S., Maier, Wolfgang, Mallet, Jacques, Marsal, Sara, Mattheisen, Manuel, Mattingsdal, Morten, McCarley, Robert W., McDonald, Colm, McIntosh, Andrew M., Meier, Sandra, Meijer, Carin J., Melegh, Bela, Melle, Ingrid, Mesholam-Gately, Raquelle I., Metspalu, Andres, Michie, Patricia T., Milani, Lili, Milanova, Vihra, Mokrab, Younes, Morris, Derek W., Mors, Ole, Mortensen, Preben B., Murphy, Kieran C., Murray, Robin M., Myin-Germeys, Inez, Mller-Myhsok, Bertram, Nelis, Mari, Nenadic, Igor, Nertney, Deborah A., Nestadt, Gerald, Nicodemus, Kristin K., Nikitina-Zake, Liene, Nisenbaum, Laura, Nordin, Annelie, O’Callaghan, Eadbhard, O’Dushlaine, Colm, O’Neill, F. Anthony, Oh, Sang-Yun, Olincy, Ann, Olsen, Line, Van Os, Jim, Pantelis, Christos, Papadimitriou, George N., Papiol, Sergi, Parkhomenko, Elena, Pato, Michele T., Paunio, Tiina, Pejovic-Milovancevic, Milica, Perkins, Diana O., Pietilinen, Olli, Pimm, Jonathan, Pocklington, Andrew J., Powell, John, Price, Alkes, Pulver, Ann E., Purcell, Shaun M., Quested, Digby, Rasmussen, Henrik B., Reichenberg, Abraham, Reimers, Mark A., Richards, Alexander L., Roffman, Joshua L., Roussos, Panos, Ruderfer, Douglas M., Salomaa, Veikko, Sanders, Alan R., Schall, Ulrich, Schubert, Christian R., Schulze, Thomas G., Schwab, Sibylle G., Scolnick, Edward M., Scott, Rodney J., Seidman, Larry J., Shi, Jianxin, Sigurdsson, Engilbert, Silagadze, Teimuraz, Silverman, Jeremy M., Sim, Kang, Slominsky, Petr, Smoller, Jordan W., So, Hon-Cheong, Spencer, Chris C.A., Stahl, Eli A., Stefansson, Hreinn, Steinberg, Stacy, Stogmann, Elisabeth, Straub, Richard E., Strengman, Eric, Strohmaier, Jana, Stroup, T. Scott, Subramaniam, Mythily, Suvisaari, Jaana, Svrakic, Dragan M., Szatkiewicz, Jin P., Sderman, Erik, Thirumalai, Srinivas, Toncheva, Draga, Tooney, Paul A., Tosato, Sarah, Veijola, Juha, Waddington, John, Walsh, Dermot, Wang, Dai, Wang, Qiang, Webb, Bradley T., Weiser, Mark, Wildenauer, Dieter B., Williams, Nigel M., Williams, Stephanie, Witt, Stephanie H., Wolen, Aaron R., Wong, Emily H.M., Wormley, Brandon K., Wu, Jing Qin, Xi, Hualin Simon, Zai, Clement C., Zheng, Xuebin, Zimprich, Fritz, Wray, Naomi R., Stefansson, Kari, Visscher, Peter M., Adolfsson, Rolf, Andreassen, Ole A., Blackwood, Douglas H.R., Bramon, Elvira, Buxbaum, Joseph D., Børglum, Anders D., Cichon, Sven, Darvasi, Ariel, Domenici, Enrico, Ehrenreich, Hannelore, Esko, Tonu, Gejman, Pablo V., Gill, Michael, Gurling, Hugh, Hultman, Christina M., Iwata, Nakao, Jablensky, Assen V., Jonsson, Erik G., Kendler, Kenneth S., Kirov, George, Knight, Jo, Lencz, Todd, Levinson, Douglas F., Li, Qingqin S., Liu, Jianjun, Malhotra, Anil K., McCarroll, Steven A., McQuillin, Andrew, Moran, Jennifer L., Mowry, Bryan J., Nthen, Markus M., Ophoff, Roel A., Owen, Michael J., Palotie, Aarno, Pato, Carlos N., Petryshen, Tracey L., Posthuma, Danielle, Rietschel, Marcella, Riley, Brien P., Rujescu, Dan, Sham, Pak C., Sklar, Pamela, St. Clair, David, Weinberger, Daniel R., Wendland, Jens R., Werge, Thomas, Daly, Mark J., Sullivan, Patrick F., O’Donovan, Michael C., Kraft, Peter, Hunter, David J., Adank, Muriel, Ahsan, Habibul, Aittomäki, Kristiina, Baglietto, Laura, Berndt, Sonja, Blomquist, Carl, Canzian, Federico, Chang-Claude, Jenny, Chanock, Stephen J., Crisponi, Laura, Czene, Kamila, Dahmen, Norbert, Silva, Isabel dos Santos, Easton, Douglas, Eliassen, A. Heather, Figueroa, Jonine, Fletcher, Olivia, Garcia-Closas, Montserrat, Gaudet, Mia M., Gibson, Lorna, Haiman, Christopher A., Hall, Per, Hazra, Aditi, Hein, Rebecca, Henderson, Brian E., Hofman, Albert, Hopper, John L., Irwanto, Astrid, Johansson, Mattias, Kaaks, Rudolf, Kibriya, Muhammad G., Lichtner, Peter, Lindström, Sara, Lund, Eiliv, Makalic, Enes, Meindl, Alfons, Meijers-Heijboer, Hanne, Müller-Myhsok, Bertram, Muranen, Taru A., Nevanlinna, Heli, Peeters, Petra H., Peto, Julian, Prentice, Ross L., Rahman, Nazneen, Sánchez, María José, Schmidt, Daniel F., Schmutzler, Rita K., Southey, Melissa C., Tamimi, Rulla, Travis, Ruth, Turnbull, Clare, Uitterlinden, Andre G., van der Luijt, Rob B., Waisfisz, Quinten, Wang, Zhaoming, Whittemore, Alice S., Yang, Rose, Zheng, Wei, Vilhjálmsson, Bjarni J., Yang, Jian, Finucane, Hilary K., Gusev, Alexander, Loh, Po-Ru, Bhatia, Gaurav, Do, Ron, Hayeck, Tristan, Won, Hong-Hee, Kathiresan, Sekar, Pato, Michele, Pato, Carlos, Stahl, Eli, Zaitlen, Noah, Pasaniuc, Bogdan, Belbin, Gillian, Kenny, Eimear E., Schierup, Mikkel H., De Jager, Philip, Patsopoulos, Nikolaos A., McCarroll, Steve, Daly, Mark, Purcell, Shaun, Chasman, Daniel, Neale, Benjamin, Goddard, Michael, Patterson, Nick, and Price, Alkes L.

Published
2015
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31. Single-cell analysis maps distinct cellular responses to rhizobia and identifies the novel infection regulator SYMRKL1 inLotus japonicus

Author

Frank, Manuel, primary, Fechete, Lavinia Ioana, additional, Tedeschi, Francesca, additional, Nadzieja, Marcin, additional, Malekzadeh Nørgaard, Malita Malou, additional, Montiel, Jesus, additional, Andersen, Kasper Røjkjær, additional, Schierup, Mikkel H., additional, Reid, Dugald, additional, and Andersen, Stig Uggerhøj, additional

Published
2022
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33. The Mutationathon highlights the importance of reaching standardization in estimates of pedigree-based germline mutation rates

Author

Bergeron, Lucie A., Besenbacher, Søren, Turner, Tychele N., Versoza, Cyril J., Wang, Richard J., Price, Alivia Lee, Armstrong, Ellie, Riera, Meritxell, Carlson, Jedidiah, Chen, Hwei-Yen, Hahn, Matthew W., Harris, Kelley, Kleppe, April Snøfrid, López-Nandam, Elora H., Moorjani, Priya, Pfeifer, Susanne P., Tiley, George P., Yoder, Anne D., Zhang, Guojie, Schierup, Mikkel H., Bergeron, Lucie A., Besenbacher, Søren, Turner, Tychele N., Versoza, Cyril J., Wang, Richard J., Price, Alivia Lee, Armstrong, Ellie, Riera, Meritxell, Carlson, Jedidiah, Chen, Hwei-Yen, Hahn, Matthew W., Harris, Kelley, Kleppe, April Snøfrid, López-Nandam, Elora H., Moorjani, Priya, Pfeifer, Susanne P., Tiley, George P., Yoder, Anne D., Zhang, Guojie, and Schierup, Mikkel H.

Abstract

In the past decade, several studies have estimated the human per-generation germline mutation rate using large pedigrees. More recently, estimates for various non-human species have been published. However, methodological differences among studies in detecting germline mutations and estimating mutation rates make direct comparisons difficult. Here, we describe the many different steps involved in estimating pedigree-based mutation rates, including sampling, sequencing, mapping, variant calling, filtering, and how to appropriately account for false-positive and false-negative rates. For each step, we review the different methods and parameter choices that have been used in the recent literature. Additionally, we present the results from a “Mutationathon”, a competition organized among five research labs to compare germline mutation rate estimates for a single pedigree of rhesus macaques. We report almost a two-fold variation in the final estimated rate among groups using different post-alignment processing, calling, and filtering criteria and provide details into the sources of variation across studies. Though the difference among estimates is not statistically significant, this discrepancy emphasizes the need for standardized methods in mutation rate estimations and the difficulty in comparing rates from different studies. Finally, this work aims to provide guidelines for computational and statistical benchmarks for future studies interested in identifying germline mutations from pedigrees.

Published
2022

38. The Mutationathon highlights the importance of reaching standardization in estimates of pedigree-based germline mutation rates

Author

Bergeron, Lucie A, primary, Besenbacher, Søren, additional, Turner, Tychele, additional, Versoza, Cyril J, additional, Wang, Richard J, additional, Price, Alivia Lee, additional, Armstrong, Ellie, additional, Riera, Meritxell, additional, Carlson, Jedidiah, additional, Chen, Hwei-yen, additional, Hahn, Matthew W, additional, Harris, Kelley, additional, Kleppe, April Snøfrid, additional, López-Nandam, Elora H, additional, Moorjani, Priya, additional, Pfeifer, Susanne P, additional, Tiley, George P, additional, Yoder, Anne D, additional, Zhang, Guojie, additional, and Schierup, Mikkel H, additional

Published
2022
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39. Author response: The Mutationathon highlights the importance of reaching standardization in estimates of pedigree-based germline mutation rates

Author

Bergeron, Lucie A, primary, Besenbacher, Søren, additional, Turner, Tychele, additional, Versoza, Cyril J, additional, Wang, Richard J, additional, Price, Alivia Lee, additional, Armstrong, Ellie, additional, Riera, Meritxell, additional, Carlson, Jedidiah, additional, Chen, Hwei-yen, additional, Hahn, Matthew W, additional, Harris, Kelley, additional, Kleppe, April Snøfrid, additional, López-Nandam, Elora H, additional, Moorjani, Priya, additional, Pfeifer, Susanne P, additional, Tiley, George P, additional, Yoder, Anne D, additional, Zhang, Guojie, additional, and Schierup, Mikkel H, additional

Published
2022
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42. Mutationathon: towards standardization in estimates of pedigree-based germline mutation rates

Author

Bergeron, Lucie A., primary, Besenbacher, Søren, additional, Turner, Tychele N., additional, Versoza, Cyril J., additional, Wang, Richard J., additional, Price, Alivia Lee, additional, Armstrong, Ellie, additional, Riera, Meritxell, additional, Carlson, Jedidiah, additional, Chen, Hwei-yen, additional, Hahn, Matthew W., additional, Harris, Kelley, additional, Snøfrid Lo Natalie M Kleppe, April, additional, López-Nandam, Elora H., additional, Moorjani, Priya, additional, Pfeifer, Susanne P., additional, Tiley, George P., additional, Yoder, Anne D., additional, Zhang, Guojie, additional, and Schierup, Mikkel H., additional

Published
2021
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43. Studying mutation rate evolution in primates - a need for systematic comparison of computational pipelines

Author

Bergeron, Lucie A., Besenbacher, Søren, Schierup, Mikkel H., Zhang, Guojie, Bergeron, Lucie A., Besenbacher, Søren, Schierup, Mikkel H., and Zhang, Guojie

Abstract

The lack of consensus methods to estimate germline mutation rates from pedigrees has led to substantial differences in computational pipelines in the published literature. Here, we answer Susanne Pfeifer's opinion piece discussing the pipeline choices of our recent article estimating the germline mutation rate of rhesus macaques (Macaca mulatta). We acknowledge the differences between the method that we applied and the one preferred by Pfeifer. Yet, we advocate for full transparency and justification of choices as long as rigorous comparison of pipelines remains absent because it is the only way to conclude on best practices for the field.

Published
2021

44. The germline mutational process in rhesus macaque and its implications for phylogenetic dating

Author

Bergeron, Lucie A., Besenbacher, Søren, Bakker, Jaco, Zheng, Jiao, Li, Panyi, Pacheco, George, Sinding, Mikkel Holger S., Kamilari, Maria, Gilbert, M. Thomas P., Schierup, Mikkel H., Zhang, Guojie, Bergeron, Lucie A., Besenbacher, Søren, Bakker, Jaco, Zheng, Jiao, Li, Panyi, Pacheco, George, Sinding, Mikkel Holger S., Kamilari, Maria, Gilbert, M. Thomas P., Schierup, Mikkel H., and Zhang, Guojie

Abstract

BACKGROUND: Understanding the rate and pattern of germline mutations is of fundamental importance for understanding evolutionary processes. RESULTS: Here we analyzed 19 parent-offspring trios of rhesus macaques (Macaca mulatta) at high sequencing coverage of ∼76× per individual and estimated a mean rate of 0.77 × 10-8de novo mutations per site per generation (95% CI: 0.69 × 10-8 to 0.85 × 10-8). By phasing 50% of the mutations to parental origins, we found that the mutation rate is positively correlated with the paternal age. The paternal lineage contributed a mean of 81% of the de novo mutations, with a trend of an increasing male contribution for older fathers. Approximately 3.5% of de novo mutations were shared between siblings, with no parental bias, suggesting that they arose from early development (postzygotic) stages. Finally, the divergence times between closely related primates calculated on the basis of the yearly mutation rate of rhesus macaque generally reconcile with divergence estimated with molecular clock methods, except for the Cercopithecoidea/Hominoidea molecular divergence dated at 58 Mya using our new estimate of the yearly mutation rate. CONCLUSIONS: When compared to the traditional molecular clock methods, new estimated rates from pedigree samples can provide insights into the evolution of well-studied groups such as primates.

Published
2021

45. Small rnas in seminal plasma as novel biomarkers for germ cell tumors

Author

Mørup, Nina, Stakaitis, Rytis, Golubickaite, Ieva, Riera, Meritxell, Dalgaard, Marlene Danner, Schierup, Mikkel H., Jørgensen, Niels, Daugaard, Gedske, Juul, Anders, Almstrup, Kristian, Mørup, Nina, Stakaitis, Rytis, Golubickaite, Ieva, Riera, Meritxell, Dalgaard, Marlene Danner, Schierup, Mikkel H., Jørgensen, Niels, Daugaard, Gedske, Juul, Anders, and Almstrup, Kristian

Abstract

Circulating miRNAs secreted by testicular germ cell tumors (TGCT) show great potential as novel non-invasive biomarkers for diagnosis of TGCT. Seminal plasma (SP) represents a biofluid closer to the primary site. Here, we investigate whether small RNAs in SP can be used to diagnose men with TGCTs or the precursor lesions, germ cell neoplasia in situ (GCNIS). Small RNAs isolated from SP from men with TGCTs (n = 18), GCNIS-only (n = 5), and controls (n = 25) were sequenced. SP from men with TGCT/GCNIS (n = 37) and controls (n = 22) were used for validation by RT-qPCR. In general, piRNAs were found at lower levels in SP from men with TGCTs. Ten small RNAs were found at significantly (q-value < 0.05) different levels in SP from men with TGCT/GCNIS than controls. Random forests classification identified sets of small RNAs that could detect either TGCT/GCNIS or GCNIS-only with an area under the curve of 0.98 and 1 in ROC analyses, respectively. RT-qPCR validated hsa-miR-6782-5p to be present at 2.3-fold lower levels (p = 0.02) in the SP from men with TGCTs compared with controls. Small RNAs in SP show potential as novel biomarkers for diagnosing men with TGCT/GCNIS but validation in larger cohorts is needed.

Published
2021

46. Comparative and demographic analysis of orang-utan genomes

Author

Locke, Devin P., Hillier, LaDeana W., Warren, Wesley C., Worley, Kim C., Nazareth, Lynne V., Muzny, Donna M., Yang, Shiaw-Pyng, Wang, Zhengyuan, Chinwalla, Asif T., Minx, Pat, Mitreva, Makedonka, Cook, Lisa, Delehaunty, Kim D., Fronick, Catrina, Schmidt, Heather, Fulton, Lucinda A., Fulton, Robert S., Nelson, Joanne O., Magrini, Vincent, Pohl, Craig, Graves, Tina A., Markovic, Chris, Cree, Andy, Dinh, Huyen H., Hume, Jennifer, Kovar, Christie L., Fowler, Gerald R., Lunter, Gerton, Meader, Stephen, Heger, Andreas, Ponting, Chris P., Marques-Bonet, Tomas, Alkan, Can, Chen, Lin, Cheng, Ze, Kidd, Jeffrey M., Eichler, Evan E., White, Simon, Searle, Stephen, Vilella, Albert J., Chen, Yuan, Flicek, Paul, Ma, Jian, Raney, Brian, Suh, Bernard, Burhans, Richard, Herrero, Javier, Haussler, David, Faria, Rui, Fernando, Olga, Darré, Fleur, Farré, Domènec, Gazave, Elodie, Oliva, Meritxell, Navarro, Arcadi, Roberto, Roberta, Capozzi, Oronzo, Archidiacono, Nicoletta, Valle, Giuliano Della, Purgato, Stefania, Rocchi, Mariano, Konkel, Miriam K., Walker, Jerilyn A., Ullmer, Brygg, Batzer, Mark A., Smit, Arian F. A., Hubley, Robert, Casola, Claudio, Schrider, Daniel R., Hahn, Matthew W., Quesada, Victor, Puente, Xose S., Ordoñez, Gonzalo R., López-Otín, Carlos, Vinar, Tomas, Brejova, Brona, Ratan, Aakrosh, Harris, Robert S., Miller, Webb, Kosiol, Carolin, Lawson, Heather A., Taliwal, Vikas, Martins, André L., Siepel, Adam, RoyChoudhury, Arindam, Ma, Xin, Degenhardt, Jeremiah, Bustamante, Carlos D., Gutenkunst, Ryan N., Mailund, Thomas, Dutheil, Julien Y., Hobolth, Asger, Schierup, Mikkel H., Ryder, Oliver A., Yoshinaga, Yuko, de Jong, Pieter J., Weinstock, George M., Rogers, Jeffrey, Mardis, Elaine R., Gibbs, Richard A., and Wilson, Richard K.

Published
2011
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48. Novel variation and de novo mutation rates in population-wide de novo assembled Danish trios

Author

Besenbacher, Søren, Liu, Siyang, Izarzugaza, José M. G., Grove, Jakob, Belling, Kirstine, Bork-Jensen, Jette, Huang, Shujia, Als, Thomas D., Li, Shengting, Yadav, Rachita, Rubio-García, Arcadio, Lescai, Francesco, Demontis, Ditte, Rao, Junhua, Ye, Weijian, Mailund, Thomas, Friborg, Rune M., Pedersen, Christian N. S., Xu, Ruiqi, Sun, Jihua, Liu, Hao, Wang, Ou, Cheng, Xiaofang, Flores, David, Rydza, Emil, Rapacki, Kristoffer, Damm Sørensen, John, Chmura, Piotr, Westergaard, David, Dworzynski, Piotr, Sørensen, Thorkild I. A., Lund, Ole, Hansen, Torben, Xu, Xun, Li, Ning, Bolund, Lars, Pedersen, Oluf, Eiberg, Hans, Krogh, Anders, Børglum, Anders D., Brunak, Søren, Kristiansen, Karsten, Schierup, Mikkel H., Wang, Jun, Gupta, Ramneek, Villesen, Palle, and Rasmussen, Simon

Published
2015
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49. Ancestral population genomics: the coalescent hidden Markov model approach

Author

Dutheil, Julien Y., Ganapathy, Ganesh, Hobolth, Asger, Mailund, Thomas, Uyenoyama, Marcy K., and Schierup, Mikkel H.

Subjects
Evolutionary genetics -- Research, Genetic recombination -- Research, Population genetics -- Research, Origin of species -- Research, Biological sciences
Published
2009

50. Expression of distinct self-incompatibility specificities in Arabidopsis thaliana

Author

Boggs, Nathan A., Dwyer, Kathleen G., Shah, Paurush, McCulloch, Amanda A., Bechsgaard, Jesper, Schierup, Mikkel H., Nasrallah, Mikhail E., and Nasrallah, June B.

Subjects
Arabidopsis thaliana -- Genetic aspects, Gene expression -- Research, Plant breeding -- Research, Plants -- Reproduction, Plants -- Research, Biological sciences
Published
2009

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