Erik Axelsson

The genomic signature of dog domestication reveals adaptation to a starch-rich diet

The domestication of dogs was an important episode in the development of human civilization. The precise timing and location of this event is debated and little is known about the genetic changes that accompanied the transformation of ancient wolves into domestic dogs. Here we conduct whole-genome resequencing 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. 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.

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

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.

Paleo-Eskimo mtDNA Genome Reveals Matrilineal Discontinuity in Greenland

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 Worlds 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 Worlds 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.

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

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 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 ≈45,000 radiocarbon years before present (14C YBP). Subsequently, musk ox genetic diversity reincreased at ca. 30,000 14C YBP, recontracted at ca. 18,000 14C 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.

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

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.

Natural selection in avian protein-coding genes expressed in brain

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 dN/dS is 0.085 and genes with their maximal expression in the eye and central nervous system have the lowest mean dN/dS 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.

The Effect of Ancient DNA Damage on Inferences of Demographic Histories

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 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.

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

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 genomewide polymorphism data sets collected from chicken populations, together with divergence data from >5,000 chicken-zebra finch gene orthologs 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 FIs 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.

Substitution Rate Heterogeneity and the Male Mutation Bias

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 the majority of mutations are due to DNA replication error, the male-to-female mutation rate ratio (αm) 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 αm and c. αm 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 αm 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 αm, which varied significantly, from 1.53 to 3.51, among the introns (ANOVA: F13,14 =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 αm.

Segregation distortion in chicken and the evolutionary consequences of female meiotic drive in birds

As all four meiotic products give rise to sperm in males, female meiosis result in a single egg in most eukaryotes. Any genetic element with the potential to influence chromosome segregation, so that it is preferentially included in the egg, should therefore gain a transmission advantage; a process termed female meiotic drive. We are aware of two chromosomal components, centromeres and telomeres, which share the potential to influence chromosome movement during meioses and make the following predictions based on the presence of female meiotic drive: (1) centromere-binding proteins should experience rapid evolution as a result of a conflict between driving centromeres and the rest of the genome; and (2) segregation patterns should be skewed near centromeres and telomeres. To test these predictions, we first analyze the molecular evolution of seven centromere-binding proteins in nine divergent bird species. We find strong evidence for positive selection in two genes, lending support to the genomic conflict hypothesis. Then, to directly test for the presence of segregation distortion, we also investigate the transmission of ∼9000 single-nucleotide polymorphisms in 197 chicken families. By simulating fair Mendelian meioses, we locate chromosomal regions with statistically significant transmission ratio distortion. One region is located near the centromere on chromosome 1 and a second region is located near the telomere on the p-arm of chromosome 1. Although these observations do not provide conclusive evidence in favour of the meiotic drive/genome conflict hypothesis, they do lend support to the hypothesis that centromeres and telomeres drive during female meioses in chicken.