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The diversity of mutations in human chromosomes is nowadays very well documented. The mutations characterize populations in the world as well as genetic causes of diseases. In the approach that we follow, we study the patterns of gaps between mutations by means of the rescaled range analysis and the fractal dimension estimates. The results for chromosomes 1 to 22 and X indicate the existence of the so-called Hurst phenomenon in all of them. The interpretation of this outcome entails the presence of long-range correlations and we propose an explanation based on the genomic feature dubbed linkage disequilibrium, a nonrandom association of alleles at different loci. An unexpected outcome is the noteworthy uniform reduction in the Hurst phenomenon when considering the centimorgan metric instead of base position units. By contrast, such uniform reduction is not observed with the fractal dimension values.

Background There is increasing evidence of the importance of copy number variants (CNV) in genetic diversity among individuals and populations, as well as in some common genetic diseases. We previously characterized a common 32-kb insertion/deletion variant of the PSORS4 locus at chromosome 1q21 that harbours the LCE3C and LCE3B genes. This variant allele (LCE3C_LCE3B-del) is common in patients with psoriasis and other autoimmune disorders from certain ethnic groups. Results Using array-CGH (Agilent 244 K) in samples from the HapMap and Human Genome Diversity Panel (HGDP) collections, we identified 54 regions showing population differences in comparison to Africans. We provided here a comprehensive population-genetic analysis of one of these regions, which involves the 32-kb deletion of the PSORS4 locus. By a PCR-based genotyping assay we characterised the profiles of the LCE3C_LCE3B-del and the linkage disequilibrium (LD) pattern between the variant allele and the tag SNP rs4112788. Our results show that most populations tend to have a higher frequency of the deleted allele than Sub-Saharan Africans. Furthermore, we found strong LD between rs4112788G and LCE3C_LCE3B-del in most non-African populations (r2 >0.8), in contrast to the low concordance between loci (r2 Conclusions These results are another example of population variability in terms of biomedical interesting CNV. The frequency distribution of the LCE3C_LCE3B-del allele and the LD pattern across populations suggest that the differences between ethnic groups might not be due to natural selection, but the consequence of genetic drift caused by the strong bottleneck that occurred during “out of Africa” expansion.

Myelodysplastic syndromes (MDS) are hematopoietic stem cell malignancies. Known predisposing factors to adult MDS include rare germline mutations, cytotoxic therapy, age-related clonal hematopoiesis, and autoimmune or chronic inflammatory disorders. To date, no published studies characterizing MDS-associated germline susceptibility polymorphisms exist. We performed a genome-wide association study of 2 sample sets (555 MDS cases vs 2964 control subjects; 352 MDS cases vs 2640 control subjects) in non-del(5q) MDS cases of European genomic ancestry. Meta-analysis identified 8 MDS-associated loci at 1q31.1 (PLA2G4A), 3p14.1 (FAM19A4), 5q21.3 (EFNA5), 6p21.33, 10q23.1 (GRID1), 12q24.32, 15q26.1, and 20q13.12 (EYA2) that approached genome-wide significance. Gene expression for 5 loci that mapped within or near genes was significantly upregulated in MDS bone marrow cells compared with those of control subjects (P < .01). Higher PLA2G4A expression and lower EYA2 expression were associated with poorer overall survival (P = .039 and P = .037, respectively). Higher PLA2G4A expression is associated with mutations in NRAS (P < .001), RUNX1 (P = .012), ASXL1 (P = .007), and EZH2 (P = .038), all of which are known to contribute to MDS development. EYA2 expression was an independently favorable risk factor irrespective of age, sex, and Revised International Scoring System score (relative risk, 0.67; P = .048). Notably, these genes have regulatory roles in innate immunity, a critical driver of MDS pathogenesis. EYA2 overexpression induced innate immune activation, whereas EYA2 inhibition restored colony-forming potential in primary MDS cells indicative of hematopoietic restoration and possible clinical relevance. In conclusion, among 8 suggestive MDS-associated loci, 5 map to genes upregulated in MDS with functional roles in innate immunity and potential biological relevance to MDS.

Annals of the rheumatic diseases 76(5), 906-913 (2017). doi:10.1136/annrheumdis-2016-210324, Published by BMJ Publ. Group, London

Dental calculus (calcified dental plaque) is prevalent in archaeological skeletal collections and is a rich source of oral microbiome and host-derived ancient biomolecules. Recently, it has been proposed that dental calculus may provide a more robust environment for DNA preservation than other skeletal remains, but this has not been systematically tested. In this study, shotgun-sequenced data from paired dental calculus and dentin samples from 48 globally distributed individuals are compared using a metagenomic approach. Overall, we find DNA from dental calculus is consistently more abundant and less contaminated than DNA from dentin. The majority of DNA in dental calculus is microbial and originates from the oral microbiome; however, a small but consistent proportion of DNA (mean 0.08 ± 0.08%, range 0.007–0.47%) derives from the host genome. Host DNA content within dentin is variable (mean 13.70 ± 18.62%, range 0.003–70.14%), and for a subset of dentin samples (15.21%), oral bacteria contribute > 20% of total DNA. Human DNA in dental calculus is highly fragmented, and is consistently shorter than both microbial DNA in dental calculus and human DNA in paired dentin samples. Finally, we find that microbial DNA fragmentation patterns are associated with guanine-cytosine (GC) content, but not aspects of cellular structure.

BACKGROUND: The fraction of exhaled nitric oxide (Feno) value is a biomarker of eosinophilic airway inflammation and is associated with childhood asthma. Identification of common genetic variants associated with childhood Feno values might help to define biological mechanisms related to specific asthma phenotypes. OBJECTIVE: We sought to identify the genetic variants associated with childhood Feno values and their relation with asthma. METHODS: Feno values were measured in children age 5 to 15 years. In 14 genome-wide association studies (N = 8,858), we examined the associations of approximately 2.5 million single nucleotide polymorphisms (SNPs) with Feno values. Subsequently, we assessed whether significant SNPs were expression quantitative trait loci in genome-wide expression data sets of lymphoblastoid cell lines (n = 1,830) and were related to asthma in a previously published genome-wide association data set (cases, n = 10,365; control subjects: n = 16,110). RESULTS: We identified 3 SNPs associated with Feno values: rs3751972 in LYR motif containing 9 (LYRM9; P = 1.97 × 10(-10)) and rs944722 in inducible nitric oxide synthase 2 (NOS2; P = 1.28 × 10(-9)), both of which are located at 17q11.2-q12, and rs8069176 near gasdermin B (GSDMB; P = 1.88 × 10(-8)) at 17q12-q21. We found a cis expression quantitative trait locus for the transcript soluble galactoside-binding lectin 9 (LGALS9) that is in linkage disequilibrium with rs944722. rs8069176 was associated with GSDMB and ORM1-like 3 (ORMDL3) expression. rs8069176 at 17q12-q21, but not rs3751972 and rs944722 at 17q11.2-q12, were associated with physician-diagnosed asthma. CONCLUSION: This study identified 3 variants associated with Feno values, explaining 0.95% of the variance. Identification of functional SNPs and haplotypes in these regions might provide novel insight into the regulation of Feno values. This study highlights that both shared and distinct genetic factors affect Feno values and childhood asthma. C.O. is supported by a NIH grant that supported the Hutterite studies (R01 HL085197). D.E. is supported by UK Medical Research Council Centre (G0600705). G.S. is supported by UK Medical Research Council Centre (G0600705). J.K. is funded by a Wellcome Trust 4-year PhD studentship in molecular, genetic, and life course epidemiology (WT083431MA). L.D. is supported by a European Respiratory Society/Marie Curie Joint Research Fellowship of the European Respiratory Society and the European Community’s Seventh Framework Programme FP7/2007-2013–Marie Curie Actions under grant agreement RESPIRE, PCOFUND-GA-2008-229571 (no. MC 1226- 2009). N.T. is supported by UK Medical Research Council Centre (G0600705). R.V. was partly supported by an unrestricted personal grant from GlaxoSmithKline, NL. V.J. is supported by the Netherlands Organization for Health Research and Development (ZonMw 90700303, 916.10159). L. Duijts is supported by a European Respiratory Society/Marie Curie Joint Research Fellowship of the European Respiratory Society and the European Community’s Seventh Framework Programme (FP7/2007-2013-Marie Curie Actions under grant agreement RESPIRE, PCOFUND-GA-2008-229571 [no. MC 1226-2009]). M. T. Salam has received research support from the National Heart, Lung, and Blood Institute (NHLBI; 5R01HL61768 and 5R01HL76647); the Southern California Environmental Health Sciences Center funded by the National Institute of Environmental Health Sciences (5P30ES007048); and the Environmental Protection Agency (EPA; 5P01ES009581, R826708-01, and RD831861-01), the National Institute of Environmental Health Sciences (5P01ES011627), and the Hastings Foundation. J. Genuneit has received grant EuFP6 (018996 under IP LSH-2004-1.25- 1). Evans has received a grant in the form of the MRC New Investigator Award G0600705. B. St Pourcain has received research support with Autism Speaks (7132). O. Fuchs has received research support from the European Commission within Seventh Framework Programme (theme FP7-KBBE-2007- 1) as part of EFRAIM (Impact of exogenous factors in the development of Allergy, contract no. 211911), the European Respiratory Society for a long-term research fellowship (no. 675). F. D. Gilliand has received research support from the NHLBI (5R01HL61768 and 5R01HL76647), Southern California Environmental Health Sciences Center funded by the National Institute of Environmental Health Sciences (5P30ES007048), the Children’s Environmental Health Center funded by the National Institute of Environmental Health Sciences and the Environmental Protection Agency (5P01Es009581, R826708-01, and RD831861-01), the National Institute of Environmental Health Sciences (5P01ES011627)

We present 42 new Y-chromosomal sequences from diverse Indian tribal and non-tribal populations, including the Jarawa and Onge from the Andaman Islands, which are analysed within a calibrated Y-chromosomal phylogeny incorporating South Asian (in total 305 individuals) and worldwide (in total 1286 individuals) data from the 1000 Genomes Project. In contrast to the more ancient ancestry in the South than in the North that has been claimed, we detected very similar coalescence times within Northern and Southern non-tribal Indian populations. A closest neighbour analysis in the phylogeny showed that Indian populations have an affinity towards Southern European populations and that the time of divergence from these populations substantially predated the Indo-European migration into India, probably reflecting ancient shared ancestry rather than the Indo-European migration, which had little effect on Indian male lineages. Among the tribal populations, the Birhor (Austro-Asiatic-speaking) and Irula (Dravidian-speaking) are the nearest neighbours of South Asian non-tribal populations, with a common origin in the last few millennia. In contrast, the Riang (Tibeto-Burman-speaking) and Andamanese have their nearest neighbour lineages in East Asia. The Jarawa and Onge shared haplogroup D lineages with each other within the last ~7000 years, but had diverged from Japanese haplogroup D Y-chromosomes ~53000 years ago, most likely by a split from a shared ancestral population. This analysis suggests that Indian populations have complex ancestry which cannot be explained by a single expansion model. Funding was provided by the joint Spain–India bilateral grant PRI-PIBIN-2011-0942 and BFU2016-77961-P (AEI/ FEDER, UE) both awarded by the Ministerio de Economía y Competitividad (Spain) and with the support of Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya (GRC 2014 SGR 866). Anders Bergström, YaliXue and Chris Tyler-Smith were supported by The Wellcome Trust (Grant 098051)

A polymorphic inversion that lies on chromosome 17q21 comprises two major haplotype families (H1 and H2) that not only differ in orientation but also in copy-number. Although the processes driving the spread of the inversion-associated lineage (H2) in humans remain unclear, a selective advantage has been proposed for one of its subtypes. Here, we genotyped a large panel of individuals from previously overlooked populations using a custom array with a unique panel of H2-specific single nucleotide polymorphisms and found a patchy distribution of H2 haplotypes in Africa, with North Africans displaying a higher frequency of inverted subtypes, when compared with Sub-Saharan groups. Interestingly, North African H2s were found to be closer to “non-African” chromosomes further supporting that these populations may have diverged more recently from groups outside Africa. Our results uncovered higher diversity within the H2 family than previously described, weakening the hypothesis of a strong selective sweep on all inverted chromosomes and suggesting a rather complex evolutionary history at this locus., IPATIMUP integrates the i3S Research Unit, which is partially supported by FCT, the Portuguese Foundation for Science and Technology. This work is also partially funded by FEDER funds through the Operational Programme for Competitiveness Factors—COMPETE and National Funds through the FCT—Foundation for Science and Technology, under the project “PEst-C/SAU/LA0003/2013.” IPATIMUP is also supported by NORTE-07-0162-FEDER-00018 and NORTE-07-0162-FEDER-000067, under Programa Operacional Regional do Norte (ON.2—O Novo Norte), through FEDER funds under the Quadro de Referência Estratégico Nacional (QREN). J.M.A. is funded by a doctoral fellowship from FCT (SFRH/BD/51004/2010) and a European Molecular Biology Organization (EMBO) short-term fellowship (ASFT 520-2013). A.C.L. is funded by an FCT doctoral fellowship (SFRH/BD/51695/2011). D.C. was funded by a Spanish MINECO project (CGL2013-44351-P). L.C. is partly funded by the Laboratoire d’Excellence (LABEX) entitled TULIP (ANR-10-LABX-41) and by the FCT project (PTDC/BIA-BIC/4476/2012). A.M.L. is the recipient of a research contract from FCT (IF/01262/2014).

Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 × 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population. Some individuals, studies, and centers received individual support. The grant numbers are: Addiction (U01HG004422, NIAAA: U10AA008401, NCI: P01CA089392, NIDA: R01DA013423, R01DA019963); Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (U.S. Public Health Service contracts: N01-CN-45165, N01-RC-45035, N01-RC-37004, NCI contract: HHSN261201000006C); Birth weight (U01HG004415); Blood clotting (R37 HL 039693); Broad Center for Genotyping and Analysis (U01HG04424); Cancer Prevention Study-II (American Cancer Society); Center for Inherited Disease Research (U01HG004438, HHSN268200782096C); Cleft lip/palate (NIDCR: U01DE018993 and R01DE016148, NIH contract: HHSN268200782096C); Dental Caries (NIDCR:U01DE018903 and R01DE014899, NIH CIDR contract: HHSN268200-782096C); Endometrial cancer (R01 CA134958); Fudan Lung Cancer Study (Ministry of Health (201002007); Ministry of Science and Technology (2011BAI09B00); National S&T Major Special Project (2011ZX09102-010-01); China National High-Tech Research and Development Program (2012AA02A517, 2012AA02A518); National Science Foundation of China (30890034); National Basic Research Program (2012CB944600); Scientific and Technological Support Plans from Jiangsu Province (BE2010715)); Gene-Environment Association Studies (Coordinating Center :U01 HG004446, Manuscript preparation: P01-GM099568); Genes and Environment in Lung Cancer, Singapore Study (National Medical Research Council Singapore grant (NMRC/0897/2004, NMRC/1075/2006); Agency for Science, Technology and Research (A*STAR) of Singapore); Genetic Epidemiological Study of Lung Adenocarcinoma (National Research Program on Genomic Medicine in Taiwan (DOH98-TD-G-111-015); National Research Program for Biopharmaceuticals in Taiwan (DOH 100-TD-PB-111-TM013); National Science Council,Taiwan (NSC 100-2319-B-400-001)); Glaucoma (NHGRI: U01HG004728, NEI: R01EY015473, NEI: R01EY015872, Harvard Medical School Distinguished Ophthalmology Scholar Award: Louis Pasquale); Guangdong Study (Foundation of Guangdong Science and Technology Department (2006B60101010, 2007A032000002, 2011A030400010); Guangzhou Science and Information Technology Bureau (2011Y2-00014); Chinese Lung Cancer Research Foundation; National Natural Science Foundation of China (81101549); Natural Science Foundation of Guangdong Province (S2011010000792)); Health Professionals Follow-up Study (UM1 CA167552, R01 HL35464); Hong Kong Study (General Research Fund of Research Grant Council, Hong Kong (781511M)); Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH; Intramural Research Program of the NIH, National Library of Medicine; Intramural Research Program of the National Institute for Occupational Safety and Health; Japanese Female Lung Cancer Collaborative Study (Grants-in-Aid from the Ministry of Health, Labor, and Welfare for Research on Applying Health Technology and for the 3rd-term Comprehensive 10-year Strategy for Cancer Control; National Cancer Center Research and Development Fund; Grant-in-Aid for Scientific Research on Priority Areas and on Innovative Area from the Ministry of Education, Science, Sports, Culture and Technology of Japan; NCI (R01-CA121210)); Lung cancer (Z01CP010200); Lung health (U01HG004738); Ministry of Health (201002007); Ministry of Science and Technology (2011BAI09B00); Melanoma (NCI R29CA70334, R01CA100264, P50CA093459); NLCS (China National High-Tech Research and Development Program Grant (2009AA022705); Priority Academic Program Development of Jiangsu Higher Education Institution; National Key Basic Research Program Grant (2011CB503805)); Nurses’ Health Study (P01 CA87969, R01 CA49449); Nurses’ Health Study II (UM1 CA176726, R01, 67262); OpPancreatic cancer (Mayo Clinic SPORE in Pancreatic Cancer: P50CA102701); Prematurity (U01HG004423); Prostate cancer (U01HG004726, NCI: CA63464, CA54281, CA1326792, RC2 CA148085); Shanghai Women’s Health Cohort Study (National Institutes of Health (R37 CA70867); National Cancer Institute intramural research program; NCI Intramural Research Program contract (N02 CP1101066)); Shenyang Lung Cancer Study (National Nature Science Foundation of China (81102194); Liaoning Provincial Department of Education (LS2010168); China Medical Board (00726)); Singapore Chinese Health Study (NIH grants: NCI R01 CA55069, R35 CA53890, R01 CA80205, and R01 CA144034); South Korea Multi-Center Lung Cancer Study (National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (2011-0016106); National R&D Program for Cancer Control, Ministry of Health &Welfare, Republic of Korea (0720550-2); (A010250)); Tianjin Lung Cancer Study (Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT); China (IRT1076), Tianjin Cancer Institute and Hospital, National Foundation for Cancer Research US); Venous thromboembolism (U01HG004735); Wuhan lung cancer study (National Key Basic Research and Development Program (2011CB503800)) and Yunnan Lung Cancer Study (Intramural program of U.S. National Institutes of Health; National Cancer Institute). Additionally, K.C.B. was supported in part by the Mary Beryl Patch Turnbull Scholar Program. The GENEVA consortium thanks the participants and the staff of all GENEVA studies for their important contributions. Support for the GENEVA genome-wide association studies was provided through the NIH Genes, Environment and Health Initiative (GEI).

Genome-wide association studies (GWAS) of colorectal cancer (CRC) have led to the identification of a number of common variants associated with modest risk. Several risk variants map within the vicinity of TGFβ/BMP signaling pathway genes, including rs4939827 within an intron of SMAD7 at 18q21.1. A previous study implicated a novel SNP (novel 1 or rs58920878) as a functional variant within an enhancer element in SMAD7 intron 4. In this study, we show that four SNPs including novel 1 (rs6507874, rs6507875, rs8085824, and rs58920878) in linkage disequilibrium (LD) with the index SNP rs4939827 demonstrate allele-specific enhancer effects in a large, multi-component enhancer of SMAD7. All four SNPs demonstrate allele-specific protein binding to nuclear extracts of CRC cell lines. Furthermore, some of the risk-associated alleles correlate with increased expression of SMAD7 in normal colon tissues. Finally, we show that the enhancer is responsive to BMP4 stimulation. Taken together, we propose that the associated CRC risk at 18q21.1 is due to four functional variants that regulate SMAD7 expression and potentially perturb a BMP negative feedback loop in TGFβ/BMP signaling pathways.

[Background] By reshuffling genomes, structural genomic reorganizations provide genetic variation on which natural selection can work. Understanding the mechanisms underlying this process has been a long-standing question in evolutionary biology. In this context, our purpose in this study is to characterize the genomic regions involved in structural rearrangements between human and macaque genomes and determine their influence on meiotic recombination as a way to explore the adaptive role of genome shuffling in mammalian evolution., [Results] We first constructed a highly refined map of the structural rearrangements and evolutionary breakpoint regions in the human and rhesus macaque genomes based on orthologous genes and whole-genome sequence alignments. Using two different algorithms, we refined the genomic position of known rearrangements previously reported by cytogenetic approaches and described new putative micro-rearrangements (inversions and indels) in both genomes. A detailed analysis of the rhesus macaque genome showed that evolutionary breakpoints are in gene-rich regions, being enriched in GO terms related to immune system. We also identified defense-response genes within a chromosome inversion fixed in the macaque lineage, underlying the relevance of structural genomic changes in evolutionary and/or adaptation processes. Moreover, by combining in silico and experimental approaches, we studied the recombination pattern of specific chromosomes that have suffered rearrangements between human and macaque lineages., [Conclusions] Our data suggest that adaptive alleles - in this case, genes involved in the immune response - might have been favored by genome rearrangements in the macaque lineage. © 2014 Ullastres et al.; licensee BioMed Central Ltd., This work was supported by the Ministerio de Economia y Competitividad (CGL-2010-20170).

Contains fulltext : 118578.pdf (Publisher’s version ) (Open Access) Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9x10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.

The Levant is a region in the Near East with an impressive record of continuous human existence and major cultural developments since the Paleolithic period. Genetic and archeological studies present solid evidence placing the Middle East and the Arabian Peninsula as the first stepping-stone outside Africa. There is, however, little understanding of demographic changes in the Middle East, particularly the Levant, after the first Out-of-Africa expansion and how the Levantine peoples relate genetically to each other and to their neighbors. In this study we analyze more than 500,000 genome-wide SNPs in 1,341 new samples from the Levant and compare them to samples from 48 populations worldwide. Our results show recent genetic stratifications in the Levant are driven by the religious affiliations of the populations within the region. Cultural changes within the last two millennia appear to have facilitated/maintained admixture between culturally similar populations from the Levant, Arabian Peninsula, and Africa. The same cultural changes seem to have resulted in genetic isolation of other groups by limiting admixture with culturally different neighboring populations. Consequently, Levant populations today fall into two main groups: one sharing more genetic characteristics with modern-day Europeans and Central Asians, and the other with closer genetic affinities to other Middle Easterners and Africans. Finally, we identify a putative Levantine ancestral component that diverged from other Middle Easterners ~23,700-15,500 years ago during the last glacial period, and diverged from Europeans ~15,900-9,100 years ago between the last glacial warming and the start of the Neolithic. © 2013 Haber et al., This study was partly supported by the Lebanese American University and the National Geographic Society (The Genographic Project). CT-S was supported by grant number 098051 from The Wellcome Trust., Haber, Marc et al.

The repetitive DNA sequences found at telomeres and centromeres play a crucial role in the structure and function of eukaryotic chromosomes. This role may be related to the tendency observed in many repetitive DNAs to adopt non-canonical structures. Although there is an increasing recognition of the importance of DNA quadruplexes in chromosome biology, the co-existence of different quadruplexforming elements in the same DNA structure is still a matter of debate. Here we report the structural study of the oligonucleotide d(TCGTTTCGT) and its cyclic analog d. Both sequences form dimeric quadruplex structures consisting of a minimal i-motif capped, at both ends, by a slipped minor groove-aligned G:T:G:T tetrad. These mini i-motifs, which do not exhibit the characteristic CD spectra of other i-motif structures, can be observed at neutral pH, although they are more stable under acidic conditions. This finding is particularly relevant since these oligonucleotide sequences do not contain contiguous cytosines. Importantly, these structures resemble the loop moiety adopted by an 11-nucleotide fragment of the conserved centromeric protein B (CENP-B) box motif, which is the binding site for the CENP-B. © 2012 The Author(s).

Background: Congenital malformations are present in approximately 2–3% of liveborn babies and 20% of stillborn fetuses. The mechanisms underlying the majority of sporadic and isolated congenital malformations are poorly understood, although it is hypothesized that the accumulation of rare genetic, genomic and epigenetic variants converge to deregulate developmental networks. Methodology/Principal Findings: We selected samples from 95 fetuses with congenital malformations not ascribed to a specific syndrome (68 with isolated malformations, 27 with multiple malformations). Karyotyping and Multiplex Ligation-dependent Probe Amplification (MLPA) discarded recurrent genomic and cytogenetic rearrangements. DNA extracted from the affected tissue (46%) or from lung or liver (54%) was analyzed by molecular karyotyping. Validations and inheritance were obtained by MLPA. We identified 22 rare copy number variants (CNV) [>100 kb, either absent (n = 7) or very uncommon (n = 15

VKORC1 (vitamin K epoxide reductase complex subunit 1, 16p11.2) is the main genetic determinant of human response to oral anticoagulants of antivitamin K type (AVK). This gene was recently suggested to be a putative target of positive selection in East Asian populations. In this study, we genotyped the HGDP-CEPH Panel for six VKORC1 SNPs and downloaded chromosome 16 genotypes from the HGDP-CEPH database in order to characterize the geographic distribution of footprints of positive selection within and around this locus. A unique VKORC1 haplotype carrying the promoter mutation associated with AVK sensitivity showed especially high frequencies in all the 17 HGDP-CEPH East Asian population samples. VKORC1 and 24 neighboring genes were found to lie in a 505 kb region of strong linkage disequilibrium in these populations. Patterns of allele frequency differentiation and haplotype structure suggest that this genomic region has been submitted to a near complete selective sweep in all East Asian populations and only in this geographic area. The most extreme scores of the different selection tests are found within a smaller 45 kb region that contains VKORC1 and three other genes (BCKDK, MYST1 (KAT8), and PRSS8) with different functions. Because of the strong linkage disequilibrium, it is not possible to determine if VKORC1 or one of the three other genes is the target of this strong positive selection that could explain present-day differences among human populations in AVK dose requirement. Our results show that the extended region surrounding a presumable single target of positive selection should be analyzed for genetic variation in a wide range of genetically diverse populations in order to account for other neighboring and confounding selective events and the hitchhiking effect. © 2012 Patillon et al., This work was supported by the Spanish National Institute for Bioinformatics (www.inab.org). PL is supported by a PhD fellowship from “Acción Estratégica de Salud, en el Marco del Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica 2008–2011” from Instituto de Salud Carlos III. BP is supported by a PhD fellowship from the doctoral program in Public Health (ED420: www.ed-sante-publique.u-psud.fr) from Paris Sud University.

The NB4 promyelocytic cell line exhibits many of the characteristics of acute promyelocytic leukemia blast cells, including the translocation (15 : 17) that fuses the PML gene on chromosome 15 to the RARαgene on chromosome 17. These cells have a very high fibrinolytic capacity. In addition to a high secretion of urokinase, NB4 cells exhibit a 10-fold higher plasminogen binding capacity compared with other leukemic cell lines. When tissue-type plasminogen activator was added to acid-treated cells, plasmin generation was 20–26-fold higher than that generated by U937 cells or peripheral blood neutrophils, respectively. We found that plasminogen bound to these cells can be detected by fluorescence-activated cell sorting using an antiplasminogen monoclonal antibody that specifically reacts with this antigen when it is bound to cell surfaces. All-transretinoid acid treatment of NB4 cells markedly decreased the binding of this monoclonal antibody. This cell line constitutes a unique model to explore plasminogen binding and activation on cell surfaces that can be modulated by all-transretinoid acid treatment.

To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 × 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 × 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height, their effects on infant head circumference were largely independent of height (P = 3.8 × 10(-7) for rs7980687 and P = 1.3 × 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 × 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume, Parkinson's disease and other neurodegenerative diseases, indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life. Major funding for the research in this paper is as follows: Academy of Finland (project grants 104781, 120315, 129269, 1114194 and Center of Excellence in Complex Disease Genetics); Canadian Institutes of Health Research (grant MOP 82893); The European Community’s Seventh Framework Programme (FP7/2007-2013), ENGAGE project, grant agreement HEALTH-F4-2007-201413; Instituto de Salud Carlos III (FIS PI081151, and PS09/00432); Medical Research Council UK (G0500539, G0600331, PrevMetSyn/Salve/MRC, G0600705); National Health and Medical Research Council of Australia (ID 403981 and ID 003209); Netherlands Organisation for Scientific Research (NOW)/Netherlands Organisation for Health Reseacrh and Development (ZonMw) (grants SPI 56-464-14192, 904-61-090, 904-61-193, 480-04-004, 400-05-717); NHLBI (grant 5R01HL087679-02 through the STAMPEED program (1RL1MH083268-01)); NIH (grant 1R01HD056465-01A1); University of Leipzig; Wellcome Trust (project grant GR069224); Western Australian DNA Bank; Western Australian Genetic Epidemiology Resource; ZonMW (grant 21000074). Personal funding is as follows: H.R.T by the Dutch Kidney Foundation (C08.2251) , S.D. by the Medical Research Council UK (G0500539, PrevMetSyn, and PS0476), R.M.F by a Sir Henry Wellcome Postdoctoral Fellowship (Wellcome Trust grant: 085541/Z/08/Z), D.M.E. by a Medical Research Council New Investigator Award (MRC G0800582 to D.M.E.), J.P.K. by a Wellcome Trust 4-year PhD studentship (WT083431MA), I.P. and J.F.B. in part supported by the European Community’s ENGAGE grant HEALTH-F4-2007-201413. A.T.H. is employed as a core member of the Peninsula NIHR Clinical Research Facility, V.W.V.J by the Netherlands Organization for Health Research (ZonMw 90700303, 916.10159)

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

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. This work was supported by grants from the Swiss National Science Foundation (R.L., A.R., and S.E.A.), the NCCR Frontiers in Genetics (S.E.A.), the European Commission (BioSapiens NoE to R.G. and S.E.A. and AnEUploidy IP to A.R. and S.E.A.), Blanceflor-Boncompagni Ludovisi Foundation (P.P.) and ChildCare foundations (S.E.A.), a bilateral scientific and technological cooperation project between the University of Antwerp and Shanghai Chinese National Human Genome Centre (C.V.B. and S.-Y.W.), and NIH grant HG002385 (E.E.E.). E.E.E. is an investigator of the Howard Hughes Medical Institute

The implication of MALT1 gene in the pathogenesis of primary cutaneous marginal zone B-cell lymphomas (PCMZL) has been a matter of controversy. We examined the presence of MALT1 translocations in a series of 23 PCMZL. FISH assay with a MALT1 dual color break apart translocation probe revealed the absence of MALT1 translocations in all cases.

Com a membres del Consorci europeu EuroImage el nostre laboratori es va centrar en la cerca de nous gens a la regió q24-q26 del cromosoma 15 humà. Aquesta tesi conté un recull dels gens identificats com a resultat d'aquesta participació. L'identificació de gens a 15q24-q26 ha permès descriure paralogia amb la regió 19p13.3-p12 en suport de la teoria existent sobre un origen evolutiu comú per aquests dos cromosomes. Entre els gens identificats a 15q24-q26, LRRN6A/LERN1 ha estat caracteritzat més profundament a nivell transcripcional i proteic. LERN1 és una proteïna transmembrana amb dominis rics en leucina i similitud a proteïnes crucials en el desenvolupament i manteniment del sistema nerviós de vertebrats. LERN1 s'expressa a estructures del sistema límbic en l'adult i amb patró més generalitzat i abundant durant el desenvolupament. LERN1 interacciona in vitro amb el factor de transcripció Myt1-like.ENGLISH, In the context of the EuroImage Consortium our laboratory focused on the discovery of novel genes in the q24-q26 region of human chromosome 15. This work contains a collection of genes identified as result of our involvement. The identification of genes on 15q24-q26 has revealed paralogy with the p13.3-p12 region on chromosome 19 in agreement with the previous observations which suggest a common evolutionary origin for these two chromosomes. One of the genes identified during this project has been further characterized in this thesis, LRRN6A/LERN1. LERN1 is transmembrane protein with leucine-rich repeat domains and similarity with essencial proteins in the development and maintenance of the vertebrate nervous system. LERN1 is expressed in the adult limbic system and broadly during development. In vitro assays show that LERN1 interacts with the transcription factor Myt1-like.

El cromosoma humà 21 (HSA21), és el cromosoma autosòmic humà més petit. La trisomia total o parcial del HSA21 està associada a síndrome de Down (SD). El fet de tenir la seqüència del HSA21 pràcticament complerta, ha accelerat molt el procés d'identificació de gens, pas previ per a l 'establiment de relacions causa-efecte entre els gens del HSA21 i els fenotips clínics de la SD.L'objectiu final d'aquesta tesi és la identificació i caracterització de nous gens del HSA21. Els resultats obtinguts es poden resumir en :· S'ha participat en la construcció d'un contig de cosmidis de tres regions del HSA21, cobrint al voltant de 3 Mb. · S' ha participat en la construcció d'un mapa transcripcional de les tres regions. Es va realitzar una selecció de cDNAs, aïllant en total 45 cDNAs parcials no redundants, dels quals 25 no mostraven similitud amb cap seqüència de les bases de dades. Tots s'expressaven en una barreja de RNA poliA+ de cervell, pulmó, fetge i ronyó fetals. Els intents d'aïllar els cDNAs complerts corresponents a cada un dels clons varen resultar negatius. · S' ha aïllat un nou gen del HSA21, KCNE2, identificat inicialmente mitjançant una anàlisi computacional de la seqüència genòmica AP000052. El cDNA complert té 850 pb. KCNE2 codifica per a una proteïna de 123 aa amb elevada homologia a KCNE1, una subunitat ß de canals de potassi depenents de voltage. L'estructura genòmica té un únic exó codificant i mapa a 21q22.1. KCNE2 s'expressa com un RNA de 1.2 kb, majoritàriament a estómac. La seqüència de la proteína KCNE2 conté 2 llocs consens de N-glicosilació, es prediu una regió transmembrana i un lloc consens de fosforilació per PKC. En experiments de western amb extractes de cèl·lules de mamífer transfectades, la proteïna es detecta com a tres bandes entre 16 kDa i 20 kDa, essent la més petita la del pes molecular esperat. Experiments amb tunicamicina han demostrat que KCNE2 es glicosila en asparagines, in vivo. Es van generar dos mutants en els llocs consens de glicosilació, N6Q i N29Q, que han demostrat que ambdós llocs són susceptibles de ser glicosilats. Experiments d'immunofluorescència indirecta suggereixen que KCNE2 s'inserta en la membrana amb el seu extrem N-terminal cap al medi extracel·lular i que amb un únic residu glicosilat n'hi ha prou per integrar-s'hi. Experiments de RT-PCR semiquantitativa indiquen que no hi ha sobre-expressió en SD ni de KCNE1 ni de KCNE2, a cors fetals SD. Es van buscar mutacions a KCNE2 en pacients de sordesa no sindròmica i es va trobar un canvi de nucleòtid A22G, que dóna lloc a un canvi d'aminoàcid T8A. Aquest canvi afectaria el punt de glicosilació.· Es va identificar un nou gen, por homologia a KCNE1 i KCNE2, al qual se li va donar el nom de KCNE3. El cDNA complert té 1646 pb i conté una pauta de lectura oberta de 103 aa. L'estructura genòmica és similar a la de KCNE1 i KCNE2, amb un únic exó codificant, per tant podria tractar-se d'una família de gens paràlegs. KCNE3 es va mapar a la regió 11q13-14, utilitzant el pannell d'híbrids de radiació G3 d'Stanford. KCNE3 s'expresa com a un mRNA de 3 Kb a colon, intestí prim, ovari i a sang perifèrica. La seqüència de aminoácidos conté 3 llocs consens de N-glicosilació, es prediu una regió transmembrana i un lloc consens de fosforilació per PKC. S' ha demostrat que KCNE3 es N-glicosila en cèl·lules de mamífer i que s'inserta a la membrana amb l'extrem N-terminal dirigit cap al medi extracel·lular. S'ha trobat un polimorfisme T198C, que provoca el canvi d'aminoàcid F66L, amb una freqüència del 15% en la población general.

Els darrers temps s'esta parlant molt del mapa genètic deis éssers humans. En el següent article s'intenten explicar conceptes bàsics com ara què és una base o un gen o un cromosoma o una mutació, entre d'altres, en un intent per acostar el significat d'aquests termes a les persones que llegeixen aquesta revista. Tanmateix s'hi parla del gran esforç d'investigació realitzat per diver­sos països per aconseguir un mapa de tots els gens del genoma humà. L'objectiu dels investiga­dors és obtenir una llista completa de tots els gens humans i de les proteïnes codificades per ells per que serveixi com una especie de tau/a periòdica per a la investigació biomèdica i poder aplicar aquests coneixements en la prevenció i el tractament de diverses malalties.

We report here the solution structure of several repetitive DNA sequences containing d(TCGTTCCGT) and related repeats. At physiological pH, these sequences fold into i-motif like quadruplexes in which every two repeats a globular structure is stabilized by two hemiprotonated C:C base pairs, flanked by two minor groove tetrads resulting from the association of G:C or G:T base pairs. The interaction between the minor groove tetrads and the nearby C:C base pairs affords a strong stabilization, which results in effective pH values above 7.5. Longer sequences with more than two repeats are able to fold in tandem, forming a rosary bead-like structure. Bioinformatics analysis shows that these sequences are prevalent in the human genome, and are present in development-related genes.

As chromosomes 2p and 3p are frequent targets for genomic instability in lung cancer, we have addressed whether alterations of simple (CA)n DNA repeats occur in non-small-cell lung cancer (NSCLC) at early stages. We have analysed by polymerase chain reaction (PCR) assay replication errors (RER) and loss of heterozygosity (LOH) at microsatellites mapped on chromosomes 2p and 3p in 64 paired tumour-normal DNA samples from consecutively resected stage I, II or IIIA NSCLC. DNA samples were also examined for K-ras and p53 gene mutations by PCR-single-stranded conformational polymorphism (PCR-SSCP) analysis and cyclic sequencing, as well as their relationship with clinical outcome. Forty-two of the 64 (66%) NSCLC patients showed RER at single or multiple loci. LOH was detected in 23 tumours (36%). Among patients with stage I disease, the 5-year survival rate was 80% in those whose tumours had no evidence of RER and 26% in those with RER (P = 0.005). No correlation was established between RER phenotype and LOH, K-ras or p53 mutations. RER remained a strong predictive factor (hazard ratio for death, 2.89; 95% confidence interval, 2.23-3.79; P = 0.002) after adjustment for all other evaluated factors, including p53, K-ras, LOH, histological type, tumour differentiation and TNM stage, suggesting that microsatellite instability on chromosomes 2p and 3p may play a role in NSCLC progression through a different pathway from the traditional tumour mechanisms of oncogene activation and/or tumour-suppressor gene inactivation. Images Figure 1