Nucleotide, cytogenetic and expression impact of the human chromosome 8p23.1 inversion polymorphism

Background: The human chromosome 8p23.1 region contains a 3.8–4.5 Mb segment which can be found in different orientations (defined as genomic inversion) among individuals. The identification of single nucleotide polymorphisms (SNPs) tightly linked to the genomic orientation of a given region should be useful to indirectly evaluate the genotypes of large genomic orientations in the individuals. Results: We have identified 16 SNPs, which are in linkage disequilibrium (LD) with the 8p23.1 inversion as detected by fluorescent in situ hybridization (FISH). The variability of the 8p23.1 orientation in 150 HapMap samples was predicted using this set of SNPs and was verified by FISH in a subset of samples. Four genes (NEIL2, MSRA, CTSB and BLK) were found differentially expressed (p<0.0005) according to the orientation of the 8p23.1 region. Finally, we have found variable levels of mosaicism for the orientation of the 8p23.1 as determined by FISH. Conclusion: By means of dense SNP genotyping of the region, haplotype-based computational analyses and FISH experiments we could infer and verify the orientation status of alleles in the 8p23.1 region by detecting two short haplotype stretches at both ends of the inverted region, which are likely the relic of the chromosome in which the original inversion occurred. Moreover, an impact of 8p23.1 inversion on gene expression levels cannot be ruled out, since four genes from this region have statistically significant different expression levels depending on the inversion status. FISH results in lymphoblastoid cell lines suggest the presence of mosaicism regarding the 8p23.1 inversion.

Recent human evolution has shaped geographical differences in susceptibility to disease

Background: Searching for associations between genetic variants and complex diseases has been a very active area of research for over two decades. More than 51,000 potential associations have been studied and published, a figure that keeps increasing, especially with the recent explosion of array-based Genome-Wide Association Studies. Even if the number of true associations described so far is high, many of the putative risk variants detected so far have failed to be consistently replicated and are widely considered false positives. Here, we focus on the world-wide patterns of replicability of published association studies.Results: We report three main findings. First, contrary to previous results, genes associated to complex diseases present lower degrees of genetic differentiation among human populations than average genome-wide levels. Second, also contrary to previous results, the differences in replicability of disease associated-loci between Europeans and East Asians are highly correlated with genetic differentiation between these populations. Finally, highly replicated genes present increased levels of high-frequency derived alleles in European and Asian populations when compared to African populations. Conclusions: Our findings highlight the heterogeneous nature of the genetic etiology of complex disease, confirm the importance of the recent evolutionary history of our species in current patterns of disease susceptibility and could cast doubts on the status as false positives of some associations that have failed to replicate across populations.

Islands of euchromatin-like sequence and expressed polymorphic sequences within the short arm of human chromosome 21

The goals of the human genome project did not include sequencing of the heterochromatic regions. We describe here an initial sequence of 1.1 Mb of the short arm of human chromosome 21 (HSA21p), estimated to be 10% of 21p. This region contains extensive euchromatic-like sequence and includes on average one transcript every 100 kb. These transcripts show multiple inter- and intrachromosomal copies, and extensive copy number and sequence variability. The sequencing of the "heterochromatic" regions of the human genome is likely to reveal many additional functional elements and provide important evolutionary information.

Prominent use of distal 5’ transcription start sites and discovery of a large number of additional exons in ENCODE regions

This report presents systematic empirical annotation of transcript products from 399 annotated protein-coding loci across the 1% of the human genome targeted by the Encyclopedia of DNA elements (ENCODE) pilot project using a combination of 5' rapid amplification of cDNA ends (RACE) and high-density resolution tiling arrays. We identified previously unannotated and often tissue- or cell-line-specific transcribed fragments (RACEfrags), both 5' distal to the annotated 5' terminus and internal to the annotated gene bounds for the vast majority (81.5%) of the tested genes. Half of the distal RACEfrags span large segments of genomic sequences away from the main portion of the coding transcript and often overlap with the upstream-annotated gene(s). Notably, at least 20% of the resultant novel transcripts have changes in their open reading frames (ORFs), most of them fusing ORFs of adjacent transcripts. A significant fraction of distal RACEfrags show expression levels comparable to those of known exons of the same locus, suggesting that they are not part of very minority splice forms. These results have significant implications concerning (1) our current understanding of the architecture of protein-coding genes; (2) our views on locations of regulatory regions in the genome; and (3) the interpretation of sequence polymorphisms mapping to regions hitherto considered to be "noncoding," ultimately relating to the identification of disease-related sequence alterations.

Tandem chimeric transcription as a means to increase protein diversity in the human genome

The “one-gene, one-protein” rule, coined by Beadle and Tatum, has been fundamental to molecular biology. The rule implies that the genetic complexity of an organism depends essentially on its gene number. The discovery, however, that alternative gene splicing and transcription are widespread phenomena dramatically altered our understanding of the genetic complexity of higher eukaryotic organisms; in these, a limited number of genes may potentially encode a much larger number of proteins. Here we investigate yet another phenomenon that may contribute to generate additional protein diversity. Indeed, by relying on both computational and experimental analysis, we estimate that at least 4%–5% of the tandem gene pairs in the human genome can be eventually transcribed into a single RNA sequence encoding a putative chimeric protein. While the functional significance of most of these chimeric transcripts remains to be determined, we provide strong evidence that this phenomenon does not correspond to mere technical artifacts and that it is a common mechanism with the potential of generating hundreds of additional proteins in the human genome.

Characterization and evolution of the novel gene family FAM90A in primates originated by multiple duplication and rearrangement events

Genomic plasticity of human chromosome 8p23.1 region is highly influenced by two groups of complex segmental duplications (SDs), termed REPD and REPP, that mediate different kinds of rearrangements. Part of the difficulty to explain the wide range of phenotypes associated with 8p23.1 rearrangements is that REPP and REPD are not yet well characterized, probably due to their polymorphic status. Here, we describe a novel primate-specific gene family, named FAM90A (family with sequence similarity 90), found within these SDs. According to the current human reference sequence assembly, the FAM90A family includes 24 members along 8p23.1 region plus a single member on chromosome 12p13.31, showing copy number variation (CNV) between individuals. These genes can be classified into subfamilies I and II, which differ in their upstream and 5′-untranslated region sequences, but both share the same open reading frame and are ubiquitously expressed. Sequence analysis and comparative fluorescence in situ hybridization studies showed that FAM90A subfamily II suffered a big expansion in the hominoid lineage, whereas subfamily I members were likely generated sometime around the divergence of orangutan and African great apes by a fusion process. In addition, the analysis of the Ka/Ks ratios provides evidence of functional constraint of some FAM90A genes in all species. The characterization of the FAM90A gene family contributes to a better understanding of the structural polymorphism of the human 8p23.1 region and constitutes a good example of how SDs, CNVs and rearrangements within themselves can promote the formation of new gene sequences with potential functional consequences.

Association of NTRK3 and its interaction with NGF suggest an altered cross-regulation of the neurotrophin signaling pathway in eating disorders

Eating disorders (EDs) are complex psychiatric diseases that include anorexia nervosa and bulimia nervosa, and have higher than 50% heritability. Previous studies have found association of BDNF and NTRK2 to ED, while animal models suggest that other neurotrophin genes might also be involved in eating behavior. We have performed a family-based association study with 151 TagSNPs covering 10 neurotrophin signaling genes: NGFB, BDNF, NTRK1, NGFR/p75, NTF4/5, NTRK2, NTF3, NTRK3, CNTF and CNTFR in 371 ED trios of Spanish, French and German origin. Besides several nominal associations, we found a strong significant association after correcting for multiple testing (P = 1.04 × 10−4) between ED and rs7180942, located in the NTRK3 gene, which followed an overdominant model of inheritance. Interestingly, HapMap unrelated individuals carrying the rs7180942 risk genotypes for ED showed higher levels of expression of NTRK3 in lymphoblastoid cell lines. Furthermore, higher expression of the orthologous murine Ntrk3 gene was also detected in the hypothalamus of the anx/anx mouse model of anorexia. Finally, variants in NGFB gene appear to modify the risk conferred by the NTRK3 rs7180942 risk genotypes (P = 4.0 × 10−5) showing a synergistic epistatic interaction. The reported data, in addition to the previous reported findings for BDNF and NTRK2, point neurotrophin signaling genes as key regulators of eating behavior and their altered cross-regulation as susceptibility factors for EDs.

In silico meets in vivo

A report of the 6th Georgia Tech-Oak Ridge National Lab International Conference on Bioinformatics 'In silico Biology: Gene Discovery and Systems Genomics', Atlanta, USA, 15-17 November, 2007.

X-chromosome tiling path array detection of copy number variants in patients with chromosome X-linked mental retardation

Background: Aproximately 5–10% of cases of mental retardation in males are due to copy number variations (CNV) on the X chromosome. Novel technologies, such as array comparative genomic hybridization (aCGH), may help to uncover cryptic rearrangements in X-linked mental retardation (XLMR) patients. We have constructed an X-chromosome tiling path array using bacterial artificial chromosomes (BACs) and validated it using samples with cytogenetically defined copy number changes. We have studied 54 patients with idiopathic mental retardation and 20 controls subjects. Results: Known genomic aberrations were reliably detected on the array and eight novel submicroscopic imbalances, likely causative for the mental retardation (MR) phenotype, were detected. Putatively pathogenic rearrangements included three deletions and five duplications (ranging between 82 kb to one Mb), all but two affecting genes previously known to be responsible for XLMR. Additionally, we describe different CNV regions with significant different frequencies in XLMR and control subjects (44% vs. 20%). Conclusion:This tiling path array of the human X chromosome has proven successful for the detection and characterization of known rearrangements and novel CNVs in XLMR patients.

African signatures of recent positive selection in human FOXI1

Background: The human FOXI1 gene codes for a transcription factor involved in the physiology of the inner ear, testis, and kidney. Using three interspecies comparisons, it has been suggested that this may be a gene underhuman-specific selection. We sought to confirm this finding by using an extended set of orthologous sequences.Additionally, we explored for signals of natural selection within humans by sequencing the gene in 20 Europeans,20 East Asians and 20 Yorubas and by analysing SNP variation in a 2 Mb region centered on FOXI1 in 39worldwide human populations from the HGDP-CEPH diversity panel.Results: The genome sequences recently available from other primate and non-primate species showed that FOXI1divergence patterns are compatible with neutral evolution. Sequence-based neutrality tests were not significant inEuropeans, East Asians or Yorubas. However, the Long Range Haplotype (LRH) test, as well as the iHS and XP-Rsbstatistics revealed significantly extended tracks of homozygosity around FOXI1 in Africa, suggesting a recentepisode of positive selection acting on this gene. A functionally relevant SNP, as well as several SNPs either on theputatively selected core haplotypes or with significant iHS or XP-Rsb values, displayed allele frequencies stronglycorrelated with the absolute geographical latitude of the populations sampled.Conclusions: We present evidence for recent positive selection in the FOXI1 gene region in Africa. Climate mightbe related to this recent adaptive event in humans. Of the multiple functions of FOXI1, its role in kidney-mediatedwater-electrolyte homeostasis is the most obvious candidate for explaining a climate-related adaptation.

Analysis of the multi-copy gene family FAM90A as a copy number variant in different ethnic backgrounds

Copy number variants contribute extensively to inter-individual genomic differences, but little is known about their inter-population variability and diversity. In a previous study (Bosch et al., 2007; 16:2572-2582), we reported that the primate-specific gene family FAM90A, which accounts for as many as 25 members in the human reference assembly, has expanded the number of FAM90A clusters across the hominoid lineage. Here we examined the copy number variability of FAM90A genes in 260 HapMap samples of European, African, and Asian ancestry, and showed significant inter-population differences (p<0.0001). Based on the recent study of Stranger et al. (2007; 315:848-853), we also explored the correlation between copy number variability and expression levels of the FAM90A gene family. Despite the high genomic variability, we found a low correlation between FAM90A copy number and expression levels, which could be due to the action of independent trans-acting factors. Our results show that FAM90A is highly variable in copy number between individuals and between populations. However, this variability has little impact on gene expression levels, thus highlighting the importance of genomic variability for genes located in regions containing segmental duplications.

Le corps révélé: la représentation du corps dans le cinéma de Maurice Pialat

Cette étude part à la recherche des oeuvres qui font de l’esthétique incarnée leur quêteinconsciente. A travers le cinéma de Maurice Pialat, il s’agit de voir par quels moyens ilest possible de valoriser la présence du corps dans le cinéma. Dans la première partie de l’étude, nous chercherons à saisir les enjeux qui sous-tendent une nouvellereprésentation des corps au cinéma. Nous verrons donc en quoi le style de la narration, de la mise en scène et en particulier le travail avec les acteurs permettent de mettre en valeur de façon nouvelle les corps à l’écran. Puis dans la seconde partie, en étudiant les modes d’apparition des corps dans les films du réalisateur français, nous verrons dequelle manière le corps peut devenir un acteur à part entière de l’action

La Gestió econòmico-empresarial d'un club de futbol

Hi ha records que perduraran sempre; el gol d’Iniesta contra el Chelsea, la boleia de Zidane a Hampden Park… Aquests moments memorables que queden gravats a les retines de tots nosaltres i produeixen una immensa felicitat a l’ésser humà, que l’emocionen, que el fan casi plorar. Tot això es produeix gràcies a un esport de masses molt present en les nostres vides, el futbol. Una activitat merament esportiva que s’ha convertit, amb el pas dels anys, en quelcom més que un esport, ha travessat l’àmbit purament sentimental d’una regió fins a assolir nivells d’autèntica globalització arreu del món. I és precisament el fet que el futbol porta una immensa passió a tots els racons de la societat, el que fa plantejar-nos el funcionament d’aquesta gran indústria de l’entreteniment.La realitat, tanmateix, revela l’existència de tot un món econòmico-empresarial que s’amaga darrere aquest espectacle, del qual, els veritables protagonistes són els clubs de futbol. Sense ells no es produiria mai l’espectacle. És per aquest motiu, que centrarem el nostre anàlisi sobre aquestes entitats esportives: veure el seu funcionament en la seva vessant més econòmica (1).En el present estudi s’analitzarà tot el funcionament intern d’un club, des del seu marc legal fins a l’econòmic, parant molta atenció en el que és el mercat futbolístic, el qual, al cap i a la fi, acaba relacionant la part més esportiva amb l’empresarial. A partir d’aquí intentarem extrapolar aquest entramat al que és el món futbolístic en general.Amb això, intentarem qüestionar-nos el perquè del gran moviment de divises existent, actualment, en aquest esport. Com pot ser que un club inverteixi més de 30 milions d’euros (2) només en el que seria contractar un nou treballador? Com es podengenerar tants recursos per després gastar-los en nòmines astronòmiques pels jugadors?Doncs aquest seguit de qüestions es el que pretenem respondre en aquest treball, de la forma més amena i clara possible, amb els gràfics i taules més adients.(1) Com que de clubs de futbol n’hi ha molts i no els podem analitzar tots un per un, partirem de la based’agafar-ne un com a model, en aquest cas, per la seva proximitat i facilitat d’obtenció de dades hemescollit el FC Barcelona.(2) Quantitat que equival, ni més ni menys, a 500 vegades el sou d’un treballador mitjà al llarg de tota la seva vida

Propostes de polítiques laborals

Us preocupa el problema de l’atur? Us heu preguntat mai per què Espanya té unes taxes d’atur superiors als països de referència en polítiques laborals? Creieu que el mercat laboral espanyol té moltes mancances? Penseu que el model productiu actual, basat en la construcció i el turisme, és sostenible a llarg termini? Aquestes preguntes, juntament amb la gran destrucció d’ocupació arran de la crisi, -durant l’últim trimestre del 2008 a l’economia espanyola li correspon el 70% (1) de la destrucció de llocs de treball a Europa- ens ha portat a reflexionar sobre els determinants i lesconseqüències de l’atur espanyol. Seguint aquesta línia, ens preguntàvem si,mitjançant un seguit de propostes laborals, Espanya podria arribar a reduir les sevestaxes d’atur a llarg termini i equiparar-les a nivells europeus.Si voleu saber més sobre les possibles solucions, en aquest treball exposemun seguit de mesures originals i d’altres basades en idees d’economistes experts queintenten millorar el capital humà de l’economia, el model productiu, els valors imentalitat de la societat, les institucions laborals i la legislació laboral existent , amb laqual cosa es pretén, com a fi últim, augmentar els nivells d’ocupació de l’economia.Algunes d’aquestes són:· Un nou contracte únic i flexibilització laboral· Canvis en la negociació col·lectiva, fiscalitat empresarial i programes formatius· Model original en les prestacions d’atur· Impuls a un nou model productiuAplicant aquestes propostes creiem que és possible reduir la temporalitat almercat laboral espanyol així com també lluitar per aconseguir la plena ocupaciópromocionant el treball estable i de qualitat. Tot i que el problema de l’atur genera moltdebat social entre els diferents agents socials, les propostes han intentat cercar elconsens i, sobretot, la millora econòmica de la societat.