Erik Axelsson

Publications of Erik Axelsson

• Death of PRDM9 coincides with stabilization of the recombination landscape in the dog genome.

  Authors: Erik Axelsson, Matthew T Webster, Abhirami Ratnakumar, Chris P Ponting, Kerstin Lindblad-Toh

  Genome research. 01/2012; 22(1):51-63.

  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 initiateAnalysis 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.

• Identification of genomic regions associated with phenotypic variation between dog breeds using selection mapping.

  Authors: Amaury Vaysse, Abhirami Ratnakumar, Thomas Derrien, Erik Axelsson, Gerli Rosengren Pielberg, Snaevar Sigurdsson, Tove Fall, Eija H Seppälä, Mark S T Hansen, Cindy T Lawley [......] Carles Vilà, Hannes Lohi, Francis Galibert, Merete Fredholm, Jens Häggström, Ake Hedhammar, Catherine André, Kerstin Lindblad-Toh, Christophe Hitte, Matthew T Webster

  PLoS genetics. 10/2011; 7(10):e1002316.

  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 analysisThe 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.

• Ancient DNA analyses exclude humans as the driving force behind late Pleistocene musk ox (Ovibos moschatus) population dynamics.

  Authors: Paula F Campos, Eske Willerslev, Andrei Sher, Ludovic Orlando, Erik Axelsson, Alexei Tikhonov, Kim Aaris-Sørensen, Alex D Greenwood, Ralf-Dietrich Kahlke, Pavel Kosintsev, Tatiana Krakhmalnaya, Tatyana Kuznetsova, Philippe Lemey, Ross MacPhee, Christopher A Norris, Kieran Shepherd, Marc A Suchard, Grant D Zazula, Beth Shapiro, M Thomas P Gilbert

  Proceedings of the National Academy of Sciences of the United States of America. 03/2010; 107(12):5675-80.

  The causes of the late Pleistocene megafaunal extinctions are poorly understood. Different lines of evidence point to climate change, the arrival of humans, or a combination of these events as theThe causes of the late Pleistocene megafaunal extinctions are poorly understood. Different lines of evidence point to climate change, the arrival of humans, or a combination of these events as the trigger. Although many species went extinct, others, such as caribou and bison, survived to the present. The musk ox has an intermediate story: relatively abundant during the Pleistocene, it is now restricted to Greenland and the Arctic Archipelago. In this study, we use ancient DNA sequences, temporally unbiased summary statistics, and Bayesian analytical techniques to infer musk ox population dynamics throughout the late Pleistocene and Holocene. Our results reveal that musk ox genetic diversity was much higher during the Pleistocene than at present, and has undergone several expansions and contractions over the past 60,000 years. Northeast Siberia was of key importance, as it was the geographic origin of all samples studied and held a large diverse population until local extinction at approximately 45,000 radiocarbon years before present ((14)C YBP). Subsequently, musk ox genetic diversity reincreased at ca. 30,000 (14)C YBP, recontracted at ca. 18,000 (14)C YBP, and finally recovered in the middle Holocene. The arrival of humans into relevant areas of the musk ox range did not affect their mitochondrial diversity, and both musk ox and humans expanded into Greenland concomitantly. Thus, their population dynamics are better explained by a nonanthropogenic cause (for example, environmental change), a hypothesis supported by historic observations on the sensitivity of the species to both climatic warming and fluctuations.

• Quantification of adaptive evolution of genes expressed in avian brain and the population size effect on the efficacy of selection.

  Authors: Erik Axelsson, Hans Ellegren

  Molecular biology and evolution. 02/2009;

  Whether protein evolution is mainly due to fixation of beneficial alleles by positive selection or to random genetic drift has remained a contentious issue over the years. Here we use two genome-wideWhether protein evolution is mainly due to fixation of beneficial alleles by positive selection or to random genetic drift has remained a contentious issue over the years. Here we use two genome-wide polymorphism data sets collected from chicken populations, together with divergence data from >5,000 chicken - zebra finch gene orthologues expressed in brain, to assess the amount of adaptive evolution in protein-coding genes of birds. First, we show that estimates of the fixation index (FI, the ratio of fixed nonsynonymous to synonymous changes over the ratio of the corresponding polymorphisms) are highly dependent on the character of the underlying data sets. Second, by using polymorphism data from high-frequency alleles, to avoid the confounding effect of slightly deleterious mutations segregating at low frequency, we estimate that about 20% of amino acid changes have been brought to fixation through positive selection during avian evolution. This estimate is intermediate to that obtained in humans (lower) and flies as well as bacteria (higher), and is consistent with population genetics theory that stipulates a positive relationship between the efficiency of selection and the effective population size. Further, by comparing the fixation indexes for common and all alleles, we estimate that approximately 20% of nonsynonymous variation segregating in chicken populations represent slightly deleterious mutations, which is less than in Drosophila. Overall, these results highlight the link between the effective population size and positive as well as negative selection.

• The effect of ancient DNA damage on inferences of demographic histories.

  Authors: Erik Axelsson, Eske Willerslev, M Thomas P Gilbert, Rasmus Nielsen

  Molecular biology and evolution. 10/2008; 25(10):2181-7.

  The field of ancient DNA (aDNA) is casting new light on many evolutionary questions. However, problems associated with the postmortem instability of DNA may complicate the interpretation of aDNAThe field of ancient DNA (aDNA) is casting new light on many evolutionary questions. However, problems associated with the postmortem instability of DNA may complicate the interpretation of aDNA data. For example, in population genetic studies, the inclusion of damaged DNA may inflate estimates of diversity. In this paper, we examine the effect of DNA damage on population genetic estimates of ancestral population size. We simulate data using standard coalescent simulations that include postmortem damage and show that estimates of effective population sizes are inflated around, or right after, the sampling time of the ancestral DNA sequences. This bias leads to estimates of increasing, and then decreasing, population sizes, as observed in several recently published studies. We reanalyze a recently published data set of DNA sequences from the Bison (Bison bison/Bison priscus) and show that the signal for a change in effective population size in this data set vanishes once the effects of putative damage are removed. Our results suggest that population genetic analyses of aDNA sequences, which do not accurately account for damage, should be interpreted with great caution.

• Paleo-Eskimo mtDNA genome reveals matrilineal discontinuity in Greenland.

  Authors: M Thomas P Gilbert, Toomas Kivisild, Bjarne Grønnow, Pernille K Andersen, Ene Metspalu, Maere Reidla, Erika Tamm, Erik Axelsson, Anders Götherström, Paula F Campos [......] Jean-Luc Schwenninger, Roger Nathan, Cees-Jan de Hoog, Anders Koch, Lone Nukaaraq Møller, Claus Andreasen, Morten Meldgaard, Richard Villems, Christian Bendixen, Eske Willerslev

  Science (New York, N.Y.). 07/2008; 320(5884):1787-9.

  The Paleo-Eskimo Saqqaq and Independence I cultures, documented from archaeological remains in Northern Canada and Greenland, represent the earliest human expansion into the New World's northernThe Paleo-Eskimo Saqqaq and Independence I cultures, documented from archaeological remains in Northern Canada and Greenland, represent the earliest human expansion into the New World's northern extremes. However, their origin and genetic relationship to later cultures are unknown. We sequenced a mitochondrial genome from a Paleo-Eskimo human by using 3400-to 4500-year-old frozen hair excavated from an early Greenlandic Saqqaq settlement. The sample is distinct from modern Native Americans and Neo-Eskimos, falling within haplogroup D2a1, a group previously observed among modern Aleuts and Siberian Sireniki Yuit. This result suggests that the earliest migrants into the New World's northern extremes derived from populations in the Bering Sea area and were not directly related to Native Americans or the later Neo-Eskimos that replaced them.

• Natural selection in avian protein-coding genes expressed in brain.

  Authors: Erik Axelsson, Lina Hultin-Rosenberg, Mikael Brandström, Martin Zwahlén, David F Clayton, Hans Ellegren

  Molecular ecology. 06/2008; 17(12):3008-17.

  The evolution of birds from theropod dinosaurs took place approximately 150 million years ago, and was associated with a number of specific adaptations that are still evident among extant birds,The evolution of birds from theropod dinosaurs took place approximately 150 million years ago, and was associated with a number of specific adaptations that are still evident among extant birds, including feathers, song and extravagant secondary sexual characteristics. Knowledge about the molecular evolutionary background to such adaptations is lacking. Here, we analyse the evolution of > 5000 protein-coding gene sequences expressed in zebra finch brain by comparison to orthologous sequences in chicken. Mean d(N)/d(S) is 0.085 and genes with their maximal expression in the eye and central nervous system have the lowest mean d(N)/d(S) value, while those expressed in digestive and reproductive tissues exhibit the highest. We find that fast-evolving genes (those which have higher than expected rate of nonsynonymous substitution, indicative of adaptive evolution) are enriched for biological functions such as fertilization, muscle contraction, defence response, response to stress, wounding and endogenous stimulus, and cell death. After alignment to mammalian orthologues, we identify a catalogue of 228 genes that show a significantly higher rate of protein evolution in the two bird lineages than in mammals. These accelerated bird genes, representing candidates for avian-specific adaptations, include genes implicated in vocal learning and other cognitive processes. Moreover, colouration genes evolve faster in birds than in mammals, which may have been driven by sexual selection for extravagant plumage characteristics.

• Rapid evolution of female-biased, but not male-biased, genes expressed in the avian brain.

  Authors: Judith E Mank, Lina Hultin-Rosenberg, Erik Axelsson, Hans Ellegren

  Molecular biology and evolution. 12/2007; 24(12):2698-706.

  The powerful pressures of sexual and natural selection associated with species recognition and reproduction are thought to manifest in a faster rate of evolution in sex-biased genes, an effect thatThe powerful pressures of sexual and natural selection associated with species recognition and reproduction are thought to manifest in a faster rate of evolution in sex-biased genes, an effect that has been documented particularly for male-biased genes expressed in the reproductive tract. However, little is known about the rate of evolution for genes involved in sexually dimorphic behaviors, which often form the neurological basis of intrasexual competition and mate choice. We used microarray data, designed to uncover sex-biased expression patterns in embryonic chicken brain, in conjunction with data on the rate of sequence evolution for >4,000 coding regions aligned between chicken and zebra finch in order to study the role of selection in governing the molecular evolution for sex-biased and unbiased genes. Surprisingly, we found that female-biased genes, defined across a range of cutoff values, show a higher rate of functional evolution than both male-biased and unbiased genes. Autosomal male-biased genes evolve at a similar rate as unbiased genes. Sex-specific genomic properties, such as heterogeneity in genomic distribution and GC content, and codon usage bias for sex-biased classes fail to explain this surprising result, suggesting that selective pressures may be acting differently on the male and female brain.

• Fast-X on the Z: rapid evolution of sex-linked genes in birds.

  Authors: Judith E Mank, Erik Axelsson, Hans Ellegren

  Genome research. 06/2007; 17(5):618-24.

  Theoretical work predicts natural selection to be more efficient in the fixation of beneficial mutations in X-linked genes than in autosomal genes. This "fast-X effect" should be evident by anTheoretical work predicts natural selection to be more efficient in the fixation of beneficial mutations in X-linked genes than in autosomal genes. This "fast-X effect" should be evident by an increased ratio of nonsynonymous to synonymous substitutions (dN/dS) for sex-linked genes; however, recent studies have produced mixed support for this expectation. To make an independent test of the idea of fast-X evolution, we focused on birds, which have female heterogamety (males ZZ, females ZW), where analogous arguments would predict a fast-Z effect. We aligned 2.8 Mb of orthologous protein-coding sequence of zebra finch and chicken from 172 Z-linked and 4848 autosomal genes. Zebra finch data were in the form of EST sequences from brain cDNA libraries, while chicken genes were from the draft genome sequence. The dN/dS ratio was significantly higher for Z-linked (0.110) than for all autosomal genes (0.085; P=0.002), as well as for genes linked to similarly sized autosomes 1-10 (0.0948; P=0.04). This pattern of fast-Z was evident even after we accounted for the nonrandom distribution of male-biased genes. We also examined the nature of standing variation in the chicken protein-coding regions. The ratio of nonsynonymous to synonymous polymorphism (pN/pS) did not differ significantly between genes on the Z chromosome (0.104) and on the autosomes (0.0908). In conjunction, these results suggest that evolution proceeds more quickly on the Z chromosome, where hemizygous exposure of beneficial nondominant mutations increases the rate of fixation.

• Strong regional biases in nucleotide substitution in the chicken genome.

  Authors: Matthew T Webster, Erik Axelsson, Hans Ellegren

  Molecular biology and evolution. 07/2006; 23(6):1203-16.

  Interspersed repeats have emerged as a valuable tool for studying neutral patterns of molecular evolution. Here we analyze variation in the rate and pattern of nucleotide substitution across allInterspersed repeats have emerged as a valuable tool for studying neutral patterns of molecular evolution. Here we analyze variation in the rate and pattern of nucleotide substitution across all autosomes in the chicken genome by comparing the present-day CR1 repeat sequences with their ancestral copies and reconstructing nucleotide substitutions with a maximum likelihood model. The results shed light on the origin and evolution of large-scale heterogeneity in GC content found in the genomes of birds and mammals--the isochore structure. In contrast to mammals, where GC content is becoming homogenized, heterogeneity in GC content is being reinforced in the chicken genome. This is also supported by patterns of substitution inferred from alignments of introns in chicken, turkey, and quail. Analysis of individual substitution frequencies is consistent with the biased gene conversion (BGC) model of isochore evolution, and it is likely that patterns of evolution in the chicken genome closely resemble those in the ancestral amniote genome, when it is inferred that isochores originated. Microchromosomes and distal regions of macrochromosomes are found to have elevated substitution rates and a more GC-biased pattern of nucleotide substitution. This can largely be accounted for by a strong correlation between GC content and the rate and pattern of substitution. The results suggest that an interaction between increased mutability at CpG motifs and fixation biases due to BGC could explain increased levels of divergence in GC-rich regions.

• Substitution rate heterogeneity and the male mutation bias.

  Authors: Sofia Berlin, Mikael Brandström, Niclas Backström, Erik Axelsson, Nick G C Smith, Hans Ellegren

  Journal of molecular evolution. 03/2006; 62(2):226-33.

  Germline mutation rates have been found to be higher in males than in females in many organisms, a likely consequence of cell division being more frequent in spermatogenesis than in oogenesis. If theGermline mutation rates have been found to be higher in males than in females in many organisms, a likely consequence of cell division being more frequent in spermatogenesis than in oogenesis. If the majority of mutations are due to DNA replication error, the male-to-female mutation rate ratio (alpha(m)) is expected to be similar to the ratio of the number of germ line cell divisions in males and females (c), an assumption that can be tested with proper estimates of alpha(m) and c. Alpha(m) is usually estimated by comparing substitution rates in putatively neutral sequences on the sex chromosomes. However, substantial regional variation in substitution rates across chromosomes may bias estimates of alpha(m) based on the substitution rates of short sequences. To investigate regional substitution rate variation, we estimated sequence divergence in 16 gametologous introns located on the Z and W chromosomes of five bird species of the order Galliformes. Intron ends and potentially conserved blocks were excluded to reduce the effect of using sequences subject to negative selection. We found significant substitution rate variation within Z chromosome (G15 = 37.6, p = 0.0010) as well as within W chromosome introns (G15 = 44.0, p = 0.0001). This heterogeneity also affected the estimates of alpha(m), which varied significantly, from 1.53 to 3.51, among the introns (ANOVA: F(13,14) = 2.68, p = 0.04). Our results suggest the importance of using extensive data sets from several genomic regions to avoid the effects of regional mutation rate variation and to ensure accurate estimates of alpha(m).

• Comparison of the chicken and turkey genomes reveals a higher rate of nucleotide divergence on microchromosomes than macrochromosomes.

  Authors: Erik Axelsson, Matthew T Webster, Nick G C Smith, David W Burt, Hans Ellegren

  Genome research. 02/2005; 15(1):120-5.

  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.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.

• Male-biased mutation rate and divergence in autosomal, z-linked and w-linked introns of chicken and Turkey.

  Authors: Erik Axelsson, Nick G C Smith, Hannah Sundström, Sofia Berlin, Hans Ellegren

  Molecular biology and evolution. 09/2004; 21(8):1538-47.

  To investigate mutation-rate variation between autosomes and sex chromosomes in the avian genome, we have analyzed divergence between chicken (Gallus gallus) and turkey (Meleagris galopavo) sequencesTo investigate mutation-rate variation between autosomes and sex chromosomes in the avian genome, we have analyzed divergence between chicken (Gallus gallus) and turkey (Meleagris galopavo) sequences from 33 autosomal, 28 Z-linked, and 14 W-linked introns with a total ungapped alignment length of approximately 43,000 bp. There are pronounced differences in the mean divergence among autosomes and sex chromosomes (autosomes [A] = 10.08%, Z chromosome = 10.99%, and W chromosome = 5.74%), and we use these data to estimate the male-to-female mutation-rate ratio (alpha(m)) from Z/A, Z/W, and A/W comparisons at 1.71, 2.37, and 2.52, respectively. Because the alpha(m) estimates of the three comparisons do not differ significantly, we find no statistical support for a specific reduction in the Z chromosome mutation rate (Z reduction estimated at 4.89%, P = 0.286). The idea of mutation-rate reduction in the sex chromosome hemizygous in one sex (i.e., X in mammals, Z in birds) has been suggested on the basis of theory on adaptive mutation-rate evolution. If it exists in birds, the effect would, thus, seem to be weak; a preliminary power analysis suggests that it is significantly less than 18%. Because divergence may vary within chromosomal classes as a result of variation in mutation and/or selection, we developed a novel double-bootstrapping method, bootstrapping both by introns and sites from concatenated alignments, to estimate confidence intervals for chromosomal class rates and for alpha(m). The narrowest interval for the alpha(m) estimate is 1.88 to 2.97 from the Z/W comparison. We also estimated alpha(m) using maximum likelihood on data from all three chromosome classes; this method yielded alpha(m) = 2.47 and approximate 95% confidence intervals of 2.27 to 2.68. Our data are broadly consistent with the idea that mutation-rate differences between chromosomal classes can be explained by the male mutation bias alone.