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  • 1.
    Almén, Markus Sällman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lamichhaney, Sangeet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Berglund, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Grant, B. Rosemary
    Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA..
    Grant, Peter R.
    Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA..
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden.;Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX USA..
    Adaptive radiation of Darwin's finches revisited using whole genome sequencing2016In: Bioessays, ISSN 0265-9247, E-ISSN 1521-1878, Vol. 38, no 1, p. 14-20Article in journal (Refereed)
    Abstract [en]

    We recently used genome sequencing to study the evolutionary history of the Darwin's finches. A prominent feature of our data was that different polymorphic sites in the genome tended to indicate different genetic relationships among these closely related species. Such patterns are expected in recently diverged genomes as a result of incomplete lineage sorting. However, we uncovered conclusive evidence that these patterns have also been influenced by interspecies hybridisation, a process that has likely played an important role in the radiation of Darwin's finches. A major discovery was that segregation of two haplotypes at the ALX1 locus underlies variation in beak shape among the Darwin's finches, and that differences between the two haplotypes in a 240 kb region in blunt and pointed beaked birds involve both coding and regulatory changes. As we review herein, the evolution of such adaptive haplotypes comprising multiple causal changes appears to be an important mechanism contributing to the evolution of biodiversity.

  • 2.
    Axelsson, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ratnakumar, Abhirami
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Arendt, Maja Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Maqbool, Khurram
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Perloski, Michele
    Liberg, Olof
    Arnemo, Jon M.
    Hedhammar, Ake
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    The genomic signature of dog domestication reveals adaptation to a starch-rich diet2013In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 495, no 7441, p. 360-364Article in journal (Refereed)
    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.

  • 3.
    Axelsson, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ratnakumar, Abhirami
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ponting, Chris P.
    Univ Oxford, MRC Funct Genom Unit, Dept Physiol Anat & Genet, Oxford OX1 3QX, England.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Broad Inst Massachusetts Inst Technol & Harvard, Cambridge, MA 02139 USA.
    Death of PRDM9 coincides with stabilization of the recombination landscape in the dog genome2011In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 22, no 1, p. 51-63Article in journal (Refereed)
    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.

  • 4.
    Axelsson, Erik
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics, Evolutionary Biology. Evolutionsbiologi.
    Webster, Matthew T
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics, Evolutionary Biology. Evolutionsbiologi.
    Smith, Nick G C
    Burt, David W
    Ellegren, Hans
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics, Evolutionary Biology. Evolutionsbiologi.
    Comparison of the chicken and turkey genomes reveals a higher rate of nucleotide divergence on microchromosomes than macrochromosomes.2005In: Genome Res, ISSN 1088-9051, Vol. 15, no 1, p. 120-5Article in journal (Refereed)
    Abstract [en]

    A distinctive feature of the avian genome is the large heterogeneity in the size of chromosomes, which are usually classified into a small number of macrochromosomes and numerous microchromosomes. These chromosome classes show characteristic differences in a number of interrelated features that could potentially affect the rate of sequence evolution, such as GC content, gene density, and recombination rate. We studied the effects of these factors by analyzing patterns of nucleotide substitution in two sets of chicken-turkey sequence alignments. First, in a set of 67 orthologous introns, divergence was significantly higher in microchromosomes (chromosomes 11-38; 11.7% divergence) than in both macrochromosomes (chromosomes 1-5; 9.9% divergence; P = 0.016) and intermediate-sized chromosomes (chromosomes 6-10; 9.5% divergence; P = 0.026). At least part of this difference was due to the higher incidence of CpG sites on microchromosomes. Second, using 155 orthologous coding sequences we noted a similar pattern, in which synonymous substitution rates on microchromosomes (13.1%) were significantly higher than were rates on macrochromosomes (10.3%; P = 0.024). Broadly assuming neutrality of introns and synonymous sites, or constraints on such sequences do not differ between chromosomal classes, these observations imply that microchromosomal genes are exposed to more germ line mutations than those on other chromosomes. We also find that dN/dS ratios for genes located on microchromosomes (average, 0.094) are significantly lower than those of macrochromosomes (average, 0.185; P = 0.025), suggesting that the proteins of genes on microchromosomes are under greater evolutionary constraint.

  • 5.
    Backström, Niclas
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Forstmeier, Wolfgang
    Schielzeth, Holger
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Mellenius, Harriet
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Nam, Kiwoong
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Bolund, Elisabeth
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Öst, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Schneider, Melanie
    Kempenaers, Bart
    Ellegren, Hans
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    The recombination landscape of the zebra finch Taeniopygia guttata genome2010In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 20, no 4, p. 485-495Article in journal (Refereed)
    Abstract [en]

    Understanding the causes and consequences of variation in the rate of recombination is essential since this parameter is considered to affect levels of genetic variability, the efficacy of selection, and the design of association and linkage mapping studies. However, there is limited knowledge about the factors governing recombination rate variation. We genotyped 1920 single nucleotide polymorphisms in a multigeneration pedigree of more than 1000 zebra finches (Taeniopygia guttata) to develop a genetic linkage map, and then we used these map data together with the recently available draft genome sequence of the zebra finch to estimate recombination rates in 1 Mb intervals across the genome. The average zebra finch recombination rate (1.5 cM/Mb) is higher than in humans, but significantly lower than in chicken. The local rates of recombination in chicken and zebra finch were only weakly correlated, demonstrating evolutionary turnover of the recombination landscape in birds. The distribution of recombination events was heavily biased toward ends of chromosomes, with a stronger telomere effect than so far seen in any organism. In fact, the recombination rate was as low as 0.1 cM/Mb in intervals up to 100 Mb long in the middle of the larger chromosomes. We found a positive correlation between recombination rate and GC content, as well as GC-rich sequence motifs. Levels of linkage disequilibrium (LD) were significantly higher in regions of low recombination, showing that heterogeneity in recombination rates have left a footprint on the genomic landscape of LD in zebra finch populations.

  • 6. Bannasch, Danika
    et al.
    Young, Amy
    Myers, Jeffrey
    Truvé, Katarina
    Dickinson, Peter
    Gregg, Jeffrey
    Davis, Ryan
    Bongcam-Rudloff, Eric
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pedersen, Niels
    Localization of canine brachycephaly using an across breed mapping approach2010In: PLoS ONE, ISSN 1932-6203, Vol. 5, no 3, p. e9632-Article in journal (Refereed)
    Abstract [en]

    The domestic dog, Canis familiaris, exhibits profound phenotypic diversity and is an ideal model organism for the genetic dissection of simple and complex traits. However, some of the most interesting phenotypes are fixed in particular breeds and are therefore less tractable to genetic analysis using classical segregation-based mapping approaches. We implemented an across breed mapping approach using a moderately dense SNP array, a low number of animals and breeds carefully selected for the phenotypes of interest to identify genetic variants responsible for breed-defining characteristics. Using a modest number of affected (10-30) and control (20-60) samples from multiple breeds, the correct chromosomal assignment was identified in a proof of concept experiment using three previously defined loci; hyperuricosuria, white spotting and chondrodysplasia. Genome-wide association was performed in a similar manner for one of the most striking morphological traits in dogs: brachycephalic head type. Although candidate gene approaches based on comparable phenotypes in mice and humans have been utilized for this trait, the causative gene has remained elusive using this method. Samples from nine affected breeds and thirteen control breeds identified strong genome-wide associations for brachycephalic head type on Cfa 1. Two independent datasets identified the same genomic region. Levels of relative heterozygosity in the associated region indicate that it has been subjected to a selective sweep, consistent with it being a breed defining morphological characteristic. Genotyping additional dogs in the region confirmed the association. To date, the genetic structure of dog breeds has primarily been exploited for genome wide association for segregating traits. These results demonstrate that non-segregating traits under strong selection are equally tractable to genetic analysis using small sample numbers.

  • 7. Belle, Elise M S
    et al.
    Webster, Matthew T
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics, Evolutionary Biology. Evolutionsbiologi.
    Eyre-Walker, Adam
    Why are young and old repetitive elements distributed differently in the human genome?2005In: J Mol Evol, ISSN 0022-2844, Vol. 60, no 3, p. 290-6Article in journal (Refereed)
    Abstract [en]

    Alu elements are not distributed homogeneously throughout the human genome: old elements are preferentially found in the GC-rich parts of the genome, while young Alus are more often found in the GC-poor parts of the genome. The process giving rise to this differential distribution remains poorly understood. Here we investigate whether this pattern could be due to a preferential degradation of Alu elements integrated in GC-poor regions by small indel mutations. We aligned 5.1 Mb of human and chimpanzee sequences and examined whether the rate of insertion and deletion inside Alu elements differed according to the base composition surrounding them. We found that Alu elements are not preferentially degraded in GC-poor regions by indel events. We also looked at whether very young L1 elements show the same change in distribution compared to older ones. This analysis indicated that L1 elements also show a shift in their distribution, although we could not assess it as precisely as for Alu elements. We propose that the differential distribution of Alu elements is likely to be due to a change in their pattern of insertion or their probability of fixation through evolutionary time.

  • 8.
    Berglund, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nevalainen, Elisa M
    Molin, Anna-Maja
    Perloski, Michele
    André, Catherine
    Zody, Michael C
    Sharpe, Ted
    Hitte, Christophe
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lohi, Hannes
    Webster, Matthew T
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Novel origins of copy number variation in the dog genome2012In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 13, no 8, p. R73-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Copy number variants (CNVs) account for substantial variation between genomes and are a major source of normal and pathogenic phenotypic differences. The dog is an ideal model to investigate mutational mechanisms that generate CNVs as its genome lacks a functional ortholog of the PRDM9 gene implicated in recombination and CNV formation in humans. Here we comprehensively assay CNVs using high-density array comparative genomic hybridization in 50 dogs from 17 dog breeds and 3 gray wolves. RESULTS: We use a stringent new method to identify a total of 430 high-confidence CNV loci, which range in size from 9 kb to 1.6 Mb and span 26.4 Mb, or 1.08%, of the assayed dog genome, overlapping 413 annotated genes. Of CNVs observed in each breed, 98% are also observed in multiple breeds. CNVs predicted to disrupt gene function are significantly less common than expected by chance. We identify a significant overrepresentation of peaks of GC content, previously shown to be enriched in dog recombination hotspots, in the vicinity of CNV breakpoints. CONCLUSIONS: A number of the CNVs identified by this study are candidates for generating breed-specific phenotypes. Purifying selection seems to be a major factor shaping structural variation in the dog genome, suggesting that many CNVs are deleterious. Localized peaks of GC content appear to be novel sites of CNV formation in the dog genome by non-allelic homologous recombination, potentially activated by the loss of PRDM9. These sequence features may have driven genome instability and chromosomal rearrangements throughout canid evolution.

  • 9.
    Berglund, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pollard, Katherine S.
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hotspots of biased nucleotide substitutions in human genes2009In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 7, no 1, p. e26-Article in journal (Refereed)
    Abstract [en]

    Genes that have experienced accelerated evolutionary rates on the human lineage during recent evolution are candidates for involvement in human-specific adaptations. To determine the forces that cause increased evolutionary rates in certain genes, we analyzed alignments of 10,238 human genes to their orthologues in chimpanzee and macaque. Using a likelihood ratio test, we identified protein-coding sequences with an accelerated rate of base substitutions along the human lineage. Exons evolving at a fast rate in humans have a significant tendency to contain clusters of AT-to-GC (weak-to-strong) biased substitutions. This pattern is also observed in noncoding sequence flanking rapidly evolving exons. Accelerated exons occur in regions with elevated male recombination rates and exhibit an excess of nonsynonymous substitutions relative to the genomic average. We next analyzed genes with significantly elevated ratios of nonsynonymous to synonymous rates of base substitution (dN/dS) along the human lineage, and those with an excess of amino acid replacement substitutions relative to human polymorphism. These genes also show evidence of clusters of weak-to-strong biased substitutions. These findings indicate that a recombination-associated process, such as biased gene conversion (BGC), is driving fixation of GC alleles in the human genome. This process can lead to accelerated evolution in coding sequences and excess amino acid replacement substitutions, thereby generating significant results for tests of positive selection.

  • 10.
    Berglund, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Quilez, Javier
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Arndt, Peter F.
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Germ line Methylation Patterns Determine the Distribution of Recombination Events in the Dog Genome2015In: Genome Biology and Evolution, ISSN 1759-6653, E-ISSN 1759-6653, Vol. 7, no 2, p. 522-530Article in journal (Refereed)
    Abstract [en]

    The positive-regulatory domain containing nine gene, PROMO, which strongly associates with the location of recombination events in several vertebrates, is inferred to be inactive in the dog genome. Here, we address several questions regarding the control of recombination and its influence on genome evolution in dogs. First, we address whether the association between CpG islands (CGIs) and recombination hotspots is generated by lack of methylation, GC-biased gene conversion (gBGC), or both. Using a genome-wide dog single nucleotide polymorphism data set and comparisons of the dog genome with related species, we show that recombination-associated CGIs have low CpG mutation rates, and that CpG mutation rate is negatively correlated with recombination rate genome wide, indicating that nonmethylation attracts the recombination machinery. We next use a neighbor-dependent model of nucleotide substitution to disentangle the effects of CpG mutability and gBGC and analyze the effects that loss of PROMO has on these rates. We infer that methylation patterns have been stable during canid genome evolution, but that dog CGIs have experienced a drastic increase in substitution rate due to gBGC, consistent with increased levels of recombination in these regions. We also show that gBGC is likely to have generated many new CGIs in the dog genome, but these mostly occur away from genes, whereas the number of C GIs in gene promoter regions has not increased greatly in recent evolutionary history. Recombination has a major impact on the distribution of CGIs that are detected in the dog genome due to the interaction between methylation and gBGC. The results indicate that germline methylation patterns are the main determinant of recombination rates in the absence of PRDM9.

  • 11.
    Berglund, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Quilez, Javier
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Webster, Matthew
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Germline Metyhlation Patterns Determine The Distribution Of Recombination Events In The Dog GenomeIn: Genome Biology and Evolution, ISSN 1759-6653, E-ISSN 1759-6653Article in journal (Refereed)
  • 12.
    Björnerfeldt, Susanne
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Vilà, Carles
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Relaxation of selective constraint on dog mitochondrial DNA following domestication2006In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 16, no 8, p. 990-994Article in journal (Refereed)
    Abstract [en]

    The domestication of dogs caused a dramatic change in their way of life compared with that of their ancestor, the gray wolf. We hypothesize that this new life style changed the selective forces that acted upon the species, which in turn had an effect on the dog's genome. We sequenced the complete mitochondrial DNA genome in 14 dogs, six wolves, and three coyotes. Here we show that dogs have accumulated nonsynonymous changes in mitochondrial genes at a faster rate than wolves, leading to elevated levels of variation in their proteins. This suggests that a major consequence of domestication in dogs was a general relaxation of selective constraint on their mitochondrial genome. If this change also affected other parts of the dog genome, it could have facilitated the generation of novel functional genetic diversity. This diversity could thus have contributed raw material upon which artificial selection has shaped modern breeds and may therefore be an important source of the extreme phenotypic variation present in modern-day dogs.

  • 13. Borge, Kaja Sverdrup
    et al.
    Melin, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rivera, Patricio
    Thoresen, Stein Istre
    Webster, Matthew Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    von Euler, Henrik
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lingaas, Frode
    The ESR1 gene is associated with risk for canine mammary tumours2013In: BMC Veterinary Research, ISSN 1746-6148, E-ISSN 1746-6148, Vol. 9, p. 69-Article in journal (Refereed)
    Abstract [en]

    Background: The limited within-breed genetic heterogeneity and an enrichment of disease-predisposing alleles have made the dog a very suitable model for the identification of genes associated with risk for specific diseases. Canine mammary cancer is an example of such a disease. However, the underlying inherited risk factors for canine mammary tumours (CMTs) are still largely unknown. In this study, 52 single nucleotide polymorphisms (SNPs) in ten human cancer-associated genes were genotyped in two different datasets in order to identify genes/alleles associated with the development of CMTs. The first dataset consisted of English Springer Spaniel (ESS) CMT cases and controls. ESS is a dog breed known to be at increased risk of developing CMTs. In the second dataset, dogs from breeds known to have a high frequency of CMTs were compared to dogs from breeds with a lower occurrence of these tumours. Results: We found significant associations to CMT for SNPs and haplotypes in the estrogen receptor 1 (ESR1) gene in the ESS material (best P-Bonf = 0.021). A large number of SNPs, among them several SNPs in ESR1, showed significantly different allele frequencies between the high and low risk breed groups (best P-Bonf = 8.8E-32, best P-BPerm = 0.076). Conclusions: The identification of CMT-associated SNPs in ESR1 in two independent datasets suggests that this gene might be involved in CMT development. These findings also support that CMT may serve as a good model for human breast cancer research.

  • 14. Borge, Thomas
    et al.
    Webster, Matthew T
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics.
    Andersson, Gunilla
    Saetre, Glenn-Peter
    Contrasting patterns of polymorphism and divergence on the Z chromosome and autosomes in two Ficedula flycatcher species2005In: Genetics, ISSN 0016-6731, E-ISSN 1943-2631, Vol. 171, no 4, p. 1861-1873Article in journal (Refereed)
    Abstract [en]

    In geographic areas where pied and collared flycatchers (Ficedula hypoleuca and F. albicollis) breed in sympatry, hybridization occurs, leading to gene flow (introgression) between the two recently diverged species. Notably, while such introgression is observable at autosomal loci it is apparently absent at the Z chromosome, suggesting an important role for genes on the Z chromosome in creating reproductive isolation during speciation. To further understand the role of Z-linked loci in the formation of new species, we studied genetic variation of the two species from regions where they live in allopatry. We analyzed patterns of polymorphism and divergence in introns from 9 Z-linked and 23 autosomal genes in pied and collared flycatcher males. Average variation on the Z chromosome is greatly reduced compared to neutral expectations based on autosomal diversity in both species. We also observe significant heterogeneity between patterns of polymorphism and divergence at Z-linked loci and a relative absence of polymorphisms that are shared by the two species on the Z chromosome compared to the autosomes. We suggest that these observations may indicate the action of recurrent selective sweeps on the Z chromosome during the evolution of the two species, which may be caused by sexual selection acting on Z-linked genes. Alternatively, reduced variation on the Z chromosome could result from substantially higher levels of introgression at autosomal than at Z-linked loci or from a complex demographic history, such as a population bottleneck.

  • 15.
    Christmas, Matthew J
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wallberg, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bunikis, Ignas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Olsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wallerman, Ola
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Webster, Matthew T
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Chromosomal inversions associated with environmental adaptation in honeybees2019In: Molecular Ecology, ISSN 0962-1083, E-ISSN 1365-294X, Vol. 28, no 6, p. 1358-1374Article in journal (Refereed)
    Abstract [en]

    Chromosomal inversions can facilitate local adaptation in the presence of gene flow by suppressing recombination between well-adapted native haplotypes and poorly adapted migrant haplotypes. East African mountain populations of the honeybee Apis mellifera are highly divergent from neighbouring lowland populations at two extended regions in the genome, despite high similarity in the rest of the genome, suggesting that these genomic regions harbour inversions governing local adaptation. Here, we utilize a new highly contiguous assembly of the honeybee genome to characterize these regions. Using whole-genome sequencing data from 55 highland and lowland bees, we find that the highland haplotypes at both regions are present at high frequencies in three independent highland populations but extremely rare elsewhere. The boundaries of both divergent regions are characterized by regions of high homology with each other positioned in opposite orientations and contain highly repetitive, long inverted repeats with homology to transposable elements. These regions are likely to represent inversion breakpoints that participate in nonallelic homologous recombination. Using long-read data, we confirm that the lowland samples are contiguous across breakpoint regions. We do not find evidence for disruption of functional sequence by these breakpoints, which suggests that the inversions are likely maintained due to their allelic content conferring local adaptation in highland environments. Finally, we identify a third divergent genomic region, which contains highly divergent segregating haplotypes that also may contain inversion variants under selection. The results add to a growing body of evidence indicating the importance of chromosomal inversions in local adaptation.

  • 16. Cruz, F.
    et al.
    Vilà, C.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    The legacy of domestication: Accumulation of deleterious mutations in the dog genome2008In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 25, no 11, p. 2331-2336Article in journal (Refereed)
    Abstract [en]

    Dogs exhibit more phenotypic variation than any other mammal and are affected by a wide variety of genetic diseases. However, the origin and genetic basis of this variation is still poorly understood. We examined the effect of domestication on the dog genome by comparison with its wild ancestor, the gray wolf. We compared variation in dog and wolf genes using whole-genome single nucleotide polymorphism (SNP) data. The d(N)/d(S) ratio (omega) was around 50% greater for SNPs found in dogs than in wolves, indicating that a higher proportion of nonsynonymous alleles segregate in dogs compared with nonfunctional genetic variation. We suggest that the majority of these alleles are slightly deleterious and that two main factors may have contributed to their increase. The first is a relaxation of selective constraint due to a population bottleneck and altered breeding patterns accompanying domestication. The second is a reduction of effective population size at loci linked to those under positive selection due to Hill-Robertson interference. An increase in slightly deleterious genetic variation could contribute to the prevalence of disease in modern dog breeds.

  • 17.
    Han, Fan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lamichhaney, Sangeet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Grant, B Rosemary
    Princeton Univ, Dept Ecol & Evolut Biol, Princeton, NJ 08544 USA.
    Grant, Peter R
    Princeton Univ, Dept Ecol & Evolut Biol, Princeton, NJ 08544 USA.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Swedish Univ Agr Sci, Dept Anim Breeding & Genet, S-75007 Uppsala, Sweden; Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX 77843 USA.
    Webster, Matthew Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gene flow, ancient polymorphism, and ecological adaptation shape the genomic landscape of divergence among Darwin's finches2017In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 27, no 6, p. 1004-1015Article in journal (Refereed)
    Abstract [en]

    Genomic comparisons of closely related species have identified "islands" of locally elevated sequence divergence. Genomic islands may contain functional variants involved in local adaptation or reproductive isolation and may therefore play an important role in the speciation process. However, genomic islands can also arise through evolutionary processes unrelated to speciation, and examination of their properties can illuminate how new species evolve. Here, we performed scans for regions of high relative divergence (FST) in 12 species pairs of Darwin's finches at different genetic distances. In each pair, we identify genomic islands that are, on average, elevated in both relative divergence (FST) and absolute divergence (dXY). This signal indicates that haplotypes within these genomic regions became isolated from each other earlier than the rest of the genome. Interestingly, similar numbers of genomic islands of elevated dXY are observed in sympatric and allopatric species pairs, suggesting that recent gene flow is not a major factor in their formation. We find that two of the most pronounced genomic islands contain the ALX1 and HMGA2 loci, which are associated with variation in beak shape and size, respectively, suggesting that they are involved in ecological adaptation. A subset of genomic island regions, including these loci, appears to represent anciently diverged haplotypes that evolved early during the radiation of Darwin's finches. Comparative genomics data indicate that these loci, and genomic islands in general, have exceptionally low recombination rates, which may play a role in their establishment.

  • 18.
    Han, Fan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wallberg, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Webster, Matthew T
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    From where did the Western honeybee (Apis mellifera) originate?2012In: Ecology and evolution, ISSN 2045-7758, Vol. 2, no 8, p. 1949-1957Article in journal (Refereed)
    Abstract [en]

    The native range of the honeybee Apis mellifera encompasses Europe, Africa, and the Middle East, whereas the nine other species of Apis are found exclusively in Asia. It is therefore commonly assumed that A. mellifera arose in Asia and expanded into Europe and Africa. However, other hypotheses for the origin of A. mellifera have also been proposed based on phylogenetic trees constructed from genetic markers. In particular, an analysis based on >1000 single-nucleotide polymorphism markers placed the root of the tree of A. mellifera subspecies among samples from Africa, suggestive of an out-of-Africa expansion. Here, we re-evaluate the evidence for this and other hypotheses by testing the robustness of the tree topology to different tree-building methods and by removing specimens with a potentially hybrid background. These analyses do not unequivocally place the root of the tree of A. mellifera subspecies within Africa, and are potentially consistent with a variety of hypotheses for honeybee evolution, including an expansion out of Asia. Our analyses also support high divergence between western and eastern European populations of A. mellifera, suggesting they are likely derived from two distinct colonization routes, although the sources of these expansions are still unclear.

  • 19.
    Henriques, Dora
    et al.
    Univ Minho, Ctr Mol & Environm Biol CBMA, Braga, Portugal;Polytech Inst Braganca, Mt Res Ctr CIMO, Braganca, Portugal.
    Parejo, Melanie
    Agroscope, Swiss Bee Res Ctr, Bern, Switzerland;Univ Bern, Vetsuisse Fac, Inst Bee Hlth, Bern, Switzerland.
    Vignal, Alain
    Univ Toulouse, GenPhySE, INRA, INPT,INP ENVT, Castanet Tolosan, France.
    Wragg, David
    Univ Edinburgh, Roslin Inst, Edinburgh, Midlothian, Scotland.
    Wallberg, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Webster, Matthew Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pinto, M. Alice
    Polytech Inst Braganca, Mt Res Ctr CIMO, Braganca, Portugal.
    Developing reduced SNP assays from whole-genome sequence data to estimate introgression in an organism with complex genetic patterns, the Iberian honeybee (Apis mellifera iberiensis)2018In: Evolutionary Applications, ISSN 1752-4571, E-ISSN 1752-4571, Vol. 11, no 8, p. 1270-1282Article in journal (Refereed)
    Abstract [en]

    The most important managed pollinator, the honeybee (Apis mellifera L.), has been subject to a growing number of threats. In western Europe, one such threat is large-scale introductions of commercial strains (C-lineage ancestry), which is leading to introgressive hybridization and even the local extinction of native honeybee populations (M-lineage ancestry). Here, we developed reduced assays of highly informative SNPs from 176 whole genomes to estimate C-lineage introgression in the most diverse and evolutionarily complex subspecies in Europe, the Iberian honeybee (Apis mellifera iberiensis). We started by evaluating the effects of sample size and sampling a geographically restricted area on the number of highly informative SNPs. We demonstrated that a bias in the number of fixed SNPs (F-ST=1) is introduced when the sample size is small (N10) and when sampling only captures a small fraction of a population's genetic diversity. These results underscore the importance of having a representative sample when developing reliable reduced SNP assays for organisms with complex genetic patterns. We used a training data set to design four independent SNP assays selected from pairwise F-ST between the Iberian and C-lineage honeybees. The designed assays, which were validated in holdout and simulated hybrid data sets, proved to be highly accurate and can be readily used for monitoring populations not only in the native range of A.m.iberiensis in Iberia but also in the introduced range in the Balearic islands, Macaronesia and South America, in a time- and cost-effective manner. While our approach used the Iberian honeybee as model system, it has a high value in a wide range of scenarios for the monitoring and conservation of potentially hybridized domestic and wildlife populations.

  • 20.
    Henriques, Dora
    et al.
    Polytech Inst Braganca, Mt Res Ctr CIMO, Campus Sta Apolonia, P-5300253 Braganca, Portugal;Univ Minho, Ctr Mol & Environm Biol CBMA, Campus Gualtar, P-4710057 Braga, Portugal.
    Wallberg, Andreas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Chavez-Galarza, Julio
    Inst Nacl Innovac Agr, Av La Molina 1981, Lima, Peru;Polytech Inst Braganca, Mt Res Ctr CIMO, Campus Sta Apolonia, P-5300253 Braganca, Portugal.
    Johnston, J. Spencer
    Texas A&M Univ, Dept Entomol, College Stn, TX 77843 USA.
    Webster, Matthew Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Alice Pinto, M.
    Polytech Inst Braganca, Mt Res Ctr CIMO, Campus Sta Apolonia, P-5300253 Braganca, Portugal.
    Whole genome SNP-associated signatures of local adaptation in honeybees of the Iberian Peninsula2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 11145Article in journal (Refereed)
    Abstract [en]

    The availability of powerful high-throughput genomic tools, combined with genome scans, has helped identifying genes and genetic changes responsible for environmental adaptation in many organisms, including the honeybee. Here, we resequenced 87 whole genomes of the honeybee native to Iberia and used conceptually different selection methods (Sam beta ada, LFMM, PCAdapt, iHs) together with in sillico protein modelling to search for selection footprints along environmental gradients. We found 670 outlier SNPs, most of which associated with precipitation, longitude and latitude. Over 88.7% SNPs laid outside exons and there was a significant enrichment in regions adjacent to exons and UTRs. Enrichment was also detected in exonic regions. Furthermore, in silico protein modelling suggests that several non-synonymous SNPs are likely direct targets of selection, as they lead to amino acid replacements in functionally important sites of proteins. We identified genomic signatures of local adaptation in 140 genes, many of which are putatively implicated in fitness-related functions such as reproduction, immunity, olfaction, lipid biosynthesis and circadian clock. Our genome scan suggests that local adaptation in the Iberian honeybee involves variations in regions that might alter patterns of gene expression and in protein-coding genes, which are promising candidates to underpin adaptive change in the honeybee.

  • 21. Hillier, Ladeana W
    et al.
    Miller, Webb
    Birney, Ewan
    Warren, Wesley
    Hardison, Ross C
    Ponting, Chris P
    Bork, Peer
    Burt, David W
    Groenen, Martien A M
    Delany, Mary E
    Dodgson, Jerry B
    Chinwalla, Asif T
    Cliften, Paul F
    Clifton, Sandra W
    Delehaunty, Kimberly D
    Fronick, Catrina
    Fulton, Robert S
    Graves, Tina A
    Kremitzki, Colin
    Layman, Dan
    Magrini, Vincent
    McPherson, John D
    Miner, Tracie L
    Minx, Patrick
    Nash, William E
    Nhan, Michael N
    Nelson, Joanne O
    Oddy, Lachlan G
    Pohl, Craig S
    Randall-Maher, Jennifer
    Smith, Scott M
    Wallis, John W
    Yang, Shiaw-Pyng
    Romanov, Michael N
    Rondelli, Catherine M
    Paton, Bob
    Smith, Jacqueline
    Morrice, David
    Daniels, Laura
    Tempest, Helen G
    Robertson, Lindsay
    Masabanda, Julio S
    Griffin, Darren K
    Vignal, Alain
    Fillon, Valerie
    Jacobbson, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kerje, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Crooijmans, Richard P M
    Aerts, Jan
    van der Poel, Jan J
    Ellegren, Hans
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology. Evolutionsbiologi.
    Caldwell, Randolph B
    Hubbard, Simon J
    Grafham, Darren V
    Kierzek, Andrzej M
    McLaren, Stuart R
    Overton, Ian M
    Arakawa, Hiroshi
    Beattie, Kevin J
    Bezzubov, Yuri
    Boardman, Paul E
    Bonfield, James K
    Croning, Michael D R
    Davies, Robert M
    Francis, Matthew D
    Humphray, Sean J
    Scott, Carol E
    Taylor, Ruth G
    Tickle, Cheryll
    Brown, William R A
    Rogers, Jane
    Buerstedde, Jean-Marie
    Wilson, Stuart A
    Stubbs, Lisa
    Ovcharenko, Ivan
    Gordon, Laurie
    Lucas, Susan
    Miller, Marcia M
    Inoko, Hidetoshi
    Shiina, Takashi
    Kaufman, Jim
    Salomonsen, Jan
    Skjoedt, Karsten
    Wong, Gane Ka-Shu
    Wang, Jun
    Liu, Bin
    Wang, Jian
    Yu, Jun
    Yang, Huanming
    Nefedov, Mikhail
    Koriabine, Maxim
    Dejong, Pieter J
    Goodstadt, Leo
    Webber, Caleb
    Dickens, Nicholas J
    Letunic, Ivica
    Suyama, Mikita
    Torrents, David
    von Mering, Christian
    Zdobnov, Evgeny M
    Makova, Kateryna
    Nekrutenko, Anton
    Elnitski, Laura
    Eswara, Pallavi
    King, David C
    Yang, Shan
    Tyekucheva, Svitlana
    Radakrishnan, Anusha
    Harris, Robert S
    Chiaromonte, Francesca
    Taylor, James
    He, Jianbin
    Rijnkels, Monique
    Griffiths-Jones, Sam
    Ureta-Vidal, Abel
    Hoffman, Michael M
    Severin, Jessica
    Searle, Stephen M J
    Law, Andy S
    Speed, David
    Waddington, Dave
    Cheng, Ze
    Tuzun, Eray
    Eichler, Evan
    Bao, Zhirong
    Flicek, Paul
    Shteynberg, David D
    Brent, Michael R
    Bye, Jacqueline M
    Huckle, Elizabeth J
    Chatterji, Sourav
    Dewey, Colin
    Pachter, Lior
    Kouranov, Andrei
    Mourelatos, Zissimos
    Hatzigeorgiou, Artemis G
    Paterson, Andrew H
    Ivarie, Robert
    Brandström, Mikael
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Axelsson, Erik
    Backström, Niclas
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Berlin, Sofia
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Webster, Matthew T
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Pourquie, Olivier
    Reymond, Alexandre
    Ucla, Catherine
    Antonarakis, Stylianos E
    Long, Manyuan
    Emerson, J J
    Betrán, Esther
    Dupanloup, Isabelle
    Kaessmann, Henrik
    Hinrichs, Angie S
    Bejerano, Gill
    Furey, Terrence S
    Harte, Rachel A
    Raney, Brian
    Siepel, Adam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kent, W James
    Haussler, David
    Eyras, Eduardo
    Castelo, Robert
    Abril, Josep F
    Castellano, Sergi
    Camara, Francisco
    Parra, Genis
    Guigo, Roderic
    Bourque, Guillaume
    Tesler, Glenn
    Pevzner, Pavel A
    Smit, Arian
    Fulton, Lucinda A
    Mardis, Elaine R
    Wilson, Richard K
    Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution2004In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 432, no 7018, p. 695-716Article in journal (Refereed)
    Abstract [en]

    We present here a draft genome sequence of the red jungle fowl, Gallus gallus. Because the chicken is a modern descendant of the dinosaurs and the first non-mammalian amniote to have its genome sequenced, the draft sequence of its genome--composed of approximately one billion base pairs of sequence and an estimated 20,000-23,000 genes--provides a new perspective on vertebrate genome evolution, while also improving the annotation of mammalian genomes. For example, the evolutionary distance between chicken and human provides high specificity in detecting functional elements, both non-coding and coding. Notably, many conserved non-coding sequences are far from genes and cannot be assigned to defined functional classes. In coding regions the evolutionary dynamics of protein domains and orthologous groups illustrate processes that distinguish the lineages leading to birds and mammals. The distinctive properties of avian microchromosomes, together with the inferred patterns of conserved synteny, provide additional insights into vertebrate chromosome architecture.

  • 22.
    Kawakami, Takeshi
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Wallberg, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Olsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wintermantel, Dimitry
    INRA, UE APIS 1255, F-17700 Le Magneraud, Surgeres, France;CNRS, UMR 7372, Ctr Etud Biol Chize, F-79360 Villiers En Bois, France;Univ La Rochelle, F-79360 Villiers En Bois, France.
    de Miranda, Joachim R.
    Swedish Univ Agr Sci, Dept Ecol, S-75007 Uppsala, Sweden.
    Allsopp, Mike
    Agr Res Council, Plant Protect Res Inst, ZA-7608 Stellenbosch, South Africa.
    Rundlof, Maj
    Lund Univ, Dept Biol, S-22362 Lund, Sweden.
    Webster, Matthew Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Substantial Heritable Variation in Recombination Rate on Multiple Scales in Honeybees and Bumblebees2019In: Genetics, ISSN 0016-6731, E-ISSN 1943-2631, Vol. 212, no 4, p. 1101-1119Article in journal (Refereed)
    Abstract [en]

    Meiotic recombination shuffles genetic variation and promotes correct segregation of chromosomes. Rates of recombination vary on several scales, both within genomes and between individuals, and this variation is affected by both genetic and environmental factors. Social insects have extremely high rates of recombination, although the evolutionary causes of this are not known. Here, we estimate rates of crossovers and gene conversions in 22 colonies of the honeybee, Apis mellifera, and 9 colonies of the bumblebee, Bombus terrestris, using direct sequencing of 299 haploid drone offspring. We confirm that both species have extremely elevated crossover rates, with higher rates measured in the highly eusocial honeybee than the primitively social bumblebee. There are also significant differences in recombination rate between subspecies of honeybee. There is substantial variation in genome-wide recombination rate between individuals of both A. mellifera and B. terrestris and the distribution of these rates overlap between species. A large proportion of interindividual variation in recombination rate is heritable, which indicates the presence of variation in trans-acting factors that influence recombination genome-wide. We infer that levels of crossover interference are significantly lower in honeybees compared to bumblebees, which may be one mechanism that contributes to higher recombination rates in honeybees. We also find a significant increase in recombination rate with distance from the centromere, mirrored by methylation differences. We detect a strong transmission bias due to GC-biased gene conversion associated with noncrossover gene conversions. Our results shed light on the mechanistic causes of extreme rates of recombination in social insects and the genetic architecture of recombination rate variation.

  • 23.
    Lamichhaney, Sangeet
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Barrio, Alvaro Martinez
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rafati, Nima
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sundström, Görel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gilbert, Elizabeth R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Berglund, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wetterbom, Anna
    Laikre, Linda
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Grabherr, Manfred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ryman, Nils
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Population-scale sequencing reveals genetic differentiation due to local adaptation in Atlantic herring2012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 47, p. 19345-19350Article in journal (Refereed)
    Abstract [en]

    The Atlantic herring (Clupea harengus), one of the most abundant marine fishes in the world, has historically been a critical food source in Northern Europe. It is one of the few marine species that can reproduce throughout the brackish salinity gradient of the Baltic Sea. Previous studies based on few genetic markers have revealed a conspicuous lack of genetic differentiation between geographic regions, consistent with huge population sizes and minute genetic drift. Here, we present a cost-effective genome-wide study in a species that lacks a genome sequence. We first assembled amuscle transcriptome and then aligned genomic reads to the transcripts, creating an "exome assembly," capturing both exons and flanking sequences. We then resequenced pools of fish from a wide geographic range, including the Northeast Atlantic, as well as different regions in the Baltic Sea, aligned the reads to the exome assembly, and identified 440,817 SNPs. The great majority of SNPs showed no appreciable differences in allele frequency among populations; however, several thousand SNPs showed striking differences, some approaching fixation for different alleles. The contrast between low genetic differentiation at most loci and striking differences at others implies that the latter category primarily reflects natural selection. A simulation study confirmed that the distribution of the fixation index F-ST deviated significantly from expectation for selectively neutral loci. This study provides insights concerning the population structure of an important marine fish and establishes the Atlantic herring as a model for population genetic studies of adaptation and natural selection.

  • 24.
    Lamichhaney, Sangeet
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Berglund, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Almen, Markus Sällman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Maqbool, Khurram
    Grabherr, Manfred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Martinez-Barrio, Alvaro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Promerova, Marta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wang, Chao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zamani, Neda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Grant, B. Rosemary
    Grant, Peter R.
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Evolution of Darwin's finches and their beaks revealed by genome sequencing2015In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 518, no 7539Article in journal (Refereed)
    Abstract [en]

    Darwin's finches, inhabiting the Galapagos archipelago and Cocos Island, constitute an iconic model for studies of speciation and adaptive evolution. Here we report the results of whole-genome re-sequencing of 120 individuals representing all of the Darwin's finch species and two close relatives' Phylogenetic analysis reveals important discrepancies with the phenotype-based taxonomy. We find extensive evidence for interspecific gene flow throughout the radiation. Hybridization has given rise to species of mixed ancestry. A 240 kilobase haplotype encompassing the ALX1 gene that encodes a transcription factor affecting craniofacial. development is strongly associated with beak shape diversity across Darwin's finch species as well as within the medium ground finch (Geospiza fortis) a species that has undergone rapid evolution of beak shape in response to environmental changes. The ALX1 haplotype has contributed to diversification of beak shapes among the Darwin's finches and thereby, to an expanded utilization of food resources.

  • 25.
    Lamichhaney, Sangeet
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Han, Fan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Berglund, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wang, Chao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sällman Almen, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    T. Webster, Matthew
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Grant, B. Rosemary
    Department of Ecology and Evolutionary Biology, Princeton University, Princeton, NJ, USA..
    R. Grant, Peter
    Department of Ecology and Evolutionary Biology, Princeton University, Princeton, NJ, USA..
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    A beak size locus in Darwin’s finches facilitated character displacement during a drought2016In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 352, no 6284, p. 470-474Article in journal (Refereed)
    Abstract [en]

    Ecological character displacement is a process of morphological divergence that reducescompetition for limited resources. We used genomic analysis to investigate the geneticbasis of a documented character displacement event in Darwin’s finches on Daphne Majorin the Galápagos Islands: The medium ground finch diverged from its competitor, the largeground finch, during a severe drought. We discovered a genomic region containing theHMGA2gene that varies systematically among Darwin’s finch species with different beaksizes. Two haplotypes that diverged early in the radiation were involved in the characterdisplacement event: Genotypes associated with large beak size were at a strong selectivedisadvantage in medium ground finches (selection coefficients= 0.59). Thus, a majorlocus has apparently facilitated a rapid ecological diversification in the adaptive radiationof Darwin’s finches.

  • 26.
    Lamichhaney, Sangeet
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Han, Fan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Webster, Matthew Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden.; Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX USA.; Harvard Univ, Dept Organism & Evolutionary Biol, Cambridge, MA 02138 USA.; Harvard Univ, Museum Comparat Zool, Cambridge, MA 02138 USA..
    Grant, B Rosemary
    Grant, Peter R
    Rapid hybrid speciation in Darwin's finches.2018In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 359, no 6372, p. 224-228Article in journal (Refereed)
    Abstract [en]

    Homoploid hybrid speciation in animals has been inferred frequently from patterns of variation, but few examples have withstood critical scrutiny. Here we report a directly documented example, from its origin to reproductive isolation. An immigrant Darwin's finch to Daphne Major in the Galápagos archipelago initiated a new genetic lineage by breeding with a resident finch (Geospiza fortis). Genome sequencing of the immigrant identified it as a G. conirostris male that originated on Española >100 kilometers from Daphne Major. From the second generation onward, the lineage bred endogamously and, despite intense inbreeding, was ecologically successful and showed transgressive segregation of bill morphology. This example shows that reproductive isolation, which typically develops over hundreds of generations, can be established in only three.

  • 27. Larson, Greger
    et al.
    Karlsson, Elinor K
    Perri, Angela
    Webster, Matthew T
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ho, Simon Y W
    Peters, Joris
    Stahl, Peter W
    Piper, Philip J
    Lingaas, Frode
    Fredholm, Merete
    Comstock, Kenine E
    Modiano, Jaime F
    Schelling, Claude
    Agoulnik, Alexander I
    Leegwater, Peter A
    Dobney, Keith
    Vigne, Jean-Denis
    Vilà, Carles
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rethinking dog domestication by integrating genetics, archeology, and biogeography2012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 23, p. 8878-8883Article in journal (Refereed)
    Abstract [en]

    The dog was the first domesticated animal but it remains uncertain when the domestication process began and whether it occurred just once or multiple times across the Northern Hemisphere. To ascertain the value of modern genetic data to elucidate the origins of dog domestication, we analyzed 49,024 autosomal SNPs in 1,375 dogs (representing 35 breeds) and 19 wolves. After combining our data with previously published data, we contrasted the genetic signatures of 121 breeds with a worldwide archeological assessment of the earliest dog remains. Correlating the earliest archeological dogs with the geographic locations of 14 so-called "ancient" breeds (defined by their genetic differentiation) resulted in a counterintuitive pattern. First, none of the ancient breeds derive from regions where the oldest archeological remains have been found. Second, three of the ancient breeds (Basenjis, Dingoes, and New Guinea Singing Dogs) come from regions outside the natural range of Canis lupus (the dog's wild ancestor) and where dogs were introduced more than 10,000 y after domestication. These results demonstrate that the unifying characteristic among all genetically distinct so-called ancient breeds is a lack of recent admixture with other breeds likely facilitated by geographic and cultural isolation. Furthermore, these genetically distinct ancient breeds only appear so because of their relative isolation, suggesting that studies of modern breeds have yet to shed light on dog origins. We conclude by assessing the limitations of past studies and how next-generation sequencing of modern and ancient individuals may unravel the history of dog domestication.

  • 28.
    Makino, Takashi
    et al.
    Department of Ecology and Evolutionary Biology, Graduate School of Life Sciences, Tohoku University, 6 - 3, Aramaki Aza Aoba, Aoba - ku, Sendai 980 - 8578, Japan.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Carneiro, Miguel
    CIBIO/InBIO, Centro de Investiga ção em Biodiversidade e Recursos Genéticos, Campus Agrário de Vairão, Universidade do Porto, 4485 - 661, Vairão, Portugal.
    Axelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Webster, Matthew Thomas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Elevated proportions of deleterious genetic variation in domestic animals and plants2018In: Genome Biology and Evolution, ISSN 1759-6653, E-ISSN 1759-6653, Vol. 10, no 1, p. 276-290Article in journal (Refereed)
    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.

  • 29.
    Mank, Judith E.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Hultin-Rosenberg, Lina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Ellegren, Hans
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    The unique genomic properties of sex-biased genes: insights from avian microarray data2008In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 9, p. 148-Article in journal (Refereed)
    Abstract [en]

    Background: In order to develop a framework for the analysis of sex-biased genes, we present a characterization of microarray data comparing male and female gene expression in 18 day chicken embryos for brain, gonad, and heart tissue. Results: From the 15982 significantly expressed coding regions that have been assigned to either the autosomes or the Z chromosome ( 12979 in brain, 13301 in gonad, and 12372 in heart), roughly 18% were significantly sex- biased in any one tissue, though only 4 gene targets were biased in all tissues. The gonad was the most sex- biased tissue, followed by the brain. Sex- biased autosomal genes tended to be expressed at lower levels and in fewer tissues than unbiased gene targets, and autosomal somatic sex- biased genes had more expression noise than similar unbiased genes. Sex-biased genes linked to the Z- chromosome showed reduced expression in females, but not in males, when compared to unbiased Z- linked genes, and sex- biased Z- linked genes were also expressed in fewer tissues than unbiased Z coding regions. Third position GC content, and codon usage bias showed some sex- biased effects, primarily for autosomal genes expressed in the gonad. Finally, there were several over-represented Gene Ontology terms in the sex- biased gene sets. Conclusion: On the whole, this analysis suggests that sex- biased genes have unique genomic and organismal properties that delineate them from genes that are expressed equally in males and females.

  • 30. Mausberg, Theresa-Bernadette
    et al.
    Wess, Gerhard
    Simak, Julia
    Keller, Lisa
    Droegemueller, Michaela
    Droegemueller, Cord
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Stephenson, Hannah
    Dukes-McEwan, Joanna
    Leeb, Tosso
    A Locus on Chromosome 5 Is Associated with Dilated Cardiomyopathy in Doberman Pinschers2011In: PLoS One, ISSN 1932-6203, Vol. 6, no 5, p. e20042-Article in journal (Refereed)
    Abstract [en]

    Dilated cardiomyopathy (DCM) is a heterogeneous group of heart diseases with a strong genetic background. Currently, many human DCM cases exist where no causative mutation can be identified. DCM also occurs with high prevalence in several large dog breeds. In the Doberman Pinscher a specific DCM form characterized by arrhythmias and/or echocardiographic changes has been intensively studied by veterinary cardiologists. We performed a genome-wide association study in Doberman Pinschers. Using 71 cases and 70 controls collected in Germany we identified a genome-wide significant association to DCM on chromosome 5. We validated the association in an independent cohort collected in the United Kingdom. There is no known DCM candidate gene under the association signal. Therefore, DCM in Doberman Pinschers offers the chance of identifying a novel DCM gene that might also be relevant for human health.

  • 31.
    Molin, Anna-Maja
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Berglund, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genome-wide copy number variant discovery in dogs using the CanineHD genotyping array2014In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 15, p. 210-Article in journal (Refereed)
    Abstract [en]

    Background: Substantial contribution to phenotypic diversity is accounted for by copy number variants (CNV). In human, as well as other species, the effect of CNVs range from benign to directly disease-causing which motivates the continued investigations of CNVs. Previous canine genome-wide screenings for CNVs have been performed using high-resolution comparative genomic hybridisation arrays which have contributed with a detailed catalogue of CNVs. Here, we present the first CNV investigation in dogs based on the recently reported CanineHD 170 K genotyping array. The hitherto largest dataset in canine CNV discovery was assessed, 351 dogs from 30 different breeds, enabling identification of novel CNVs and a thorough characterisation of breed-specific CNVs. Results: A stringent procedure identified 72 CNV regions with the smallest size of 38 kb and of the 72 CNV regions, 38 overlapped 148 annotated genes. A total of 29 novel CNV regions were found containing 44 genes. Furthermore, 15 breed specific CNV regions were identified of which 14 were novel and some of them overlapped putative disease susceptibility genes. In addition, the human ortholog of 23 canine copy number variable genes identified herein has been previously suggested to be dosage-sensitive in human. Conclusions: The present study evaluated the performance of the CanineHD in detecting CNVs and extends the current catalogue of canine CNV regions with several dozens of novel CNV regions. These novel CNV regions, which harbour candidate genes that possibly contribute to phenotypic variation in dogs or to disease-susceptibility, are a rich resource for future investigations.

  • 32.
    Montero-Mendieta, Santiago
    et al.
    CSIC, Donana Biol Stn EBD, Dept Integrat Ecol, Conservat & Evolutionary Genet Grp, Seville, Spain..
    Grabherr, Manfred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lantz, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    De la Riva, Ignacio
    CSIC, Museo Nacl Ciencias Nat, Dept Biodivers & Evolutionary Biol, Madrid, Spain..
    Leonard, Jennifer A.
    CSIC, Donana Biol Stn EBD, Dept Integrat Ecol, Conservat & Evolutionary Genet Grp, Seville, Spain..
    Webster, Matthew Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Vila, Carles
    CSIC, Donana Biol Stn EBD, Dept Integrat Ecol, Conservat & Evolutionary Genet Grp, Seville, Spain..
    A practical guide to build de-novo assemblies for single tissues of non-model organisms: the example of a Neotropical frog2017In: PeerJ, ISSN 2167-8359, E-ISSN 2167-8359, Vol. 5, article id e3702Article in journal (Refereed)
    Abstract [en]

    Whole genome sequencing (WGS) is a very valuable resource to understand the evolutionary history of poorly known species. However, in organisms with large genomes, as most amphibians, WGS is still excessively challenging and transcriptome sequencing (RNA-seq) represents a cost-effective tool to explore genome-wide variability. Non-model organisms do not usually have a reference genome and the transcriptome must be assembled de-novo. Weused RNA-seq to obtain the transcriptomic profile for Oreobates cruralis, a poorly known South American direct-developing frog. In total, 550,871 transcripts were assembled, corresponding to 422,999 putative genes. Of those, we identified 23,500, 37,349, 38,120 and 45,885 genes present in the Pfam, EggNOG, KEGG and GO databases, respectively. Interestingly, our results suggested that genes related to immune system and defense mechanisms are abundant in the transcriptome of O. cruralis. We also present a pipeline to assist with pre-processing, assembling, evaluating and functionally annotating a de-novo transcriptome from RNA-seq data of non-model organisms. Our pipeline guides the inexperienced user in an intuitive way through all the necessary steps to build de-novo transcriptome assemblies using readily available software and is freely available at: https://github. com/biomendi/TRANSCRIPTOMEASSEMBLY- PIPELINE/wiki.

  • 33.
    Montero-Mendieta, Santiago
    et al.
    Donana Biol Stn EBD CSIC, Conservat & Evolutionary Genet Grp, Seville, Spain.
    Tan, Ken
    Chinese Acad Sci, Xishuangbanna Trop Bot Garden, Key Lab Trop Forest Ecol, Kunming, Yunnan, Peoples R China.
    Christmas, Matthew
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Olsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Vila, Carles
    Donana Biol Stn EBD CSIC, Conservat & Evolutionary Genet Grp, Seville, Spain.
    Wallberg, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Webster, Matthew Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    The genomic basis of adaptation to high-altitude habitats in the eastern honey bee (Apis cerana)2019In: Molecular Ecology, ISSN 0962-1083, E-ISSN 1365-294X, Vol. 28, no 4, p. 746-760Article in journal (Refereed)
    Abstract [en]

    The eastern honey bee (Apis cerana) is of central importance for agriculture in Asia. It has adapted to a wide variety of environmental conditions across its native range in southern and eastern Asia, which includes high-altitude regions. eastern honey bees inhabiting mountains differ morphologically from neighbouring lowland populations and may also exhibit differences in physiology and behaviour. We compared the genomes of 60 eastern honey bees collected from high and low altitudes in Yunnan and Gansu provinces, China, to infer their evolutionary history and to identify candidate genes that may underlie adaptation to high altitude. Using a combination of F-ST-based statistics, long-range haplotype tests and population branch statistics, we identified several regions of the genome that appear to have been under positive selection. These candidate regions were strongly enriched for coding sequences and had high haplotype homozygosity and increased divergence specifically in highland bee populations, suggesting they have been subjected to recent selection in high-altitude habitats. Candidate loci in these genomic regions included genes related to reproduction and feeding behaviour in honey bees. Functional investigation of these candidate loci is necessary to fully understand the mechanisms of adaptation to high-altitude habitats in the eastern honey bee.

  • 34.
    Nelson, Ronald M.
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wallberg, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Paulino Simoes, Zila Luz
    Univ Sao Paulo, FFCLRP, Dept Biol, Ribeirao Preto, Brazil.;Univ Sao Paulo, FMRP, Dept Genet, Ribeirao Preto, Brazil..
    Lawson, Daniel J.
    Univ Bristol, Dept Math, Bristol, Avon, England..
    Webster, Matthew Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genomewide analysis of admixture and adaptation in the Africanized honeybee2017In: Molecular Ecology, ISSN 0962-1083, E-ISSN 1365-294X, Vol. 26, no 14, p. 3603-3617Article in journal (Refereed)
    Abstract [en]

    Genetic exchange by hybridization or admixture can make an important contribution to evolution, and introgression of favourable alleles can facilitate adaptation to new environments. A small number of honeybees (Apis mellifera) with African ancestry were introduced to Brazil similar to 60 years ago, which dispersed and hybridized with existing managed populations of European origin, quickly spreading across much of the Americas in an example of a massive biological invasion. Here, we analyse whole-genome sequences of 32 Africanized honeybees sampled from throughout Brazil to study the effect of this process on genome diversity. By comparison with ancestral populations from Europe and Africa, we infer that these samples have 84% African ancestry, with the remainder from western European populations. However, this proportion varies across the genome and we identify signals of positive selection in regions with high European ancestry proportions. These observations are largely driven by one large gene-rich 1.4-Mbp segment on chromosome 11 where European haplotypes are present at a significantly elevated frequency and likely confer an adaptive advantage in the Africanized honeybee population. This region has previously been implicated in reproductive traits and foraging behaviour in worker bees. Finally, by analysing the distribution of ancestry tract lengths in the context of the known time of the admixture event, we are able to infer an average generation time of 2.0 years. Our analysis highlights the processes by which populations of mixed genetic ancestry form and adapt to new environments.

  • 35.
    Olsson, Mia
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Meadows, Jennifer R. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Truve, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pielberg, Gerli Rosengren
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Puppo, Francesca
    Mauceli, Evan
    Quilez, Javier
    Tonomura, Noriko
    Zanna, Giordana
    Jose Docampo, Maria
    Bassols, Anna
    Avery, Anne C.
    Karlsson, Elinor K.
    Thomas, Anne
    Kastner, Daniel L.
    Bongcam-Rudloff, Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sanchez, Armand
    Hedhammar, Åke
    Remmers, Elaine F.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ferrer, Lluis
    Tintle, Linda
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    A Novel Unstable Duplication Upstream of HAS2 Predisposes to a Breed-Defining Skin Phenotype and a Periodic Fever Syndrome in Chinese Shar-Pei Dogs2011In: PLoS Genetics, ISSN 1553-7390, Vol. 7, no 3, p. e1001332-Article in journal (Refereed)
    Abstract [en]

    Hereditary periodic fever syndromes are characterized by recurrent episodes of fever and inflammation with no known pathogenic or autoimmune cause. In humans, several genes have been implicated in this group of diseases, but the majority of cases remain unexplained. A similar periodic fever syndrome is relatively frequent in the Chinese Shar-Pei breed of dogs. In the western world, Shar-Pei have been strongly selected for a distinctive thick and heavily folded skin. In this study, a mutation affecting both these traits was identified. Using genome-wide SNP analysis of Shar-Pei and other breeds, the strongest signal of a breed-specific selective sweep was located on chromosome 13. The same region also harbored the strongest genome-wide association (GWA) signal for susceptibility to the periodic fever syndrome (p(raw) = 2.3 x 10(-6), p(genome) = 0.01). Dense targeted resequencing revealed two partially overlapping duplications, 14.3 Kb and 16.1 Kb in size, unique to Shar-Pei and upstream of the Hyaluronic Acid Synthase 2 (HAS2) gene. HAS2 encodes the rate-limiting enzyme synthesizing hyaluronan (HA), a major component of the skin. HA is up-regulated and accumulates in the thickened skin of Shar-Pei. A high copy number of the 16.1 Kb duplication was associated with an increased expression of HAS2 as well as the periodic fever syndrome (p, < 0.0001). When fragmented, HA can act as a trigger of the innate immune system and stimulate sterile fever and inflammation. The strong selection for the skin phenotype therefore appears to enrich for a pleiotropic mutation predisposing these dogs to a periodic fever syndrome. The identification of HA as a major risk factor for this canine disease raises the potential of this glycosaminoglycan as a risk factor for human periodic fevers and as an important driver of chronic inflammation.

  • 36. Owczarek-Lipska, Marta
    et al.
    Lauber, Béatrice
    Molitor, Vivianne
    Meury, Sabrina
    Kierczak, Marcin
    Tengvall, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jagannathan, Vidhya
    Schlotter, Yvette
    Willemse, Ton
    Hendricks, Anke
    Bergvall, Kerstin
    Hedhammar, Åke
    Andersson, Göran
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Favrot, Claude
    Roosje, Petra
    Marti, Eliane
    Leeb, Tosso
    Two Loci on Chromosome 5 Are Associated with Serum IgE Levels in Labrador Retrievers2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 6, p. e39176-Article in journal (Refereed)
    Abstract [en]

    Crosslinking of immunoglobulin E antibodies (IgE) bound at the surface of mast cells and subsequent mediator release is considered the most important trigger for allergic reactions. Therefore, the genetic control of IgE levels is studied in the context of allergic diseases, such as asthma, atopic rhinitis, or atopic dermatitis (AD). We performed genome-wide association studies in 161 Labrador Retrievers with regard to total and allergen-specific immunoglobulin E (IgE) levels. We identified a genome-wide significant association on CFA 5 with the antigen-specific IgE responsiveness to Acarus siro. We detected a second genome-wide significant association with respect to the antigen-specific IgE responsiveness to Tyrophagus putrescentiae at a different locus on chromosome 5. A. siro and T. putrescentiae both belong to the family Acaridae and represent so-called storage or forage mites. These forage mites are discussed as major allergen sources in canine AD. No obvious candidate gene for the regulation of IgE levels is located under the two association signals. Therefore our studies offer a chance of identifying a novel mechanism controlling the host's IgE response.

  • 37. Ramirez, Oscar
    et al.
    Olalde, Inigo
    Berglund, Jonas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lorente-Galdos, Belen
    Hernandez-Rodriguez, Jessica
    Quilez, Javier
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wayne, Robert K.
    Lalueza-Fox, Carles
    Vila, Carles
    Marques-Bonet, Tomas
    Analysis of structural diversity in wolf-like canids reveals post-domestication variants2014In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 15, p. 465-Article in journal (Refereed)
    Abstract [en]

    Background: Although a variety of genetic changes have been implicated in causing phenotypic differences among dogs, the role of copy number variants (CNVs) and their impact on phenotypic variation is still poorly understood. Further, very limited knowledge exists on structural variation in the gray wolf, the ancestor of the dog, or other closely related wild canids. Documenting CNVs variation in wild canids is essential to identify ancestral states and variation that may have appeared after domestication. Results: In this work, we genotyped 1,611 dog CNVs in 23 wolf-like canids (4 purebred dogs, one dingo, 15 gray wolves, one red wolf, one coyote and one golden jackal) to identify CNVs that may have arisen after domestication. We have found an increase in GC-rich regions close to the breakpoints and around 1 kb away from them suggesting that some common motifs might be associated with the formation of CNVs. Among the CNV regions that showed the largest differentiation between dogs and wild canids we found 12 genes, nine of which are related to two known functions associated with dog domestication; growth (PDE4D, CRTC3 and NEB) and neurological function (PDE4D, EML5, ZNF500, SLC6A11, ELAVL2, RGS7 and CTSB). Conclusions: Our results provide insight into the evolution of structural variation in canines, where recombination is not regulated by PRDM9 due to the inactivation of this gene. We also identified genes within the most differentiated CNV regions between dogs and wolves, which could reflect selection during the domestication process.

  • 38. Rands, Chris M.
    et al.
    Darling, Aaron
    Fujita, Matthew
    Kong, Lesheng
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Clabaut, Celine
    Emes, Richard D.
    Heger, Andreas
    Meader, Stephen
    Hawkins, Michael Brent
    Eisen, Michael B.
    Teiling, Clotilde
    Affourtit, Jason
    Boese, Benjamin
    Grant, Peter R.
    Grant, Barbara Rosemary
    Eisen, Jonathan A.
    Abzhanov, Arhat
    Ponting, Chris P.
    Insights into the evolution of Darwin's finches from comparative analysis of the Geospiza magnirostris genome sequence2013In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 14, p. 95-Article in journal (Refereed)
    Abstract [en]

    Background: A classical example of repeated speciation coupled with ecological diversification is the evolution of 14 closely related species of Darwin's (Galapagos) finches (Thraupidae, Passeriformes). Their adaptive radiation in the Galapagos archipelago took place in the last 2-3 million years and some of the molecular mechanisms that led to their diversification are now being elucidated. Here we report evolutionary analyses of genome of the large ground finch, Geospiza magnirostris. Results: 13,291 protein-coding genes were predicted from a 991.0 Mb G. magnirostris genome assembly. We then defined gene orthology relationships and constructed whole genome alignments between the G. magnirostris and other vertebrate genomes. We estimate that 15% of genomic sequence is functionally constrained between G. magnirostris and zebra finch. Genic evolutionary rate comparisons indicate that similar selective pressures acted along the G. magnirostris and zebra finch lineages suggesting that historical effective population size values have been similar in both lineages. 21 otherwise highly conserved genes were identified that each show evidence for positive selection on amino acid changes in the Darwin's finch lineage. Two of these genes (Igf2r and Pou1f1) have been implicated in beak morphology changes in Darwin's finches. Five of 47 genes showing evidence of positive selection in early passerine evolution have cilia related functions, and may be examples of adaptively evolving reproductive proteins. Conclusions: These results provide insights into past evolutionary processes that have shaped G. magnirostris genes and its genome, and provide the necessary foundation upon which to build population genomics resources that will shed light on more contemporaneous adaptive and non-adaptive processes that have contributed to the evolution of the Darwin's finches.

  • 39.
    Ratnakumar, Abhirami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mousset, Sylvain
    Glémin, Sylvain
    Berglund, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Galtier, Nicolas
    Duret, Laurent
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Detecting positive selection within genomes: the problem of biased gene conversion2010In: Philosophical Transactions of the Royal Society of London. Biological Sciences, ISSN 0962-8436, E-ISSN 1471-2970, Vol. 365, no 1552, p. 2571-2580Article in journal (Refereed)
    Abstract [en]

    The identification of loci influenced by positive selection is a major goal of evolutionary genetics. A popular approach is to perform scans of alignments on a genome-wide scale in order to find regions evolving at accelerated rates on a particular branch of a phylogenetic tree. However, positive selection is not the only process that can lead to accelerated evolution. Notably, GC-biased gene conversion (gBGC) is a recombination-associated process that results in the biased fixation of G and C nucleotides. This process can potentially generate bursts of nucleotide substitutions within hotspots of meiotic recombination. Here, we analyse the results of a scan for positive selection on genes on branches across the primate phylogeny. We show that genes identified as targets of positive selection have a significant tendency to exhibit the genomic signature of gBGC. Using a maximum-likelihood framework, we estimate that more than 20 per cent of cases of significantly elevated non-synonymous to synonymous substitution rates ratio (d(N)/d(S)), particularly in shorter branches, could be due to gBGC. We demonstrate that in some cases, gBGC can lead to very high d(N)/d(S) (more than 2). Our results indicate that gBGC significantly affects the evolution of coding sequences in primates, often leading to patterns of evolution that can be mistaken for positive selection.

  • 40.
    Rubin, Carl-Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zody, Michael C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Meadows, Jennifer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sherwood, Ellen
    Karolinska Institutet, Department of cell and Molecular Biology.
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Jiang, Lin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ingman, Max
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sharpe, Ted
    Broad Institute.
    Besnier, Francois
    Swedish University of Agricultural Sciences, Department of Animal Breeding and Genetics.
    Ka, Sojeong
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Carlborg, Örjan
    Swedish University of Agricultural Sciences, Department of Animal Breeding and Genetics.
    Bed'hom, Bertrand
    INRA, AgroParisTech, Animal Genetics and Integrative Biology.
    Tixier-Boichard, Michèle
    INRA, AgroParisTech, Animal Genetics and Integrative Biology.
    Jensen, Per
    Linköping University, IFM Biology.
    Siegel, Paul
    Virginia Polytechnic Institute and State University, Department of Animal and Poultry Sciences.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Whole genome resequencing reveals loci under selection during chicken domestication2010In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 464, no 7288, p. 587-591Article in journal (Refereed)
    Abstract [en]

    Domestic animals are excellent models for genetic studies of phenotypic evolution. They have evolved genetic adaptations to a new environment, the farm, and have been subjected to strong human-driven selection leading to remarkable phenotypic changes in morphology, physiology and behaviour. Identifying the genetic changes underlying these developments provides new insight into general mechanisms by which genetic variation shapes phenotypic diversity. Here we describe the use of massively parallel sequencing to identify selective sweeps of favourable alleles and candidate mutations that have had a prominent role in the domestication of chickens (Gallus gallus domesticus) and their subsequent specialization into broiler (meat-producing) and layer (egg-producing) chickens. We have generated 44.5-fold coverage of the chicken genome using pools of genomic DNA representing eight different populations of domestic chickens as well as red jungle fowl (Gallus gallus), the major wild ancestor. We report more than 7,000,000 single nucleotide polymorphisms, almost 1,300 deletions and a number of putative selective sweeps. One of the most striking selective sweeps found in all domestic chickens occurred at the locus for thyroid stimulating hormone receptor (TSHR), which has a pivotal role in metabolic regulation and photoperiod control of reproduction in vertebrates. Several of the selective sweeps detected in broilers overlapped genes associated with growth, appetite and metabolic regulation. We found little evidence that selection for loss-of-function mutations had a prominent role in chicken domestication, but we detected two deletions in coding sequences that we suggest are functionally important. This study has direct application to animal breeding and enhances the importance of the domestic chicken as a model organism for biomedical research.

  • 41. Seppala, Eija H.
    et al.
    Jokinen, Tarja S.
    Fukata, Masaki
    Fukata, Yuko
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Karlsson, Elinor K.
    Kilpinen, Sami K.
    Steffen, Frank
    Dietschi, Elisabeth
    Leeb, Tosso
    Eklund, Ranja
    Zhao, Xiaochu
    Rilstone, Jennifer J.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Minassian, Berge A.
    Lohi, Hannes
    LGI2 Truncation Causes a Remitting Focal Epilepsy in Dogs2011In: PLoS Genetics, ISSN 1553-7390, Vol. 7, no 7, p. e1002194-Article in journal (Refereed)
    Abstract [en]

    One quadrillion synapses are laid in the first two years of postnatal construction of the human brain, which are then pruned until age 10 to 500 trillion synapses composing the final network. Genetic epilepsies are the most common neurological diseases with onset during pruning, affecting 0.5% of 2-10-year-old children, and these epilepsies are often characterized by spontaneous remission. We previously described a remitting epilepsy in the Lagotto romagnolo canine breed. Here, we identify the gene defect and affected neurochemical pathway. We reconstructed a large Lagotto pedigree of around 34 affected animals. Using genome-wide association in 11 discordant sib-pairs from this pedigree, we mapped the disease locus to a 1.7 Mb region of homozygosity in chromosome 3 where we identified a protein-truncating mutation in the Lgi2 gene, a homologue of the human epilepsy gene LGI1. We show that LGI2, like LGI1, is neuronally secreted and acts on metalloproteinase-lacking members of the ADAM family of neuronal receptors, which function in synapse remodeling, and that LGI2 truncation, like LGI1 truncations, prevents secretion and ADAM interaction. The resulting epilepsy onsets at around seven weeks (equivalent to human two years), and remits by four months (human eight years), versus onset after age eight in the majority of human patients with LGI1 mutations. Finally, we show that Lgi2 is expressed highly in the immediate post-natal period until halfway through pruning, unlike Lgi1, which is expressed in the latter part of pruning and beyond. LGI2 acts at least in part through the same ADAM receptors as LGI1, but earlier, ensuring electrical stability (absence of epilepsy) during pruning years, preceding this same function performed by LGI1 in later years. LGI2 should be considered a candidate gene for common remitting childhood epilepsies, and LGI2-to-LGI1 transition for mechanisms of childhood epilepsy remission.

  • 42.
    Sundström, Hannah
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Evolutionary Biology.
    Webster, Matthew T
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Evolutionary Biology.
    Ellegren, Hans
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Evolutionary Biology.
    Reduced variation on the chicken Z chromosome2004In: Genetics, ISSN 0016-6731, E-ISSN 1943-2631, Vol. 167, no 1, p. 377-385Article in journal (Refereed)
    Abstract [en]

    Understanding the population genetic factors that shape genome variability is pivotal to the design and interpretation of studies using large-scale polymorphism data. We analyzed patterns of polymorphism and divergence at Z-linked and autosomal loci in the domestic chicken (Gallus gallus) to study the influence of mutation, effective population size, selection, and demography on levels of genetic diversity. A total of 14 autosomal introns (8316 bp) and 13 Z-linked introns (6856 bp) were sequenced in 50 chicken chromosomes from 10 highly divergent breeds. Genetic variation was significantly lower at Z-linked than at autosomal loci, with one segregating site every 39 bp at autosomal loci (θW = 5.8 ± 0.8 × 10–3) and one every 156 bp on the Z chromosome (θW = 1.4 ± 0.4 × 10–3). This difference may in part be due to a low male effective population size arising from skewed reproductive success among males, evident both in the wild ancestor—the red jungle fowl—and in poultry breeding. However, this effect cannot entirely explain the observed three- to fourfold reduction in Z chromosome diversity. Selection, in particular selective sweeps, may therefore have had an impact on reducing variation on the Z chromosome, a hypothesis supported by the observation of heterogeneity in diversity levels among loci on the Z chromosome and the lower recombination rate on Z than on autosomes. Selection on sex-linked genes may be particularly important in organisms with female heterogamety since the heritability of sex-linked sexually antagonistic alleles advantageous to males is improved when fathers pass a Z chromosome to their sons.

  • 43. Vaysse, Amaury
    et al.
    Ratnakumar, Abhirami
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Derrien, Thomas
    Axelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rosengren Pielberg, Gerli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sigurdsson, Snaevar
    Fall, Tove
    Seppälä, Eija H
    Hansen, Mark S T
    Lawley, Cindy T
    Karlsson, Elinor K
    Bannasch, Danika
    Vilà, Carles
    Lohi, Hannes
    Galibert, Francis
    Fredholm, Merete
    Häggström, Jens
    Hedhammar, Ake
    André, Catherine
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hitte, Christophe
    Webster, Matthew T
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Identification of genomic regions associated with phenotypic variation between dog breeds using selection mapping2011In: PLoS Genetics, ISSN 1553-7404, Vol. 7, no 10, p. e1002316-Article in journal (Refereed)
    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.

  • 44.
    Wallberg, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bunikis, Ignas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Vinnere, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mosbech, Mai-Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Childers, Anna K.
    USDA ARS, Insect Genet & Biochem Res Unit, Fargo, ND USA;USDA ARS, Bee Res Lab, Beltsville, MD USA.
    Evans, Jay D.
    USDA ARS, Bee Res Lab, Beltsville, MD USA.
    Mikheyev, Alexander S.
    Okinawa Inst Sci & Technol, Onna, Okinawa, Japan.
    Robertson, Hugh M.
    Univ Illinois, Dept Biochem, Urbana, IL USA;Univ Illinois, Carl R Woese Inst Genom Biol, Urbana, IL USA.
    Robinson, Gene E.
    Univ Illinois, Dept Biochem, Urbana, IL USA;Univ Illinois, Carl R Woese Inst Genom Biol, Urbana, IL USA.
    Webster, Matthew Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    A hybrid de novo genome assembly of the honeybee, Apis mellifera, with chromosome-length scaffolds2019In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 20, article id 275Article in journal (Refereed)
    Abstract [en]

    Background

    The ability to generate long sequencing reads and access long-range linkage information is revolutionizing the quality and completeness of genome assemblies. Here we use a hybrid approach that combines data from four genome sequencing and mapping technologies to generate a new genome assembly of the honeybee Apis mellifera. We first generated contigs based on PacBio sequencing libraries, which were then merged with linked-read 10x Chromium data followed by scaffolding using a BioNano optical genome map and a Hi-C chromatin interaction map, complemented by a genetic linkage map.

    Results

    Each of the assembly steps reduced the number of gaps and incorporated a substantial amount of additional sequence into scaffolds. The new assembly (Amel_HAv3) is significantly more contiguous and complete than the previous one (Amel_4.5), based mainly on Sanger sequencing reads. N50 of contigs is 120-fold higher (5.381 Mbp compared to 0.053 Mbp) and we anchor >98% of the sequence to chromosomes. All of the 16 chromosomes are represented as single scaffolds with an average of three sequence gaps per chromosome. The improvements are largely due to the inclusion of repetitive sequence that was unplaced in previous assemblies. In particular, our assembly is highly contiguous across centromeres and telomeres and includes hundreds of AvaI and AluI repeats associated with these features.

    Conclusions

    The improved assembly will be of utility for refining gene models, studying genome function, mapping functional genetic variation, identification of structural variants, and comparative genomics.

  • 45.
    Wallberg, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Glemin, Sylvain
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Extreme Recombination Frequencies Shape Genome Variation and Evolution in the Honeybee, Apis mellifera2015In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 4, article id e1005189Article in journal (Refereed)
    Abstract [en]

    Meiotic recombination is a fundamental cellular process, with important consequences for evolution and genome integrity. However, we know little about how recombination rates vary across the genomes of most species and the molecular and evolutionary determinants of this variation. The honeybee, Apis mellifera, has extremely high rates of meiotic recombination, although the evolutionary causes and consequences of this are unclear. Here we use patterns of linkage disequilibrium in whole genome resequencing data from 30 diploid honeybees to construct a fine-scale map of rates of crossing over in the genome. We find that, in contrast to vertebrate genomes, the recombination landscape is not strongly punctate. Crossover rates strongly correlate with levels of genetic variation, but not divergence, which indicates a pervasive impact of selection on the genome. Germ-line methylated genes have reduced crossover rate, which could indicate a role of methylation in suppressing recombination. Controlling for the effects of methylation, we do not infer a strong association between gene expression patterns and recombination. The site frequency spectrum is strongly skewed from neutral expectations in honeybees: rare variants are dominated by AT-biased mutations, whereas GC-biased mutations are found at higher frequencies, indicative of a major influence of GC-biased gene conversion (gBGC), which we infer to generate an allele fixation bias 5 - 50 times the genomic average estimated in humans. We uncover further evidence that this repair bias specifically affects transitions and favours fixation of CpG sites. Recombination, via gBGC, therefore appears to have profound consequences on genome evolution in honeybees and interferes with the process of natural selection. These findings have important implications for our understanding of the forces driving molecular evolution.

  • 46.
    Wallberg, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Han, Fan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wellhagen, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dahle, Bjørn
    Kawata, Masakado
    Haddad, Nizar
    Simões, Zilá Luz Paulino
    Allsopp, Mike H
    Kandemir, Irfan
    De la Rúa, Pilar
    Pirk, Christian W
    Webster, Matthew T
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    A worldwide survey of genome sequence variation provides insight into the evolutionary history of the honeybee Apis mellifera2014In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 46, no 10, p. 1081-1088Article in journal (Refereed)
    Abstract [en]

    The honeybee Apis mellifera has major ecological and economic importance. We analyze patterns of genetic variation at 8.3 million SNPs, identified by sequencing 140 honeybee genomes from a worldwide sample of 14 populations at a combined total depth of 634×. These data provide insight into the evolutionary history and genetic basis of local adaptation in this species. We find evidence that population sizes have fluctuated greatly, mirroring historical fluctuations in climate, although contemporary populations have high genetic diversity, indicating the absence of domestication bottlenecks. Levels of genetic variation are strongly shaped by natural selection and are highly correlated with patterns of gene expression and DNA methylation. We identify genomic signatures of local adaptation, which are enriched in genes expressed in workers and in immune system- and sperm motility-related genes that might underlie geographic variation in reproduction, dispersal and disease resistance. This study provides a framework for future investigations into responses to pathogens and climate change in honeybees.

  • 47.
    Wallberg, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pirk, Christian W.
    Univ Pretoria, Dept Zool & Entomol, Pretoria, South Africa..
    Allsopp, Mike H.
    Agr Res Council, Plant Protect Res Inst, Stellenbosch, South Africa..
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Identification of Multiple Loci Associated with Social Parasitism in Honeybees2016In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 12, no 6, article id e1006097Article in journal (Refereed)
    Abstract [en]

    In colonies of the honeybee Apis mellifera, the queen is usually the only reproductive female, which produces new females (queens and workers) by laying fertilized eggs. However, in one subspecies of A. mellifera, known as the Cape bee (A. m. capensis), worker bees reproduce asexually by thelytoky, an abnormal form of meiosis where two daughter nucleii fuse to form single diploid eggs, which develop into females without being fertilized. The Cape bee also exhibits a suite of phenotypes that facilitate social parasitism whereby workers lay such eggs in foreign colonies so their offspring can exploit their resources. The genetic basis of this switch to social parasitism in the Cape bee is unknown. To address this, we compared genome variation in a sample of Cape bees with other African populations. We find genetic divergence between these populations to be very low on average but identify several regions of the genome with extreme differentiation. The regions are strongly enriched for signals of selection in Cape bees, indicating that increased levels of positive selection have produced the unique set of derived phenotypic traits in this subspecies. Genetic variation within these regions allows unambiguous genetic identification of Cape bees and likely underlies the genetic basis of social parasitism. The candidate loci include genes involved in ecdysteroid signaling and juvenile hormone and dopamine biosynthesis, which may regulate worker ovary activation and others whose products localize at the centrosome and are implicated in chromosomal segregation during meiosis. Functional analysis of these loci will yield insights into the processes of reproduction and chemical signaling in both parasitic and non-parasitic populations and advance understanding of the process of normal and atypical meiosis.

  • 48.
    Wallberg, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Schoening, Caspar
    Inst Bee Res, Hohen Neuendorf, Germany..
    Webster, Matthew Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hasselmann, Martin
    Univ Hohenheim, Stuttgart, Germany..
    Two extended haplotype blocks are associated with adaptation to high altitude habitats in East African honey bees2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 5, article id e1006792Article in journal (Refereed)
    Abstract [en]

    Understanding the genetic basis of adaption is a central task in biology. Populations of the honey bee Apis mellifera that inhabit the mountain forests of East Africa differ in behavior and morphology from those inhabiting the surrounding lowland savannahs, which likely reflects adaptation to these habitats. We performed whole genome sequencing on 39 samples of highland and lowland bees from two pairs of populations to determine their evolutionary affinities and identify the genetic basis of these putative adaptations. We find that in general, levels of genetic differentiation between highland and lowland populations are very low, consistent with them being a single panmictic population. However, we identify two loci on chromosomes 7 and 9, each several hundred kilobases in length, which exhibit near fixation for different haplotypes between highland and lowland populations. The highland haplotypes at these loci are extremely rare in samples from the rest of the world. Patterns of segregation of genetic variants suggest that recombination between haplotypes at each locus is suppressed, indicating that they comprise independent structural variants. The haplotype on chromosome 7 harbors nearly all octopamine receptor genes in the honey bee genome. These have a role in learning and foraging behavior in honey bees and are strong candidates for adaptation to highland habitats. Molecular analysis of a putative breakpoint indicates that it may disrupt the coding sequence of one of these genes. Divergence between the highland and lowland haplotypes at both loci is extremely high suggesting that they are ancient balanced polymorphisms that greatly predate divergence between the extant honey bee subspecies.

  • 49.
    Webster, Matthew
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology.
    J.B., Clegg
    R.M., Harding
    Common 5' beta-globin RFLP haplotype harbour a surprising level of ancestral sequence mosaicism2003In: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 113, no 2, p. 123-139Article in journal (Other academic)
    Abstract [en]

    Blocks of linkage disequilibrium (LD) in the human genome represent segments of ancestral chromosomes. To investigate the relationship between LD and genealogy, we analysed diversity associated with restriction fragment length polymorphism (RFLP) haplotypes of the 5' beta-globin gene complex. Genealogical analyses were based on sequence alleles that spanned a 12.2-kb interval, covering 3.1 kb around the psibeta gene and 6.2 kb of the delta-globin gene and its 5' flanking sequence known as the R/T region. Diversity was sampled from a Kenyan Luo population where recent malarial selection has contributed to substantial LD. A single common sequence allele spanning the 12.2-kb interval exclusively identified the ancestral chromosome bearing the "Bantu" beta(s) (sickle-cell) RFLP haplotype. Other common 5' RFLP haplotypes comprised interspersed segments from multiple ancestral chromosomes. Nucleotide diversity was similar between psibeta and R/T-delta-globin but was non-uniformly distributed within the R/T-delta-globin region. High diversity associated with the 5' R/T identified two ancestral lineages that probably date back more than 2 million years. Within this genealogy, variation has been introduced into the 3' R/T by gene conversion from other ancestral chromosomes. Diversity in delta-globin was found to lead through parts of the main genealogy but to coalesce in a more recent ancestor. The well-known recombination hotspot is clearly restricted to the region 3' of delta-globin. Our analyses show that, whereas one common haplotype in a block of high LD represents a long segment from a single ancestral chromosome, others are mosaics of short segments from multiple ancestors related in genealogies of unsuspected complexity.

  • 50.
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Patterns of autosomal divergence between the human and chimpanzee genomes support an allopatric model of speciation2009In: Gene, ISSN 1879-0038, Vol. 443, no 1-2, p. 70-75Article in journal (Refereed)
    Abstract [en]

    There is a large variation in divergence times across genomic regions between human and chimpanzee. It has been suggested that this could partly result from selection against ancestral gene flow between incipient species in regions of the genome containing genetic incompatibilities. It is possible that such barriers to gene flow could arise in specific genes or in chromosomal inversions. I analysed patterns of lineage sorting that occur between human, chimpanzee and gorilla genomic sequences by examining divergent site patterns in >18 Mb genomic alignments. I develop a method to normalise site patterns by the mutational spectrum to minimise errors caused by misinference caused by recurrent mutation. Here I show that divergence times appear to be uniform between coding and noncoding sequences and between inverted and non-rearranged portions of chromosomes. I therefore find no evidence to support the large-scale accumulation of genetic incompatibilities at speciation genes or chromosomal inversions in the ancestral population of humans and chimpanzees. In addition, site patterns that are discordant with the species tree occur more frequently in regions with high human recombination rates. This could indicate the action of selective sweeps in the ancestral population, but could also be indicative of increased rates of homoplasy in these regions. I argue that these observations are compatible with a neutral allopatric model of speciation.

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