Refinement of primate copy number variationhotspots identifies candidate genomic regions evolving under positive selection
- Omer Gokcumen†1, 2,
- Paul L Babb†3,
- Rebecca C Iskow1, 2,
- Qihui Zhu1, 2,
- Xinghua Shi1, 2,
- Ryan E Mills1, 2,
- Iuliana Ionita-Laza4,
- Eric J Vallender2, 5,
- Andrew G Clark6,
- Welkin E Johnson2, 5Email author and
- Charles Lee1, 2Email author
© Gokcumen O et al.; licensee BioMed Central Ltd 2011
Received: 20 December 2010
Accepted: 31 May 2011
Published: 31 May 2011
Copy number variants (CNVs), defined as losses and gains of segments of genomic DNA, are a major source of genomic variation.
In this study, we identified over 2,000 human CNVs that overlap with orthologous chimpanzee or orthologous macaque CNVs. Of these, 170 CNVs overlap with both chimpanzee and macaque CNVs, and these were collapsed into 34 hotspot regions of CNV formation. Many of these hotspot regions of CNV formation are functionally relevant, with a bias toward genes involved in immune function, some of which were previously shown to evolve under balancing selection in humans. The genes in these primate CNV formation hotspots have significant differential expression levels between species and show evidence for positive selection, indicating that they have evolved under species-specific, directional selection.
These hotspots of primate CNV formation provide a novel perspective on divergence and selective pressures acting on these genomic regions.
Copy number variants (CNVs) are gains or losses of genomic material, and are now known to constitute a major source of genetic polymorphism in humans . High resolution studies of human CNVs permit the investigation of the mechanisms causing CNV genesis [2–5], the potential impact of CNVs on gene expression , the contribution of CNVs to phenotypic variation , and the role that CNVs have in disease manifestation and mitigation [8–10].
CNV hotspots are highly plastic genomic regions where mutations leading to copy number differences between individuals occur more frequently than expected [11, 12]. Among non-human primates, CNV maps have been developed for the chimpanzee (Pan troglodytes) [11, 13] and rhesus macaque (Macaca mulatta). We have constructed a second-generation, high-resolution CNV map for the rhesus macaque and combined it with similar CNV data for the chimpanzee and ultra-high-resolution CNV data from humans to determine comprehensively the location and structure of primate CNV hotspots. These genomic regions appear to have an elevated likelihood of positive selection, based on nucleotide level conservation and transcriptional data.
Generating a high-resolution rhesus macaque CNV map
In order to identify primate hotspots for CNV formation, we compiled CNV datasets for human, chimpanzee and rhesus macaque. We used two recently published CNV discovery studies in humans [1, 15] to assemble a non-redundant dataset of 12,146 human CNVs that are larger than 437 bp in size (Table S1 in Additional file 1). The chimpanzee dataset was composed of 438 merged CNV regions from the most comprehensive study documenting within-chimpanzee copy number variation . For generating a comparable rhesus macaque CNV dataset, we designed a rhesus macaque-specific array comparative genomic hybridization (aCGH) platform containing 950,843 unique 60-mer oligonucleotide probes.
The size distribution of the rhesus macaque CNVs identified in this study is similar to that reported for human CNVs, in that the number of smaller CNVs increases exponentially. However, the large differences in resolution between these studies create substantial disparity in the size distribution of known human and rhesus macaque CNVs (Figure 1b). Rhesus macaque CNVs overlap with annotated sequences, such as segmental duplications and repeats, in proportions comparable to CNVs in humans (Figure 1c). In contrast to human CNVs, 843 (approximately 74%) of the macaque CNVs overlap with Ensembl gene predictions  (P < 0.001, Kolmogorov-Smirnov test; Figure S6 in Additional file 2). This is concordant with the study by Lee et al. , which showed that 68 of the 124 (55%) rhesus macaque CNVs identified are genic. In particular, we found that almost 90% (82 of 92) of the multiallelic rhesus macaque CNVs overlap with genes (Figure 1d).
Human CNVs overlap with non-human primate CNVs more than expected by chance alone
To test whether the overlap of human CNVs with chimpanzee and rhesus macaque CNVs is more than expected, we simulated 1,000 CNV datasets that mimic the size distribution of the actual human CNVs. In this manner, we effectively eliminated any bias in size distribution due to differences in resolution of the different human and nonhuman primate CNV discovery projects. From these simulated datasets, we constructed expected distributions of HC, HR and HCR CNVs with existing chimpanzee and macaque CNV datasets (Figure 2b). We subsequently calculated the deviation of the actual values from the expected distribution and found that there was significant enrichment for HR, HC and HCR, with HCR being the most enriched (P < 0.01, Kolmogorov-Smirnov test; Figure 2c). Finally, we conducted a similar, reciprocal analysis to show that macaque CNVs overlap with human CNVs more than expected by chance (Figure S6 in Additional file 2), and that there is no particular size cluster driving this enrichment (Figure S7 in Additional file 2).
Primate CNV hotspots overlap regions of recurrent human CNV formation
Only a small fraction of HCR CNVs evolve under neutral conditions
To quantify and understand the evolutionary mechanisms through which the primate CNV hotspots evolved and to delineate their possible functional impact, we collapsed the 170 HCR CNVs into a manually curated, non-redundant list of 34 primate CNV hotspot regions (Table S4 in Additional file 1). We found only four regions that do not overlap a gene, regulatory element, or disease-associated region. These four hotspot regions do not contain complex CNVs in humans (that is, each harbors CNVs with similar breakpoints) and are much smaller in size, with a mean length of approximately 2.7 kb, in contrast to a mean length of approximately 71 kb for the other CNV hotspot regions. Two of the four non-complex hotspot regions are overlapped almost entirely by transposable elements and repeat-rich DNA segments. The third hotspot region is entirely composed of a single segmental duplication and the fourth hotspot region resides in the repeat-rich subtelomeric region of chromosome 8.
The simplest explanation for the presence of a primate CNV hotspot is that it evolved under neutral conditions with little or no selective pressure acting on it. The first task is to distinguish between events that evolved under neutral conditions and non-neutral conditions. Because it is unlikely that the genomic plasticity itself is selected for or against, we suggest that the selection acts not on the elements that maintain genomic plasticity, but rather on the functional elements that reside within the CNVs. Hence, the selection for the genomic plasticity occurs indirectly and should be parallel to the selection acting on the functional content of the CNV. As such, if no significant selective pressure is acting on randomly generated genomic plasticity, we would expect to observe a depletion of functional loci, which by definition are under selection.
HCR CNVs evolve primarily under directional positive selection in humans
Most HCR CNVs are associated with genes, and primarily with gene families (Table S4 in Additional file 1). To quantify possible selection on these genes, we used the recently published dataset of positively selected genes in primates . Specifically, this study examines the heterozygosity-within-species at a given locus and its surrounding area, while controlling for neutral mutation rate using the cross-species divergence, in order to calculate an empirical measure of positive selection, K (0 ≤ K ≤ 1), within a species. Loci with lower κ values are more likely to have evolved under positive selection. Using this measure, we found that approximately 36% of the genes located within HCR CNVs are positively selected, as opposed to only 9% of the genes that overlap with H CNVs (P < 0.01, χ2 with Yates correction; Figure 4c; Figure S8c in Additional file 2). We further observed that K values for the genes that overlap with HCR CNVs are significantly lower than those that overlap with H CNVs (P < 0.01, Kolmogorov-Smirnov test).
In addition, we found that at the nucleotide level, HCR CNVs are much less conserved than CNVs found only in humans (Figure 4d; Figure S8d in Additional file 2). Given that most of the HCR CNVs overlap with functional sequences, one explanation for the sequence divergence between species could be that these genomic regions are evolving under species-specific selective pressures. The sequence divergence could subsequently lead to different transcripts or differences in expression levels, as a result of changes in gene regulatory elements. Because several well-studied immune gene families (for example, beta defensins, HLA, PCDHB and LILR families) are indeed riddled with HCR CNVs and are known to evolve under balancing selection [19, 20], it is possible that balancing selection has prevented the copy number at these loci from being fixed within the three different species.
In this study, we identified 170 human CNVs located within 34 primate hotspot regions of CNV formation. The structurally plastic hotspots appear to have remained active in the three lineages despite being separated by over 25 million years of evolution. The majority of primate hotspots overlap with functional genomic elements, especially genes related to immunity. A significant portion of these genes that overlap primate hotspots appear to have evolved under positive selection (Figure 4c) and some of these genes are also known to be evolving under balancing selection in humans (for example, the HLA, PHDB, and LILR families). As such, the evolution and maintenance of primate CNV hotspots may be a response to diverse environmental pressures acting on the genes residing in these hotspots. The maintained plasticity may then provide the mutational flexibility for these genes to adapt rapidly to changing selective pressures. Therefore, it is not surprising to see that multiple immune system-related genes are variable in copy number across primates, possibly resonating with the 'Red Queen hypothesis': that the constant diversification of the host immune system genes and the parasite defense genes is in response to changes in each other's defenses .
For example, we observed a significant enrichment of HCR CNVs in a chromosome 19 region corresponding to the leukocyte receptor cluster (LRC). In humans, this 1 Mb region encompasses several families of immunoglobulin (Ig)-like receptor genes, including gene clusters encoding multiple leukocyte Ig-like receptors (LILRs), leukocyte-associated Ig-like receptors (LAIRs) and killer-cell Ig-like receptors (KIRs). The KIRs have a multifaceted role in two processes, immune defense and reproduction, and interact with cell-surface molecules encoded by the MHC class I locus, another region that displays rapid evolution and copy number variation. These epistatic interactions likely require the co-evolution of MHC and KIR, similar to the co-evolution of parasitic and host defenses described above. Under ever-changing pathogenic pressures, more of this variation could be maintained, especially among primates, which, due to their complex social dynamics, have higher pathogenic transfer rates . Therefore, at least some of these primate CNV hotspots are likely maintained under dynamic selective pressures, allowing for copy number variability at these loci.
Other gene ontological categories are represented, albeit less frequently, in the observed primate CNV hotspots. For instance, the pepsinogens (PGA family) are precursors for pepsin (a major digestive enzyme) and may be involved in local environmental adaptation of primates . Such adaptation would be akin to that of the amylase encoding gene in humans, where different copy numbers of the amylase gene evolved as an adaptation to dietary habits . Similarly, genes such as CHYS1, involved in wound healing, are also noteworthy. More surprising are gene families such as PHDB and CBX, which may be involved in neural function  and, among other functions, testis development , respectively. These findings provide an initial framework for functional studies to establish the extent to which the variation in these genes has contributed to primate evolution.
In addition, two recent studies demonstrated that copy number variation in one locus affects the expression levels in other loci. One of these studies showed that the expression level of a gene can be changed through alteration of the copy number variation of another gene that shares the same promoter region . The other study demonstrated that the expressed pseudogene of PTEN acts as a sponge for microRNAs. As such, the deletion of the pseudogene subsequently increased the number of microRNA molecules, which can, in turn, negatively regulate the expression of the parental gene .
This study provides a critical framework for describing and delineating the functional, biomedical and evolutionary impact of hotspots of CNV formation in primates. Our results underscore the significance of copy number variation as a widespread source of genomic variation among primates, and the implication of natural selection acting on these regions indicates that CNVs have contributed to the evolution of quantitative traits in primates.
Materials and methods
The existing data for rhesus macaque CNVs  is limited. In order to produce a complementary CNV dataset, we identified and characterized CNVs among 17 unrelated rhesus macaques using a platform with a 15 kb effective resolution (Figure S2 in Additional file 2). Genomic DNA was obtained through the New England Primate Research Center (NEPRC) Primate Genetics Core. All animals in the study were housed at the NEPRC and maintained in accordance with the guidelines of the Committee on Animals of the Harvard Medical School and the Guide for Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources, National Research Council, Department of Health and Human Services, publication no. (NIH) 85-23, revised 1985. NEPRC is accredited by the American Association for the Accreditation of Laboratory Animal Care. All normalized Cy3/Cy5 intensity data from the aCGH experiments have been uploaded to the Gene Expression Omnibus (GEO) database under the accession number [GEO:GSE19881]. All CNV calls with corresponding log2 values are provided in Table S2 in Additional file 1.
We analyzed the patterns of these primate hotspots with respect to the human reference genome, due to the high level of accurate annotation of the human genome assembly compared to the draft chimpanzee and rhesus macaque reference sequences. We compiled a non-redundant human CNV dataset using data from two recent, high-resolution studies that had an effective resolution of 450 bp [1, 15]. This dataset, which includes 12,146 CNVs, represents one of the highest resolution human CNV maps currently available. We have not incorporated recently released 1000 Genomes Project CNV calls because they are incomplete and biased towards deletions. As a chimpanzee CNV dataset, we used data primarily generated by Perry et al. .
To compare the locations of macaque and human CNVs, we used the Lift-Over tool developed by the UCSC Genome Bioinformatics Group to convert rhesus CNV loci to human coordinates (hg18). This computational tool utilizes the BLAT algorithm to align orthologous sequences between species . Using this methodology, we were able to map 1,073 macaque CNVs (approximately 93%) onto the human reference genome. Chimpanzee CNVs were detected using an array design based on the human reference genome (hg18) and therefore subsequent conversion to human coordinates was not necessary.
For statistical calculations and visualization, we used the R statistical package.
array comparative genomic hybridization
copy number variant
human chimpanzee hotspot
human rhesus macaque hotspot
human chimpanzee macaque hotspot
killer-cell Ig-like receptor
major histocompatibility complex
New England Primate Research Center.
This work was supported in part by an award from the Harvard University Center for AIDS Research (WEJ), NIH grants AI057039 and AI083118 (WEJ), NIH grants RO1GM081533 and P41HG004221 (CL), and an NIH grant RR00168 (NEPRC). We also acknowledge Arthur Lee, Sunita Setlur, Kim Brown, Kim Dobrinski, George Perry and Edward Hollox for their insightful comments on earlier versions of this manuscript and the NEPRC Primate Genetics Core for access to samples.
- Conrad DF, Pinto D, Redon R, Feuk L, Gokcumen O, Zhang Y, Aerts J, Andrews TD, Barnes C, Campbell P, Fitzgerald T, Hu M, Ihm CH, Kristiansson K, Macarthur DG, Macdonald JR, Onyiah I, Pang AW, Robson S, Stirrups K, Valsesia A, Walter K, Wei J, Tyler-Smith C, Carter NP, Lee C, Scherer SW, Hurles ME: Origins and functional impact of copy number variation in the human genome. Nature. 2010, 464: 704-712. 10.1038/nature08516.PubMedPubMed CentralView ArticleGoogle Scholar
- Perry GH, Ben-Dor A, Tsalenko A, Sampas N, Rodriguez-Revenga L, Tran CW, Scheffer A, Steinfeld I, Tsang P, Yamada NA, Park HS, Kim JI, Seo JS, Yakhini Z, Laderman S, Bruhn L, Lee C: The fine-scale and complex architecture of human copy-number variation. Am J Hum Genet. 2008, 82: 685-695. 10.1016/j.ajhg.2007.12.010.PubMedPubMed CentralView ArticleGoogle Scholar
- Hastings PJ, Lupski JR, Rosenberg SM, Ira G: Mechanisms of change in gene copy number. Nat Rev Genet. 2009, 10: 551-564.PubMedPubMed CentralView ArticleGoogle Scholar
- Locke DP, Segraves R, Carbone L, Archidiacono N, Albertson DG, Pinkel D, Eichler EE: Large-scale variation among human and great ape genomes determined by array comparative genomic hybridization. Genome Res. 2003, 13: 347-357. 10.1101/gr.1003303.PubMedPubMed CentralView ArticleGoogle Scholar
- Wilson GM, Flibotte S, Missirlis PI, Marra MA, Jones S, Thornton K, Clark AG, Holt RA: Identification by full-coverage array CGH of human DNA copy number increases relative to chimpanzee and gorilla. Genome Res. 2006, 16: 173-181.PubMedPubMed CentralView ArticleGoogle Scholar
- Stranger BE, Forrest MS, Dunning M, Ingle CE, Beazley C, Thorne N, Redon R, Bird CP, de Grassi A, Lee C, Tyler-Smith C, Carter N, Scherer SW, Tavare S, Deloukas P, Hurles ME, Dermitzakis ET: Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science. 2007, 315: 848-853. 10.1126/science.1136678.PubMedPubMed CentralView ArticleGoogle Scholar
- Perry GH, Dominy NJ, Claw KG, Lee AS, Fiegler H, Redon R, Werner J, Villanea FA, Mountain JL, Misra R, Carter NP, Lee C, Stone AC: Diet and the evolution of human amylase gene copy number variation. Nat Genet. 2007, 39: 1256-1260. 10.1038/ng2123.PubMedPubMed CentralView ArticleGoogle Scholar
- Marshall CR, Noor A, Vincent JB, Lionel AC, Feuk L, Skaug J, Shago M, Moessner R, Pinto D, Ren Y, Thiruvahindrapduram B, Fiebig A, Schreiber S, Friedman J, Ketelaars CE, Vos YJ, Ficicioglu C, Kirkpatrick S, Nicolson R, Sloman L, Summers A, Gibbons CA, Teebi A, Chitayat D, Weksberg R, Thompson A, Vardy C, Crosbie V, Luscombe S, Baatjes R, et al: Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet. 2008, 82: 477-488. 10.1016/j.ajhg.2007.12.009.PubMedPubMed CentralView ArticleGoogle Scholar
- McCarroll SA, Huett A, Kuballa P, Chilewski SD, Landry A, Goyette P, Zody MC, Hall JL, Brant SR, Cho JH, Duerr RH, Silverberg MS, Taylor KD, Rioux JD, Altshuler D, Daly MJ, Xavier RJ: Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn's disease. Nat Genet. 2008, 40: 1107-1112. 10.1038/ng.215.PubMedPubMed CentralView ArticleGoogle Scholar
- Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, Regan R, Conroy J, Magalhaes TR, Correia C, Abrahams BS, Almeida J, Bacchelli E, Bader GD, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bölte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Bryson SE, Carson AR, Casallo G, Casey J, Chung BH, Cochrane L, Corsello C, et al: Functional impact of global rare copy number variation in autism spectrum disorders. Nature. 2010, 466: 368-372. 10.1038/nature09146.PubMedPubMed CentralView ArticleGoogle Scholar
- Perry GH, Tchinda J, McGrath SD, Zhang J, Picker SR, Caceres AM, Iafrate AJ, Tyler-Smith C, Scherer SW, Eichler EE, Stone AC, Lee C: Hotspots for copy number variation in chimpanzees and humans. Proc Natl Acad Sci USA. 2006, 103: 8006-8011. 10.1073/pnas.0602318103.PubMedPubMed CentralView ArticleGoogle Scholar
- Dumas L, Kim YH, Karimpour-Fard A, Cox M, Hopkins J, Pollack JR, Sikela JM: Gene copy number variation spanning 60 million years of human and primate evolution. Genome Res. 2007, 17: 1266-1277. 10.1101/gr.6557307.PubMedPubMed CentralView ArticleGoogle Scholar
- Perry GH, Yang F, Marques-Bonet T, Murphy C, Fitzgerald T, Lee AS, Hyland C, Stone AC, Hurles ME, Tyler-Smith C, Eichler EE, Carter NP, Lee C, Redon R: Copy number variation and evolution in humans and chimpanzees. Genome Res. 2008, 18: 1698-1710. 10.1101/gr.082016.108.PubMedPubMed CentralView ArticleGoogle Scholar
- Lee AS, Gutierrez-Arcelus M, Perry GH, Vallender EJ, Johnson WE, Miller GM, Korbel JO, Lee C: Analysis of copy number variation in the rhesus macaque genome identifies candidate loci for evolutionary and human disease studies. Hum Mol Genet. 2008, 17: 1127-1136. 10.1093/hmg/ddn002.PubMedView ArticleGoogle Scholar
- Park H, Kim JI, Ju YS, Gokcumen O, Mills RE, Kim S, Lee S, Suh D, Hong D, Kang HP, Yoo YJ, Shin JY, Kim HJ, Yavartanoo M, Chang YW, Ha JS, Chong W, Hwang GR, Darvishi K, Kim H, Yang SJ, Yang KS, Hurles ME, Scherer SW, Carter NP, Tyler-Smith C, Lee C, Seo JS: Discovery of common Asian copy number variants using integrated high-resolution array CGH and massively parallel DNA sequencing. Nat Genet. 2010, 42: 400-405. 10.1038/ng.555.PubMedPubMed CentralView ArticleGoogle Scholar
- Curwen V, Eyras E, Andrews TD, Clarke L, Mongin E, Searle SM, Clamp M: The Ensembl automatic gene annotation system. Genome Res. 2004, 14: 942-950. 10.1101/gr.1858004.PubMedPubMed CentralView ArticleGoogle Scholar
- Mills RE, Walter K, Stewart C, Handsaker RE, Chen K, Alkan C, Abyzov A, Yoon SC, Ye K, Cheetham RK, Chinwalla A, Conrad DF, Fu Y, Grubert F, Hajirasouliha I, Hormozdiari F, Iakoucheva LM, Iqbal Z, Kang S, Kidd JM, Konkel MK, Korn J, Khurana E, Kural D, Lam HY, Leng J, Li R, Li Y, Lin CY, Luo R, et al: Mapping copy number variation by population-scale genome sequencing. Nature. 2011, 470: 59-65. 10.1038/nature09708.PubMedPubMed CentralView ArticleGoogle Scholar
- Enard D, Depaulis F, Roest Crollius H: Human and non-human primate genomes share hotspots of positive selection. PLoS Genet. 2010, 6: e1000840-10.1371/journal.pgen.1000840.PubMedPubMed CentralView ArticleGoogle Scholar
- Andres AM, Hubisz MJ, Indap A, Torgerson DG, Degenhardt JD, Boyko AR, Gutenkunst RN, White TJ, Green ED, Bustamante CD, Clark AG, Nielsen R: Targets of balancing selection in the human genome. Mol Biol Evol. 2009, 26: 2755-2764. 10.1093/molbev/msp190.PubMedPubMed CentralView ArticleGoogle Scholar
- Hollox EJ, Armour JA: Directional and balancing selection in human beta-defensins. BMC Evol Biol. 2008, 8: 113-10.1186/1471-2148-8-113.PubMedPubMed CentralView ArticleGoogle Scholar
- Van Valen L: A new evolutionary law. Evol Theory. 1973, 1: 1-30.Google Scholar
- Nunn CL, Altizer S, Sechrest W, Jones KE, Barton RA, Gittleman JL: Parasites and the evolutionary diversification of primate clades. Am Nat. 2004, 164 (Suppl 5): S90-103.PubMedView ArticleGoogle Scholar
- Narita Y, Oda S, Takenaka O, Kageyama T: Lineage-specific duplication and loss of pepsinogen genes in hominoid evolution. J Mol Evol. 2010, 70: 313-324. 10.1007/s00239-010-9320-8.PubMedView ArticleGoogle Scholar
- Junghans D, Heidenreich M, Hack I, Taylor V, Frotscher M, Kemler R: Postsynaptic and differential localization to neuronal subtypes of protocadherin beta16 in the mammalian central nervous system. Eur J Neurosci. 2008, 27: 559-571. 10.1111/j.1460-9568.2008.06052.x.PubMedView ArticleGoogle Scholar
- Ostrer H, Huang HY, Masch RJ, Shapiro E: A cellular study of human testis development. Sex Dev. 2007, 1: 286-292. 10.1159/000108930.PubMedView ArticleGoogle Scholar
- King MC, Wilson AC: Evolution at two levels in humans and chimpanzees. Science. 1975, 188: 107-116. 10.1126/science.1090005.PubMedView ArticleGoogle Scholar
- Frankel N, Davis GK, Vargas D, Wang S, Payre F, Stern DL: Phenotypic robustness conferred by apparently redundant transcriptional enhancers. Nature. 2010, 466: 490-493. 10.1038/nature09158.PubMedPubMed CentralView ArticleGoogle Scholar
- Lower KM, Hughes JR, De Gobbi M, Henderson S, Viprakasit V, Fisher C, Goriely A, Ayyub H, Sloane-Stanley J, Vernimmen D, Langford C, Garrick D, Gibbons RJ, Higgs DR: Adventitious changes in long-range gene expression caused by polymorphic structural variation and promoter competition. Proc Natl Acad Sci USA. 2009, 106: 21771-21776. 10.1073/pnas.0909331106.PubMedPubMed CentralView ArticleGoogle Scholar
- Poliseno L, Salmena L, Zhang J, Carver B, Haveman WJ, Pandolfi PP: A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature. 2010, 465: 1033-1038. 10.1038/nature09144.PubMedPubMed CentralView ArticleGoogle Scholar
- Kent WJ: BLAT - the BLAST-like alignment tool. Genome Res. 2002, 12: 656-664.PubMedPubMed CentralView ArticleGoogle Scholar
- Felsenstein J, Churchill GA: A hidden Markov model approach to variation among sites in rate of evolution. Mol Biol Evol. 1996, 13: 93-104.PubMedView ArticleGoogle Scholar
- Blekhman R, Marioni JC, Zumbo P, Stephens M, Gilad Y: Sex-specific and lineage-specific alternative splicing in primates. Genome Res. 2010, 20: 180-189. 10.1101/gr.099226.109.PubMedPubMed CentralView ArticleGoogle Scholar
- Rosenbloom KR, Dreszer TR, Pheasant M, Barber GP, Meyer LR, Pohl A, Raney BJ, Wang T, Hinrichs AS, Zweig AS, Fujita PA, Learned K, Rhead B, Smith KE, Kuhn RM, Karolchik D, Haussler D, Kent WJ: ENCODE whole-genome data in the UCSC Genome Browser. Nucleic Acids Res. 2010, 38: D620-625. 10.1093/nar/gkp961.PubMedPubMed CentralView ArticleGoogle Scholar
- Ionita-Laza I, Lange C, N ML: Estimating the number of unseen variants in the human genome. Proc Natl Acad Sci USA. 2009, 106: 5008-5013. 10.1073/pnas.0807815106.PubMedPubMed CentralView ArticleGoogle Scholar
- Felsenstein J, Churchill GA: A hidden Markov model approach to variation among sites in rate of evolution. Mol Biol Evol. 1996, 13: 93-104.PubMedView ArticleGoogle Scholar
- Pickrell JK, Marioni JC, Pai AA, Degner JF, Engelhardt BE, Nkadori E, Veyrieras JB, Stephens M, Gilad Y, Pritchard JK: Understanding mechanisms underlying human gene expression variation with RNA sequencing. Nature. 2010, 464: 768-772. 10.1038/nature08872.PubMedPubMed CentralView ArticleGoogle Scholar
- Montgomery SB, Sammeth M, Gutierrez-Arcelus M, Lach RP, Ingle C, Nisbett J, Guigo R, Dermitzakis ET: Transcriptome genetics using second generation sequencing in a Caucasian population. Nature. 2010, 464: 773-777. 10.1038/nature08903.PubMedView ArticleGoogle Scholar
- Bandelt HJ, Forster P, Rohl A: Median-joining networks for inferring intraspecific phylogenies. Mol Biol Evol. 1999, 16: 37-48.PubMedView ArticleGoogle Scholar
- Rhesus Macaque Genome Sequencing and Analysis Consortium, Gibbs RA, Rogers J, Katze MG, Bumgarner R, Weinstock GM, Mardis ER, Remington KA, Strausberg RL, Venter JC, Wilson RK, Batzer MA, Bustamante CD, Eichler EE, Hahn MW, Hardison RC, Makova KD, Miller W, Milosavljevic A, Palermo RE, Siepel A, Sikela JM, Attaway T, Bell S, Bernard KE, Buhay CJ, Chandrabose MN, Dao M, Davis C, Delehaunty KD, et al: Evolutionary and biomedical insights from the rhesus macaque genome. Science. 2007, 316: 222-234.View ArticleGoogle Scholar
- Degenhardt JD, de Candia P, Chabot A, Schwartz S, Henderson L, Ling B, Hunter M, Jiang Z, Palermo RE, Katze M, Eichler EE, Ventura M, Rogers J, Marx P, Gilad Y, Bustamante CD: Copy number variation of CCL3-like genes affects rate of progression to simian-AIDS in rhesus macaques (Macaca mulatta). PLoS Genet. 2009, 5: e1000346-10.1371/journal.pgen.1000346.PubMedPubMed CentralView ArticleGoogle Scholar
- Bostik P, Kobkitjaroen J, Tang W, Villinger F, Pereira LE, Little DM, Stephenson ST, Bouzyk M, Ansari AA: Decreased NK cell frequency and function is associated with increased risk of KIR3DL allele polymorphism in simian immunodeficiency virus-infected rhesus macaques with high viral loads. J Immunol. 2009, 182: 3638-3649. 10.4049/jimmunol.0803580.PubMedView ArticleGoogle Scholar
- Gokcumen O, Lee C: Copy number variants (CNVs) in primate species using array-based comparative genomic hybridization. Methods. 2009, 49: 18-25. 10.1016/j.ymeth.2009.06.001.PubMedPubMed CentralView ArticleGoogle Scholar
- Sekar C, Deming W: On a method of estimating birth and death rates and the extent of registration. J Am Stat Assoc. 1949, 44: 101-115. 10.2307/2280353.View ArticleGoogle Scholar
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