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Axelsson, Erik
Publications (10 of 24) Show all publications
Makino, T., Rubin, C.-J., Carneiro, M., Axelsson, E., Andersson, L. & Webster, M. T. (2018). Elevated proportions of deleterious genetic variation in domestic animals and plants. Genome Biology and Evolution, 10(1), 276-290
Open this publication in new window or tab >>Elevated proportions of deleterious genetic variation in domestic animals and plants
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2018 (English)In: Genome Biology and Evolution, ISSN 1759-6653, E-ISSN 1759-6653, Vol. 10, no 1, p. 276-290Article in journal (Refereed) Published
Abstract [en]

A fraction of genetic variants segregating in any population are deleterious, which negatively impacts individual fitness. The domestication of animals and plants is associated with population bottlenecks and artificial selection, which are predicted to increase the proportion of deleterious variants. However, the extent to which this is a general feature of domestic species is unclear. Here we examine the effects of domestication on the prevalence of deleterious variation using pooled whole-genome resequencing data from five domestic animal species (dog, pig, rabbit, chicken and silkworm) and two domestic plant species (rice and soybean) compared to their wild ancestors. We find significantly reduced genetic variation and increased proportion of nonsynonymous amino acid changes in all but one of the domestic species. These differences are observable across a range of allele frequencies, both common and rare. We find proportionally more SNPs in highly conserved elements in domestic species and a tendency for domestic species to harbour a higher proportion of changes classified as damaging. Our findings most likely reflect an increased incidence of deleterious variants in domestic species, which is most likely attributable to population bottlenecks that lead to a reduction in the efficacy of selection. An exception to this pattern is displayed by European domestic pigs, which do not show traces of a strong population bottleneck and probably continued to exchange genes with wild boar populations after domestication. The results presented here indicate that an elevated proportion of deleterious variants is a common, but not ubiquitous, feature of domestic species.

Place, publisher, year, edition, pages
Oxford University Press, 2018
Keywords
artificial selection, domestication, effective population size, mutational load, natural selection, population bottleneck
National Category
Evolutionary Biology Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-339437 (URN)10.1093/gbe/evy004 (DOI)000424893500020 ()29325102 (PubMedID)
Available from: 2018-01-18 Created: 2018-01-18 Last updated: 2018-04-10Bibliographically approved
Sakthikumar, S., Elvers, I., Kim, J., Arendt, M. L., Thomas, R., Turner-Maier, J., . . . Lindblad-Toh, K. (2018). SETD2 Is Recurrently Mutated in Whole-Exome Sequenced Canine Osteosarcoma. Cancer Research, 78(13), 3421-3431
Open this publication in new window or tab >>SETD2 Is Recurrently Mutated in Whole-Exome Sequenced Canine Osteosarcoma
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2018 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, no 13, p. 3421-3431Article in journal (Refereed) Published
Abstract [en]

Osteosarcoma is a debilitating bone cancer that affects humans, especially children and adolescents. A homologous form of osteosarcoma spontaneously occurs in dogs, and its differential incidence observed across breeds allows for the investigation of tumor mutations in the context of multiple genetic backgrounds. Using whole-exome sequencing and dogs from three susceptible breeds (22 golden retrievers, 21 Rottweilers, and 23 greyhounds), we found that osteosarcoma tumors show a high frequency of somatic copy-number alterations (SCNA), affecting key oncogenes and tumor-suppressor genes. The across-breed results are similar to what has been observed for human osteosarcoma, but the disease frequency and somatic mutation counts vary in the three breeds. For all breeds, three mutational signatures (one of which has not been previously reported) and 11 significantly mutated genes were identified. TP53 was the most frequently altered gene (83% of dogs have either mutations or SCNA in TP53), recapitulating observations in human osteosarcoma. The second most frequently mutated gene, histone methyltransferase SETD2, has known roles in multiple cancers, but has not previously been strongly implicated in osteosarcoma. This study points to the likely importance of histone modifications in osteosarcoma and highlights the strong genetic similarities between human and dog osteosarcoma, suggesting that canine osteosarcoma may serve as an excellent model for developing treatment strategies in both species. Significance: Canine osteosarcoma genomics identify SETD2 as a possible oncogenic driver of osteosarcoma, and findings establish the canine model as a useful comparative model for the corresponding human disease.

Place, publisher, year, edition, pages
AMER ASSOC CANCER RESEARCH, 2018
National Category
Genetics
Identifiers
urn:nbn:se:uu:diva-360424 (URN)10.1158/0008-5472.CAN-17-3558 (DOI)000437214300003 ()29724721 (PubMedID)
Funder
EU, European Research CouncilSwedish Research Council FormasSwedish Research CouncilEU, European Research Council
Available from: 2018-09-19 Created: 2018-09-19 Last updated: 2018-09-19Bibliographically approved
Ollivier, M., Tresset, A., Bastian, F., Lagoutte, L., Axelsson, E., Arendt, M. L., . . . Hanni, C. (2016). Amy2B copy number variation reveals starch diet adaptations in ancient European dogs. Royal Society Open Science, 3(11), Article ID 160449.
Open this publication in new window or tab >>Amy2B copy number variation reveals starch diet adaptations in ancient European dogs
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2016 (English)In: Royal Society Open Science, E-ISSN 2054-5703, Vol. 3, no 11, article id 160449Article in journal (Refereed) Published
Abstract [en]

Extant dog and wolf DNA indicates that dog domestication was accompanied by the selection of a series of duplications on the Amy2B gene coding for pancreatic amylase. In this study, we used a palaeogenetic approach to investigate the timing and expansion of the Amy2B gene in the ancient dog populations of Western and Eastern Europe and Southwest Asia. Quantitative polymerase chain reaction was used to estimate the copy numbers of this gene for 13 ancient dog samples, dated to between 15 000 and 4000 years before present (cal. BP). This evidenced an increase of Amy2B copies in ancient dogs from as early as the 7th millennium cal. BP in Southeastern Europe. We found that the gene expansion was not fixed across all dogs within this early farming context, with ancient dogs bearing between 2 and 20 diploid copies of the gene. The results also suggested that selection for the increased Amy2B copy number started 7000 years cal. BP, at the latest. This expansion reflects a local adaptation that allowed dogs to thrive on a starch rich diet, especially within early farming societies, and suggests a biocultural coevolution of dog genes and human culture.

Keywords
domestication, palaeogenomics, amylase, dog, Neolithic
National Category
Zoology Genetics
Identifiers
urn:nbn:se:uu:diva-312101 (URN)10.1098/rsos.160449 (DOI)000389244400020 ()
Available from: 2017-01-12 Created: 2017-01-04 Last updated: 2017-11-29Bibliographically approved
Olsson, M., Tengvall, K., Frankowiack, M., Kierczak, M., Bergvall, K., Axelsson, E., . . . Lindblad-Toh, K. (2015). Genome-Wide Analyses Suggest Mechanisms Involving Early B-cell Development in Canine IgA Deficiency. PLoS ONE, 10(7), Article ID e0133844.
Open this publication in new window or tab >>Genome-Wide Analyses Suggest Mechanisms Involving Early B-cell Development in Canine IgA Deficiency
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2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 7, article id e0133844Article in journal (Refereed) Published
Abstract [en]

Immunoglobulin A deficiency (IgAD) is the most common primary immune deficiency disorder in both humans and dogs, characterized by recurrent mucosal tract infections and a predisposition for allergic and other immune mediated diseases. In several dog breeds, low IgA levels have been observed at a high frequency and with a clinical resemblance to human IgAD. In this study, we used genome-wide association studies (GWAS) to identify genomic regions associated with low IgA levels in dogs as a comparative model for human IgAD. We used a novel percentile groups-approach to establish breed-specific cut-offs and to perform analyses in a close to continuous manner. GWAS performed in four breeds prone to low IgA levels (German shepherd, Golden retriever, Labrador retriever and Shar-Pei) identified 35 genomic loci suggestively associated (p <0.0005) to IgA levels. In German shepherd, three genomic regions (candidate genes include KIRREL3 and SERPINA9) were genome-wide significantly associated (p <0.0002) with IgA levels. A ~20kb long haplotype on CFA28, significantly associated (p = 0.0005) to IgA levels in Shar-Pei, was positioned within the first intron of the gene SLIT1. Both KIRREL3 and SLIT1 are highly expressed in the central nervous system and in bone marrow and are potentially important during B-cell development. SERPINA9 expression is restricted to B-cells and peaks at the time-point when B-cells proliferate into antibody-producing plasma cells. The suggestively associated regions were enriched for genes in Gene Ontology gene sets involving inflammation and early immune cell development.

Keywords
Genome-wide association studies, Dogs, IgA, immunodeficieny, B-cell
National Category
Medical Genetics Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-259595 (URN)10.1371/ journal.pone.0133844 (DOI)000358837700039 ()26225558 (PubMedID)
Funder
Swedish Research Council, 521-2012-2826, 521-2011-3515Swedish Research Council Formas, 221-2009-1689EU, European Research Council, 310203EU, FP7, Seventh Framework Programme, GA-201370
Available from: 2015-08-10 Created: 2015-08-10 Last updated: 2018-01-11Bibliographically approved
Webster, M. T., Kamgari, N., Perloski, M., Höppner, M. P., Axelsson, E., Hedhammar, A., . . . Lindblad-Toh, K. (2015). Linked genetic variants on chromosome 10 control ear morphology and body mass among dog breeds. BMC Genomics, 16, Article ID 474.
Open this publication in new window or tab >>Linked genetic variants on chromosome 10 control ear morphology and body mass among dog breeds
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2015 (English)In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 16, article id 474Article in journal (Refereed) Published
Abstract [en]

Background: The domestic dog is a rich resource for mapping the genetic components of phenotypic variation due to its unique population history involving strong artificial selection. Genome-wide association studies have revealed a number of chromosomal regions where genetic variation associates with morphological characters that typify dog breeds. A region on chromosome 10 is among those with the highest levels of genetic differentiation between dog breeds and is associated with body mass and ear morphology, a common motif of animal domestication. We characterised variation in this region to uncover haplotype structure and identify candidate functional variants. Results: We first identified SNPs that strongly associate with body mass and ear type by comparing sequence variation in a 3 Mb region between 19 breeds with a variety of phenotypes. We next genotyped a subset of 123 candidate SNPs in 288 samples from 46 breeds to identify the variants most highly associated with phenotype and infer haplotype structure. A cluster of SNPs that associate strongly with the drop ear phenotype is located within a narrow interval downstream of the gene MSRB3, which is involved in human hearing. These SNPs are in strong genetic linkage with another set of variants that correlate with body mass within the gene HMGA2, which affects human height. In addition we find evidence that this region has been under selection during dog domestication, and identify a cluster of SNPs within MSRB3 that are highly differentiated between dogs and wolves. Conclusions: We characterise genetically linked variants that potentially influence ear type and body mass in dog breeds, both key traits that have been modified by selective breeding that may also be important for domestication. The finding that variants on long haplotypes have effects on more than one trait suggests that genetic linkage can be an important determinant of the phenotypic response to selection in domestic animals.

Keywords
Artificial selection, Dogs, Ear morphology, Body mass, Genome-wide association study
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-258328 (URN)10.1186/s12864-015-1702-2 (DOI)000356583300001 ()26100605 (PubMedID)
Funder
Swedish Research CouncilEU, FP7, Seventh Framework Programme, LUPA-GA201370
Available from: 2015-07-15 Created: 2015-07-13 Last updated: 2017-12-04Bibliographically approved
Arendt, M., Fall, T., Lindblad-Toh, K. & Axelsson, E. (2014). Amylase activity is associated with AMY2B copy numbers in dog: implications for dog domestication, diet and diabetes. Animal Genetics, 45(5), 716-722
Open this publication in new window or tab >>Amylase activity is associated with AMY2B copy numbers in dog: implications for dog domestication, diet and diabetes
2014 (English)In: Animal Genetics, ISSN 0268-9146, E-ISSN 1365-2052, Vol. 45, no 5, p. 716-722Article in journal (Refereed) Published
Abstract [en]

High amylase activity in dogs is associated with a drastic increase in copy numbers of the gene coding for pancreatic amylase, AMY2B, that likely allowed dogs to thrive on a relatively starch-rich diet during early dog domestication. Although most dogs thus probably digest starch more efficiently than do wolves, AMY2B copy numbers vary widely within the dog population, and it is not clear how this variation affects the individual ability to handle starch nor how it affects dog health. In humans, copy numbers of the gene coding for salivary amylase, AMY1, correlate with both salivary amylase levels and enzyme activity, and high amylase activity is related to improved glycemic homeostasis and lower frequencies of metabolic syndrome. Here, we investigate the relationship between AMY2B copy numbers and serum amylase activity in dogs and show that amylase activity correlates with AMY2B copy numbers. We then describe how AMY2B copy numbers vary in individuals from 20 dog breeds and find strong breed-dependent patterns, indicating that the ability to digest starch varies both at the breed and individual level. Finally, to test whether AMY2B copy number is strongly associated with the risk of developing diabetes mellitus, we compare copy numbers in cases and controls as well as in breeds with varying diabetes susceptibility. Although we see no such association here, future studies using larger cohorts are needed before excluding a possible link between AMY2B and diabetes mellitus.

National Category
Genetics
Identifiers
urn:nbn:se:uu:diva-232427 (URN)10.1111/age.12179 (DOI)000341682200012 ()24975239 (PubMedID)
Available from: 2014-09-17 Created: 2014-09-17 Last updated: 2017-12-05Bibliographically approved
Axelsson, E., Ratnakumar, A., Arendt, M. L., Maqbool, K., Webster, M. T., Perloski, M., . . . Lindblad-Toh, K. (2013). The genomic signature of dog domestication reveals adaptation to a starch-rich diet. Nature, 495(7441), 360-364
Open this publication in new window or tab >>The genomic signature of dog domestication reveals adaptation to a starch-rich diet
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2013 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 495, no 7441, p. 360-364Article in journal (Refereed) Published
Abstract [en]

The domestication of dogs. was an important episode in the development of human civilization. The precise timing and location of this event is debated(1-5) and little is known about the genetic changes that accompanied the transformation of ancient wolves into domestic dogs. Here we conduct whole-genome resequencimg of dogs and wolves to identify 3.8 million genetic variants used to identify 36 genomic regions that probably represent targets for selection during dog domestication. Nineteen of these regions contain genes important in brain function, eight of which belong to nervous system development pathways and potentially underlie behavioural changes central to dog domestication(6). Ten genes with key roles in starch digestion and fat metabolism also show signals of selection. We identify candidate mutations in key genes and provide functional support for an increased starch digestion in dogs relative to wolves. Our results indicate that novel adaptations allowing the early ancestors of modern dogs to thrive on a diet rich in starch, relative to the carnivorous diet of wolves, constituted a crucial step in the early domestication of dogs.

National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-198620 (URN)10.1038/nature11837 (DOI)000316650500041 ()
Available from: 2013-04-22 Created: 2013-04-22 Last updated: 2017-12-06Bibliographically approved
Axelsson, E. & Webster, M. (2011). Base Composition Patterns [Review]. Encyclopedia of Life Sciences
Open this publication in new window or tab >>Base Composition Patterns
2011 (English)In: Encyclopedia of Life Sciences, ISSN 1561592617 9781561592616Article, book review (Refereed) Published
National Category
Evolutionary Biology
Identifiers
urn:nbn:se:uu:diva-170494 (URN)
Available from: 2012-03-12 Created: 2012-03-12 Last updated: 2016-04-08
Axelsson, E., Webster, M. T., Ratnakumar, A., Ponting, C. P. & Lindblad-Toh, K. (2011). Death of PRDM9 coincides with stabilization of the recombination landscape in the dog genome. Genome Research, 22(1), 51-63
Open this publication in new window or tab >>Death of PRDM9 coincides with stabilization of the recombination landscape in the dog genome
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2011 (English)In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 22, no 1, p. 51-63Article in journal (Refereed) Published
Abstract [en]

Analysis of diverse eukaryotes has revealed that recombination events cluster in discrete genomic locations known as hotspots. In humans, a zinc-finger protein, PRDM9, is believed to initiate recombination in >40% of hotspots by binding to a specific DNA sequence motif. However, the PRDM9 coding sequence is disrupted in the dog genome assembly, raising questions regarding the nature and control of recombination in dogs. By analyzing the sequences of PRDM9 orthologs in a number of dog breeds and several carnivores, we show here that this gene was inactivated early in canid evolution. We next use patterns of linkage disequilibrium using more than 170,000 SNP markers typed in almost 500 dogs to estimate the recombination rates in the dog genome using a coalescent-based approach. Broad-scale recombination rates show good correspondence with an existing linkage-based map. Significant variation in recombination rate is observed on the fine scale, and we are able to detect over 4000 recombination hotspots with high confidence. In contrast to human hotspots, 40% of canine hotspots are characterized by a distinct peak in GC content. A comparative genomic analysis indicates that these peaks are present also as weaker peaks in the panda, suggesting that the hotspots have been continually reinforced by accelerated and strongly GC biased nucleotide substitutions, consistent with the long-term action of biased gene conversion on the dog lineage. These results are consistent with the loss of PRDM9 in canids, resulting in a greater evolutionary stability of recombination hotspots. The genetic determinants of recombination hotspots in the dog genome may thus reflect a fundamental process of relevance to diverse animal species.

National Category
Biochemistry and Molecular Biology Genetics
Identifiers
urn:nbn:se:uu:diva-162828 (URN)10.1101/gr.124123.111 (DOI)000298854200005 ()22006216 (PubMedID)
Funder
Swedish National Infrastructure for Computing (SNIC), b2009001Swedish Research CouncilEU, European Research Council
Available from: 2011-12-05 Created: 2011-12-05 Last updated: 2017-12-08Bibliographically approved
Vaysse, A., Ratnakumar, A., Derrien, T., Axelsson, E., Rosengren Pielberg, G., Sigurdsson, S., . . . Webster, M. T. (2011). Identification of genomic regions associated with phenotypic variation between dog breeds using selection mapping. PLoS Genetics, 7(10), e1002316
Open this publication in new window or tab >>Identification of genomic regions associated with phenotypic variation between dog breeds using selection mapping
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2011 (English)In: PLoS Genetics, ISSN 1553-7404, Vol. 7, no 10, p. e1002316-Article in journal (Refereed) Published
Abstract [en]

The extraordinary phenotypic diversity of dog breeds has been sculpted by a unique population history accompanied by selection for novel and desirable traits. Here we perform a comprehensive analysis using multiple test statistics to identify regions under selection in 509 dogs from 46 diverse breeds using a newly developed high-density genotyping array consisting of >170,000 evenly spaced SNPs. We first identify 44 genomic regions exhibiting extreme differentiation across multiple breeds. Genetic variation in these regions correlates with variation in several phenotypic traits that vary between breeds, and we identify novel associations with both morphological and behavioral traits. We next scan the genome for signatures of selective sweeps in single breeds, characterized by long regions of reduced heterozygosity and fixation of extended haplotypes. These scans identify hundreds of regions, including 22 blocks of homozygosity longer than one megabase in certain breeds. Candidate selection loci are strongly enriched for developmental genes. We chose one highly differentiated region, associated with body size and ear morphology, and characterized it using high-throughput sequencing to provide a list of variants that may directly affect these traits. This study provides a catalogue of genomic regions showing extreme reduction in genetic variation or population differentiation in dogs, including many linked to phenotypic variation. The many blocks of reduced haplotype diversity observed across the genome in dog breeds are the result of both selection and genetic drift, but extended blocks of homozygosity on a megabase scale appear to be best explained by selection. Further elucidation of the variants under selection will help to uncover the genetic basis of complex traits and disease.

National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-162827 (URN)10.1371/journal.pgen.1002316 (DOI)000296665400017 ()22022279 (PubMedID)
Available from: 2011-12-05 Created: 2011-12-05 Last updated: 2014-09-19Bibliographically approved
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