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#22 Jan 27, 2013
AQP7 and human endurance running
It has been suggested that in order for humans to have successfully adapted to the open hot savanna, a series of anatomical and physiological changes occurred that resulted in humans becoming unusually adept at endurance running (Bramble and Lieberman 2004), a property that likely contributed to their eventual emergence as efficient diurnal endurance predators and/or scavengers (Carrier 1984). Among the most important of these changes were (1) the development of an exceptional sweating response that allowed the high levels of metabolic heat that would be generated by endurance running to be dissipated efficiently (sweating would also cool the expanding brain and may have contributed to the selection for human hairlessness, a trait that would facilitate evaporative cooling in a sweating animal), and (2) the development of a mechanism for maintaining large body stores of glycogen and fatty acids and an effective means for mobilizing these stores during prolonged periods of high energy demand (Carrier 1984).

These important phenotypic changes would be expected to leave traces in the human genome, and several factors have led us to speculate that the human lineage-specific copy number expansion of the aquaporin 7 (AQP7) gene may be central to one or both of these human adaptations. Aquaporins are thought to play a key role in water transport across membranes (Preston et al. 1992), and of the eight aquaporin family members that were tested here, the only one that showed a human LS copy number increase was AQP7 (avg. log2 ratio for non-human primates = −1.20). Interestingly, all human copies (five) are part of segmental duplications, each of which encompasses an entire ~17-kb AQP7-like gene copy. The great majority of these map to the pericentromeric region of chr 9, one of the most evolutionarily dynamic regions of the human genome and the location of the greatest concentration of human LS gene copy number increases (Fortna et al. 2004)(Fig. 5; Supplemental Table S5).

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#23 Jan 27, 2013
It has been shown that AQP7 is abundantly expressed in fat cells and is an aquaglyceroporin, capable of transporting glycerol as well as water (Kondo et al. 2002). Glycerol transport is a major mechanism for using energy stored in fat, and, interestingly, AQP7 expression in fat cells is elevated during intense exercise, resulting in an increase in glycerol transport (Kondo et al. 2002). Consistent with this observation, AQP7-null mice show an inability to transport glycerol and a pronounced weight gain due to the accumulation of glycerol and triglycerides (Hara-Chikuma et al. 2005). These findings, taken together, suggest that the human lineage-specific duplications of the AQP7 gene may underlie the increased glycerol transport capability found in humans and, as a result, facilitated the development of the exceptional capacity for endurance running in humans.

In a similar manner, the genes underlying humans enhanced capacity to sweat, which efficiently reduces heat load during endurance running, might also be expected to increase in expression as a function of exercise. Several additional human-specific copies of AQP7 retain long open reading frames and upstream regulatory regions (Kondo et al. 2002), making it plausible that they may also retain the AQP7 genes ability to be up-regulated as a function of exercise. These factors, and the observation that AQP7 can transport both glycerol and water, have led us to suggest the possibility that one or more of the additional human AQP7 copies may also be involved in exercise-induced sweating in humans.

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#24 Jan 27, 2013
CGB/LHB and gorilla reproduction
In gorilla, several additional genes were identified that showed gorilla-specific amplifications and are associated with biologically interesting processes. These include three adjacent cDNAs (IMAGE clones 1671903, 259973, and 2365721) corresponding to the chorionic gonadotropin/leutenizing hormone, beta-subunit (CGB/LHB) genes on human 9q13.11 that are essential to several key reproductive processes including maintenance of pregnancy, male gonad development, and sex determination. While the human genome is predicted to contain seven CGB/LHB genes, the strong lineage-specific aCGH signals obtained in gorilla (avg. log2 ratio = 2.93 for gorilla) indicate that the number of genes in gorilla will be unusually high (e.g.,~50), with the great majority of these copies found exclusively in gorilla. While there does not appear to be an obvious gorilla-specific reproductive characteristic to which this expansion might be linked, it is noteworthy that a frameshift in two of the seven CGB/LHB genes has been identified in humans and great apes that creates a completely different protein (Hallast et al. 2006), raising the possibility that the gorilla-specific copy number expansion identified here may have functional effects quite distinct from those typically associated with the CGB/LHB genes.

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#25 Jan 27, 2013
Distant primate genes that show LS copy number changes
Numerous biologically intriguing genes were identified that showed LS copy number expansions in distant primate lineages (Supplemental Tables S7, S8), and a few are highlighted here. Genes on chr 6 that encode the histocompatibility antigen Class I (HLA-I) proteins are known to be increased in copy number in macaque relative to humans and great apes (Daza-Vamenta et al. 2004; Macaque Genome Sequencing and Analysis Consortium 2007), a finding that may partly explain the higher HLA complexity of the macaque and may have implications for the use of the macaque as a model of human immune function. cDNA aCGH data presented here indicate that the HLA copy number (for HLA-A, HLA-C, and HLA-F) is elevated in macaque, baboon, and marmoset relative to all other species tested including lemur (Supplemental Fig. S1). This suggests that either these sequences were expanded independently in each of these three species or that, by parsimony, an expansion occurred in the last common ancestor of macaque, baboon, and marmoset, followed by a reduction in copy number in the last common ancestor of humans and apes.

Regions of high genomic variability may produce genes that exhibit both intra- and interspecies copy number variation, and an example of this occurs with the pregnancy-specific glycoprotein (111) gene family that clusters at 19q12. These genes encode immunoglobulin-related proteins that are the most abundant fetal protein in the maternal circulation at term and have been postulated to be linked with maternal-fetal conflict (Haig 1993). aCGH data show dramatic fluctuation in PSG copy number among different primate lineages, most notably an overall increase in OWM lineages (avg. log2 ratio = 0.744) and a pronounced decrease in marmoset and lemur (avg. log2 ratio = −2.092). In addition, variation between human samples is also evident with two (log2 ratios of 0.495 and 0.607) of four samples showing increases relative to the reference human.

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#26 Jan 27, 2013
As mentioned previously (Fig. 4), a striking orangutan-specific amplification (avg. log2 ratio = 1.37) was found for the carbonic anhydrase (CA) genes that cluster at 8q21.2 in humans. CA proteins catalyze the reversible hydration of carbon dioxide, and, because they are involved in numerous biological processes (e.g., respiration, acidbase balance, bone resorption, and the formation of aqueous humor, cerebrospinal fluid, saliva, and gastric acid), the additional gene copies in orangutan, if functional, may have important effects on the physiology of this primate. Another gene increase was observed for the lactate dehydrogenase beta gene (LDHB) specifically in the monkey lineages (avg. log2 ratio = 1.89), a change that may be related to phenotypic effects on anaerobic glycolysis in these species. The highest predicted copy number increase specific for the marmoset was found for the SRP9 gene (avg. log2 ratio = 4.74), which is thought to be involved in signal recognition and transport of secretory proteins to the rough endoplasmic reticulum. Another gene demonstrating copy number variation among the primates is GALNT1 (UDP-N-acetyl-α-D-gal actosamine: polypeptide-N-acetylgalactosam inyltransferase 1) located on 18q12.1, the product of which catalyzes the initial reaction in O-linked oligosaccharide biosynthesis. Both aCGH and Q-PCR results indicate that this gene is increased in copy number in marmoset and lemur (avg. log2 value = 1.70). Other lemur-specific increases were found for multiple cDNAs corresponding to the zinc finger 91 gene (ZNF91)(lemur avg. log2 ratio = 1.39) located at 4p14 in human and for a poliovirus receptor-related gene (PVRL3; lemur avg. log2 ratio = 1.44), also termed nectin, that is related to immunoglobulin-like adhesion molecules and maps to 3q13.12.

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#27 Jan 27, 2013
An example of the utility of this extended cross-species aCGH survey can be found with respect to the RANBP2 gene, which encodes a nuclear export protein. Previous genomic sequencing of chr 2 identified eight new RANBP2-like genes in humans, while only one copy is found in mouse (Ciccarelli et al. 2005; Hillier et al. 2005). Here we demonstrate that the human and great ape lineages show a significant copy number increase of RANBP2 sequences relative to all other primates tested (great ape avg. log2 = 0.11; other primates avg. log2 ratio = −2.18). These data suggest that a dramatic copy number expansion occurred for RANBP2 in a common ancestor of humans and great apes after the ancestral human/great ape lineage diverged from the gibbon/monkey lineages sometime between 13 and 18 Mya.

The work presented here provides a genome-wide, sequence-independent assessment of gene duplication and loss that covers much of primate evolutionary history. As such it should both aid in our understanding of gene and genome evolution as well as in the identification of genes underlying lineage-specific traits. Finally because genome-wide aCGH does not rely on sequence data to predict copy number differences, it should provide a valuable complement to genomic sequencing efforts that seek to generate the most accurate genome assemblies.

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#28 Jan 27, 2013
Go to:Methods.DNA
The DNA used for this study was derived from human (two females, two males), bonobo (three males), chimpanzee (two males, two females), gorilla (one male, two females), orangutan (three females), gibbon (three males), macaque (one male, two females), baboon (two males, one female), marmoset (three females), and lemur (two males, one female). Human and chimpanzee genomic DNA samples were isolated from blood cells using Super Quick-Gene kits from AGTC. One gorilla and two bonobo samples were isolated from cell lines using DNeasy Tissue kits from QIAGEN. The macaque genomic DNA samples, an orangutan sample, and a gorilla sample were isolated by other laboratories. The remaining DNA (gibbon, baboon, marmoset, and lemur) was obtained from the Coriell Institute and originally derived from primary fibroblast cell lines or whole blood samples.

Array CGH
Labeling of genomic DNA and hybridization to cDNA microarrays were performed according to the method previously described (Pollack et al. 1999, 2002). In brief, 4 μg of genomic DNA from test (hominoid DNA) and 4 μg of sex-matched normal human genomic DNA reference samples (with the exception of samples human 4, macaque 487, and baboon 976, which were not sex-matched) were DpnII-digested and random-primer-labeled, incorporating Cy5 (red) and Cy3 (green) fluorescent dyes, respectively. Test and reference samples were cohybridized to a cDNA microarray containing 41,126 nonredundant clones, representing 24,473 human genes (i.e., UniGene clusters); 34,244 cDNAs had single map positions, and 4857 had multiple map positions, with the remainder (2025) not yet assigned. Following hybridization, microarrays were imaged using a GenePix 4000B scanner (Axon Instruments). Fluorescence intensities for array elements were extracted using GenePix Pro 4.0 software, and uploaded into the Stanford Microarray Database (SMD)(Gollub et al. 2003) for subsequent analysis.

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#29 Jan 27, 2013
Array CGH data analysis
Fluorescence ratios were normalized for each experiment by setting the average log2 fluorescence ratio (test/reference) for all array elements equal to 0. We included for analysis only those genes that were reliably measured, having a fluorescence intensity/background >1.4 in the reference channel. Map positions for cDNA clones on the array were assigned using the UCSC GoldenPath assembly ( http://genome.ucsc.edu ), November 2002 freeze (hg13). This freeze was used because, of the map files available for the human cDNA arrays we used, this one retained a significantly greater number of genes that had multiple map locations (e.g., likely represented recently duplicated genes). Gene copy number ratios were visualized according to chromosome position using Treeview ( http://rana.lbl.gov/EisenSoftware.htm ). cDNAs with multiple genome map positions >1Mb apart were displayed in Treeview at each assigned map location.

Selection criteria for array data
To select lineage-specific cDNAs, the values used were the log2 of the red (test genomic DNA signal) to green (reference genomic DNA signal) normalized ratio (mean). The criteria for selection of LS cDNAs were similar to that described previously (Fortna et al. 2004) and were based on the following. First, a threshold of 0.5 was used, in which case at least two out of three (one could be missing or not meet the threshold) of the absolute values of the signal intensity ratio for the individuals in one species needed to be equal to or larger than 0.5 in the same direction (both positive or both negative), while at least two out of three (one could be missing or not meet the threshold) of the absolute values for all of the other individuals of the other species had to be less than the threshold and in the opposite direction. Second, the absolute value of the average of the intensity ratios for the nonhuman primate species compared to human was required to be at least 2.5 times greater than the absolute value of each of the remaining species average, including human versus human comparisons. For genes showing human LS changes, the absolute value of each species average of the non-human primate versus human comparisons had to be at least 2.5-fold greater than the average of the absolute value of the human versus human comparisons.

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#30 Jan 27, 2013
Gene copy number changes specific to multiple species
In cases in which the copy number was either increased or decreased in more than one primate species, the same criteria as above were used. However, the cDNA had to meet the 0.5 selection criterion for the species in question. Additionally, the species in question was required to be at least 2.5-fold greater than the average of the absolute values of the fluorescence ratios compared to the pairwise comparisons for the other species.

Or-case: Genes that show copy number variation between human and at least one other primate lineage
An analysis was conducted to detect cDNAs for which the log2 fluorescence signal was different in one or more species of primates relative to human. In order for the human aCGH signal to be considered different from one or more primate species, the human log2 aCGH ratio had to fall within the range of +0.5 to −0.5 and the non-human primate species had to exceed the threshold of 0.5 and had to have all (three out of three) individuals within the species meet or exceed a ratio of at least 2.5 times greater than that found in human.

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#31 Jan 27, 2013
The annoying − stands for -

Quantitative Real-Time PCR
Q-PCR, using an ABI 7300, was carried out on genes for each individual across species using optimal primer and fluorogenic probe sets that are unique to the exonic DNA sequence of the gene of interest. Optimal primers and probes were designed using PrimerExpress (ABI software). The amplicon sequence was used as a BLAT query ( http://genome.ucsc.edu/cgi-bin/hgBlat ) against the human March 2006 (hg18), chimpanzee March 2006 (PanTro2), and rhesus macaque January 2006 (rheMac2) assemblies to ensure that the primer/probe sets had no or minimal mismatches. The functionality of each primer pair was then verified using the UCSC database for in silico PCR ( http://genome.ucsc.edu/cgi-bin/hgPcr... ). Gene copy number was determined by the number of cycles and amount of amplification product determined by Q-PCR. These assays were done in duplicate, and the copy numbers were normalized to CFTR, cystic fibrosis transmembrane conductance regulator, an ATP-binding cassette that was used as a control gene thought to represent one gene per haploid genome across humans and the great apes (Hallast et al. 2006). To further confirm CFTR copy number across primates, BLAT searches using the CFTR primer/probe sequences as a query were done for available human, chimp, and macaque genome assemblies. The CFTR sequence was also used as a BLAT query against the mouse and rat genomes, which both showed one copy per haploid genome.

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#33 Jan 27, 2013
I'll give the site later on, so yall can sort this one (plus post 28 4&#956:9).

Computational analyses: BLAT comparisons
The sequences for GenBank accession numbers that corresponded to IMAGE clones whose signals were determined to be either HLS, chimp LS, or macaque LS by the abovementioned selection criteria were used as BLAT queries against the most recent human (hg18), chimp (PanTro2), and macaque (rheMac2) genome assemblies to determine if available primate genome assemblies were in agreement with the aCGH data set. BLAT hits were screened with a Perl ( http://www.perl.org ) script for scores of >200, to eliminate spurious matches. Those BLAT hits that met the score cutoff were then tallied for each genome, and the numbers were compared to determine whether or not the BLAT searches were in agreement with the proportions of human, chimp, and macaque LS increases and decreases discovered using aCGH.

Go to:Acknowledgments.We thank B. Soriano and J. Gaydos for offering their expertise regarding microarray analysis; M. Popesco, E. MacLaren, and A. Fortna for helpful discussions; and J. Chang, S. Williams, A. Komura, S. Glidewell, and S. Friedrichs for technical help. We also thank L. Lyons at UC, Davis, for providing genomic DNAs from Macaca mulatta; D.G. Smith at UC, Davis for a gorilla DNA sample; Yerkes National Primate Research Center (Atlanta, Georgia); the Coriell Institute (Camden, New Jersey) for bonobo, orangutan, and gorilla DNA samples; M. Goodman and D. Wildman at Wayne State University School of Medicine for an orangutan DNA sample; and the Human Genome Sequencing Consortium, the Chimpanzee Sequencing and Analysis Consortium, and the Macaque Genome Sequence and Analysis Consortium for generation and pre-publication release of genome sequence assemblies for these species. This work was supported by a Butcher foundation grant and NIH grant AA11853 (J.M.S.) and NIH grant CA97139 (J.R.P.).

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#35 Jan 27, 2013
Cheng Z., Ventura M., She X., Khaitovich P., Graves T., Osoegawa K., Church D., DeJong P., Wilson R.K., Paabo S., Ventura M., She X., Khaitovich P., Graves T., Osoegawa K., Church D., DeJong P., Wilson R.K., Paabo S., She X., Khaitovich P., Graves T., Osoegawa K., Church D., DeJong P., Wilson R.K., Paabo S., Khaitovich P., Graves T., Osoegawa K., Church D., DeJong P., Wilson R.K., Paabo S., Graves T., Osoegawa K., Church D., DeJong P., Wilson R.K., Paabo S., Osoegawa K., Church D., DeJong P., Wilson R.K., Paabo S., Church D., DeJong P., Wilson R.K., Paabo S., DeJong P., Wilson R.K., Paabo S., Wilson R.K., Paabo S., Paabo S., et al. A genome-wide comparison of recent chimpanzee and human segmental duplications. Nature. 2005;437:8893.[PubMed]
Cheung J., Estivill X., Khaja R., MacDonald J.R., Lau K., Tsui L.C., Scherer S.W., Estivill X., Khaja R., MacDonald J.R., Lau K., Tsui L.C., Scherer S.W., Khaja R., MacDonald J.R., Lau K., Tsui L.C., Scherer S.W., MacDonald J.R., Lau K., Tsui L.C., Scherer S.W., Lau K., Tsui L.C., Scherer S.W., Tsui L.C., Scherer S.W., Scherer S.W. Genome-wide detection of segmental duplications and potential assembly errors in the human genome sequence. Genome Biol. 2003;4:R25.[PMC free article][PubMed]
Chimpanzee Sequencing and Analysis Consortium Initial sequence of the chimpanzee genome and comparison with the human genome. Nature. 2005;437:6987.[PubMed]
Ciccarelli F.D., von Mering C., Suyama M., Harrington E.D., Izaurralde E., Bork P., von Mering C., Suyama M., Harrington E.D., Izaurralde E., Bork P., Suyama M., Harrington E.D., Izaurralde E., Bork P., Harrington E.D., Izaurralde E., Bork P., Izaurralde E., Bork P., Bork P. Complex genomic rearrangements lead to novel primate gene function. Genome Res. 2005;15:343351.[PMC free article][PubMed]
Daza-Vamenta R., Glusman G., Rowen L., Guthrie B., Geraghty D.E., Glusman G., Rowen L., Guthrie B., Geraghty D.E., Rowen L., Guthrie B., Geraghty D.E., Guthrie B., Geraghty D.E., Geraghty D.E. Genetic divergence of the rhesus macaque major histocompatibility complex. Genome Res. 2004;14:15011515.[PMC free article][PubMed]

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#36 Jan 27, 2013
de Vries B.B.A., Pfundt R., Leisink M., Koolen D.A., Vissers L.E.L.M., Janssen I.M., Reijmersdal S., Nillesen W.M., Huys E.H.L.P., Leeuw N., Pfundt R., Leisink M., Koolen D.A., Vissers L.E.L.M., Janssen I.M., Reijmersdal S., Nillesen W.M., Huys E.H.L.P., Leeuw N., Leisink M., Koolen D.A., Vissers L.E.L.M., Janssen I.M., Reijmersdal S., Huys E.H.L.P., Leeuw N., Huys E.H.L.P., Leeuw N., Leeuw N., et al. Diagnostic genome profiling in mental retardation. Am. J. Hum. Genet. 2005;77:606616.[PMC free article][PubMed]
Edwards Y.H., Putt W., Fox M., Ives J.H., Putt W., Fox M., Ives J.H., Fox M., Ives J.H., Ives J.H. A novel human phosphoglucomutase (PGM5) maps to the centromeric region of chromosome 9. Genomics. 1995;30:350353.[PubMed]
Fortna A., Kim Y., MacLaren E., Marshall K., Hahn G., Meltesen L., Brenton M., Hink R., Burgers S., Hernandez-Boussard T., Kim Y., MacLaren E., Marshall K., Hahn G., Meltesen L., Brenton M., Hink R., Burgers S., Hernandez-Boussard T., MacLaren E., Marshall K., Hahn G., Meltesen L., Brenton M., Hink R., Burgers S., Hernandez-Boussard T., Marshall K., Hahn G., Meltesen L., Brenton M., Hink R., Burgers S., Hernandez-Boussard T., Hahn G., Meltesen L., Brenton M., Hink R., Burgers S., Hernandez-Boussard T., Meltesen L., Brenton M., Hink R., Burgers S., Hernandez-Boussard T., Brenton M., Hink R., Burgers S., Hernandez-Boussard T., Hink R., Burgers S., Hernandez-Boussard T., Burgers S., Hernandez-Boussard T., Hernandez-Boussard T., et al. Lineage-specific gene duplication and loss in human and great ape evolution. PLoS Biol. 2004;2:937954.
Gieffers C., Peters B.H., Kramer E.R., Dotti C.G., Peters J.M., Peters B.H., Kramer E.R., Dotti C.G., Peters J.M., Kramer E.R., Dotti C.G., Peters J.M., Dotti C.G., Peters J.M., Peters J.M. Expression of the CDH1-associated form of the anaphase-promoting complex in postmitotic neurons. Proc. Natl. Acad. Sci. 1999;96:1131711322.[PMC free article][PubMed]

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#37 Jan 27, 2013
Goidts V., Armengol L., Schempp W., Conroy J., Nowak N., Muller S., Cooper D.N., Estivill X., Enard W., Szamalek J.M., Armengol L., Schempp W., Szamalek J.M., et al. Identification of large-scale human-specific copy number differences by inter-species array comparative genomic hybridization. Hum. Genet. 2006;119:185198.[PubMed]
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#39 Jan 27, 2013
Stankiewicz P., Lupski J.R., Lupski J.R. Genome architecture, rearrangements and genomic disorders. Trends Genet. 2002;18:7482.[PubMed]
Vandepoele K., Van Roy N., Staes K., Speleman F., van Roy F., Staes K. A novel gene family NBPF: Intricate structure generated by gene duplications during primate evolution. Mol. Biol. Evol. 2005;22:22652274.[PubMed]
Verde I., Pahlke G., Salanova M., Zhang G., Wang S., Coletti D., Onuffer J., Jin S.L., Conti M., Salanova M.,. Myomegalin is a novel protein of the golgi/centrosome that interacts with a cyclic nucleotide phosphodiesterase. J. Biol. Chem. 2001;276:1118911198.[PubMed]
Wilson G.M., Flibotte S., Missirlis P.I., Marra M.A., Jones S., Thornton K., Clark A.G., Holt R.A., Identification by full-coverage array CGH of human DNA copy number increases relative to chimpanzee and gorilla. Genome Res. 2006;16:173181.[PMC free article][PubMed]

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#40 Jan 27, 2013
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1...
Gene copynumber variations spanning 60 M yrs. of human and primate evolution.

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#41 Jan 27, 2013
post 28. 4 micrograms
On the dna sequence - 5 '(never mind the position number) would give all the codes.

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#42 Jan 27, 2013

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#43 Jan 27, 2013
Conclusion
Identification and analysis of chr 3 regions 3p12-p13 and 3q21.3-q22.1, involved in tumor-related breaks, showed that they have also played an important role both in the recent evolution of primates and generally in mammalian evolution. The main feature common to both regions was the presence of specific SDs, designated tumor break-prone segmental duplications (TBSDs). The chromosomal regions containing TBSD share common sequence features related to the regional instability:

1.They are located at the transition between more and less CG-rich areas at sites, which may represent ancestral terminal chromosomal segments.
2.They contain large segmental duplications. The gene clusters and the functional diversity created within contributes to speciation.
3.They remain structurally unstable both in evolution and in malignancy. Their instability may be explained by disturbed replication at the transition between different isochores, which is catalyzed by the presence of unusual structures like large SDs, satellite repeats, and by reactivation of retroviral elements during evolution and in cancer cells.
4.The plasticity in these sites is maintained during long evolutionary time. Among the explanations, it may be that the regional instability leads to chromosomal rearrangements that fuse areas that are even more dissimilar CG-content, and to increased ability to accept satellite repeats, transposable elements, and SDs. These changes would in turn perpetuate the instability.

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#44 Jan 27, 2013
Segmental duplications and evolutionary plasticity at tumor chromosome break-prone regions
Eva Darai-Ramqvist,1 Agneta Sandlund,1 Stefan Mller,2 George Klein,1 Stefan Imreh,1 and Maria Kost-Alimova1,3
1 Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm SE-171 77, Sweden;2 Institute for Anthropology and Human Genetics, Department of Biology II, Ludwig-Maximilians-University, Planegg-Martinsried DE-82152, Germany3Corresponding author.E-mail Maria.Kost-Alimova@mtc.ki.se; fax 46-8-330498.
Author information ► Article notes ► Copyright and License information ►
Received August 11, 2007; Accepted November 29, 2007.
Copyright 2008, Cold Spring Harbor Laboratory Press
This article has been cited by other articles in PMC.
Go to:Abstract.We have previously found that the borders of evolutionarily conserved chromosomal regions often coincide with tumor-associated deletion breakpoints within human 3p12-p22. Moreover, a detailed analysis of a frequently deleted region at 3p21.3 (CER1) showed associations between tumor breaks and gene duplications. We now report on the analysis of 54 chromosome 3 breaks by multipoint FISH (mpFISH) in 10 carcinoma-derived cell lines. The centromeric region was broken in five lines. In lines with highly complex karyotypes, breaks were clustered near known fragile sites, FRA3B, FRA3C, and FRA3D (three lines), and in two other regions: 3p12.3-p13 (~75 Mb position) and 3q21.3-q22.1 (~130 Mb position)(six lines). All locations are shown based on NCBI Build 36.1 human genome sequence. The last two regions participated in three of four chromosome 3 inversions during primate evolution. Regions at 75, 127, and 131 Mb positions carry a large (~250 kb) segmental duplication (tumor break-prone segmental duplication [TBSD]). TBSD homologous sequences were found at 15 sites on different chromosomes. They were located within bands frequently involved in carcinoma-associated breaks. Thirteen of them have been involved in inversions during primate evolution; 10 were reused by breaks during mammalian evolution; 14 showed copy number polymorphism in man. TBSD sites showed an increase in satellite repeats, retrotransposed sequences, and other segmental duplications. We propose that the instability of these sites stems from specific organization of the chromosomal region, associated with location at a boundary between different CG-content isochores and with the presence of TBSDs and instability elements, including satellite repeats and retroviral sequences.

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