Deciphering the genetic basis of phenotypic diversity is one of the central aims of biological research. Domestic animals provide a unique opportunity for making substantial progress towards this goal. Intense positive selection has lead to a rich reservoir of phenotypes and underlying genotypes that can be interrogated using genetic tools to gain insight into the genetic basis of phenotypic diversity. The dog is the most phenotypically diverse mammal. It was domesticated from the grey wolf 11-30,000 years ago. After domestication, a period of intense breeding has lead to the massive phenotypic diversity seen amongst dog breeds today. These two phases of strong positive selection at domestication and at breed creation are likely to have left their signature on the genome. In this thesis, we have analysed genome-wide patterns to detect genomic regions involved in selection in both of these phases. We used whole genome sequences from 60 dogs and 12 wolves, to detect dog domestication selective sweeps. We find evidence for genes involved in memory formation, neurotransmission and starch digestion. To decipher the genetic signals underlying breed diversity, we used genome-wide genotype data from >170,000 SNPs in 509 dogs from 46 different breeds. We find evidence for genes under selection in many breeds, and only a few breeds. In addition, we identify novel sweeps underlying morphology and behavior. Recombination can influence the configuration of alleles present on a haplotype, and can thus increase or decrease the efficiency of selection. The PRDM9 protein has been shown to be important for determining recombination hotspot locations in humans and other mammals, but of all the mammals studied so far the dog is the only one to have a non-functional PRDM9. We used the genome-wide genotype data described above to characterise the fine scale recombination map in dogs. We find that recombination hotspots exist in dogs despite the absence of PRDM9. Moreover, we show that these hotspots are enriched for GC rich peaks and that these peaks are getting stronger over time. Our results show that the absence of PRDM9 has lead to the stabilisation of the recombination landscape in dogs.

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Ce projet vise à comprendre comment la structure génétique intra-spécifique d'espèces végétales tropicales emblématiques et de l’espèce humaine a été affectée par les variations spatio-temporelles de l’environnement actuel et passé. Nous avons développé une approche d’inférence génétique basée sur la théorie de la coalescence pour évaluer l’influence potentielle des changements climatiques passés sur l’évolution de la distribution géographique et de la diversité génétique neutre et/ou adaptative d’Amborella trichopoda Baill. en Nouvelle-Calédonie (espèce-sœur des angiospermes, données NGS et microsatellites), de Coffea canephora Pierre ex A. Froehn en Afrique tropicale (caféier Robusta, données NGS) et de populations européenne et africaine (Luhya, Kenya) d’humains anatomiquement modernes (données NGS issues du Projet 1000 Génomes). Nos travaux suggèrent que les fluctuations climatiques du Pleistocène tardif ont joué un rôle majeur sur l’évolution de la diversité génétique des espèces étudiées de milieux tropicaux et tempérés, avec une empreinte remarquable du Dernier Maximum Glaciaire (DMG, 21 000 ans avant le présent). Les contractions démographiques associées à la glaciation planétaire ont vraisemblablement conduit à la divergence entre les lignées génétiques d’Amborella et participé à l’accumulation des différences génétiques entre les lignées de C. canephora. Nos résultats suggèrent que les événements de glaciation planétaire ont probablement entraîné une différenciation génétique idiosyncratique dans les forêts tropicales humides mais l’intensité de cette réponse semble avoir varié entre espèces. Nous avons également identifié de nombreux événements passés de sélection dans les génomes de la population humaine européenne qui ont été vraisemblablement provoquées par les conditions environnementales au cours du DMG. Les adaptations phénotypiques associées ont probablement assuré le maintien de l’expansion démographique en dépit des pressions de sélection nouvelles auxquelles les populations étaient confrontées au cours du dernier âge glaciaire en Europe. / This project aims at understanding how the structure of the intra-specific genetic diversity in emblematic tropical plant species and in the human species was shaped by the spatiotemporal variation of current and past environments. We developed a genetic inference approach based on the coalescent theory to assess the potential impact of past climatic change onto the evolution of the geographic range and of the neutral and/or adaptive genetic diversity in Amborella trichopoda Baill. in New Caledonia (sister-species of all extant angiosperms, NGS and microsatellite datasets), in Coffea canephora Pierre ex A. Froehn in tropical Africa (Robusta coffee, NGS dataset) and in North-Western European and African (Luhya, Kenya) human populations (NGS dataset 1000 Genomes Project). We found that the climatic fluctuations of the Late Pleistocene influenced the evolution of genetic diversity in these species distributed in temperate and tropical environments. The environmental conditions during the Last Glacial Maximum (LGM, 21.000 years before present) appear as an important factor. The demographic contraction associated with the last global glaciation influenced the divergence between Amborella genetic lineages and contributed to the accumulation of genetic differences between C. canephora lineages. Our results suggest that global glaciation events likely drove idiosyncratic genetic differentiation in tropical rain forests but the intensity of this response varied between species. We also identified multiple events of selection in the genomes of the European human population which were likely triggered by the environmental conditions during the LGM. The associated phenotypic adaptations probably allowed the paleo-populations to maintain their demographic expansion despite the new kinds of selective pressure they faced during the last glacial age in Europe.

<p>Sex chromosomes are useful for the study of how factors such as mutation, selection, recombination and effective population size affect diversity and divergence.</p><p>A comparison of gametologous introns in seven different bird species revealed a complete lack of diversity on the female-specific W chromosome. In contrast, Z had at least one segregating site in all examined species. This can be explained by the lower mutation rate and lower effective population size of W but also suggests that selection affects diversity levels on the non-recombining W chromosome.</p><p>In a diverse set of chicken breeds, the Z chromosome showed reduced diversity compared to autosomes and significant heterogeneity in levels of variation. High variance in male reproductive success, leading to a reduced Z chromosome effective population size, can partly explain this observation. In addition, we suggest that selective sweeps frequently act on the Z chromosome and are responsible for a significant part of the observed Z reduction. </p><p>Differences in the mutation rate of Z and W chromosome sequences indicate that the time spent in male germ line is important for the mutation rate, but does not exclude a specifically reduced mutation rate on the Z chromosome. Estimates of mutation rate in autosomal, Z- and W-linked chicken and turkey sequences indicate a slight reduction in the rate on Z. However, due to rate heterogeneity among introns this reduction is not significant and we cannot exclude male biased mutation as the single cause of rate variation between the chromosomal classes.</p><p>Analysis of indel mutation rates in avian and mammalian gametologous introns show frequent occurrence of indels on both W and Y, excluding meiotic recombination as the only source of this type of mutation. The different indel rate patterns in birds (Z>W) and mammals (X=Y) suggest that indels are caused by both replication and recombination.</p>

Sex chromosomes are useful for the study of how factors such as mutation, selection, recombination and effective population size affect diversity and divergence. A comparison of gametologous introns in seven different bird species revealed a complete lack of diversity on the female-specific W chromosome. In contrast, Z had at least one segregating site in all examined species. This can be explained by the lower mutation rate and lower effective population size of W but also suggests that selection affects diversity levels on the non-recombining W chromosome. In a diverse set of chicken breeds, the Z chromosome showed reduced diversity compared to autosomes and significant heterogeneity in levels of variation. High variance in male reproductive success, leading to a reduced Z chromosome effective population size, can partly explain this observation. In addition, we suggest that selective sweeps frequently act on the Z chromosome and are responsible for a significant part of the observed Z reduction. Differences in the mutation rate of Z and W chromosome sequences indicate that the time spent in male germ line is important for the mutation rate, but does not exclude a specifically reduced mutation rate on the Z chromosome. Estimates of mutation rate in autosomal, Z- and W-linked chicken and turkey sequences indicate a slight reduction in the rate on Z. However, due to rate heterogeneity among introns this reduction is not significant and we cannot exclude male biased mutation as the single cause of rate variation between the chromosomal classes. Analysis of indel mutation rates in avian and mammalian gametologous introns show frequent occurrence of indels on both W and Y, excluding meiotic recombination as the only source of this type of mutation. The different indel rate patterns in birds (Z&gt;W) and mammals (X=Y) suggest that indels are caused by both replication and recombination.

This thesis presents results from genetic studies conducted in the chicken (Gallus gallus). The domestication of chicken is believed to have been initiated approximately 7,000 – 9,000 years ago in Southeast Asia. Since that time, selective breeding has altered the appearance of the wild ancestor, creating highly specialized chicken lines developed for egg and meat production. The first part of this thesis describes a detailed genetic analysis conducted on an F2 intercross between two phenotypically diverse chicken lines. The two parental lines used in this experiment originated from the same base population and have been developed by divergent selection for juvenile body-weight. Selection during forty generations has resulted in an eight-fold difference in body-weight between the High-Weight Selected (HWS) and Low-Weight Selected (LWS) line. In an attempt to identify the genetic factors differentiating the two lines, a large intercross population was bred to map Quantitative Trait Loci (QTL) affecting body-weight traits. A linkage map was constructed which included 434 genetic markers covering 31 of the 38 chicken autosomes. Although there is a dramatic phenotypic difference between the two founder lines, the QTL analysis for marginal effect could only identify seven QTL, each with small additive effects, influencing body-weight. We extended the genetic analysis to also include a model testing for pair-wise interactions between loci (epistasis). The analysis revealed 15 QTL pairs that affect body-weight and several of those formed a network of interacting loci. These results suggest that the genetic basis for the large difference in body-weight is most likely a result of a combined effect of multiple genetic factors, including QTL with small additive effects in combination with pair-wise interactions between QTL. The second part of this thesis presents two linkage maps. The first map constructed was of the chicken Z chromosome, the second used a genome-wide marker set, including 12,945 SNP markers, to build an updated consensus map of the chicken genome. The resulting consensus map includes 9,268 genetic markers and covers 33 chromosomes, still leaving five microchromosomes without marker coverage. The genome average rate of recombination was estimated to 3.1 cM/Mb, but varied considerably between and within chromosomes. A general trend of elevated recombination rates towards telomeric ends and lower rates near centromeres was observed. This was in concordance to previous reports from mammalian species. Recombination rates in chicken were also found to be highly positively correlated with GC-rich sequences.

The process of evolution is of both scientific and medical interest. This thesis presents several studies using complete genomic reference sequences, comparative genomic data, and intraspecific diversity data to study the two key processes of evolution: mutation and selection. Large duplications, deletions, inversions, and translocations of DNA contribute to genomic variation both between and within species. Human chromosomes 15 and 17 contain a high percentage of dispersed, recently duplicated sequences. Examination of the relationships between these sequences showed that the majority of all duplications within each chromosome could be linked through core sequences that are prone to duplication. Comparison to orthologous sequences in other mammals allowed a reconstruction of the ancestral state of the human chromosomes, revealing that regions of rearrangement specific to the human lineage are highly enriched in chromosome-specific duplications. Comparison to copy number variation data from other studies also shows that these regions are enriched in current human structural variation. One specific region, the MAPT locus at 17q21.31, known to contain an inversion polymorphism in Europeans, was resequenced completely across both human orientation haplotypes and in chimpanzee and orangutan, revealing complex duplication structures at the inversion breakpoints, with the human region being more complex than chimpanzee or orangutan. Fluorescent in-situ hybridization analysis of human, chimpanzee, and orangutan chromosomes showed inversion polymorphisms of independent origin in all three species, demonstrating that this region has been a hotspot of genomic rearrangement for at least twelve million years. These results reveal a mechanistic relationship between sequence duplication and rearrangement in the great apes. We also generated a draft sequence of the chimpanzee genome and compared it to that of the human. Among other findings, this showed that CpG dinucleotides contribute 25% of all single base mutations, with a rate of mutation ~10-fold that of other bases, and that the male mutation rate in great apes is ~5-6 times the female rate, a higher ratio than had been observed in comparisons of primates and rodents. We detected six regions of probable recent positive selection in humans with a statistical method relying on chimpanzee sequence to control for regional variation in mutation rates. Finally, resequencing of several lines of domestic chicken and comparison to the reference chicken genome identified a number of gene deletions fixed in domestic lines and also several potential selective sweeps. Of particular interest are a missense mutation in TSHR nearly fixed in all domestic chickens and a partial deletion of SH3RF2 fixed in a high growth line. The TSHR mutation may play a role in relaxation of seasonal reproduction. A high-resolution QTL mapping experiment showed that the SH3RF2 deletion is significantly associated with increased growth. This work provides important new insights into the mechanics of evolutionary change at both the single nucleotide and structural level and identifies potential targets of natural and artificial selection in humans and chickens.

The distribution of the expressed genotype is moved around in the population over time byevolution. Natural selection is one of the forces that act on the phenotype to change the patterns ofnucleotide variation underlying those distributions. How the phenotype changes over aheterogeneous environment describes the type of evolutionary force acting on this trait and thisshould be reflected in the variation at loci underlying this trait. While the variation in phenotypesand at the nucleotide level in a population indicates the same evolutionary force, it does notnecessarily mean that they are connected. In natural populations the continuous shifting of geneticmaterial through recombination events break down possible associations between loci facilitates theexamination of possible causal loci to single base pair differences in DNA-sequences. Connecting thegenotype and the phenotype thus provides an important step in the understanding the geneticarchitecture of complex traits and the forces that shape the observed patterns.This thesis examines the European aspen, Populus tremula, sampled from subpopulations overan extensive latitudinal gradient covering most of Sweden. Results show a clear geneticdifferentiation in the timing of bud set, a measure of the autumnal cessation of growth, betweendifferent parts of Sweden pointing at local adaptation. In the search for candidate genes thatunderlie the local adaptation found, most genes (25) in the photoperiodic gene network wereexamined for signals of selection. Genes in the photoperiodic network show an increase in theheterogeneity of differentiation between sampled subpopulations in Sweden. Almost half (12) of theexamined genes are under some form of selection. Eight of these genes show positive directionalselection on protein evolution and the gene that code for a photoreceptor, responsible for mediatingchanging light conditions to downstream targets in the network, has the hallmarks of a selectivesweep. The negative correlation between positive directional selection and synonymous diversityindicates that the majority of the photoperiod gene network has undergone recurrent selectivesweeps. A phenomenon that likely has occurred when P. tremula has readapted to the northern lightregimes during population expansion following retracting ice between periods of glaciations. Two ofthe genes under selection also have single nucleotide polymorphisms (SNP) that associate with budset, two in the PHYB2 gene and one in the LHY2 gene. Furthermore, there is an additional SNP inLHY1 that explain part of the variation in timing of bud set, despite the lack of a signal of selection atthe LHY1 gene. Together these SNPs explain 10-15% of the variation in the timing of bud set and 20-30% more if accounting for the positive co-variances between SNPs. There is thus rather extensiveevidence that genes in the photoperiod gene network control the timing of bud set, and reflect localadaptation in this trait.

Abstract Plants and animals colonized Northern Europe after the last Ice Age from different refugia, not covered by the ice sheet. Many plants, such as the northern rock cress (Arabidopsis lyrata ssp. petraea) adapted to the short growing season in the North. We thus expect that colonization of the new environment was accompanied by directional selection for traits conferring this adaptation. In this thesis I studied whether recent directional selection can be detected in two important genes, PHYTOCHROME A (PHYA) and FLOWERING LOCUS C1 (FLC1), related to the flowering time pathway. To detect directional selection, I compared DNA sequence variation from the samples of a southern (Plech, Germany) and a northern (Spiterstulen, Norway) population. I also studied the current response potential to changing conditions in the marginal Spiterstulen population. Adaptation potential was characterized by assessing plasticity and amount of additive genetic variation, focusing on flowering traits. In addition, associations of 21 flowering time candidate genes for phenological and fitness traits were studied. There were several lines of evidence for recent directional selection in both candidate genes, PHYA and FLC1, in the northern Spiterstulen population Variation was strongly reduced around both genes and in addition they were highly differentiated between populations. In the Spiterstulen population there was a remarkable reduction in additive genetic variation for flowering traits, for instance when compared with morphological traits. On the other hand, phenological traits showed high plasticity. Some of the photoperiodic pathway genes showed association to flowering or reproductive fitness. The results suggest that directional selection during the colonization of the northern areas has impacted the two studied genes. Genetic changes were likely involved in altered photoperiodic and vernalization responses which might be adaptive for a short growing season. Further, directional selection was probably responsible for reducing additive genetic variation in flowering traits. Because there was only little genetic variation, adaptation to future environmental change of the marginal Spiterstulen population is likely to rely largely on plastic reactions to environmental signals, or tracking the environment by dispersal. / Tiivistelmä Kasvit ja eläimet levittäytyivät Pohjois-Eurooppaan viimeisen jääkauden jälkeen mannerjäätikön ulkopuolella jääneistä refugioista. Useat kasvit, kuten idänpitkäpalko (Arabidopsis lyrata ssp. petraea) sopeutuivat pohjoisen lyhyeen kasvukauteen. On syytä olettaa, että suuntaava valinta vaikutti sopeutumisessa tärkeisiin ominaisuuksiin. Tässä väitöskirjassa tutkin voidaanko suuntaavan valinnan aiheuttamia jalanjälkiä löytää kahdesta tärkeästä kukkimisaikageenistä, FYTOKROMI A (PHYA) ja FLOWERING LOCUS C1 (FLC1) geeneistä. Tätä varten vertasin DNA sekvenssimuuntelua pohjoisessa (Norja) ja eteläisessä (Saksa) populaatiossa, kiinnittäen erityisesti huomiota geneettisen muuntelun määrään ja erilaistumiseen. Lisäksi tutkin miten Spiterstulenin reunapopulaatio voi vastata tulevaisuudessa muuttuvaan ympäristöön. Sopeutumispotentiaalia arvioitiin sekä fenotyyppisen plastisuuden että additiivisen geneettisen muuntelun määrällä. Lisäksi tutkin miten vaihtelu 21 kukkimisaikageenissä liittyy fenologisiin ja kelpoisuusominaisuuksiin. Useat merkit viittasivat siihen, että suuntaava valinta oli vaikuttanut kummassakin tutkitussa geenissä. Muuntelu oli vähentynyt voimakkaasti kumpaakin geeniä ympäröiviltä kromosomialueilta, jotka olivat myös selkeästi erilaistuneet. Additiivinen geneettinen muuntelu oli selvästi vähentynyt kukkimisominaisuuksissa verrattuna morfologisiin ominaisuuksiin, mahdollisesti suuntaavan valinnan johdosta. Kukkimisominaisuudet olivat kuitenkin plastisia. Jotkin valojaksoreitin geenit vaikuttivat sekä kukkimiseen että lisääntymiskykyyn. Nämä tulokset osoittavat että suuntaava valinta vaikutti kahteen tutkittuun geeniin pohjoiseen levittäytymisen aikana. Geneettiset muutokset liittyivät todennäköisesti muuttuneisiin valojakso-, ja vernalisaatiovasteisiin, jotka saattoivat edistää sopeutumista lyhyeen kasvukauteen. Koska geneettistä muuntelua oli vain hyvin vähän, fenotyyppisellä plastisuudella on todennäköisesti tärkeä rooli sopeutumisessa muuttuvaan ympäristöön Spiterstulenin reunapopulaatiossa.

Abstract Demographic history and natural selection are central forces shaping the genetic diversity of populations. Knowledge on these forces increases understanding of processes shaping genetic variability of populations. In this PhD thesis I investigated demographic history and selection in multiple populations of Arabidopsis lyrata, an outcrossing herbaceous plant species of the Brassicaceae family. Due to its wide distribution in the temperate and boreal regions, A. lyrata serves as a good model system to study population genetic consequences of colonization of northern latitudes. The first aim of this study was to characterize the demographic and colonization history of the species using site frequency spectra estimated from whole-genome diversity data. Another aim was to detect genetic loci targeted by recent selective sweeps at genome-wide scale as well as at candidate flowering time genes. Patterns of genome-wide selection at linked sites (linked selection) were also compared between populations of Capsella grandiflora and A. lyrata with contrasting demographic histories. Evidence for strong effective population size decline in the past few hundred thousand years was detected in A. lyrata populations species-wide. This study also suggests recent Scandinavian colonization from an unknown refugium, distinct from the Central European source population. Selection analyses revealed loci targeted by positive selection in two Scandinavian lineages after the recent population split as well as selective sweeps in flowering time genes in the colonizing populations. In comparison with the studied C. grandiflora population, the Norwegian A. lyrata population had weaker purifying selection and no evidence for reduction of diversity around genes was found. This thesis offers novel information on species colonization history and its genome-wide effects, which is important for understanding the framework of local adaptation. / Tiivistelmä Populaation demografinen historia ja luonnonvalinta ovat keskeisiä populaation perinnöllisen muuntelun muokkaajia. Näiden tekijöiden tutkimus on tärkeää eliöiden sopeutumisen ymmärtämiselle. Tässä väitöskirjassa tutkin demografista historiaa ja valintaa monivuotisen ristisiittoiseen ruohovartisen Brassicaceae-heimon kasvilajin idänpitkäpalon (Arabidopsis lyrata) useissa eri populaatioissa. Idänpitkäpalko on erinomainen mallilaji pohjoiseen ympäristöön sopeutumisen tutkimukseen, koska sen toisistaan eristäytyneet paikalliset populaatiot ovat levittäytyneet laajalle boreaalisella ja lauhkealla ilmastovyöhykkeellä. Tutkimuksen tarkoituksena oli luonnehtia populaatioiden demografista historiaa ja kolonisaatioreittejä käyttäen koko perimän laajuisesta muunteluaineistosta estimoituja alleelifrekvenssispektrejä. Lisäksi koko perimän laajuista aineistoa sekä kukkimisaikaa ohjaavien geenien sekvenssejä käytettiin positiivisen luonnonvalinnan merkkien tunnistukseen. Genominlaajuista kytkeytynyttä valintaa vertailtiin toiseen ristisiittoiseen Brassicaceae-heimon lajin Capsella grandifloran populaatioon, jonka demografinen historia poikkeaa huomattavasti tutkituista idänpitkäpalon populaatioista. Tutkimuksessa havaittiin, että kaikissa tutkituissa idänpitkäpalon populaatioissa tehollinen populaatiokoko oli pienentynyt viimeisen muutaman sadantuhannen vuoden aikana. Kolonisaatiohistorian tarkastelu osoitti, että idänpitkäpalon skandinaaviset populaatiot ovat todennäköisesti peräisin keskieurooppalaisesta refugiosta erillisestä läntisestä refugiosta. Skandinavian kolonisaation yhteydessä vaikuttaneen positiivisen luonnonvalinnan merkkejä havaittiin useissa eri genomin osissa sekä erityisesti valojaksoa mittaavissa geeneissä. Tämä kertoo erilaisiin valojaksoihin sopeutumisen tärkeydestä skandinaavisen kolonisaation yhteydessä. Verrattuna tutkittuun C. grandifloran populaatioon, idänpitkäpalolla puhdistavan valinnan havaittiin olevan heikompaa ja muuntelun vähenemistä geenien ympärillä ei havaittu. Tämä tutkimus tarjoaa uutta tietoa Skandinavian kolonisaatiohistoriasta ja sen genominlaajuisista vaikutuksista. Tutkimuksessa tuotettua tietoa voidaan hyödyntää paikallisen sopeutumisen ymmärtämisessä.