The Many Landscapes of Recombination in

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Recombination is a fundamental biological process with profound evolutionary implications. Theory predicts that recombination increases the effectiveness of selection in natural populations. Yet, direct tests of this prediction have been restricted to qualitative trends due to the lack of detailed characterization of recombination rate variation across genomes and within species. The use of imprecise recombination rates can also skew population genetic analyses designed to assess the presence and mode of selection across genomes. Here we report the first integrated high-resolution description of genomic and population variation in recombination, which also distinguishes between the two outcomes of meiotic recombination: crossing over (CO) and gene conversion (GC). We characterized the products of 5,860 female meioses in Drosophila melanogaster by genotyping a total of 139 million informative SNPs and mapped 106,964 recombination events at a resolution down to 2 kilobases. This approach allowed us to generate whole-genome CO and GC maps as well as a detailed description of variation in recombination among individuals of this species. We describe many levels of variation in recombination rates. At a large-scale (100 kb), CO rates exhibit extreme and highly punctuated variation along chromosomes, with hot and coldspots. We also show extensive intra-specific variation in CO landscapes that is associated with hotspots at low frequency in our sample. GC rates are more uniformly distributed across the genome than CO rates and detectable in regions with reduced or absent CO. At a local scale, recombination events are associated with numerous sequence motifs and tend to occur within transcript regions, thus suggesting that chromatin accessibility favors double-strand breaks. All these non-independent layers of variation in recombination across genomes and among individuals need to be taken into account in order to obtain relevant estimates of recombination rates, and should be included in a new generation of population genetic models of the interaction between selection and linkage.

Vyšlo v časopise: The Many Landscapes of Recombination in. PLoS Genet 8(10): e32767. doi:10.1371/journal.pgen.1002905
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002905

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Zdroje

1. John B (2005) Meiosis. New York: Cambridge University Press.

2. FelsensteinJ (1974) The evolutionary advantage of recombination. Genetics 78 : 737–756.

3. CrowJF (1992) An advantage of sexual reproduction in a rapidly changing environment. J Hered 83 : 169–173.

4. BartonNH, CharlesworthB (1998) Why sex and recombination? Science 281 : 1986–1990.

5. BartonNH, OttoSP (2005) Evolution of recombination due to random drift. Genetics

6. MartinG, OttoSP, LenormandT (2006) Selection for recombination in structured populations. Genetics 172 : 593–609.

7. KeightleyPD, OttoSP (2006) Interference among deleterious mutations favours sex and recombination in finite populations. Nature 443 : 89–92.

8. RozeD, BartonNH (2006) The Hill-Robertson effect and the evolution of recombination. Genetics

9. BartonNH (2009) Why sex and recombination? Cold Spring Harb Symp Quant Biol 74 : 187–195.

10. BegunDJ, AquadroCF (1992) Levels of naturally occurring DNA polymorphism correlate with recombination rates in D. melanogaster. Nature 356 : 519–520.

11. KlimanRM, HeyJ (1993) Reduced natural selection associated with low recombination in Drosophila melanogaster. Mol Biol Evol 1239–1258.

12. ComeronJM, KreitmanM, AguadeM (1999) Natural selection on synonymous sites is correlated with gene length and recombination in Drosophila. Genetics 151 : 239–249.

13. HeyJ, KlimanRM (2002) Interactions between natural selection, recombination and gene density in the genes of Drosophila. Genetics 160 : 595.

14. BachtrogD (2003) Adaptation shapes patterns of genome evolution on sexual and asexual chromosomes in Drosophila. Nat Genet 34 : 215–219.

15. NordborgM, HuTT, IshinoY, JhaveriJ, ToomajianC, et al. (2005) The pattern of polymorphism in Arabidopsis thaliana. PLoS Biol 3: e196 doi:10.1371/journal.pbio.0030196.

16. PresgravesDC (2005) Recombination enhances protein adaptation in Drosophila melanogaster. Current Biology 15 : 1651–1656.

17. BegunDJ, HollowayAK, StevensK, HillierLW, PohYP, et al. (2007) Population genomics: Whole-genome analysis of polymorphism and divergence in Drosophila simulans. PLoS Biol 5: e310 doi:10.1371/journal.pbio.0050310.

18. HaddrillPR, HalliganDL, TomarasD, CharlesworthB (2007) Reduced efficacy of selection in regions of the Drosophila genome that lack crossing over. Genome Biol 8: R18.

19. ShapiroJA, HuangW, ZhangC, HubiszMJ, LuJ, et al. (2007) Adaptive genic evolution in the Drosophila genomes. Proc Natl Acad Sci U S A 104 : 2271–2276.

20. ConnallonT, KnowlesLL (2007) Recombination rate and protein evolution in yeast. BMC Evol Biol 7 : 235.

21. LarracuenteAM, SacktonTB, GreenbergAJ, WongA, SinghND, et al. (2008) Evolution of protein-coding genes in Drosophila. Trends Genet 24 : 114–123.

22. CharlesworthB, BetancourtAJ, KaiserVB, GordoI (2009) Genetic recombination and molecular evolution. Cold Spring Harb Symp Quant Biol 74 : 177–186.

23. RockmanMV, SkrovanekSS, KruglyakL (2010) Selection at linked sites shapes heritable phenotypic variation in C. elegans. Science 330 : 372–376.

24. CutterAD, ChoiJY (2010) Natural selection shapes nucleotide polymorphism across the genome of the nematode Caenorhabditis briggsae. Genome Res 20 : 1103–1111.

25. HortonMW, HancockAM, HuangYS, ToomajianC, AtwellS, et al. (2012) Genome-wide patterns of genetic variation in worldwide Arabidopsis thaliana accessions from the RegMap panel. Nat Genet 44 : 212–216.

26. Lindsley DL, Zimm GG (1992) The genome of Drosophila melanogaster. San Diego, CA: Academic Press.

27. SingerT, FanY, ChangHS, ZhuT, HazenSP, et al. (2006) A high-resolution map of Arabidopsis recombinant inbred lines by whole-genome exon array hybridization. PLoS Genet 2: e144 doi: 10.1371/journal.pgen.0020144.

28. CoopG, WenX, OberC, PritchardJK, PrzeworskiM (2008) High-resolution mapping of crossovers reveals extensive variation in fine-scale recombination patterns among humans. Science 319 : 1395.

29. KulathinalRJ, BennettSM, FitzpatrickCL, NoorMA (2008) Fine-scale mapping of recombination rate in Drosophila refines its correlation to diversity and divergence. Proc Natl Acad Sci U S A 105 : 10051–10056.

30. RockmanMV, KruglyakL (2009) Recombinational landscape and population genomics of Caenorhabditis elegans. PLoS Genet 5: e1000419 doi:10.1371/journal.pgen.1000419.

31. GraveleyBR, BrooksAN, CarlsonJW, DuffMO, LandolinJM, et al. (2011) The developmental transcriptome of Drosophila melanogaster. Nature 471 : 473–479.

32. ManceraE, BourgonR, BrozziA, HuberW, SteinmetzLM (2008) High-resolution mapping of meiotic crossovers and non-crossovers in yeast. Nature 454 : 479–485.

33. KoehlerKE, CherryJP, LynnA, HuntPA, HassoldTJ (2002) Genetic control of mammalian meiotic recombination. I. Variation in exchange frequencies among males from inbred mouse strains. Genetics 162 : 297–306.

34. Yandeau-NelsonMD, NikolauBJ, SchnablePS (2006) Effects of trans-acting genetic modifiers on meiotic recombination across the a1-sh2 interval of maize. Genetics 174 : 101–112.

35. GreyC, BaudatF, de MassyB (2009) Genome-wide control of the distribution of meiotic recombination. PLoS Biol 7: e35 doi:10.1371/journal.pbio.1000035.

36. ChinniciJP (1971) Modification of recombination frequency in Drosophila. I. Selection for increased and decreased crossing over. Genetics 69 : 71–83.

37. ChinniciJP (1971) Modification of recombination frequency in Drosophila. II. The polygenic control of crossing over. Genetics 69 : 85–96.

38. KidwellMG (1972) Genetic change of recombination value in Drosophila melanogaster. II. Simulated natural selection. Genetics 70 : 433–443.

39. AbdullahNF, CharlesworthB (1974) Selection for reduced crossing over in Drosophila melanogaster. Genetics 76 : 447–451.

40. BrooksLD, MarksRW (1986) The organization of genetic variation for recombination in Drosophila melanogaster. Genetics 114 : 525–547.

41. WilliamsCG, GoodmanMM, StuberCW (1995) Comparative recombination distances among Zea mays L. inbreds, wide crosses and interspecific hybrids. Genetics 141 : 1573–1581.

42. NeumannR, JeffreysAJ (2006) Polymorphism in the activity of human crossover hotspots independent of local DNA sequence variation. Hum Mol Genet 15 : 1401–1411.

43. EschE, SzymaniakJM, YatesH, PawlowskiWP, BucklerES (2007) Using crossover breakpoints in recombinant inbred lines to identify quantitative trait loci controlling the global recombination frequency. Genetics 177 : 1851–1858.

44. DumontBL, WhiteMA, SteffyB, WiltshireT, PayseurBA (2011) Extensive recombination rate variation in the house mouse species complex inferred from genetic linkage maps. Genome Res 21 : 114–125.

45. AndolfattoP, NordborgM (1998) The effect of gene conversion on intralocus associations. Genetics 148 : 1397–1399.

46. LangleyCH, LazzaroBP, PhillipsW, HeikkinenE, BravermanJM (2000) Linkage disequilibria and the site frequency spectra in the su(s) and su(wa) regions of the Drosophila melanogaster X chromosome. Genetics 156 : 1837–1852.

47. FrisseL, HudsonRR, BartoszewiczA, WallJD, DonfackJ, et al. (2001) Gene conversion and different population histories may explain the contrast between polymorphism and linkage disequilibrium levels. Am J Hum Genet 69 : 831–843.

48. LoeweL, CharlesworthB (2007) Background selection in single genes may explain patterns of codon bias. Genetics 175 : 1381–1393.

49. MortonNE, RaoDC, YeeS (1976) An inferred chiasma map of Drosophila melanogaster. Heredity (Edinb) 37 : 405–411.

50. CharlesworthB (1996) Background selection and patterns of genetic diversity in Drosophila melanogaster. Genet Res 68 : 131–149.

51. CarvalhoAB, ClarkAG (1999) Intron size and natural selection. Nature 401 : 344.

52. SinghND, DavisJC, PetrovDA (2005) Codon bias and noncoding GC content correlate negatively with recombination rate on the Drosophila X chromosome. J Mol Evol 61 : 315–324.

53. Fiston-LavierAS, SinghND, LipatovM, PetrovDA (2010) Drosophila melanogaster recombination rate calculator. Gene 463 : 18–20.

54. HawleyRS, TheurkaufWE (1993) Requiem for distributive segregation: achiasmate segregation in Drosophila females. Trends Genet 9 : 310–317.

55. CirulliET, KlimanRM, NoorMAF (2007) Fine-scale crossover rate heterogeneity in Drosophila pseudoobscura. J Mol Evol 64 : 129–135.

56. SinghND, AquadroCF, ClarkAG (2009) Estimation of fine-scale recombination intensity variation in the white-echinus interval of D. melanogaster. J Mol Evol 69 : 42–53.

57. SternC (1926) An effect of temperature and age on crossing-over in the first chromosome of Drosophila melanogaster. Proc Natl Acad Sci U S A 12 : 530–532.

58. NeelJV (1941) A relation between larval nutrition and the frequency of crossing over in the third chromosome of Drosophila melanogaster. Genetics 26 : 506–516.

59. RedfieldH (1966) Delayed mating and the relationship of recombination to maternal age in Drosophila melanogaster. Genetics 53 : 593–607.

60. PriestNK, GallowayLF, RoachDA (2008) Mating frequency and inclusive fitness in Drosophila melanogaster. Am Nat 171 : 10–21.

61. Brooks LD (1988) The evolution of recombination rates. In: Michod REaL, B.R., editor. The evolution of sex. Sunderland, MA: Sinauer Associates. pp. 87–105.

62. HillikerAJ, HarauzG, ReaumeAG, GrayM, ClarkSH, et al. (1994) Meiotic gene conversion tract length distribution within the rosy locus of Drosophila melanogaster. Genetics 137 : 1019–1026.

63. HillikerAJ, ChovnickA (1981) Further observations on intragenic recombination in Drosophila melanogaster. Genet Res 38 : 281–296.

64. Hilliker AJ, Clark SH, Chovnick A (1988) Genetic analysis of intragenic recombination in Drosophila. In: Low KB, editor. The Recombination of Genetic Material. New York: Academic Press. pp. 73–90.

65. ClarkSH, HillikerAJ, ChovnickA (1988) Recombination can initiate and terminate at a large number of sites within the rosy locus of Drosophila melanogaster. Genetics 118 : 261–266.

66. HillikerAJ, ClarkSH, ChovnickA (1991) The effect of DNA sequence polymorphisms on intragenic recombination in the rosy locus of Drosophila melanogaster. Genetics 129 : 779–781.

67. JangJK, SherizenDE, BhagatR, ManheimEA, McKimKS (2003) Relationship of DNA double-strand breaks to synapsis in Drosophila. J Cell Sci 116 : 3069–3077.

68. MehrotraS, McKimKS (2006) Temporal analysis of meiotic DNA double-strand break formation and repair in Drosophila females. PLoS Genet 2: e200 doi:10.1371/journal.pgen.0020200.

69. MaraisG (2003) Biased gene conversion: implications for genome and sex evolution. Trends Genet 19 : 330–338.

70. DuretL, ArndtPF (2008) The impact of recombination on nucleotide substitutions in the human genome. PLoS Genet 4: e1000071 doi:10.1371/journal.pgen.1000071.

71. BerglundJ, PollardKS, WebsterMT (2009) Hotspots of biased nucleotide substitutions in human genes. PLoS Biol 7: e26 doi:10.1371/journal.pbio.1000026.

72. MaraisG, MouchiroudD, DuretL (2001) Does recombination improve selection on codon usage? Lessons from nematode and fly complete genomes. Proc Natl Acad Sci U S A 98 : 5688–5692.

73. MaraisG, MouchiroudD, DuretL (2003) Neutral effect of recombination on base composition in Drosophila. Genet Res 81 : 79–87.

74. MaraisG, PiganeauG (2002) Hill-Robertson interference is a minor determinant of variations in codon bias across Drosophila melanogaster and Caenorhabditis elegans genomes. Mol Biol Evol 19 : 1399–1406.

75. GaltierN, BazinE, BierneN (2006) GC-biased segregation of noncoding polymorphisms in Drosophila. Genetics 172 : 221–228.

76. KlimanRM, HeyJ (2003) Hill-Robertson interference in Drosophila melanogaster: reply to Marais, Mouchiroud and Duret. Genet Res 81 : 89–90.

77. BaudatF, de MassyB (2007) Regulating double-stranded DNA break repair towards crossover or non-crossover during mammalian meiosis. Chromosome Res 15 : 565–577.

78. PaigenK, SzatkiewiczJP, SawyerK, LeahyN, ParvanovED, et al. (2008) The recombinational anatomy of a mouse chromosome. PLoS Genet 4: e1000119 doi:10.1371/journal.pgen.1000119.

79. AdamsM, CelnikerS, HoltR, EvansC, GocayneJ, et al. (2000) The genome sequence of Drosophila melanogaster. Science 287 : 2185–2195.

80. ManakJR, DikeS, SementchenkoV, KapranovP, BiemarF, et al. (2006) Biological function of unannotated transcription during the early development of Drosophila melanogaster. Nat Genet 38 : 1151–1158.

81. DainesB, WangH, WangL, LiY, HanY, et al. (2011) The Drosophila melanogaster transcriptome by paired-end RNA sequencing. Genome Res 21 : 315–324.

82. StevisonLS, NoorMA (2010) Genetic and evolutionary correlates of fine-scale recombination rate variation in Drosophila persimilis. J Mol Evol 71 : 332–345.

83. MillerDE, TakeoS, NandananK, PaulsonA, GogolMM, et al. (2012) A whole-chromosome analysis of meiotic recombination in Drosophila melanogaster. G3 (Bethesda) 2 : 249–260.

84. ParvanovED, PetkovPM, PaigenK (2010) Prdm9 controls activation of mammalian recombination hotspots. Science 327 : 835.

85. BaudatF, BuardJ, GreyC, Fledel-AlonA, OberC, et al. (2010) PRDM9 is a major determinant of meiotic recombination hotspots in humans and mice. Science 327 : 836–840.

86. MyersS, FreemanC, AutonA, DonnellyP, McVeanG (2008) A common sequence motif associated with recombination hot spots and genome instability in humans. Nat Genet 40 : 1124–1129.

87. MyersS, BottoloL, FreemanC, McVeanG, DonnellyP (2005) A fine-scale map of recombination rates and hotspots across the human genome. Science 310 : 321–324.

88. FitzGeraldPC, SturgillD, ShyakhtenkoA, OliverB, VinsonC (2006) Comparative genomics of Drosophila and human core promoters. Genome Biol 7: R53.

89. WahlsWP, WallaceLJ, MoorePD (1990) The Z-DNA motif d(TG)30 promotes reception of information during gene conversion events while stimulating homologous recombination in human cells in culture. Mol Cell Biol 10 : 785–793.

90. BegunDJ, AquadroCF (1995) Evolution at the tip and base of the X chromosome in an African population of Drosophila melanogaster. Mol Biol Evol 12 : 382–390.

91. JensenMA, CharlesworthB, KreitmanM (2002) Patterns of genetic variation at a chromosome 4 locus of Drosophila melanogaster and D. simulans. Genetics 160 : 493–507.

92. WangW, ThorntonK, BerryA, LongM (2002) Nucleotide variation along the Drosophila melanogaster fourth chromosome. Science 295 : 134–137.

93. SheldahlLA, WeinreichDM, RandDM (2003) Recombination, dominance and selection on amino acid polymorphism in the Drosophila genome: contrasting patterns on the X and fourth chromosomes. Genetics 165 : 1195–1208.

94. GayJ, MyersS, McVeanG (2007) Estimating meiotic gene conversion rates from population genetic data. Genetics 177 : 881.

95. ArguelloJR, ZhangY, KadoT, FanC, ZhaoR, et al. (2010) Recombination yet inefficient selection along the Drosophila melanogaster subgroup's fourth chromosome. Mol Biol Evol 27 : 848–861.

96. DuretL, MouchiroudD (1999) Expression pattern and, surprisingly, gene length shape codon usage in Caenorhabditis, Drosophila, and Arabidopsis. Proc Natl Acad Sci U S A 96 : 4482–4487.

97. ComeronJM, KreitmanM (2002) Population, evolutionary and genomic consequences of interference selection. Genetics 161 : 389–410.

98. LemosB, BettencourtBR, MeiklejohnCD, HartlDL (2005) Evolution of proteins and gene expression levels are coupled in Drosophila and are independently associated with mRNA abundance, protein length, and number of protein-protein interactions. Mol Biol Evol 22 : 1345–1354.

99. ClarkAG, EisenMB, SmithDR, BergmanCM, OliverB, et al. (2007) Evolution of genes and genomes on the Drosophila phylogeny. Nature 450 : 203–218.

100. McKimKS, JangJK, ManheimEA (2002) Meiotic recombination and chromosome segregation in Drosophila females. Annual Review of Genetics 36 : 205–232.

101. Hunter N (2006) Meiotic Recombination. In: Aguilera A, Rothstein R, editors. Topics in Current Genetics, Molecular Genetics of Recombination: Springer-Verlag; Heidelberg. pp. 381–442.

102. ChenW, Jinks-RobertsonS (1999) The role of the mismatch repair machinery in regulating mitotic and meiotic recombination between diverged sequences in yeast. Genetics 151 : 1299–1313.

103. Welz-VoegeleC, Jinks-RobertsonS (2008) Sequence divergence impedes crossover more than noncrossover events during mitotic gap repair in yeast. Genetics 179 : 1251–1262.

104. MartiniE, BordeV, LegendreM, AudicS, RegnaultB, et al. (2011) Genome-wide analysis of heteroduplex DNA in mismatch repair-deficient yeast cells reveals novel properties of meiotic recombination pathways. PLoS Genet 7: e1002305 doi:10.1371/journal.pgen.1002305.

105. LangleyC, LazzaroB, PhillipsW, HeikkinenE, BravermanJ (2000) Linkage disequilibria and the site frequency spectra in the su(s) and su(w(a)) regions of the Drosophila melanogaster X chromosome. Genetics 1837–1852.

106. FossE, LandeR, StahlF, SteinbergC (1993) Chiasma interference as a function of genetic distance. Genetics 681–691.

107. FossEJ, StahlFW (1995) A test of a counting model for chiasma interference. Genetics 139 : 1201–1209.

108. StahlFW, FossHM, YoungLS, BortsRH, AbdullahMF, et al. (2004) Does crossover interference count in Saccharomyces cerevisiae? Genetics 168 : 35–48.

109. PetesTD (2001) Meiotic recombination hot spots and cold spots. Nat Rev Genet 2 : 360–369.

110. GuillonH, de MassyB (2002) An initiation site for meiotic crossing-over and gene conversion in the mouse. Nat Genet 32 : 296–299.

111. JeffreysAJ, KauppiL, NeumannR (2001) Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex. Nat Genet 29 : 217–222.

112. JeffreysAJ, MayCA (2004) Intense and highly localized gene conversion activity in human meiotic crossover hot spots. Nat Genet 36 : 151–156.

113. BartonNH (2010) Mutation and the evolution of recombination. Philos Trans R Soc Lond B Biol Sci 365 : 1281–1294.

114. BoultonA, MyersRS, RedfieldRJ (1997) The hotspot conversion paradox and the evolution of meiotic recombination. Proc Natl Acad Sci U S A 94 : 8058–8063.

115. AllersT, LichtenM (2001) Differential timing and control of noncrossover and crossover recombination during meiosis. Cell 106 : 47–57.

116. HunterN, KlecknerN (2001) The single-end invasion: an asymmetric intermediate at the double-strand break to double-holliday junction transition of meiotic recombination. Cell 106 : 59–70.

117. BaudatF, de MassyB (2007) Cis -⁠ and Trans-Acting Elements Regulate the Mouse Psmb9 Meiotic Recombination Hotspot. PLoS Genet 3: e100 doi:10.1371/journal.pgen.0030100.

118. CalabreseP (2007) A population genetics model with recombination hotspots that are heterogeneous across the population. Proc Natl Acad Sci U S A 104 : 4748–4752.

119. CoopG, MyersSR (2007) Live hot, die young: Transmission distortion in recombination hotspots. PLoS Genet 3: e35 doi:10.1371/journal.pgen.0030035.

120. Maynard SmithJ, HaighJ (1974) The hitch-hiking effect of a favorable gene. Genet Res 23 : 23–35.

121. KaplanNL, HudsonRR, LangleyCH (1989) The “hitchhiking effect” revisited. Genetics 123 : 887–899.

122. GillespieJH (2000) Genetic drift in an infinite population. The pseudohitchhiking model. Genetics 155 : 909–919.

123. AndolfattoP (2007) Hitchhiking effects of recurrent beneficial amino acid substitutions in the Drosophila melanogaster genome. Genome Res 17 : 1755–1762.

124. SellaG, PetrovDA, PrzeworskiM, AndolfattoP (2009) Pervasive natural selection in the Drosophila genome? PLoS Genet 5: e1000495 doi:10.1371/journal.pgen.1000495.

125. CharlesworthB, MorganMT, CharlesworthD (1993) The effect of deleterious mutations on neutral molecular variation. Genetics 134 : 1289–1303.

126. NordborgM, CharlesworthB, CharlesworthD (1996) The effect of recombination on background selection. Genet Res 67 : 159–174.

127. BegunDJ, AquadroCF (1991) Molecular population genetics of the distal portion of the X chromosome in Drosophila: evidence for genetic hitchhiking of the yellow-achaete region. Genetics 129 : 1147–1158.

128. BerryAJ, AjiokaJW, KreitmanM (1991) Lack of polymorphism on the Drosophila fourth chromosome resulting from selection. Genetics 129 : 1111–1117.

129. LangleyCH, MacDonaldJ, MiyashitaN, AguadeM (1993) Lack of correlation between interspecific divergence and intraspecific polymorphism at the suppressor of forked region in Drosophila melanogaster and Drosophila simulans. Proc Natl Acad Sci USA 90 : 1800–1803.

130. ComeronJM, KreitmanM, AguadeM (1999) Natural selection on synonymous sites is correlated with gene length and recombination in Drosophila. Genetics 239–249.

131. SattathS, ElyashivE, KolodnyO, RinottY, SellaG (2011) Pervasive adaptive protein evolution apparent in diversity patterns around amino acid substitutions in Drosophila simulans. PLoS Genet 7: e1001302 doi:10.1371/journal.pgen.1001302.

132. Hudson RR (1990) Gene genealogies and the coalescent process. In: Futuyma D, Antonovics J, editors. Oxford Surveys in Evolutionary Biology. New York: Oxford University Press. pp. 1–44.

133. KaplanN, HudsonRR, IizukaM (1991) The coalescent process in models with selection, recombination and geographic subdivision. Genet Res 57 : 83–91.

134. BravermanJM, HudsonRR, KaplanNL, LangleyCH, StephanW (1995) The hitchhiking effect on the site frequency spectrum of DNA polymorphisms. Genetics 140 : 783–796.

135. NeuhauserC, KroneSM (1997) The genealogy of samples in models with selection. Genetics 145 : 519–534.

136. WallJD, PrzeworskiM (2000) When did the human population size start increasing? Genetics 155 : 1865–1874.

137. KimY, NielsenR (2004) Linkage disequilibrium as a signature of selective sweeps. Genetics 167 : 1513–1524.

138. Wakeley J (2008) Coalescent Theory: An Introduction. Greenwood Village, Colorado (USA): Roberts & Company Publishers.

139. PrzeworskiM, CoopG, WallJD (2005) The signature of positive selection on standing genetic variation. Evolution 59 : 2312–2323.

140. HuffCD, HarpendingHC, RogersAR (2010) Detecting positive selection from genome scans of linkage disequilibrium. BMC Genomics 11 : 8.

141. AyrolesJF, CarboneMA, StoneEA, JordanKW, LymanRF, et al. (2009) Systems genetics of complex traits in Drosophila melanogaster. Nat Genet 41 : 299–307.

142. MackayTFC, RichardsS, StoneEA, BarbadillaA, AyrolesJF, et al. (2012) The Drosophila melanogaster Genetic Reference Panel. Nature 482 : 173–178.

143. LiH, DurbinR (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25 : 1754–1760.

144. LiH, HandsakerB, WysokerA, FennellT, RuanJ, et al. (2009) The sequence alignment/map (SAM) format and SAMtools. Bioinformatics 25.

145. PadhukasahasramB, RannalaB (2011) Bayesian population genomic inference of crossing over and gene conversion. Genetics 189 : 607–619.

146. GillespieJH (1989) Lineage effects and the index of dispersion of molecular evolution. Mol Biol Evol 6 : 636–647.

147. BaileyTL, BodénM, BuskeFA, FrithM, GrantCE, et al. (2009) MEME SUITE: tools for motif discovery and searching. Nucleic Acids Res 37: W202–W208.

148. LiH, DurbinR (2010) Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics 26 : 589–595.