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Sample records for reveals genetic heterogeneity

  1. Genetic heterogeneity in rhabdomyosarcoma revealed by SNP array analysis.

    PubMed

    Walther, Charles; Mayrhofer, Markus; Nilsson, Jenny; Hofvander, Jakob; Jonson, Tord; Mandahl, Nils; Øra, Ingrid; Gisselsson, David; Mertens, Fredrik

    2016-01-01

    Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents. Alveolar (ARMS) and embryonal (ERMS) histologies predominate, but rare cases are classified as spindle cell/sclerosing (SRMS). For treatment stratification, RMS is further subclassified as fusion-positive (FP-RMS) or fusion-negative (FN-RMS), depending on whether a gene fusion involving PAX3 or PAX7 is present or not. We investigated 19 cases of pediatric RMS using high resolution single-nucleotide polymorphism (SNP) array. FP-ARMS displayed, on average, more structural rearrangements than ERMS; the single FN-ARMS had a genomic profile similar to ERMS. Apart from previously known amplification (e.g., MYCN, CDK4, and MIR17HG) and deletion (e.g., NF1, CDKN2A, and CDKN2B) targets, amplification of ERBB2 and homozygous loss of ASCC3 or ODZ3 were seen. Combining SNP array with cytogenetic data revealed that most cases were polyploid, with at least one case having started as a near-haploid tumor. Further bioinformatic analysis of the SNP array data disclosed genetic heterogeneity, in the form of subclonal chromosomal imbalances, in five tumors. The outcome was worse for patients with FP-ARMS than ERMS or FN-ARMS (6/8 vs. 1/9 dead of disease), and the only children with ERMS showing intratumor diversity or with MYOD1 mutation-positive SRMS also died of disease. High resolution SNP array can be useful in evaluating genomic imbalances in pediatric RMS. PMID:26482321

  2. Systems Genetics Reveals the Functional Context of PCOS Loci and Identifies Genetic and Molecular Mechanisms of Disease Heterogeneity

    PubMed Central

    Xu, Ning; Cui, Jinrui; Mengesha, Emebet; Chen, Yii-Der I.; Taylor, Kent D.; Azziz, Ricardo; Goodarzi, Mark O.

    2015-01-01

    Genome wide association studies (GWAS) have revealed 11 independent risk loci for polycystic ovary syndrome (PCOS), a common disorder in young women characterized by androgen excess and oligomenorrhea. To put these risk loci and the single nucleotide polymorphisms (SNPs) therein into functional context, we measured DNA methylation and gene expression in subcutaneous adipose tissue biopsies to identify PCOS-specific alterations. Two genes from the LHCGR region, STON1-GTF2A1L and LHCGR, were overexpressed in PCOS. In analysis stratified by obesity, LHCGR was overexpressed only in non-obese PCOS women. Although not differentially expressed in the entire PCOS group, INSR was underexpressed in obese PCOS subjects only. Alterations in gene expression in the LHCGR, RAB5B and INSR regions suggest that SNPs in these loci may be functional and could affect gene expression directly or indirectly via epigenetic alterations. We identified reduced methylation in the LHCGR locus and increased methylation in the INSR locus, changes that are concordant with the altered gene expression profiles. Complex patterns of meQTL and eQTL were identified in these loci, suggesting that local genetic variation plays an important role in gene regulation. We propose that non-obese PCOS women possess significant alterations in LH receptor expression, which drives excess androgen secretion from the ovary. Alternatively, obese women with PCOS possess alterations in insulin receptor expression, with underexpression in metabolic tissues and overexpression in the ovary, resulting in peripheral insulin resistance and excess ovarian androgen production. These studies provide a genetic and molecular basis for the reported clinical heterogeneity of PCOS. PMID:26305227

  3. Systems Genetics Reveals the Functional Context of PCOS Loci and Identifies Genetic and Molecular Mechanisms of Disease Heterogeneity.

    PubMed

    Jones, Michelle R; Brower, Meredith A; Xu, Ning; Cui, Jinrui; Mengesha, Emebet; Chen, Yii-Der I; Taylor, Kent D; Azziz, Ricardo; Goodarzi, Mark O

    2015-08-01

    Genome wide association studies (GWAS) have revealed 11 independent risk loci for polycystic ovary syndrome (PCOS), a common disorder in young women characterized by androgen excess and oligomenorrhea. To put these risk loci and the single nucleotide polymorphisms (SNPs) therein into functional context, we measured DNA methylation and gene expression in subcutaneous adipose tissue biopsies to identify PCOS-specific alterations. Two genes from the LHCGR region, STON1-GTF2A1L and LHCGR, were overexpressed in PCOS. In analysis stratified by obesity, LHCGR was overexpressed only in non-obese PCOS women. Although not differentially expressed in the entire PCOS group, INSR was underexpressed in obese PCOS subjects only. Alterations in gene expression in the LHCGR, RAB5B and INSR regions suggest that SNPs in these loci may be functional and could affect gene expression directly or indirectly via epigenetic alterations. We identified reduced methylation in the LHCGR locus and increased methylation in the INSR locus, changes that are concordant with the altered gene expression profiles. Complex patterns of meQTL and eQTL were identified in these loci, suggesting that local genetic variation plays an important role in gene regulation. We propose that non-obese PCOS women possess significant alterations in LH receptor expression, which drives excess androgen secretion from the ovary. Alternatively, obese women with PCOS possess alterations in insulin receptor expression, with underexpression in metabolic tissues and overexpression in the ovary, resulting in peripheral insulin resistance and excess ovarian androgen production. These studies provide a genetic and molecular basis for the reported clinical heterogeneity of PCOS. PMID:26305227

  4. Genetic heterogeneity in Leber hereditary optic neuroretinopathy revealed by mitochondrial DNA polymorphism.

    PubMed Central

    Vilkki, J; Savontaus, M L; Nikoskelainen, E K

    1989-01-01

    The presence or absence of a recently observed mitochondrial DNA (mtDNA) mutation associated with Leber hereditary optic neuroretinopathy (LHON) was tested in 19 Finnish families with cases of LHON. Leukocyte and muscle DNA from individuals with optic atrophy, microangiopathy, or normal fundi from maternal lineages were studied by Southern blot analysis, using mouse mtDNA as a hybridization probe. The mtDNA mutation, detected as SfaNI site polymorphism, was seen in 10 of the 19 families. In one family, the mutation was seen only in the two affected individuals, indicating recent origin for the mutation. Nine families and 28 maternally unrelated controls did not show the mutation. The results imply that alternative mtDNA mutations are associated with LHON and that this genetic heterogeneity may be the cause of the interfamilial variation in the clinical expression of LHON. In the families showing the SfaNI site mutation, the mutation was homoplasmic in all individuals irrespective of their disease status, suggesting that the intrafamilial variation in the clinical expression is not due to different ratios of mutant versus normal mtDNA. Images Figure 1 PMID:2757028

  5. Ladakh, India: the land of high passes and genetic heterogeneity reveals a confluence of migrations.

    PubMed

    Rowold, Diane J; Perez Benedico, David; Garcia-Bertrand, Ralph; Chennakrishnaiah, Shilpa; Alfonso-Sanchez, Miguel A; Gayden, Tenzin; Herrera, Rene J

    2016-03-01

    Owing to its geographic location near the longitudinal center of Asia, Ladakh, the land of high passes, has witnessed numerous demographic movements during the past millenniums of occupation. In an effort to view Ladakh's multicultural history from a paternal genetic perspective, we performed a high-resolution Y-chromosomal survey of Ladakh, within the context of Y haplogroup and haplotype distributions of 41 Asian reference populations. The results of this investigation highlight the rich ethnic and genetic diversity of Ladkah which includes genetic contributions from disparate regions of the continent including, West, East, South and Central Asia. The phylogenetic signals from Ladakh are consistent with the Indo-Aryans' occupation during the Neolithic age and its historic connection with Tibet, as well as the East-West gene flow associated with the Silk Road. PMID:25966630

  6. Single-cell triple omics sequencing reveals genetic, epigenetic, and transcriptomic heterogeneity in hepatocellular carcinomas.

    PubMed

    Hou, Yu; Guo, Huahu; Cao, Chen; Li, Xianlong; Hu, Boqiang; Zhu, Ping; Wu, Xinglong; Wen, Lu; Tang, Fuchou; Huang, Yanyi; Peng, Jirun

    2016-03-01

    Single-cell genome, DNA methylome, and transcriptome sequencing methods have been separately developed. However, to accurately analyze the mechanism by which transcriptome, genome and DNA methylome regulate each other, these omic methods need to be performed in the same single cell. Here we demonstrate a single-cell triple omics sequencing technique, scTrio-seq, that can be used to simultaneously analyze the genomic copy-number variations (CNVs), DNA methylome, and transcriptome of an individual mammalian cell. We show that large-scale CNVs cause proportional changes in RNA expression of genes within the gained or lost genomic regions, whereas these CNVs generally do not affect DNA methylation in these regions. Furthermore, we applied scTrio-seq to 25 single cancer cells derived from a human hepatocellular carcinoma tissue sample. We identified two subpopulations within these cells based on CNVs, DNA methylome, or transcriptome of individual cells. Our work offers a new avenue of dissecting the complex contribution of genomic and epigenomic heterogeneities to the transcriptomic heterogeneity within a population of cells. PMID:26902283

  7. Single-cell triple omics sequencing reveals genetic, epigenetic, and transcriptomic heterogeneity in hepatocellular carcinomas

    PubMed Central

    Hou, Yu; Guo, Huahu; Cao, Chen; Li, Xianlong; Hu, Boqiang; Zhu, Ping; Wu, Xinglong; Wen, Lu; Tang, Fuchou; Huang, Yanyi; Peng, Jirun

    2016-01-01

    Single-cell genome, DNA methylome, and transcriptome sequencing methods have been separately developed. However, to accurately analyze the mechanism by which transcriptome, genome and DNA methylome regulate each other, these omic methods need to be performed in the same single cell. Here we demonstrate a single-cell triple omics sequencing technique, scTrio-seq, that can be used to simultaneously analyze the genomic copy-number variations (CNVs), DNA methylome, and transcriptome of an individual mammalian cell. We show that large-scale CNVs cause proportional changes in RNA expression of genes within the gained or lost genomic regions, whereas these CNVs generally do not affect DNA methylation in these regions. Furthermore, we applied scTrio-seq to 25 single cancer cells derived from a human hepatocellular carcinoma tissue sample. We identified two subpopulations within these cells based on CNVs, DNA methylome, or transcriptome of individual cells. Our work offers a new avenue of dissecting the complex contribution of genomic and epigenomic heterogeneities to the transcriptomic heterogeneity within a population of cells. PMID:26902283

  8. Exome sequencing reveals a high genetic heterogeneity on familial Hirschsprung disease.

    PubMed

    Luzón-Toro, Berta; Gui, Hongsheng; Ruiz-Ferrer, Macarena; Sze-Man Tang, Clara; Fernández, Raquel M; Sham, Pak-Chung; Torroglosa, Ana; Kwong-Hang Tam, Paul; Espino-Paisán, Laura; Cherny, Stacey S; Bleda, Marta; Enguix-Riego, María Del Valle; Dopazo, Joaquín; Antiñolo, Guillermo; García-Barceló, María-Mercé; Borrego, Salud

    2015-01-01

    Hirschsprung disease (HSCR; OMIM 142623) is a developmental disorder characterized by aganglionosis along variable lengths of the distal gastrointestinal tract, which results in intestinal obstruction. Interactions among known HSCR genes and/or unknown disease susceptibility loci lead to variable severity of phenotype. Neither linkage nor genome-wide association studies have efficiently contributed to completely dissect the genetic pathways underlying this complex genetic disorder. We have performed whole exome sequencing of 16 HSCR patients from 8 unrelated families with SOLID platform. Variants shared by affected relatives were validated by Sanger sequencing. We searched for genes recurrently mutated across families. Only variations in the FAT3 gene were significantly enriched in five families. Within-family analysis identified compound heterozygotes for AHNAK and several genes (N = 23) with heterozygous variants that co-segregated with the phenotype. Network and pathway analyses facilitated the discovery of polygenic inheritance involving FAT3, HSCR known genes and their gene partners. Altogether, our approach has facilitated the detection of more than one damaging variant in biologically plausible genes that could jointly contribute to the phenotype. Our data may contribute to the understanding of the complex interactions that occur during enteric nervous system development and the etiopathology of familial HSCR. PMID:26559152

  9. Exome sequencing reveals a high genetic heterogeneity on familial Hirschsprung disease

    PubMed Central

    Luzón-Toro, Berta; Gui, Hongsheng; Ruiz-Ferrer, Macarena; Sze-Man Tang, Clara; Fernández, Raquel M.; Sham, Pak-Chung; Torroglosa, Ana; Kwong-Hang Tam, Paul; Espino-Paisán, Laura; Cherny, Stacey S.; Bleda, Marta; Enguix-Riego, María del Valle; Dopazo, Joaquín; Antiñolo, Guillermo; García-Barceló, María-Mercé; Borrego, Salud

    2015-01-01

    Hirschsprung disease (HSCR; OMIM 142623) is a developmental disorder characterized by aganglionosis along variable lengths of the distal gastrointestinal tract, which results in intestinal obstruction. Interactions among known HSCR genes and/or unknown disease susceptibility loci lead to variable severity of phenotype. Neither linkage nor genome-wide association studies have efficiently contributed to completely dissect the genetic pathways underlying this complex genetic disorder. We have performed whole exome sequencing of 16 HSCR patients from 8 unrelated families with SOLID platform. Variants shared by affected relatives were validated by Sanger sequencing. We searched for genes recurrently mutated across families. Only variations in the FAT3 gene were significantly enriched in five families. Within-family analysis identified compound heterozygotes for AHNAK and several genes (N = 23) with heterozygous variants that co-segregated with the phenotype. Network and pathway analyses facilitated the discovery of polygenic inheritance involving FAT3, HSCR known genes and their gene partners. Altogether, our approach has facilitated the detection of more than one damaging variant in biologically plausible genes that could jointly contribute to the phenotype. Our data may contribute to the understanding of the complex interactions that occur during enteric nervous system development and the etiopathology of familial HSCR. PMID:26559152

  10. Molecular diagnosis reveals genetic heterogeneity for the overlapping MKKS and BBS phenotypes.

    PubMed

    Schaefer, Elise; Durand, Myriam; Stoetzel, Corinne; Doray, Bérénice; Viville, Brigitte; Hellé, Sophie; Danse, Jean-Marc; Hamel, Christian; Bitoun, Pierre; Goldenberg, Alice; Finck, Sonia; Faivre, Laurence; Sigaudy, Sabine; Holder, Muriel; Vincent, Marie-Claire; Marion, Vincent; Bonneau, Dominique; Verloes, Alain; Nisand, Israël; Mandel, Jean-Louis; Dollfus, Hélène

    2011-01-01

    Hydrometrocolpos and polydactyly diagnosed in the prenatal period or early childhood may raise diagnostic dilemmas especially in distinguishing McKusick-Kaufman syndrome (MKKS) and the Bardet-Biedl syndrome (BBS). These two conditions can initially overlap. With time, the additional features of BBS appearing in childhood, such as retinitis pigmentosa, obesity, learning disabilities and progressive renal dysfunction allow clear differentiation between BBS and MKKS. Genotype overlap also exists, as mutations in the MKKS-BBS6 gene are found in both syndromes. We report 7 patients diagnosed in the neonatal period with hydrometrocolpos and polydactyly who carry mutations in various BBS genes (BBS6, BBS2, BBS10, BBS8 and BBS12), stressing the importance of wide BBS genotyping in patients with this clinical association for diagnosis, prognosis and genetic counselling. PMID:21044901

  11. Whole genome sequencing reveals genetic heterogeneity of G3P[8] rotaviruses circulating in Italy.

    PubMed

    Medici, Maria Cristina; Tummolo, Fabio; Martella, Vito; Arcangeletti, Maria Cristina; De Conto, Flora; Chezzi, Carlo; Magrì, Alessandro; Fehér, Enikő; Marton, Szilvia; Calderaro, Adriana; Bányai, Krisztián

    2016-06-01

    After a sporadic detection in 1990s, G3P[8] rotaviruses emerged as a predominant genotype during recent years in many areas worldwide, including parts of Italy. The present study describes the molecular epidemiology and evolution of G3P[8] rotaviruses detected in Italian children with gastroenteritis during two survey periods (2004-2005 and 2008-2013). Whole genome of selected G3P[8] strains was determined and antigenic differences between these strains and rotavirus vaccine strains were analyzed. Among 819 (271 in 2004-2005 and 548 in 2008-2013) rotaviruses genotyped during the survey periods, the number of G3P[8] rotavirus markedly varied over the years (0/83 in 2004, 30/188 in 2005 and 0/96 in 2008, 6/88 in 2009, 4/97 in 2010, 0/83 in 2011, 9/82 in 2012, 56/102 cases in 2013). The genotypes of the 11 gene segments of 15 selected strains were assigned to G3-P[8]-I1-R1-C1-M1-A1-N1-T1-E1-H1; thus all strains belonged to the Wa genogroup. Phylogenetic analysis of the Italian G3P[8] strains showed a peculiar picture of segregation with a 2012 lineage for VP1-VP3, NSP1, NSP2, NSP4 and NSP5 genes and a 2013 lineage for VP6, NSP1 and NSP3 genes, with a 1.3-20.2% nucleotide difference from the oldest Italian G3P[8] strains. The genetic variability of the Italian G3P[8] observed in comparison with sequences of rotaviruses available in GenBank suggested a process of selection acting on a global scale, rather than the emergence of local strains, as several lineages were already circulating globally. Compared with the vaccine strains, the Italian G3P[8] rotaviruses segregated in different lineages (5-5.3% and 7.2-11.4% nucleotide differences in the VP7 and VP4, respectively) with some mismatches in the putative neutralizing epitopes of VP7 and VP4 antigens. The accumulation of point mutations and amino acid differences between vaccine strains and currently circulating rotaviruses might generate, over the years, vaccine-resistant variants. PMID:26980605

  12. Heterogeneous genetic structure in a Fagus crenata population in an old-growth beech forest revealed by microsatellite markers.

    PubMed

    Asuka, Y; Tomaru, N; Nisimura, N; Tsumura, Y; Yamamoto, S

    2004-05-01

    The within-population genetic structure of Fagus crenata in a 4-ha plot (200 x 200 m) of an old-growth beech forest was analysed using microsatellite markers. To assess the genetic structure, Moran's I spatial autocorrelation coefficient was calculated. Correlograms of Moran's I showed significant positive values less than 0.100 for short-distance classes, indicating weak genetic structure. The genetic structure within the population is created by limited seed dispersal, and is probably weakened by overlapping seed shadow, secondary seed dispersal, extensive pollen flow and the thinning process. Genetic structure was detected in a western subplot of 50 x 200 m with immature soils and almost no dwarf bamboos (Sasa spp.), where small and intermediate-sized individuals were distributed in aggregations with high density because of successful regeneration. By contrast, genetic structure was not found in an eastern subplot of the same size with mature soils and Sasa cover, where successful regeneration was prevented, and the density of the small and intermediate-sized individuals was low. Moreover, genetic structure of individuals in a small-size class (diameter at breast height < 12 cm) was more obvious than in a large-size class (diameter at breast height >/= 12 cm). The apparent genetic structure detected in the 4-ha plot was therefore probably the result of the structure in the western portion of the plot and in small and intermediate-sized individuals that successfully regenerated under the favourable environment. The heterogeneity in genetic structure presumably reflects variation in the density that should be affected by differences in regeneration dynamics associated with heterogeneity in environmental conditions. PMID:15078459

  13. Quartz-Seq: a highly reproducible and sensitive single-cell RNA sequencing method, reveals non-genetic gene-expression heterogeneity

    PubMed Central

    2013-01-01

    Development of a highly reproducible and sensitive single-cell RNA sequencing (RNA-seq) method would facilitate the understanding of the biological roles and underlying mechanisms of non-genetic cellular heterogeneity. In this study, we report a novel single-cell RNA-seq method called Quartz-Seq that has a simpler protocol and higher reproducibility and sensitivity than existing methods. We show that single-cell Quartz-Seq can quantitatively detect various kinds of non-genetic cellular heterogeneity, and can detect different cell types and different cell-cycle phases of a single cell type. Moreover, this method can comprehensively reveal gene-expression heterogeneity between single cells of the same cell type in the same cell-cycle phase. PMID:23594475

  14. Molecular Analysis of Collagen XVIII Reveals Novel Mutations, Presence of a Third Isoform, and Possible Genetic Heterogeneity in Knobloch Syndrome

    PubMed Central

    Suzuki, O. T.; Sertié, A. L.; Der Kaloustian, V. M.; Kok, F.; Carpenter, M.; Murray, J.; Czeizel, A. E.; Kliemann, S. E.; Rosemberg, S.; Monteiro, M.; Olsen, B. R.; Passos-Bueno, M. R.

    2002-01-01

    Knobloch syndrome (KS) is a rare disease characterized by severe ocular alterations, including vitreoretinal degeneration associated with retinal detachment and occipital scalp defect. The responsible gene, COL18A1, has been mapped to 21q22.3, and, on the basis of the analysis of one family, we have demonstrated that a mutation affecting only one of the three COL18A1 isoforms causes this phenotype. We report here the results of the screening of both the entire coding region and the exon-intron boundaries of the COL18A1 gene (which includes 43 exons), in eight unrelated patients with KS. Besides 20 polymorphic changes, we identified 6 different pathogenic changes in both alleles of five unrelated patients with KS (three compound heterozygotes and two homozygotes). All are truncating mutations leading to deficiency of one or all collagen XVIII isoforms and endostatin. We have verified that, in exon 41, the deletion c3514-3515delCT, found in three unrelated alleles, is embedded in different haplotypes, suggesting that this mutation has occurred more than once. In addition, our results provide evidence of nonallelic genetic heterogeneity in KS. We also show that the longest human isoform (NC11-728) is expressed in several tissues (including the human eye) and that lack of either the short variant or all of the collagen XVIII isoforms causes similar phenotypes but that those patients who lack all forms present more-severe ocular alterations. Despite the small sample size, we found low endostatin plasma levels in those patients with mutations leading to deficiency of all isoforms; in addition, it seems that absence of all collagen XVIII isoforms causes predisposition to epilepsy. PMID:12415512

  15. Targeted next-generation sequencing reveals further genetic heterogeneity in axonal Charcot–Marie–Tooth neuropathy and a mutation in HSPB1

    PubMed Central

    Ylikallio, Emil; Johari, Mridul; Konovalova, Svetlana; Moilanen, Jukka S; Kiuru-Enari, Sari; Auranen, Mari; Pajunen, Leila; Tyynismaa, Henna

    2014-01-01

    Charcot–Marie–Tooth disease (CMT) is a group of hereditary peripheral neuropathies. The dominantly inherited axonal CMT2 displays striking genetic heterogeneity, with 17 presently known disease genes. The large number of candidate genes, combined with lack of genotype–phenotype correlations, has made genetic diagnosis in CMT2 time-consuming and costly. In Finland, 25% of dominant CMT2 is explained by either a GDAP1 founder mutation or private MFN2 mutations but the rest of the families have remained without molecular diagnosis. Whole-exome and genome sequencing are powerful techniques to find disease mutations for CMT patients but they require large amounts of sequencing to confidently exclude heterozygous variants in all candidate genes, and they generate a vast amount of irrelevant data for diagnostic needs. Here we tested a targeted next-generation sequencing approach to screen the CMT2 genes. In total, 15 unrelated patients from dominant CMT2 families from Finland, in whom MFN2 and GDAP1 mutations had been excluded, participated in the study. The targeted approach produced sufficient sequence coverage for 95% of the 309 targeted exons, the rest we excluded by Sanger sequencing. Unexpectedly, the screen revealed a disease mutation only in one family, in the HSPB1 gene. Thus, new disease genes underlie CMT2 in the remaining families, indicating further genetic heterogeneity. We conclude that targeted next-generation sequencing is an efficient tool for genetic screening in CMT2 that also aids in the selection of patients for genome-wide approaches. PMID:23963299

  16. Genetic Heterogeneity in Algerian Human Populations

    PubMed Central

    Deba, Tahria; Calafell, Francesc; Benhamamouch, Soraya; Comas, David

    2015-01-01

    The demographic history of human populations in North Africa has been characterized by complex processes of admixture and isolation that have modeled its current gene pool. Diverse genetic ancestral components with different origins (autochthonous, European, Middle Eastern, and sub-Saharan) and genetic heterogeneity in the region have been described. In this complex genetic landscape, Algeria, the largest country in Africa, has been poorly covered, with most of the studies using a single Algerian sample. In order to evaluate the genetic heterogeneity of Algeria, Y-chromosome, mtDNA and autosomal genome-wide makers have been analyzed in several Berber- and Arab-speaking groups. Our results show that the genetic heterogeneity found in Algeria is not correlated with geography or linguistics, challenging the idea of Berber groups being genetically isolated and Arab groups open to gene flow. In addition, we have found that external sources of gene flow into North Africa have been carried more often by females than males, while the North African autochthonous component is more frequent in paternally transmitted genome regions. Our results highlight the different demographic history revealed by different markers and urge to be cautious when deriving general conclusions from partial genomic information or from single samples as representatives of the total population of a region. PMID:26402429

  17. Genome-Wide Association Analysis for Blood Lipid Traits Measured in Three Pig Populations Reveals a Substantial Level of Genetic Heterogeneity

    PubMed Central

    Yang, Hui; Huang, Xiaochang; Zeng, Zhijun; Zhang, Wanchang; Liu, Chenlong; Fang, Shaoming; Huang, Lusheng; Chen, Congying

    2015-01-01

    Serum lipids are associated with myocardial infarction and cardiovascular disease in humans. Here we dissected the genetic architecture of blood lipid traits by applying genome-wide association studies (GWAS) in 1,256 pigs from Laiwu, Erhualian and Duroc × (Landrace × Yorkshire) populations, and a meta-analysis of GWAS in more than 2,400 pigs from five diverse populations. A total of 22 genomic loci surpassing the suggestive significance level were detected on 11 pig chromosomes (SSC) for six blood lipid traits. Meta-analysis of GWAS identified 5 novel loci associated with blood lipid traits. Comparison of GWAS loci across the tested populations revealed a substantial level of genetic heterogeneity for porcine blood lipid levels. We further evaluated the causality of nine polymorphisms nearby or within the APOB gene on SSC3 for serum LDL-C and TC levels. Of the 9 polymorphisms, an indel showed the most significant association with LDL-C and TC in Laiwu pigs. But the significant association was not identified in the White Duroc × Erhualian F2 resource population, in which the QTL for LDL-C and TC was also detected on SSC3. This indicates that population-specific signals may exist for the SSC3 QTL. Further investigations are warranted to validate this assumption. PMID:26121138

  18. Genetic heterogeneity of hepatocellular carcinoma

    SciTech Connect

    Unsal, H.; Isselbacher, K.J. ); Yakicier, C.; Marcais, C.; Ozturk, M. ); Kew, M. ); Volkmann, M. ); Zentgraf, H. )

    1994-01-18

    The authors studied 80 hepatocellular carcinomas from three continents for p53 gene (TP53) mutations and hepatitis B virus (HBV) sequences. p53 mutations were frequent in tumors from Mozambique but not in tumors from South Africa, China, and Germany. Independent of geographic origin, most tumors were positive for HBV sequences. X gene coding sequences of HBV were detected in 78% of tumors, whereas viral sequences in the surface antigen- and core antigen-encoding regions were present in less than 35% of tumors. These observations indicate that hepatocellular carcinomas are genetically heterogeneous. Mozambican-types of hepatocellular carcinomas are characterized by a high incidence of p53 mutations related to aflatoxins. In other tumors, the rarity of p53 mutations combined with the frequent presence of viral X gene coding sequences suggests a possible interference of HBV with the wild-type p53 function.

  19. Genetic heterogeneity in juvenile NCL

    SciTech Connect

    Hart, Y.M.; Andermann, E.; Mitchison, H.M.

    1994-09-01

    The neuronal ceroid lipofuscinoses (NCL) are a group of related lysosomal storage diseases classified according to the age of onset, clinical syndrome, and pathology. The clinical syndromes include myoclonus, visual failure, progressive dementia, ataxia and generalized tonic clonic seizures in varying combinations depending on the age of onset and pathology. The mode of inheritance is autosomal recessive in most cases, except for several families with the adult form (Kufs` disease) which have autosomal dominant inheritance. Linkage for the infantile (Halatia-Santavuori) form (CLN1), characterized ultrastructurally by lysosomal granular osmiophilic deposits (GROD), has been demonstrated with markers on chromosome lp, while the gene for the typical juvenile (Spielmeyer-Vogt) form (CLN3), characterized by fingerprint-profile inclusions, has been linked to chromosome 16p. The gene locations of the late infantile (Jansky-Bielschowsky) and adult (Kufs` disease) forms are unknown, although it has recently been shown that the late infantile form does not link to chromosome 16p. We describe three siblings, including a pair of monozygotic twins, with juvenile onset NCL with GROD in whom linkage to the CLN3 region of chromsome 16p has been excluded. This would suggest that there is genetic heterogeneity not only among the different clinical syndromes, but also among identical clinical syndromes with different ultrastructural characteristics. Preliminary studies of linkage to chromosome 1p employing the microsatellite marker HY-TM1 have been uninformative. Further studies with other chromosome 1 markers are underway.

  20. Thyroid cancer GWAS identifies 10q26.12 and 6q14.1 as novel susceptibility loci and reveals genetic heterogeneity among populations.

    PubMed

    Mancikova, Veronika; Cruz, Raquel; Inglada-Pérez, Lucía; Fernández-Rozadilla, Ceres; Landa, Iñigo; Cameselle-Teijeiro, José; Celeiro, Catuxa; Pastor, Susana; Velázquez, Antonia; Marcos, Ricard; Andía, Victor; Álvarez-Escolá, Cristina; Meoro, Amparo; Schiavi, Francesca; Opocher, Giuseppe; Quintela, Inés; Ansede-Bermejo, Juan; Ruiz-Ponte, Clara; Santisteban, Pilar; Robledo, Mercedes; Carracedo, Angel

    2015-10-15

    Thyroid cancer is the most heritable cancer of all those not displaying typical Mendelian inheritance. However, most of the genetic factors that would explain the high heritability remain unknown. Our aim was to identify additional common genetic variants associated with susceptibility to this disease. In order to do so, we performed a genome-wide association study in a series of 398 cases and 502 controls from Spain, followed by a replication in four well-defined Southern European case-control collections contributing a total of 1,422 cases and 1,908 controls. The association between the variation at the 9q22 locus near FOXE1 and thyroid cancer risk was consistent across all series, with several SNPs identified (rs7028661: OR = 1.64, p = 1.0 × 10(-22) , rs7037324: OR = 1.54, p = 1.2 × 10(-17) ). Moreover, the rare alleles of three SNPs (rs2997312, rs10788123 and rs1254167) at 10q26.12 showed suggestive evidence of association with higher risk of the disease (OR = 1.35, p = 1.2 × 10(-04) , OR = 1.26, p = 5.2 × 10(-04) and OR = 1.38, p = 5.9 × 10(-05) , respectively). Finally, the rare allele of rs4075570 at 6q14.1 conferred protection in the series studied (OR = 0.82, p = 2.0 × 10(-04) ). This study suggests that heterogeneity in genetic susceptibility between populations is a key feature to take into account when exploring genetic risk factors related to this disease. PMID:25855579

  1. Heterogeneity and the genetics of autism.

    PubMed Central

    Szatmari, P

    1999-01-01

    The objective of this review is to summarize recent data on the genetics of autism, highlight the evidence for genetic heterogeneity and extend the implications of these findings for the identification of susceptibility genes in this disorder. Family studies have shown that autism runs in families and twin studies indicate that the basis of that familial aggregation is genetic. As a result the prospects for the identification of susceptibility genes using either linkage or association studies are quite good. However, recent evidence is accumulating suggesting that the disorder is genetically heterogeneous; higher functioning individuals with autism may arise from separate genetic mechanisms that lower functioning ones. If true, this will make the detection of linkage and association much more difficult. PMID:10212560

  2. The causes and consequences of genetic heterogeneity in cancer evolution.

    PubMed

    Burrell, Rebecca A; McGranahan, Nicholas; Bartek, Jiri; Swanton, Charles

    2013-09-19

    Recent studies have revealed extensive genetic diversity both between and within tumours. This heterogeneity affects key cancer pathways, driving phenotypic variation, and poses a significant challenge to personalized cancer medicine. A major cause of genetic heterogeneity in cancer is genomic instability. This instability leads to an increased mutation rate and can shape the evolution of the cancer genome through a plethora of mechanisms. By understanding these mechanisms we can gain insight into the common pathways of tumour evolution that could support the development of future therapeutic strategies. PMID:24048066

  3. Genetic heterogeneity reveals on-going speciation and cryptic taxonomic diversity of stream-dwelling gudgeons (Teleostei, Cyprinidae) in the middle Danubian hydrosystem (Hungary).

    PubMed

    Takács, Péter; Bihari, Péter; Erős, Tibor; Specziár, András; Szivák, Ildikó; Bíró, Péter; Csoma, Eszter

    2014-01-01

    Although stream-dwelling gudgeons (Cyprinidae, genus: Gobio) are widespread in Central Europe, the taxonomy of this group and the distribution of its species are still unexplored in detail. The aims of our study are to ascertain taxonomic composition and distribution of the former Gobio gobio superspecies in the inner area of the Carpathian Basin. Since the presence of cryptic species is suspected in this area, we examined the taxonomic and phylogenetic relationships of Central European Gobio taxa by sequencing the mitochondrial DNA control region (mtCR). Additionally, we characterized the genetic structure of 27 stream-dwelling gudgeon populations of this area by Amplified Fragment Length Polymorphism (AFLP). Results of mtCR analysis proved the presence of three species already known as G. obtusirostris (dominant in NW-Hungary), G. gobio (sporadic) and G. carpathicus (sporadic). Additionally, the analysis revealed the existence of one doubtful taxon, G. sp1 (dominant in NE-Hungary), and a new isolated haplogroup (dominant in SW-Hungary). Although Network analysis showed significant detachment among haplogroups, their genetic distances were quite small. Therefore Bayesian phylogenetic analysis showed weak nodal support for the branching pattern both for newly described haplotypes, and for the already accepted species. AFLP data showed distinct population structure and a clear pattern of isolation was revealed by distance of stocks. At the same time, level of separation was not affected by the altitudinal position of sites. Moreover we found three major clusters of populations which were separated according to hydrographic regions, and corresponded to the findings of mtCR analysis. Our results suggest the on-going speciation of gudgeons in the Carpathian Basin, however the separation of haplogroups seems to only be an intermediate phase. The discovered natural pattern seems to be only slightly influenced by anthropogenic impacts. Additionally our results put into

  4. Genetic Heterogeneity Reveals On-Going Speciation and Cryptic Taxonomic Diversity of Stream-Dwelling Gudgeons (Teleostei, Cyprinidae) in the Middle Danubian Hydrosystem (Hungary)

    PubMed Central

    Takács, Péter; Bihari, Péter; Erős, Tibor; Specziár, András; Szivák, Ildikó; Bíró, Péter; Csoma, Eszter

    2014-01-01

    Although stream-dwelling gudgeons (Cyprinidae, genus: Gobio) are widespread in Central Europe, the taxonomy of this group and the distribution of its species are still unexplored in detail. The aims of our study are to ascertain taxonomic composition and distribution of the former Gobio gobio superspecies in the inner area of the Carpathian Basin. Since the presence of cryptic species is suspected in this area, we examined the taxonomic and phylogenetic relationships of Central European Gobio taxa by sequencing the mitochondrial DNA control region (mtCR). Additionally, we characterized the genetic structure of 27 stream-dwelling gudgeon populations of this area by Amplified Fragment Length Polymorphism (AFLP). Results of mtCR analysis proved the presence of three species already known as G. obtusirostris (dominant in NW-Hungary), G. gobio (sporadic) and G. carpathicus (sporadic). Additionally, the analysis revealed the existence of one doubtful taxon, G. sp1 (dominant in NE-Hungary), and a new isolated haplogroup (dominant in SW-Hungary). Although Network analysis showed significant detachment among haplogroups, their genetic distances were quite small. Therefore Bayesian phylogenetic analysis showed weak nodal support for the branching pattern both for newly described haplotypes, and for the already accepted species. AFLP data showed distinct population structure and a clear pattern of isolation was revealed by distance of stocks. At the same time, level of separation was not affected by the altitudinal position of sites. Moreover we found three major clusters of populations which were separated according to hydrographic regions, and corresponded to the findings of mtCR analysis. Our results suggest the on-going speciation of gudgeons in the Carpathian Basin, however the separation of haplogroups seems to only be an intermediate phase. The discovered natural pattern seems to be only slightly influenced by anthropogenic impacts. Additionally our results put into

  5. Intra-tumor Genetic Heterogeneity in Rectal Cancer

    PubMed Central

    Hardiman, Karin M.; Ulintz, Peter J.; Kuick, Rork; Hovelson, Daniel H.; Gates, Christopher M.; Bhasi, Ashwini; Grant, Ana Rodrigues; Liu, Jianhua; Cani, Andi K.; Greenson, Joel; Tomlins, Scott; Fearon, Eric R.

    2015-01-01

    Colorectal cancer arises in part from the cumulative effects of multiple gene lesions. Recent studies in selected cancer types have revealed significant intra-tumor genetic heterogeneity and highlighted its potential role in disease progression and resistance to therapy. We hypothesized the existence of significant intra-tumor genetic heterogeneity in rectal cancers involving variations in localized somatic mutations and copy number abnormalities. Two or three spatially disparate regions from each of six rectal tumors were dissected and subjected to next-generation whole exome DNA sequencing, Oncoscan SNP arrays, and targeted confirmatory sequencing and analysis. The resulting data were integrated to define subclones using SciClone. Mutant-allele tumor heterogeneity (MATH) scores, mutant allele frequency correlation, and mutation percent concordance were calculated, and copy number analysis including measurement of correlation between samples was performed. Somatic mutations profiles in individual cancers were similar to prior studies, with some variants found in previously reported significantly mutated genes and many patient-specific mutations in each tumor. Significant intra-tumor heterogeneity was identified in the spatially disparate regions of individual cancers. All tumors had some heterogeneity but the degree of heterogeneity was quite variable in the samples studied. We found that 67–97% of exonic somatic mutations were shared among all regions of an individual’s tumor. The SciClone computational method identified 2 to 8 shared and unshared subclones in the spatially disparate areas in each tumor. MATH scores ranged from 7 to 41. Allele frequency correlation scores ranged from R2 = 0.69 to 0.96. Measurements of correlation between samples for copy number changes varied from R2 = 0.74 to 0.93. All tumors had some heterogeneity, but the degree was highly variable in the samples studied. The occurrence of significant intra-tumor heterogeneity may allow

  6. Genetic heterogeneity of familial hemiplegic migraine

    SciTech Connect

    Joutel, A.; Ducros, A.; Delrieu, O.; Maziaceck, J.; Tournier-Lasserve, E.; Vahedi, K. |; Bousser, M.G.; Ponsot, G.; Gouttiere, F.; Labauge, P.; Mancini, J.

    1994-12-01

    Familial hemiplegic migraine (FHM) is an autosomal dominant variety of migraine with aura. We previously mapped a gene for this disorder to the short arm of chromosome 19, within a 30-cM interval bracketed by D19S216 and D19S215. Linkage analysis conducted on two large pedigrees did not show any evidence of heterogeneity, despite their clinical differences due to the presence, in one family, of cerebellar ataxia and nystagmus. Herein we report linkage data on seven additional FHM families including another one with cerebellar ataxia. Analysis was conducted with a set of seven markers spanning the D19S216-D19S215 interval. Two-point and multipoint strong evidence for genetic heterogeneity. Strong evidence of linkage was obtained in two families and of absence of linkage in four families. The posterior probability of being of the linked type was >.95 in the first two families and <.01 in four other ones. It was not possible to draw any firm conclusion for the last family. Thus, within the nine families so far tested, four were linked, including those with associated cerebellar ataxia. We could not find any clinical difference between the pure FHM families regardless of whether they were linked. In addition to the demonstration of genetic heterogeneity of FHM, this study also allowed us to establish that the most likely location of the gene was within an interval of 12 cM between D19S413 and D19S226.

  7. Genomic and mutational profiling of ductal carcinomas in situ and matched adjacent invasive breast cancers reveals intra-tumour genetic heterogeneity and clonal selection

    PubMed Central

    Lambros, Maryou B; Campion-Flora, Adriana; Rodrigues, Daniel Nava; Gauthier, Arnaud; Cabral, Cecilia; Pawar, Vidya; Mackay, Alan; A’Hern, Roger; Marchiò, Caterina; Palacios, Jose; Natrajan, Rachael; Weigelt, Britta; Reis-Filho, Jorge S

    2016-01-01

    The mechanisms underlying the progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) of the breast are yet to be fully elucidated. Several hypotheses have been put forward to explain the progression from DCIS to IDC, including the selection of a subpopulation of cancer cells with specific genetic aberrations, the acquisition of new genetic aberrations or non-genetic mechanisms mediated by the tumour microenvironment. To determine whether synchronously diagnosed ipsilateral DCIS and IDCs have modal populations with distinct repertoires of gene copy number aberrations and mutations in common oncogenes, matched frozen samples of DCIS and IDCs were retrieved from 13 patients and subjected to microarray-based comparative genomic hybridisation (aCGH), and Sequenom MassARRAY (Oncocarta v1.0 panel). Fluorescence in situ hybridisation and Sanger sequencing were employed to validate the aCGH and Sequenom findings, respectively. Although the genomic profiles of matched DCIS and IDCs were similar, in three of 13 matched pairs amplification of distinct loci (i.e. 1q41, 2q24.2, 6q22.31, 7q11.21, 8q21.2 and 9p13.3) was either restricted to, or more prevalent in, the modal population of cancer cells of one of the components. Sequenom MassARRAY identified PIK3CA mutations restricted to the DCIS component in two cases, and in a third case, the frequency of the PIK3CA mutant allele reduced from 49% in the DCIS to 25% in the IDC component. Despite the genomic similarities between synchronous DCIS and IDC, our data provide strong circumstantial evidence to suggest that in some cases the progression from DCIS to IDC is driven by the selection of non-modal clones that harbour a specific repertoire of genetic aberrations. PMID:22252965

  8. Genetic heterogeneity of familial hemiplegic migraine

    SciTech Connect

    Joutel, A.; Ducros, A.; Vahedi, K.

    1994-09-01

    Familial hemiplegic migraine (FHM) is an autosomal dominant subtype of migraine with aura, characterized by the occurrence of a transient hemiplegia during the aura. We previously mapped the affected gene to the short arm of chromosome 19, within a 30 cM interval bracketed by D19S216 and D19S215. Linkage analysis conducted on 2 large FHM pedigrees did not show evidence of heterogeneity, despite their clinical differences due to the presence in one family of a cerebellar ataxia and a nystagmus. Herein we report linkage data on 9 additional FHM families including 2 other ones with cerebellar ataxia. Analysis was conducted with a set of 7 markers spanning the D19S216-D19S215 interval. Two point and multipoint lodscores analysis as well as HOMOG testing provided significant evidence for genetic heterogenity. Strong evidence of linkage was obtained in 3 families and absence of linkage in 6 families. Thus within the 11 families so far tested, 5 were linked, including those with an associated cerebellar ataxia. We could not find any clinical difference between the {open_quotes}pure{close_quotes} FHM families whether or not they were linked. This study also allowed us to establish that the most likely location of the gene is a 12 cM interval bracketed by D19S413 and D19S226. One of the unlinked family was large enough to conduct genetic mapping of the affected gene. Data will be presented at the meeting.

  9. Genetic analysis of environmental strains of the plant pathogen Phytophthora capsici reveals heterogeneous repertoire of effectors and possible effector evolution via genomic island.

    PubMed

    Iribarren, María Josefina; Pascuan, Cecilia; Soto, Gabriela; Ayub, Nicolás Daniel

    2015-11-01

    Phytophthora capsici is a virulent oomycete pathogen of many vegetable crops. Recently, it has been demonstrated that the recognition of the RXLR effector AVR3a1 of P. capsici (PcAVR3a1) triggers a hypersensitive response and plays a critical role in mediating non-host resistance. Here, we analyzed the occurrence of PcAVR3a1 in 57 isolates of P. capsici derived from globe squash, eggplant, tomato and bell pepper cocultivated in a small geographical area. The occurrence of PcAVR3a1 in environmental strains of P. capsici was confirmed by PCR in only 21 of these pathogen isolates. To understand the presence-absence pattern of PcAVR3a1 in environmental strains, the flanking region of this gene was sequenced. PcAVR3a1 was found within a genetic element that we named PcAVR3a1-GI (PcAVR3a1 genomic island). PcAVR3a1-GI was flanked by a 22-bp direct repeat, which is related to its site-specific recombination site. In addition to the PcAVR3a1 gene, PcAVR3a1-GI also encoded a phage integrase probably associated with the excision and integration of this mobile element. Exposure to plant induced the presence of an episomal circular intermediate of PcAVR3a1-GI, indicating that this mobile element is functional. Collectively, these findings provide evidence of PcAVR3a1 evolution via mobile elements in environmental strains of Phytophthora. PMID:26443834

  10. Heterogeneous genetic profiles in soft tissue myoepitheliomas.

    PubMed

    Hallor, Karolin H; Teixeira, Manuel R; Fletcher, Christopher D M; Bizarro, Susana; Staaf, Johan; Domanski, Henryk A; von Steyern, Fredrik Vult; Panagopoulos, Ioannis; Mandahl, Nils; Mertens, Fredrik

    2008-11-01

    Myoepithelioma, mixed tumor and parachordoma are uncommon soft tissue tumors thought to represent morphological variants of a single tumor type. The genetic basis of these neoplasms is poorly understood. However, they morphologically resemble mixed tumor of the salivary glands (also known as pleomorphic adenoma), a tumor characterized by deregulated expression of PLAG1 or HMGA2. To evaluate a possible genetic relationship between these soft tissue and salivary gland tumors, PLAG1 expression levels and the genomic status of PLAG1 and HMGA2 were investigated in five soft tissue myoepitheliomas and one pleomorphic adenoma. In addition, all tumors were cytogenetically investigated and whole genome DNA copy number imbalances were studied in five of them. The genetic profiles were heterogeneous and the only aberration common to all soft tissue myoepitheliomas was a minimally deleted region of 3.55 Mb in chromosome band 19p13. Recurrent deletion of CDKN2A suggests that inactivation of this tumor suppressor gene is pathogenetically important in a subset. Furthermore, PLAG1 rearrangement was found in a soft tissue tumor from a patient previously treated for a salivary pleomorphic adenoma, indicating either metastasis of the salivary gland lesion or that some soft tissue tumors develop through the same mechanisms as their salivary gland counterparts. PMID:18604193

  11. Genetics of multiple myeloma: another heterogeneity level?

    PubMed Central

    Corre, Jill; Munshi, Nikhil

    2015-01-01

    Our knowledge of myeloma genetics remained limited and lagged behind many other hematologic malignancies because of the inherent difficulties in generating metaphases within the malignant plasma cell clone. With the development of molecular techniques (microarrays and next-generation sequencing), our understanding has been highly improved in the past 5 years. These studies have not only confirmed the prevalence of wide heterogeneity in myeloma at the molecular level, but has also provided a much clearer picture of the disease pathogenesis and progression. Whether these data will enable improvements in the therapeutic approach is still a matter of debate. The next improvement will come from detailed analyses of these molecular features to try to move from a treatment fitted to every patient to individualized therapies, taking into account the complexity of the chromosomal changes, the mutation spectrum, and subclonality evolution. PMID:25628468

  12. Mortality Rates in a Genetically Heterogeneous Population of Caenorhabditis elegans

    NASA Astrophysics Data System (ADS)

    Brooks, Anne; Lithgow, Gordon J.; Johnson, Thomas E.

    1994-02-01

    Age-specific mortality rates in isogenic populations of the nematode Caenorhabditis elegans increase exponentially throughout life. In genetically heterogeneous populations, age-specific mortality increases exponentially until about 17 days and then remains constant until the last death occurs at about 60 days. This period of constant age-specific mortality results from genetic heterogeneity. Subpopulations differ in mean life-span, but they all exhibit near exponential, albeit different, rates of increase in age-specific mortality. Thus, much of the observed heterogeneity in mortality rates later in life could result from genetic heterogeneity and not from an inherent effect of aging.

  13. A weighted U statistic for association analyses considering genetic heterogeneity.

    PubMed

    Wei, Changshuai; Elston, Robert C; Lu, Qing

    2016-07-20

    Converging evidence suggests that common complex diseases with the same or similar clinical manifestations could have different underlying genetic etiologies. While current research interests have shifted toward uncovering rare variants and structural variations predisposing to human diseases, the impact of heterogeneity in genetic studies of complex diseases has been largely overlooked. Most of the existing statistical methods assume the disease under investigation has a homogeneous genetic effect and could, therefore, have low power if the disease undergoes heterogeneous pathophysiological and etiological processes. In this paper, we propose a heterogeneity-weighted U (HWU) method for association analyses considering genetic heterogeneity. HWU can be applied to various types of phenotypes (e.g., binary and continuous) and is computationally efficient for high-dimensional genetic data. Through simulations, we showed the advantage of HWU when the underlying genetic etiology of a disease was heterogeneous, as well as the robustness of HWU against different model assumptions (e.g., phenotype distributions). Using HWU, we conducted a genome-wide analysis of nicotine dependence from the Study of Addiction: Genetics and Environments dataset. The genome-wide analysis of nearly one million genetic markers took 7h, identifying heterogeneous effects of two new genes (i.e., CYP3A5 and IKBKB) on nicotine dependence. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26833871

  14. Evolution of genetic instability in heterogeneous tumors.

    PubMed

    Asatryan, Ani D; Komarova, Natalia L

    2016-05-01

    Genetic instability is an important characteristic of cancer. While most cancers develop genetic instability at some stage of their progression, sometimes a temporary rise of instability is followed by the return to a relatively stable genome. Neither the reasons for these dynamics, nor, more generally, the role of instability in tumor progression, are well understood. In this paper we develop a class of mathematical models to study the evolutionary competition dynamics among different sub-populations in a heterogeneous tumor. We observe that despite the complexity of this multi-component and multi-process system, there is only a small number of scenarios expected in the context of the evolution of instability. If the penalty incurred by unstable cells (the decrease in the growth due to deleterious mutations) is high compared with the gain (the production rate of advantageous mutations), then instability does not evolve. In the opposite case, instability evolves and comes to dominate the system. In the intermediate parameter regime, instability is generated but later gives way to stable clones. Moreover, the model also informs us of the patterns of instability for cancer lineages corresponding to different stages of progression. It is predicted that mutations causing instability are merely "passengers" in tumors that have undergone only a small number of malignant mutations. Further down the path of carcinogenesis, however, unstable cells are more likely to give rise to the winning clonal wave that takes over the tumor and carries the evolution forward, thus conferring a causal role of the instability in such cases. Further, each individual clonal wave (i.e. cells harboring a fixed number of malignant driver mutations) experiences its own evolutionary history. It can fall under one of three types of temporal behavior: stable throughout, unstable to stable, or unstable throughout. Which scenario is realized depends on the subtle (but predictable) interplay among

  15. Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

    PubMed Central

    Math, M.; Tarpey, Patrick; Varela, Ignacio; Phillimore, Benjamin; Begum, Sharmin; McDonald, Neil Q.; Butler, Adam; Jones, David; Raine, Keiran; Latimer, Calli; Santos, Claudio R.; Nohadani, Mahrokh; Eklund, Aron C.; Spencer-Dene, Bradley; Clark, Graham; Pickering, Lisa; Stamp, Gordon; Gore, Martin; Szallasi, Zoltan; Downward, Julian; Futreal, P. Andrew

    2016-01-01

    Background Intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized-medicine strategies that depend on results from single tumor-biopsy samples. Methods To examine intratumor heterogeneity, we performed exome sequencing, chromosome aberration analysis, and ploidy profiling on multiple spatially separated samples obtained from primary renal carcinomas and associated metastatic sites. We characterized the consequences of intratumor heterogeneity using immunohistochemical analysis, mutation functional analysis, and profiling of messenger RNA expression. Results Phylogenetic reconstruction revealed branched evolutionary tumor growth, with 63 to 69% of all somatic mutations not detectable across every tumor region. Intratumor heterogeneity was observed for a mutation within an autoinhibitory domain of the mammalian target of rapamycin (mTOR) kinase, correlating with S6 and 4EBP phosphorylation in vivo and constitutive activation of mTOR kinase activity in vitro. Mutational intratumor heterogeneity was seen for multiple tumor-suppressor genes converging on loss of function; SETD2, PTEN, and KDM5C underwent multiple distinct and spatially separated inactivating mutations within a single tumor, suggesting convergent phenotypic evolution. Gene-expression signatures of good and poor prognosis were detected in different regions of the same tumor. Allelic composition and ploidy profiling analysis revealed extensive intratumor heterogeneity, with 26 of 30 tumor samples from four tumors harboring divergent allelic-imbalance profiles and with ploidy heterogeneity in two of four tumors. Conclusions Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development. Intratumor heterogeneity, associated with heterogeneous protein function, may foster tumor adaptation and therapeutic failure through

  16. Optimal Trend Tests for Genetic Association Studies of Heterogeneous Diseases

    PubMed Central

    Lee, Wen-Chung

    2016-01-01

    The Cochran-Armitage trend test is a standard procedure in genetic association studies. It is a directed test with high power to detect genetic effects that follow the gene-dosage model. In this paper, the author proposes optimal trend tests for genetic association studies of heterogeneous diseases. Monte-Carlo simulations show that the power gain of the optimal trend tests over the conventional Cochran-Armitage trend test is striking when the genetic effects are heterogeneous. The easy-to-use R 3.1.2 software (R Foundation for Statistical Computing, Vienna, Austria) code is provided. The optimal trend tests are recommended for routine use. PMID:27278756

  17. Migration Effects of Parallel Genetic Algorithms on Line Topologies of Heterogeneous Computing Resources

    NASA Astrophysics Data System (ADS)

    Gong, Yiyuan; Guan, Senlin; Nakamura, Morikazu

    This paper investigates migration effects of parallel genetic algorithms (GAs) on the line topology of heterogeneous computing resources. Evolution process of parallel GAs is evaluated experimentally on two types of arrangements of heterogeneous computing resources: the ascending and descending order arrangements. Migration effects are evaluated from the viewpoints of scalability, chromosome diversity, migration frequency and solution quality. The results reveal that the performance of parallel GAs strongly depends on the design of the chromosome migration in which we need to consider the arrangement of heterogeneous computing resources, the migration frequency and so on. The results contribute to provide referential scheme of implementation of parallel GAs on heterogeneous computing resources.

  18. Mitochondrial DNA polymorphism reveals hidden heterogeneity within some Asian populations.

    PubMed Central

    Chakraborty, R

    1990-01-01

    Use of data on mtDNA morph distributions from six Asian populations has shown that the observed number of different mtDNA morphs is too large when compared with the number expected on the basis of the observed gene diversity in the mtDNA genome. This excess number of morphs mainly occurs through an excess of rare morphs, and this discrepancy is more pronounced in a pooled sample of five Asian populations. It is suggested that this discrepancy is probably due to internal heterogeneity in each of the anthropologically defined populations. This analysis demonstrates the utility that population data for a single locus, such as the mtDNA genome, have for detecting hidden heterogeneity in populations, provided that the locus has substantial genetic variability, so that many variant alleles can be detected. PMID:2349953

  19. Colorectal Cancer Genetic Heterogeneity Delineated by Multi-Region Sequencing

    PubMed Central

    Liang, Rui; Xie, Zhen-Rong; Luo, Hua-You; Zeng, Yu-Jian; Xu, Yu; Wang, La-Mei; Kong, Xiang-Yang; Wang, Kun-Hua

    2016-01-01

    Intratumor heterogeneity (ITH) leads to an underestimation of the mutational landscape portrayed by a single needle biopsy and consequently affects treatment precision. The extent of colorectal cancer (CRC) genetic ITH is not well understood in Chinese patients. Thus, we conducted deep sequencing by using the OncoGxOne™ Plus panel, targeting 333 cancer-specific genes in multi-region biopsies of primary and liver metastatic tumors from three Chinese CRC patients. We determined that the extent of ITH varied among the three cases. On average, 65% of all the mutations detected were common within individual tumors. KMT2C aberrations and the NCOR1 mutation were the only ubiquitous events. Subsequent phylogenetic analysis showed that the tumors evolved in a branched manner. Comparison of the primary and metastatic tumors revealed that PPP2R1A (E370X), SETD2 (I1608V), SMAD4 (G382T), and AR splicing site mutations may be specific to liver metastatic cancer. These mutations might contribute to the initiation and progression of distant metastasis. Collectively, our analysis identified a substantial level of genetic ITH in CRC, which should be considered for personalized therapeutic strategies. PMID:27023146

  20. Genetic heterogeneity of familial hemiplegic migraine

    SciTech Connect

    Ophoff, R.A.; Van Eijk, R.; Sandkuijl, L.A.

    1994-07-01

    Familial hemiplegic migraine (FHM) is a distinctive form of migraine with an autosomal dominant mode of inheritance. The migraine-like attacks are associated with transient hemiparesis. A locus for FHM has recently been assigned to chromosome 19 by linkage mapping. In the present study, five unrelated pedigrees with multiple members suffering from hemiplegic migraine were investigated. In two of the pedigrees additional symptoms, cerebellar ataxia and benign neonatal convulsions, respectively, were observed in affected members. Three pedigrees showed linkage to loci D19S391, D19S221, and D19S226 at chromosome 19p13. Haplotyping suggested a location of a FHM gene between D19S391 and D19S221. In the two remaining families, evidence against linkage was found. These results confirm the localization of a gene for familial hemiplegic migraine to the short arm of chromosome 19, but locus heterogeneity not corresponding to the observed clinical heterogeneity is likely to exist. 19 refs., 3 figs., 3 tabs.

  1. Genetic heterogeneity and Alzheimer`s disease

    SciTech Connect

    Schellenberg, G.D.; Wijsman, E.M.; Bird, T.D.

    1994-09-01

    In some early-onset Alzheimer`s disease (AD) families, inheritance is autosomal dominant. (Early-onset AD is arbitarily defined as onset at {le} 60 years.) Two loci have been identified which are causative for early-onset familial AD (FAD). One is the amyloid precursor protein gene in which specific mutation have been identified. The second is a locus at 14q24.3 (AD3) which has been localized by linkage analysis; the gene and specific mutations have not been identified. Linkage studies place this locus between D14S61 and D14S63. These 2 loci, however, do not account for all early-onset FAD. The Volga German (VG) kindreds are descendants of families which emigrated from Germany to the Volga river region of Russia and subsequently to the US; AD in these families is hypothesized to be the result of a common genetic founder. The average age-at-onset in these families is 57 years. Linkage analysis for this group has been negative for the APP gene and for chromosome 14 markers. Thus, there is at least 1 other early-onset FAD locus. Recently, the {epsilon}4 allele of apolipoprotein E (ApoE) was identified as a risk-factor for late-onset AD. In a series of 53 late-onset kindreds, a strong genetic association was observed between the ApoE {epsilon}4 allele and AD. However, when linkage analysis was performed using a highly polymorphic locus at the ApoCII gene, which is within 30 kb of ApoE, significant evidence for co-segregation was not observed. This and other data suggests that while ApoE is an age-at-onset modifying locus, another gene(s), located elsewhere, contribute(s) to late-onset AD. Thus, there is probably at least 1 other late-onset locus. Once the VG locus is identified, it will be possible to determine whether an allelic variant of this locus is responsible for late-onset FAD.

  2. Disentangling the heterogeneity of autism spectrum disorder through genetic findings

    PubMed Central

    Jeste, Shafali S.; Geschwind, Daniel H.

    2014-01-01

    Autism spectrum disorder (ASD) represents a heterogeneous group of disorders, which presents a substantial challenge to diagnosis and treatment. Over the past decade, considerable progress has been made in the identification of genetic risk factors for ASD that define specific mechanisms and pathways underlying the associated behavioural deficits. In this Review, we discuss how some of the latest advances in the genetics of ASD have facilitated parsing of the phenotypic heterogeneity of this disorder. We argue that only through such advances will we begin to define endophenotypes that can benefit from targeted, hypothesis-driven treatments. We review the latest technologies used to identify and characterize the genetics underlying ASD and then consider three themes—single-gene disorders, the gender bias in ASD, and the genetics of neurological comorbidities—that highlight ways in which we can use genetics to define the many phenotypes within the autism spectrum. We also present current clinical guidelines for genetic testing in ASD and their implications for prognosis and treatment. PMID:24468882

  3. Dopa-responsive dystonia--clinical and genetic heterogeneity.

    PubMed

    Wijemanne, Subhashie; Jankovic, Joseph

    2015-07-01

    Dopa-responsive dystonia (DRD) encompasses a group of clinically and genetically heterogeneous disorders that typically manifest as limb-onset, diurnally fluctuating dystonia and exhibit a robust and sustained response to levodopa treatment. Autosomal dominant GTP cyclohydrolase 1 deficiency, also known as Segawa disease, is the most common and best-characterized condition that manifests as DRD, but a similar presentation can be seen with genetic abnormalities that lead to deficiencies in tyrosine hydroxylase, sepiapterin reductase or other enzymes that are involved in the biosynthesis of dopamine. In rare cases, DRD can result from conditions that do not affect the biosynthesis of dopamine; single case reports have shown that DRD can be a manifestation of hereditary spastic paraplegia type 11, spinocerebellar ataxia type 3 and ataxia telangiectasia. This heterogeneity of conditions that underlie DRD frequently leads to misdiagnosis, which delays the appropriate treatment with levodopa. Correct diagnosis at an early stage requires use of the appropriate diagnostic tests, which include a levodopa trial, genetic testing (including whole-exome sequencing), cerebrospinal fluid neurotransmitter analysis, the phenylalanine loading test, and enzyme activity measurements. The selection of tests for use depends on the clinical presentation and level of complexity. This Review presents the common and rarer causes of DRD and their clinical features, and considers the most appropriate approaches to ensure early diagnosis and treatment. PMID:26100751

  4. Evidence of genetic heterogeneity in the long QT syndrome

    SciTech Connect

    Keating, M. )

    1993-06-25

    thee long QT syndrome (LQT) is a familial predisposition to sudden death from cardiac arrhythmias. M. Keating et al. performed linkage analysis in a large Utah family and found that th disease was closely linked to the Harvey ras-1 (H-ras-1) locus on chromosome 11. With the use of the probe pTBB-2 at the H-ras-1 oncogene, a logarithm of the likelihood ratio for linkage (lod score) of +16.44 was obtained by Keating et al. In a subsequent study, tight linkage of LQT to the H-ras-1 locus was found in six other small LQT families. The combined lod score from these two studies was +21.65 at a recombination fraction of 0. This tight linkage suggests that mutations at the H-ras-1 locus or at a closely linked locus resulted in LQT in the families studied. In view of the clinical heterogeneity and possible genetic heterogeneity in this syndrome, we analyzed a large Jewish family with a history of LQT. This family, whose origin is the island of Jerba near Tunic and whose members reside in Israel, is probably the largest family with LQT outside the United States. It comprises 131 individuals, of whom 28 have been affected. Clinical and electrocardiographic data collected over 7 years were available for 92 family members and blood samples for genetic analysis were available for 74. This analysis, together with that of Keating et al., provides evidence for genetic heterogeneity in the determination of the LQT.

  5. Genetic substructure of Kuwaiti population reveals migration history.

    PubMed

    Alsmadi, Osama; Thareja, Gaurav; Alkayal, Fadi; Rajagopalan, Ramakrishnan; John, Sumi Elsa; Hebbar, Prashantha; Behbehani, Kazem; Thanaraj, Thangavel Alphonse

    2013-01-01

    The State of Kuwait is characterized by settlers from Saudi Arabia, Iran, and other regions of the Arabian Peninsula. The settlements and subsequent admixtures have shaped the genetics of Kuwait. High prevalence of recessive disorders and metabolic syndromes (that increase risk of diabetes) is seen in the peninsula. Understanding the genetic structure of its population will aid studies designed to decipher the underlying causes of these disorders. In this study, we analyzed 572,366 SNP markers from 273 Kuwaiti natives genotyped using the illumina HumanOmniExpress BeadChip. Model-based clustering identified three genetic subgroups with different levels of admixture. A high level of concordance (Mantel test, p=0.0001 for 9999 repeats) was observed between the derived genetic clusters and the surname-based ancestries. Use of Human Genome Diversity Project (HGDP) data to understand admixtures in each group reveals the following: the first group (Kuwait P) is largely of West Asian ancestry, representing Persians with European admixture; the second group (Kuwait S) is predominantly of city-dwelling Saudi Arabian tribe ancestry, and the third group (Kuwait B) includes most of the tent-dwelling Bedouin surnames and is characterized by the presence of 17% African ancestry. Identity by Descent and Homozygosity analyses find Kuwait's population to be heterogeneous (placed between populations that have large amount of ROH and the ones with low ROH) with Kuwait S as highly endogamous, and Kuwait B as diverse. Population differentiation FST estimates place Kuwait P near Asian populations, Kuwait S near Negev Bedouin tribes, and Kuwait B near the Mozabite population. FST distances between the groups are in the range of 0.005 to 0.008; distances of this magnitude are known to cause false positives in disease association studies. Results of analysis for genetic features such as linkage disequilibrium decay patterns conform to Kuwait's geographical location at the nexus of Africa

  6. Evidence for further genetic heterogeneity in autosomal dominant retinitis pigmentosa

    SciTech Connect

    Kumar-Singh, R.; Kenna, P.F.; Farrar, G.J.; Humphries, P. )

    1993-01-01

    We have investigated the possible involvement of further genetic heterogeneity in autosomal dominant retinitis pigmentosa using a previously unreported large Irish family with the disease. We have utilized polymorphic microsatellite markers to exclude the disease gene segregating in this family from 3q, 6p, and the pericentric region of 8, that is, each of the three chromosomal regions to which adRP loci are known to map. Hence, we provide definitive evidence for the involvement of a fourth locus in autosomal dominant retinitis pigmentosa. 25 refs., 2 figs.

  7. Functional heterogeneity of genetically defined subclones in acute myeloid leukemia

    PubMed Central

    Klco, Jeffery M.; Spencer, David H.; Miller, Christopher A.; Griffith, Malachi; Lamprecht, Tamara L.; O’Laughlin, Michelle; Fronick, Catrina; Magrini, Vincent; Demeter, Ryan T.; Fulton, Robert S.; Eades, William C.; Link, Daniel C.; Graubert, Timothy A.; Walter, Matthew J.; Mardis, Elaine R.; Dipersio, John F.; Wilson, Richard K.; Ley, Timothy J.

    2014-01-01

    Summary The relationships between clonal architecture and functional heterogeneity in acute myeloid leukemia (AML) samples are not yet clear. We used targeted sequencing to track AML subclones identified by whole genome sequencing using a variety of experimental approaches. We found that virtually all AML subclones trafficked from the marrow to the peripheral blood, but some were enriched in specific cell populations. Subclones showed variable engraftment potential in immunodeficient mice. Xenografts were predominantly comprised of a single genetically-defined subclone, but there was no predictable relationship between the engrafting subclone and the evolutionary hierarchy of the leukemia. These data demonstrate the importance of integrating genetic and functional data in studies of primary cancer samples, both in xenograft models and in patients. PMID:24613412

  8. Array-CGH Analysis Suggests Genetic Heterogeneity in Rhombencephalosynapsis

    PubMed Central

    Démurger, F.; Pasquier, L.; Dubourg, C.; Dupé, V.; Gicquel, I.; Evain, C.; Ratié, L.; Jaillard, S.; Beri, M.; Leheup, B.; Lespinasse, J.; Martin-Coignard, D.; Mercier, S.; Quelin, C.; Loget, P.; Marcorelles, P.; Laquerrière, A.; Bendavid, C.; Odent, S.; David, V.

    2013-01-01

    Rhombencephalosynapsis is an uncommon, but increasingly recognized, cerebellar malformation defined as vermian agenesis with fusion of the hemispheres. The embryologic and genetic mechanisms involved are still unknown, and to date, no animal models are available. In the present study, we used Agilent oligonucleotide arrays in a large series of 57 affected patients to detect candidate genes. Four different unbalanced rearrangements were detected: a 16p11.2 deletion, a 14q12q21.2 deletion, an unbalanced translocation t(2p;10q), and a 16p13.11 microdeletion containing 2 candidate genes. These genes were further investigated by sequencing and in situ hybridization. This first microarray screening of a rhombencephalosynapsis series suggests that there may be heterogeneous genetic causes. PMID:24167461

  9. Genetic heterogeneity in 26 infants with a hypomyelinating leukodystrophy.

    PubMed

    Arai-Ichinoi, Natsuko; Uematsu, Mitsugu; Sato, Ryo; Suzuki, Tasuku; Kudo, Hiroki; Kikuchi, Atsuo; Hino-Fukuyo, Naomi; Matsumoto, Mitsuyo; Igarashi, Kazuhiko; Haginoya, Kazuhiro; Kure, Shigeo

    2016-01-01

    T2 hyperintensity of brain white matter lesions detected by magnetic resonance imaging (MRI) are characteristic of a heterogeneous group of diseases. Persistent T2 high intensity in combination with T1 iso- or high intensity of white matter in infants indicates a lack of normal myelination, that is, hypomyelination. However, the precise diagnosis of hypomyelinating leukodystrophy based solely on MRI findings can be difficult, especially in the early stage of the disease. We studied 26 patients who were diagnosed with hypomyelinating leukodystrophy according to MRI findings and clinical features to uncover their genetic etiology through chromosomal analyses, targeted gene analyses, and an array comparative genomic hybridization (aCGH) assay. Then, for the 17 patients with unexplained hypomyelination by traditional analyses, whole-exome sequencing (WES) was performed. The presumptive diagnoses were confirmed in 58 % of the enrolled patients (15/26) and involved 9 different genetic backgrounds. The most frequent backgrounds were 18q deletion syndrome and Pelizaeus-Merzbacher disease, with an incidence of 12 % (3/26) for both. The diagnostic rate of chromosomal analyses, targeted gene analyses, and aCGH was 31 % (8/26), and one patient was clinically diagnosed with Cockayne syndrome. Using WES, the following causative genes of hypomyelination were identified in six individuals (35 %, 6/17): TUBB4A, POLR3B, KCNT1, and MCOLN1, and some of those genes were pathogenic for not only hypomyelination but also dysmyelination or delayed myelination. Our findings suggested heterogeneous genetic backgrounds in patients with persistent white matter lesions. These data also indicate that WES may be a rapid and useful tool for identifying the underlying genetic causes of undiagnosed leukodystrophies. PMID:26597493

  10. Measuring habitat heterogeneity reveals new insights into bird community composition.

    PubMed

    Stirnemann, Ingrid A; Ikin, Karen; Gibbons, Philip; Blanchard, Wade; Lindenmayer, David B

    2015-03-01

    Fine-scale vegetation cover is a common variable used to explain animal occurrence, but we know less about the effects of fine-scale vegetation heterogeneity. Theoretically, fine-scale vegetation heterogeneity is an important driver of biodiversity because it captures the range of resources available in a given area. In this study we investigated how bird species richness and birds grouped by various ecological traits responded to vegetation cover and heterogeneity. We found that both fine-scale vegetation cover (of tall trees, medium-sized trees and shrubs) and heterogeneity (of tall trees, and shrubs) were important predictors of bird richness, but the direction of the response of bird richness to shrub heterogeneity differed between sites with different proportions of tall tree cover. For example, bird richness increased with shrub heterogeneity in sites with high levels of tall tree cover, but declined in sites with low levels of tall tree cover. Our findings indicated that an increase in vegetation heterogeneity will not always result in an increase in resources and niches, and associated higher species richness. We also found birds grouped by traits responded in a predictable way to vegetation heterogeneity. For example, we found small birds benefited from increased shrub heterogeneity supporting the textual discontinuity hypothesis and non-arboreal (ground or shrub) nesting species were associated with high vegetation cover (low heterogeneity). Our results indicated that focusing solely on increasing vegetation cover (e.g. through restoration) may be detrimental to particular animal groups. Findings from this investigation can help guide habitat management for different functional groups of birds. PMID:25376157

  11. Genetic heterogeneity in cholangiocarcinoma: a major challenge for targeted therapies.

    PubMed

    Brandi, Giovanni; Farioli, Andrea; Astolfi, Annalisa; Biasco, Guido; Tavolari, Simona

    2015-06-20

    Cholangiocarcinoma (CC) encompasses a group of related but distinct malignancies whose lack of a stereotyped genetic signature makes challenging the identification of genomic landscape and the development of effective targeted therapies. Accumulated evidences strongly suggest that the remarkable genetic heterogeneity of CC may be the result of a complex interplay among different causative factors, some shared by most human cancers while others typical of this malignancy. Currently, considerable efforts are ongoing worldwide for the genetic characterization of CC, also using advanced technologies such as next-generation sequencing (NGS). Undoubtedly this technology could offer an unique opportunity to broaden our understanding on CC molecular pathogenesis. Despite this great potential, however, the high complexity in terms of factors potentially contributing to genetic variability in CC calls for a more cautionary application of NGS to this malignancy, in order to avoid possible biases and criticisms in the identification of candidate actionable targets. This approach is further justified by the urgent need to develop effective targeted therapies in this disease. A multidisciplinary approach integrating genomic, functional and clinical studies is therefore mandatory to translate the results obtained by NGS into effective targeted therapies for this orphan disease. PMID:26142706

  12. Genetic heterogeneity in cholangiocarcinoma: a major challenge for targeted therapies

    PubMed Central

    Brandi, Giovanni; Farioli, Andrea; Astolfi, Annalisa; Biasco, Guido; Tavolari, Simona

    2015-01-01

    Cholangiocarcinoma (CC) encompasses a group of related but distinct malignancies whose lack of a stereotyped genetic signature makes challenging the identification of genomic landscape and the development of effective targeted therapies. Accumulated evidences strongly suggest that the remarkable genetic heterogeneity of CC may be the result of a complex interplay among different causative factors, some shared by most human cancers while others typical of this malignancy. Currently, considerable efforts are ongoing worldwide for the genetic characterization of CC, also using advanced technologies such as next-generation sequencing (NGS). Undoubtedly this technology could offer an unique opportunity to broaden our understanding on CC molecular pathogenesis. Despite this great potential, however, the high complexity in terms of factors potentially contributing to genetic variability in CC calls for a more cautionary application of NGS to this malignancy, in order to avoid possible biases and criticisms in the identification of candidate actionable targets. This approach is further justified by the urgent need to develop effective targeted therapies in this disease. A multidisciplinary approach integrating genomic, functional and clinical studies is therefore mandatory to translate the results obtained by NGS into effective targeted therapies for this orphan disease. PMID:26142706

  13. Genetic heterogeneity in Alzheimer disease and implications for treatment strategies.

    PubMed

    Ringman, John M; Goate, Alison; Masters, Colin L; Cairns, Nigel J; Danek, Adrian; Graff-Radford, Neill; Ghetti, Bernardino; Morris, John C

    2014-11-01

    Since the original publication describing the illness in 1907, the genetic understanding of Alzheimer's disease (AD) has advanced such that it is now clear that it is a genetically heterogeneous condition, the subtypes of which may not uniformly respond to a given intervention. It is therefore critical to characterize the clinical and preclinical stages of AD subtypes, including the rare autosomal dominant forms caused by known mutations in the PSEN1, APP, and PSEN2 genes that are being studied in the Dominantly Inherited Alzheimer Network study and its associated secondary prevention trial. Similar efforts are occurring in an extended Colombian family with a PSEN1 mutation, in APOE ε4 homozygotes, and in Down syndrome. Despite commonalities in the mechanisms producing the AD phenotype, there are also differences that reflect specific genetic origins. Treatment modalities should be chosen and trials designed with these differences in mind. Ideally, the varying pathological cascades involved in the different subtypes of AD should be defined so that both areas of overlap and of distinct differences can be taken into account. At the very least, clinical trials should determine the influence of known genetic factors in post hoc analyses. PMID:25217249

  14. Genetic heterogeneity of usher syndrome type 1 in French families

    SciTech Connect

    Larget-Piet, D.; Gerber, S.; Rozet, J.M. ); Bonneau, D. ); Marc, S.; Weissenbach, J. ); Ghazi, I.; Dufier, J.L. ); David, A. ); Bitoun, P. )

    1994-05-01

    Usher syndrome type 1 (US1) is an autosomal recessive disease characterized by profound congenital hearing impairment with unintelligible speech, early retinitis pigmentosa, and constant vestibular dysfunction. Three localizations have been described in US1: USH1A, 14q32; USH1B, 11q13.5; and USH1C, 11p15. Studying a series of 33 affected individuals belonging to 20 US1 pedigrees of French ancestry, the authors found that none of the three localizations accounted for all US1 families in the series. However, when the sample was split into two groups according to the geographic origin of the probands' grandparents, they were able to confirm the presence of a gene for US1 on chromosome 14q32 (USH1A) in 9 families originating from the Poitou region in Western France. Moreover, they refined the genetic mapping of USH1A by showing that the disease gene maps to the D14S13 locus, within the genetic interval defined by loci D14S78 and D14S250 (location score in log base 10 = 4.90). Consistent with this, nonsignificant lod score values for linkage to either USH1B or USH1C were found in this group. With regard to US1 families of other geographic origin (Normandy and Northern France, 11 families), nonsignificant lod scores for linkage to chromosome 11q13.5 were observed. However, the HOMOG test suggested that USH1B might account for the disease in 9/11 families in the series (families 10-19), the latter two families possibly being accounted for by USH1C (maximum likelihood for heterogeneity = 7.91 in lnL; heterogeneity versus homogeneity, P = 0.01; heterogeneity versus nonlinkage, P < 0.01). The present study supports the view that Usher syndrome type 1 is a genetically heterogeneous condition that is caused by at least three genes and possibly many more. 16 refs., 4 figs., 3 tabs.

  15. The Multi-allelic Genetic Architecture of a Variance-Heterogeneity Locus for Molybdenum Concentration in Leaves Acts as a Source of Unexplained Additive Genetic Variance

    PubMed Central

    Forsberg, Simon K. G.; Andreatta, Matthew E.; Huang, Xin-Yuan; Danku, John; Salt, David E.; Carlborg, Örjan

    2015-01-01

    Genome-wide association (GWA) analyses have generally been used to detect individual loci contributing to the phenotypic diversity in a population by the effects of these loci on the trait mean. More rarely, loci have also been detected based on variance differences between genotypes. Several hypotheses have been proposed to explain the possible genetic mechanisms leading to such variance signals. However, little is known about what causes these signals, or whether this genetic variance-heterogeneity reflects mechanisms of importance in natural populations. Previously, we identified a variance-heterogeneity GWA (vGWA) signal for leaf molybdenum concentrations in Arabidopsis thaliana. Here, fine-mapping of this association reveals that the vGWA emerges from the effects of three independent genetic polymorphisms that all are in strong LD with the markers displaying the genetic variance-heterogeneity. By revealing the genetic architecture underlying this vGWA signal, we uncovered the molecular source of a significant amount of hidden additive genetic variation or “missing heritability”. Two of the three polymorphisms underlying the genetic variance-heterogeneity are promoter variants for Molybdate transporter 1 (MOT1), and the third a variant located ~25 kb downstream of this gene. A fourth independent association was also detected ~600 kb upstream of MOT1. Use of a T-DNA knockout allele highlights Copper Transporter 6; COPT6 (AT2G26975) as a strong candidate gene for this association. Our results show that an extended LD across a complex locus including multiple functional alleles can lead to a variance-heterogeneity between genotypes in natural populations. Further, they provide novel insights into the genetic regulation of ion homeostasis in A. thaliana, and empirically confirm that variance-heterogeneity based GWA methods are a valuable tool to detect novel associations of biological importance in natural populations. PMID:26599497

  16. Heterogeneity of pancreatic cancer metastases in a single patient revealed by quantitative proteomics.

    PubMed

    Kim, Min-Sik; Zhong, Yi; Yachida, Shinichi; Rajeshkumar, N V; Abel, Melissa L; Marimuthu, Arivusudar; Mudgal, Keshav; Hruban, Ralph H; Poling, Justin S; Tyner, Jeffrey W; Maitra, Anirban; Iacobuzio-Donahue, Christine A; Pandey, Akhilesh

    2014-11-01

    Many patients with pancreatic cancer have metastases to distant organs at the time of initial presentation. Recent studies examining the evolution of pancreatic cancer at the genetic level have shown that clonal complexity of metastatic pancreatic cancer is already initiated within primary tumors, and organ-specific metastases are derived from different subclones. However, we do not yet understand to what extent the evolution of pancreatic cancer contributes to proteomic and signaling alterations. We hypothesized that genetic heterogeneity of metastatic pancreatic cancer results in heterogeneity at the proteome level. To address this, we employed a model system in which cells isolated from three sites of metastasis (liver, lung, and peritoneum) from a single patient were compared. We used a SILAC-based accurate quantitative proteomic strategy combined with high-resolution mass spectrometry to analyze the total proteome and tyrosine phosphoproteome of each of the distal metastases. Our data revealed distinct patterns of both overall proteome expression and tyrosine kinase activities across the three different metastatic lesions. This heterogeneity was significant because it led to differential sensitivity of the neoplastic cells to small molecule inhibitors targeting various kinases and other pathways. For example, R428, a tyrosine kinase inhibitor that targets Axl receptor tyrosine kinase, was able to inhibit cells derived from lung and liver metastases much more effectively than cells from the peritoneal metastasis. Finally, we confirmed that administration of R428 in mice bearing xenografts of cells derived from the three different metastatic sites significantly diminished tumors formed from liver- and lung-metastasis-derived cell lines as compared with tumors derived from the peritoneal metastasis cell line. Overall, our data provide proof-of-principle support that personalized therapy of multiple organ metastases in a single patient should involve the

  17. Expression profiling of uterine leiomyomata cytogenetic subgroups reveals distinct signatures in matched myometrium: transcriptional profiling of the t(12;14) and evidence in support of predisposing genetic heterogeneity

    PubMed Central

    Hodge, Jennelle C.; Kim, Tae-Min; Dreyfuss, Jonathan M.; Somasundaram, Priya; Christacos, Nicole C.; Rousselle, Marissa; Quade, Bradley J.; Park, Peter J.; Stewart, Elizabeth A.; Morton, Cynthia C.

    2012-01-01

    Uterine leiomyomata (UL), the most common neoplasm in reproductive-age women, are classified into distinct genetic subgroups based on recurrent chromosome abnormalities. To develop a molecular signature of UL with t(12;14)(q14-q15;q23-q24), we took advantage of the multiple UL arising as independent clonal lesions within a single uterus. We compared genome-wide expression levels of t(12;14) UL to non-t(12;14) UL from each of nine women in a paired analysis, with each sample weighted for the percentage of t(12;14) cells to adjust for mosaicism with normal cells. This resulted in a transcriptional profile that confirmed HMGA2, known to be overexpressed in t(12;14) UL, as the most significantly altered gene. Pathway analysis of the differentially expressed genes showed significant association with cell proliferation, particularly G1/S checkpoint regulation. This is consistent with the known larger size of t(12;14) UL relative to karyotypically normal UL or to UL in the deletion 7q22 subgroup. Unsupervised hierarchical clustering demonstrated that patient variability is relatively dominant to the distinction of t(12;14) UL compared with non-t(12;14) UL or of t(12;14) UL compared with del(7q) UL. The paired design we employed is therefore important to produce an accurate t(12;14) UL-specific gene list by removing the confounding effects of genotype and environment. Interestingly, myometrium not only clustered away from the tumors, but generally separated based on associated t(12;14) versus del(7q) status. Nine genes were identified whose expression can distinguish the myometrium origin. This suggests an underlying constitutional genetic predisposition to these somatic changes which could potentially lead to improved personalized management and treatment. PMID:22343407

  18. Genetic heterogeneity, evolution and recombination in emerging G9 rotaviruses.

    PubMed

    Phan, Tung Gia; Okitsu, Shoko; Maneekarn, Niwat; Ushijima, Hiroshi

    2007-09-01

    G9 rotavirus is recognized as the emerging genotype spreading around the world. The rapidly increasing detection of this virus in association with the genetic heterogeneity raises questions regarding its origin and epidemiological importance. A total of 380 sequences of rotavirus G9 strains including our sequence data from Vietnam and Japan, which were detected from 1983 to 2006 in five different continents, were collected from GenBank to investigate their heterogeneity and evolution. A novel nomenclature for G9 rotaviruses is proposed, in which these viruses are clustered into 6 lineages with 11 sublineages. Multiple amino acid substitutions of VP7 specific for lineages and sublineages were found. Interestingly, six short amino acid motifs correctly defined phylogenetic lineages and sublineages. Another interesting finding was the identification of recombinant G9 rotavirus, bearing different genotype sequence. In view of rotavirus evolution, this report is an additional evidence to support the notion that there might exist a genomic relatedness between human and porcine rotaviruses. PMID:17544926

  19. Using genetic data to estimate diffusion rates in heterogeneous landscapes.

    PubMed

    Roques, L; Walker, E; Franck, P; Soubeyrand, S; Klein, E K

    2016-08-01

    Having a precise knowledge of the dispersal ability of a population in a heterogeneous environment is of critical importance in agroecology and conservation biology as it can provide management tools to limit the effects of pests or to increase the survival of endangered species. In this paper, we propose a mechanistic-statistical method to estimate space-dependent diffusion parameters of spatially-explicit models based on stochastic differential equations, using genetic data. Dividing the total population into subpopulations corresponding to different habitat patches with known allele frequencies, the expected proportions of individuals from each subpopulation at each position is computed by solving a system of reaction-diffusion equations. Modelling the capture and genotyping of the individuals with a statistical approach, we derive a numerically tractable formula for the likelihood function associated with the diffusion parameters. In a simulated environment made of three types of regions, each associated with a different diffusion coefficient, we successfully estimate the diffusion parameters with a maximum-likelihood approach. Although higher genetic differentiation among subpopulations leads to more accurate estimations, once a certain level of differentiation has been reached, the finite size of the genotyped population becomes the limiting factor for accurate estimation. PMID:26707856

  20. Achondrogenesis: new nosology with evidence of genetic heterogeneity.

    PubMed

    Whitley, C B; Gorlin, R J

    1983-09-01

    Achondrogenesis is a phenotypically diverse group of lethal osteochondrodysplasias characterized by severe micromelia, a short trunk, and a disproportionately large cranium. Cases of classic achondrogenesis Type I (Parenti-Fraccaro), and classic achondrogenesis Type II (Langer-Saldino) have been grouped on the basis of clinical, radiologic, and histopathologic features. Although further genetic heterogeneity has been proposed, broad acceptance has been lacking. Review of 79 cases, including examination of available radiographs of familial cases, permitted division into four radiographic prototypes. Cases were distinguished on the basis of specific skeletal features as well as a new parameter, the "femoral cylinder index" (CIfemur). Using these criteria, the affected siblings in 11 families were found to be concordant for prototype. Thus, identification of radiographic skeletal prototypes of achondrogenesis, and the observation of familial concordance for prototype, suggested the existence of at least four genetically distinct disorders, each having autosomal recessive transmission. These observations should provide further impetus for histopathologic and biochemical studies of the defects in achondrogenesis. PMID:6878687

  1. Alleles that modulate late life hearing in genetically heterogeneous mice

    PubMed Central

    Schacht, Jochen; Altschuler, Richard; Burke, David T.; Chen, Shu; Dolan, David; Galecki, Andrzej T.; Kohrman, David; Miller, Richard A.

    2012-01-01

    A genetically heterogeneous population of mice was tested for hearing at 8, 18 and 22 months by auditory brainstem response (ABR), and genotyped at 128 markers to identify loci that modulate late life hearing loss. Half of the test mice were exposed to noise for 2 hr at age 20 months. Polymorphisms affecting hearing at 18 months were noted on chromosomes 2, 3, 7, 10, and 15. Most of these loci had effects only on responses to 48 kHz stimuli, but a subset also influenced the ABR at lower frequencies. Loci on chromosomes 4, 10, 12, and 14 had significant effects on hearing at 22 months in noise-exposed mice, and loci on chromosomes 10 and 11 had effects on mice not exposed to noise. Outer hair cell loss was modulated by polymorphisms on chromosomes 10, 11, 12, 17, and 19. Resistance to age-related hearing loss is thus modulated by a set of genetic effects, some age-specific, some frequency specific, some dependent on prior exposure to noise, and some of which compromise survival of cochlear hair cells. PMID:22305187

  2. Genetic Heterogeneity in Adolescents' Depressive Symptoms in Response to Victimization.

    PubMed

    Gottfredson, Nisha C; Foshee, Vangie A; Ennett, Susan T; Haberstick, Brett; Smolen, Andrew

    2015-01-01

    This study had two objectives: first, to determine the degree to which experiences of victimization by peers during adolescence led to a subsequent rise in depressive symptoms, and second, to identify genetic markers that predict depressive reactivity to victimization. We used a cohort sequential design to obtain a longitudinal sample of 1,475 adolescents (3,263 observations) in Grades 8 to 12 (56% female; 47% Black, 46% White). Multilevel growth curve models were used to assess whether victimization predicted depressive symptoms 6 months later, beyond baseline trajectories for depressive symptoms. We modeled the interactive effects of peer victimization with three genetic polymorphisms (on 5-HTTLPR, DRD2 TaqIA, and BDNF Val66Met) on depressive symptoms. Although victimization predicted subsequent depressive symptoms, there was substantial heterogeneity in the magnitude of the effect of victimization. Val alleles, associated with higher brain-derived neurotrophic factor (BDNF) functioning, predicted more sensitivity to victimization. Neither DRD2 TaqIA, a marker associated with dopaminergic functioning, nor 5-HTTLPR, a marker associated with serotonin activity, was associated with sensitivity to victimization. The social stress of peer victimization triggers depressive symptoms most strongly in individuals who are homozygous for the Val allele on the BDNF Val/Met polymorphism. This polymorphism has been linked with sensitivity to social defeat in animal models. Future research should explore behavioral, cognitive, and emotional explanations of the effects of BDNF Val/Met on responsivity to victimization. PMID:24819687

  3. Pathway-based outlier method reveals heterogeneous genomic structure of autism in blood transcriptome

    PubMed Central

    2013-01-01

    Background Decades of research strongly suggest that the genetic etiology of autism spectrum disorders (ASDs) is heterogeneous. However, most published studies focus on group differences between cases and controls. In contrast, we hypothesized that the heterogeneity of the disorder could be characterized by identifying pathways for which individuals are outliers rather than pathways representative of shared group differences of the ASD diagnosis. Methods Two previously published blood gene expression data sets – the Translational Genetics Research Institute (TGen) dataset (70 cases and 60 unrelated controls) and the Simons Simplex Consortium (Simons) dataset (221 probands and 191 unaffected family members) – were analyzed. All individuals of each dataset were projected to biological pathways, and each sample’s Mahalanobis distance from a pooled centroid was calculated to compare the number of case and control outliers for each pathway. Results Analysis of a set of blood gene expression profiles from 70 ASD and 60 unrelated controls revealed three pathways whose outliers were significantly overrepresented in the ASD cases: neuron development including axonogenesis and neurite development (29% of ASD, 3% of control), nitric oxide signaling (29%, 3%), and skeletal development (27%, 3%). Overall, 50% of cases and 8% of controls were outliers in one of these three pathways, which could not be identified using group comparison or gene-level outlier methods. In an independently collected data set consisting of 221 ASD and 191 unaffected family members, outliers in the neurogenesis pathway were heavily biased towards cases (20.8% of ASD, 12.0% of control). Interestingly, neurogenesis outliers were more common among unaffected family members (Simons) than unrelated controls (TGen), but the statistical significance of this effect was marginal (Chi squared P < 0.09). Conclusions Unlike group difference approaches, our analysis identified the samples within the case

  4. Genetic investigation within Lactococcus garvieae revealed two genomic lineages.

    PubMed

    Ferrario, Chiara; Ricci, Giovanni; Borgo, Francesca; Rollando, Alessandro; Fortina, Maria Grazia

    2012-07-01

    The diversity of a collection of 49 Lactococcus garvieae strains, including isolates of dairy, fish, meat, vegetable and cereal origin, was explored using a molecular polyphasic approach comprising PCR-ribotyping, REP and RAPD-PCR analyses and a multilocus restriction typing (MLRT) carried out on six partial genes (atpA, tuf, dltA, als, gapC, and galP). This approach allowed high-resolution cluster analysis in which two major groups were distinguishable: one group included dairy isolates, the other group meat isolates. Unexpectedly, of the 12 strains coming from fish, four grouped with dairy isolates, whereas the others with meat isolates. Likewise, strains isolated from vegetables allocated between the two main groups. These findings revealed high variability within the species at both gene and genome levels. The observed genetic heterogeneity among L. garvieae strains was not entirely coherent with the ecological niche of origin of the strains, but rather supports the idea of an early separation of L. garvieae population into two independent genomic lineages. PMID:22568590

  5. Revealing Spatially Heterogeneous Relaxation in a Model Nanocomposite.

    SciTech Connect

    Cheng, Shiwang; Mirigian, Stephen; Carrillo, Jan-Michael Y; Bocharova, Vera; Sumpter, Bobby G; Schweizer, Kenneth S; Sokolov, Alexei P

    2015-01-01

    The detailed nature of spatially heterogeneous dynamics of glycerol-silica nanocomposites is unraveled by combining dielectric spectroscopy with atomistic simulation and statistical mechanical theory. Analysis of the spatial mobility gradient shows no glassy layer, but the -relaxation time near the nanoparticle grows with cooling faster than the -relaxation time in the bulk and is 20 times longer at low temperatures. The interfacial layer thickness increases from 1.8 nm at higher temperatures to 3.5 nm upon cooling to near bulk Tg. A real space microscopic description of the mobility gradient is constructed by synergistically combining high temperature atomistic simulation with theory. Our analysis suggests that the interfacial slowing down arises mainly due to an increase of the local cage scale barrier for activated hopping induced by enhanced packing and densification near the nanoparticle surface. The theory is employed to predict how local surface densification can be manipulated to control layer dynamics and shear rigidity over a wide temperature range.

  6. Familial clustering and genetic heterogeneity in Meniere's disease.

    PubMed

    Requena, T; Espinosa-Sanchez, J M; Cabrera, S; Trinidad, G; Soto-Varela, A; Santos-Perez, S; Teggi, R; Perez, P; Batuecas-Caletrio, A; Fraile, J; Aran, I; Martin, E; Benitez, J; Pérez-Fernández, N; Lopez-Escamez, J A

    2014-03-01

    The aims of this study were to estimate the prevalence of familial cases in patients with Meniere's disease (MD) and to identify clinical differences between sporadic and familial MD. We recruited 1375 patients with definite MD according to the American Academy of Otolaryngology-Head and Neck Surgery criteria, obtaining the familial history of hearing loss or episodic vertigo by direct interview or a postal survey in 1245 cases in a multicenter study. Familial clustering was estimated by the recurrence risk ratio in siblings (λs ) and offspring (λo ) using intermediate and high prevalence values for MD in European population. A total of 431 patients (34%) reported a familial history of hearing loss or recurrent vertigo and 133 patients had a relative with possible MD. After clinical reevaluation, 93 relatives in 76 families were diagnosed of definite MD (8.4%), including three pairs of monozygotic twins. λs and λo were 16-48 and 4-12, respectively. We observed genetic heterogeneity, but most families had an autosomal dominant inheritance with anticipation. No clinical differences were found between sporadic and familial MD, except for an early onset in familial cases. We may conclude that MD has a strong familial aggregation and that sporadic and familial MDs are clinically identical. PMID:23521103

  7. Heterogeneity of HLA genetic factors in IDDM susceptibility.

    PubMed

    Martell, M; Marcadet, A; Moine, A; Boitard, C; Deschamps, I; Dausset, J; Bach, J F; Cohen, D

    1990-01-01

    The association of certain HLA-D alleles with insulin-dependent diabetes mellitus (IDDM) is well known. One hundred and sixty-one non-related diabetic individuals and 142 non-related healthy controls were typed for the HLA DR-DQw-Dw association, using a restriction fragment length polymorphism (RFLP) typing method that combines three probe/enzyme systems: DRB/Taq I, DQB/Taq I, and DQB/Bam HI. Comparison of frequencies in both diabetics and controls confirms previous results in terms of HLA class II and IDDM association. Moreover, we have found that DR3/3 heterozygous individuals are more susceptible to IDDM when they are also Dw25 (associated with B18) than when they are Dw24 (associated with B8). Using oligonucleotide dot-blot hybridizations we analyzed the HLA-DQB1 sequence of DR3,Dw24 and DR3,Dw25 homozygous individuals, and we found no difference at position 57 between these two DR3-carrying haplotypes. This observation points to the heterogeneity of HLA genetic factors in IDDM susceptibility. PMID:1970333

  8. Deep phenotyping of 89 xeroderma pigmentosum patients reveals unexpected heterogeneity dependent on the precise molecular defect

    PubMed Central

    Fassihi, Hiva; Sethi, Mieran; Fawcett, Heather; Wing, Jonathan; Chandler, Natalie; Mohammed, Shehla; Craythorne, Emma; Morley, Ana M. S.; Lim, Rongxuan; Turner, Sally; Henshaw, Tanya; Garrood, Isabel; Giunti, Paola; Hedderly, Tammy; Abiona, Adesoji; Naik, Harsha; Harrop, Gemma; McGibbon, David; Jaspers, Nicolaas G. J.; Botta, Elena; Nardo, Tiziana; Stefanini, Miria; Young, Antony R.; Sarkany, Robert P. E.; Lehmann, Alan R.

    2016-01-01

    Xeroderma pigmentosum (XP) is a rare DNA repair disorder characterized by increased susceptibility to UV radiation (UVR)-induced skin pigmentation, skin cancers, ocular surface disease, and, in some patients, sunburn and neurological degeneration. Genetically, it is assigned to eight complementation groups (XP-A to -G and variant). For the last 5 y, the UK national multidisciplinary XP service has provided follow-up for 89 XP patients, representing most of the XP patients in the United Kingdom. Causative mutations, DNA repair levels, and more than 60 clinical variables relating to dermatology, ophthalmology, and neurology have been measured, using scoring systems to categorize disease severity. This deep phenotyping has revealed unanticipated heterogeneity of clinical features, between and within complementation groups. Skin cancer is most common in XP-C, XP-E, and XP-V patients, previously considered to be the milder groups based on cellular analyses. These patients have normal sunburn reactions and are therefore diagnosed later and are less likely to adhere to UVR protection. XP-C patients are specifically hypersensitive to ocular damage, and XP-F and XP-G patients appear to be much less susceptible to skin cancer than other XP groups. Within XP groups, different mutations confer susceptibility or resistance to neurological damage. Our findings on this large cohort of XP patients under long-term follow-up reveal that XP is more heterogeneous than has previously been appreciated. Our data now enable provision of personalized prognostic information and management advice for each XP patient, as well as providing new insights into the functions of the XP proteins. PMID:26884178

  9. Deep phenotyping of 89 xeroderma pigmentosum patients reveals unexpected heterogeneity dependent on the precise molecular defect.

    PubMed

    Fassihi, Hiva; Sethi, Mieran; Fawcett, Heather; Wing, Jonathan; Chandler, Natalie; Mohammed, Shehla; Craythorne, Emma; Morley, Ana M S; Lim, Rongxuan; Turner, Sally; Henshaw, Tanya; Garrood, Isabel; Giunti, Paola; Hedderly, Tammy; Abiona, Adesoji; Naik, Harsha; Harrop, Gemma; McGibbon, David; Jaspers, Nicolaas G J; Botta, Elena; Nardo, Tiziana; Stefanini, Miria; Young, Antony R; Sarkany, Robert P E; Lehmann, Alan R

    2016-03-01

    Xeroderma pigmentosum (XP) is a rare DNA repair disorder characterized by increased susceptibility to UV radiation (UVR)-induced skin pigmentation, skin cancers, ocular surface disease, and, in some patients, sunburn and neurological degeneration. Genetically, it is assigned to eight complementation groups (XP-A to -G and variant). For the last 5 y, the UK national multidisciplinary XP service has provided follow-up for 89 XP patients, representing most of the XP patients in the United Kingdom. Causative mutations, DNA repair levels, and more than 60 clinical variables relating to dermatology, ophthalmology, and neurology have been measured, using scoring systems to categorize disease severity. This deep phenotyping has revealed unanticipated heterogeneity of clinical features, between and within complementation groups. Skin cancer is most common in XP-C, XP-E, and XP-V patients, previously considered to be the milder groups based on cellular analyses. These patients have normal sunburn reactions and are therefore diagnosed later and are less likely to adhere to UVR protection. XP-C patients are specifically hypersensitive to ocular damage, and XP-F and XP-G patients appear to be much less susceptible to skin cancer than other XP groups. Within XP groups, different mutations confer susceptibility or resistance to neurological damage. Our findings on this large cohort of XP patients under long-term follow-up reveal that XP is more heterogeneous than has previously been appreciated. Our data now enable provision of personalized prognostic information and management advice for each XP patient, as well as providing new insights into the functions of the XP proteins. PMID:26884178

  10. Revealing spatially heterogeneous relaxation in a model nanocomposite

    SciTech Connect

    Cheng, Shiwang; Mirigian, Stephen; Carrillo, Jan-Michael Y.; Bocharova, Vera; Sumpter, Bobby G.; Schweizer, Kenneth S.; Sokolov, Alexei P.

    2015-11-18

    The detailed nature of spatially heterogeneous dynamics of glycerol-silica nanocomposites is unraveled by combining dielectric spectroscopy with atomistic simulation and statistical mechanical theory. Analysis of the spatial mobility gradient shows no glassy layer, but the -relaxation time near the nanoparticle grows with cooling faster than the -relaxation time in the bulk and is ~20 times longer at low temperatures. The interfacial layer thickness increases from ~1.8 nm at higher temperatures to ~3.5 nm upon cooling to near bulk Tg. A real space microscopic description of the mobility gradient is constructed by synergistically combining high temperature atomistic simulation with theory. Our analysis suggests that the interfacial slowing down arises mainly due to an increase of the local cage scale barrier for activated hopping induced by enhanced packing and densification near the nanoparticle surface. As a result, the theory is employed to predict how local surface densification can be manipulated to control layer dynamics and shear rigidity over a wide temperature range.

  11. Revealing spatially heterogeneous relaxation in a model nanocomposite

    SciTech Connect

    Cheng, Shiwang; Bocharova, Vera; Mirigian, Stephen; Schweizer, Kenneth S.; Carrillo, Jan-Michael Y.; Sumpter, Bobby G.; Sokolov, Alexei P.

    2015-11-21

    The detailed nature of spatially heterogeneous dynamics of glycerol-silica nanocomposites is unraveled by combining dielectric spectroscopy with atomistic simulation and statistical mechanical theory. Analysis of the spatial mobility gradient shows no “glassy” layer, but the α-relaxation time near the nanoparticle grows with cooling faster than the α-relaxation time in the bulk and is ∼20 times longer at low temperatures. The interfacial layer thickness increases from ∼1.8 nm at higher temperatures to ∼3.5 nm upon cooling to near bulk T{sub g}. A real space microscopic description of the mobility gradient is constructed by synergistically combining high temperature atomistic simulation with theory. Our analysis suggests that the interfacial slowing down arises mainly due to an increase of the local cage scale barrier for activated hopping induced by enhanced packing and densification near the nanoparticle surface. The theory is employed to predict how local surface densification can be manipulated to control layer dynamics and shear rigidity over a wide temperature range.

  12. Revealing spatially heterogeneous relaxation in a model nanocomposite

    DOE PAGESBeta

    Cheng, Shiwang; Mirigian, Stephen; Carrillo, Jan-Michael Y.; Bocharova, Vera; Sumpter, Bobby G.; Schweizer, Kenneth S.; Sokolov, Alexei P.

    2015-11-18

    The detailed nature of spatially heterogeneous dynamics of glycerol-silica nanocomposites is unraveled by combining dielectric spectroscopy with atomistic simulation and statistical mechanical theory. Analysis of the spatial mobility gradient shows no glassy layer, but the -relaxation time near the nanoparticle grows with cooling faster than the -relaxation time in the bulk and is ~20 times longer at low temperatures. The interfacial layer thickness increases from ~1.8 nm at higher temperatures to ~3.5 nm upon cooling to near bulk Tg. A real space microscopic description of the mobility gradient is constructed by synergistically combining high temperature atomistic simulation with theory. Ourmore » analysis suggests that the interfacial slowing down arises mainly due to an increase of the local cage scale barrier for activated hopping induced by enhanced packing and densification near the nanoparticle surface. As a result, the theory is employed to predict how local surface densification can be manipulated to control layer dynamics and shear rigidity over a wide temperature range.« less

  13. Genetic Geostatistical Framework for Spatial Analysis of Fine-Scale Genetic Heterogeneity in Modern Populations: Results from the KORA Study.

    PubMed

    Diaz-Lacava, A N; Walier, M; Holler, D; Steffens, M; Gieger, C; Furlanello, C; Lamina, C; Wichmann, H E; Becker, T

    2015-01-01

    Aiming to investigate fine-scale patterns of genetic heterogeneity in modern humans from a geographic perspective, a genetic geostatistical approach framed within a geographic information system is presented. A sample collected for prospective studies in a small area of southern Germany was analyzed. None indication of genetic heterogeneity was detected in previous analysis. Socio-demographic and genotypic data of German citizens were analyzed (212 SNPs; n = 728). Genetic heterogeneity was evaluated with observed heterozygosity (H O ). Best-fitting spatial autoregressive models were identified, using socio-demographic variables as covariates. Spatial analysis included surface interpolation and geostatistics of observed and predicted patterns. Prediction accuracy was quantified. Spatial autocorrelation was detected for both socio-demographic and genetic variables. Augsburg City and eastern suburban areas showed higher H O values. The selected model gave best predictions in suburban areas. Fine-scale patterns of genetic heterogeneity were observed. In accordance to literature, more urbanized areas showed higher levels of admixture. This approach showed efficacy for detecting and analyzing subtle patterns of genetic heterogeneity within small areas. It is scalable in number of loci, even up to whole-genome analysis. It may be suggested that this approach may be applicable to investigate the underlying genetic history that is, at least partially, embedded in geographic data. PMID:26258132

  14. Genetic Geostatistical Framework for Spatial Analysis of Fine-Scale Genetic Heterogeneity in Modern Populations: Results from the KORA Study

    PubMed Central

    Diaz-Lacava, A. N.; Walier, M.; Holler, D.; Steffens, M.; Gieger, C.; Furlanello, C.; Lamina, C.; Wichmann, H. E.; Becker, T.

    2015-01-01

    Aiming to investigate fine-scale patterns of genetic heterogeneity in modern humans from a geographic perspective, a genetic geostatistical approach framed within a geographic information system is presented. A sample collected for prospective studies in a small area of southern Germany was analyzed. None indication of genetic heterogeneity was detected in previous analysis. Socio-demographic and genotypic data of German citizens were analyzed (212 SNPs; n = 728). Genetic heterogeneity was evaluated with observed heterozygosity (HO). Best-fitting spatial autoregressive models were identified, using socio-demographic variables as covariates. Spatial analysis included surface interpolation and geostatistics of observed and predicted patterns. Prediction accuracy was quantified. Spatial autocorrelation was detected for both socio-demographic and genetic variables. Augsburg City and eastern suburban areas showed higher HO values. The selected model gave best predictions in suburban areas. Fine-scale patterns of genetic heterogeneity were observed. In accordance to literature, more urbanized areas showed higher levels of admixture. This approach showed efficacy for detecting and analyzing subtle patterns of genetic heterogeneity within small areas. It is scalable in number of loci, even up to whole-genome analysis. It may be suggested that this approach may be applicable to investigate the underlying genetic history that is, at least partially, embedded in geographic data. PMID:26258132

  15. Image-based computational quantification and visualization of genetic alterations and tumour heterogeneity

    PubMed Central

    Zhong, Qing; Rüschoff, Jan H.; Guo, Tiannan; Gabrani, Maria; Schüffler, Peter J.; Rechsteiner, Markus; Liu, Yansheng; Fuchs, Thomas J.; Rupp, Niels J.; Fankhauser, Christian; Buhmann, Joachim M.; Perner, Sven; Poyet, Cédric; Blattner, Miriam; Soldini, Davide; Moch, Holger; Rubin, Mark A.; Noske, Aurelia; Rüschoff, Josef; Haffner, Michael C.; Jochum, Wolfram; Wild, Peter J.

    2016-01-01

    Recent large-scale genome analyses of human tissue samples have uncovered a high degree of genetic alterations and tumour heterogeneity in most tumour entities, independent of morphological phenotypes and histopathological characteristics. Assessment of genetic copy-number variation (CNV) and tumour heterogeneity by fluorescence in situ hybridization (ISH) provides additional tissue morphology at single-cell resolution, but it is labour intensive with limited throughput and high inter-observer variability. We present an integrative method combining bright-field dual-colour chromogenic and silver ISH assays with an image-based computational workflow (ISHProfiler), for accurate detection of molecular signals, high-throughput evaluation of CNV, expressive visualization of multi-level heterogeneity (cellular, inter- and intra-tumour heterogeneity), and objective quantification of heterogeneous genetic deletions (PTEN) and amplifications (19q12, HER2) in diverse human tumours (prostate, endometrial, ovarian and gastric), using various tissue sizes and different scanners, with unprecedented throughput and reproducibility. PMID:27052161

  16. Image-based computational quantification and visualization of genetic alterations and tumour heterogeneity.

    PubMed

    Zhong, Qing; Rüschoff, Jan H; Guo, Tiannan; Gabrani, Maria; Schüffler, Peter J; Rechsteiner, Markus; Liu, Yansheng; Fuchs, Thomas J; Rupp, Niels J; Fankhauser, Christian; Buhmann, Joachim M; Perner, Sven; Poyet, Cédric; Blattner, Miriam; Soldini, Davide; Moch, Holger; Rubin, Mark A; Noske, Aurelia; Rüschoff, Josef; Haffner, Michael C; Jochum, Wolfram; Wild, Peter J

    2016-01-01

    Recent large-scale genome analyses of human tissue samples have uncovered a high degree of genetic alterations and tumour heterogeneity in most tumour entities, independent of morphological phenotypes and histopathological characteristics. Assessment of genetic copy-number variation (CNV) and tumour heterogeneity by fluorescence in situ hybridization (ISH) provides additional tissue morphology at single-cell resolution, but it is labour intensive with limited throughput and high inter-observer variability. We present an integrative method combining bright-field dual-colour chromogenic and silver ISH assays with an image-based computational workflow (ISHProfiler), for accurate detection of molecular signals, high-throughput evaluation of CNV, expressive visualization of multi-level heterogeneity (cellular, inter- and intra-tumour heterogeneity), and objective quantification of heterogeneous genetic deletions (PTEN) and amplifications (19q12, HER2) in diverse human tumours (prostate, endometrial, ovarian and gastric), using various tissue sizes and different scanners, with unprecedented throughput and reproducibility. PMID:27052161

  17. [Investigation of molecular-genetic heterogeneity of clematis plants (Clematis L.) obtained by organogenesis and somatic embryogenesis in vitro].

    PubMed

    Mitrofanova, I V; Galaev, A V; Sivolap, Iu M

    2003-01-01

    Genome variability of in vitro micropropagated Clematis plants was established. The optimum concentrations of BAP and zeatin in the culture medium regulating in vitro morphogenetic processes in clematis explants cv. Serenada Kryma were determined. Molecular-genetic analysis of Clematis plants obtained via in vitro somatic embryogenesis and organogenesis was carried out. Using ISSR primers 105 amplicons have been revealed, six of them were polymorphic. The mean index of heterogeneity of clematis plants was 5.7%. PMID:15067940

  18. Unsupervised Deconvolution of Dynamic Imaging Reveals Intratumor Vascular Heterogeneity and Repopulation Dynamics

    PubMed Central

    Chen, Li; Choyke, Peter L.; Wang, Niya; Clarke, Robert; Bhujwalla, Zaver M.; Hillman, Elizabeth M. C.; Wang, Ge; Wang, Yue

    2014-01-01

    With the existence of biologically distinctive malignant cells originated within the same tumor, intratumor functional heterogeneity is present in many cancers and is often manifested by the intermingled vascular compartments with distinct pharmacokinetics. However, intratumor vascular heterogeneity cannot be resolved directly by most in vivo dynamic imaging. We developed multi-tissue compartment modeling (MTCM), a completely unsupervised method of deconvoluting dynamic imaging series from heterogeneous tumors that can improve vascular characterization in many biological contexts. Applying MTCM to dynamic contrast-enhanced magnetic resonance imaging of breast cancers revealed characteristic intratumor vascular heterogeneity and therapeutic responses that were otherwise undetectable. MTCM is readily applicable to other dynamic imaging modalities for studying intratumor functional and phenotypic heterogeneity, together with a variety of foreseeable applications in the clinic. PMID:25379705

  19. Targeted next generation sequencing of parotid gland cancer uncovers genetic heterogeneity

    PubMed Central

    Grünewald, Inga; Vollbrecht, Claudia; Meinrath, Jeannine; Meyer, Moritz F.; Heukamp, Lukas C.; Drebber, Uta; Quaas, Alexander; Beutner, Dirk; Hüttenbrink, Karl-Bernd; Wardelmann, Eva; Hartmann, Wolfgang; Büttner, Reinhard

    2015-01-01

    Salivary gland cancer represents a heterogeneous group of malignant tumors. Due to their low incidence and the existence of multiple morphologically defined subtypes, these tumors are still poorly understood with regard to their molecular pathogenesis and therapeutically relevant genetic alterations. Performing a systematic and comprehensive study covering 13 subtypes of salivary gland cancer, next generation sequencing was done on 84 tissue samples of parotid gland cancer using multiplex PCR for enrichment of cancer related gene loci covering hotspots of 46 cancer genes. Mutations were identified in 22 different genes. The most frequent alterations affected TP53, followed by RAS genes, PIK3CA, SMAD4 and members of the ERB family. HRAS mutations accounted for more than 90% of RAS mutations, occurring especially in epithelial-myoepithelial carcinomas and salivary duct carcinomas. Additional mutations in PIK3CA also affected particularly epithelial-myoepithelial carcinomas and salivary duct carcinomas, occurring simultaneously with HRAS mutations in almost all cases, pointing to an unknown and therapeutically relevant molecular constellation. Interestingly, 14% of tumors revealed mutations in surface growth factor receptor genes including ALK, HER2, ERBB4, FGFR, cMET and RET, which might prove to be targetable by new therapeutic agents. 6% of tumors revealed mutations in SMAD4. In summary, our data provide novel insight into the fundamental molecular heterogeneity of salivary gland cancer, relevant in terms of tumor classification and the establishment of targeted therapeutic concepts. PMID:26053092

  20. Targeted next generation sequencing of parotid gland cancer uncovers genetic heterogeneity.

    PubMed

    Grünewald, Inga; Vollbrecht, Claudia; Meinrath, Jeannine; Meyer, Moritz F; Heukamp, Lukas C; Drebber, Uta; Quaas, Alexander; Beutner, Dirk; Hüttenbrink, Karl-Bernd; Wardelmann, Eva; Hartmann, Wolfgang; Büttner, Reinhard; Odenthal, Margarete; Stenner, Markus

    2015-07-20

    Salivary gland cancer represents a heterogeneous group of malignant tumors. Due to their low incidence and the existence of multiple morphologically defined subtypes, these tumors are still poorly understood with regard to their molecular pathogenesis and therapeutically relevant genetic alterations.Performing a systematic and comprehensive study covering 13 subtypes of salivary gland cancer, next generation sequencing was done on 84 tissue samples of parotid gland cancer using multiplex PCR for enrichment of cancer related gene loci covering hotspots of 46 cancer genes.Mutations were identified in 22 different genes. The most frequent alterations affected TP53, followed by RAS genes, PIK3CA, SMAD4 and members of the ERB family. HRAS mutations accounted for more than 90% of RAS mutations, occurring especially in epithelial-myoepithelial carcinomas and salivary duct carcinomas. Additional mutations in PIK3CA also affected particularly epithelial-myoepithelial carcinomas and salivary duct carcinomas, occurring simultaneously with HRAS mutations in almost all cases, pointing to an unknown and therapeutically relevant molecular constellation. Interestingly, 14% of tumors revealed mutations in surface growth factor receptor genes including ALK, HER2, ERBB4, FGFR, cMET and RET, which might prove to be targetable by new therapeutic agents. 6% of tumors revealed mutations in SMAD4.In summary, our data provide novel insight into the fundamental molecular heterogeneity of salivary gland cancer, relevant in terms of tumor classification and the establishment of targeted therapeutic concepts. PMID:26053092

  1. Genetic analyses reveal unusually high diversity of infectious haematopoietic necrosis virus in rainbow trout aquaculture

    USGS Publications Warehouse

    Troyer, Ryan M.; LaPatra, Scott E.; Kurath, Gael

    2000-01-01

    Infectious haematopoietic necrosis virus (IHNV) is the most significant virus pathogen of salmon and trout in North America. Previous studies have shown relatively low genetic diversity of IHNV within large geographical regions. In this study, the genetic heterogeneity of 84 IHNV isolates sampled from rainbow trout (Oncorhynchus mykiss) over a 20 year period at four aquaculture facilities within a 12 mile stretch of the Snake River in Idaho, USA was investigated. The virus isolates were characterized using an RNase protection assay (RPA) and nucleotide sequence analyses. Among the 84 isolates analysed, 46 RPA haplotypes were found and analyses revealed a high level of genetic heterogeneity relative to that detected in other regions. Sequence analyses revealed up to 7·6% nucleotide divergence, which is the highest level of diversity reported for IHNV to date. Phylogenetic analyses identified four distinct monophyletic clades representing four virus lineages. These lineages were distributed across facilities, and individual facilities contained multiple lineages. These results suggest that co-circulating IHNV lineages of relatively high genetic diversity are present in the IHNV populations in this rainbow trout culture study site. Three of the four lineages exhibited temporal trends consistent with rapid evolution.

  2. Gene expression profiling integrated into network modelling reveals heterogeneity in the mechanisms of BRCA1 tumorigenesis

    PubMed Central

    Fernández-Ramires, R; Solé, X; De Cecco, L; Llort, G; Cazorla, A; Bonifaci, N; Garcia, M J; Caldés, T; Blanco, I; Gariboldi, M; Pierotti, M A; Pujana, M A; Benítez, J; Osorio, A

    2009-01-01

    Background: Gene expression profiling has distinguished sporadic breast tumour classes with genetic and clinical differences. Less is known about the molecular classification of familial breast tumours, which are generally considered to be less heterogeneous. Here, we describe molecular signatures that define BRCA1 subclasses depending on the expression of the gene encoding for oestrogen receptor, ESR1. Methods: For this purpose, we have used the Oncochip v2, a cancer-related cDNA microarray to analyze 14 BRCA1-associated breast tumours. Results: Signatures were found to be molecularly associated with different biological processes and transcriptional regulatory programs. The signature of ESR1-positive tumours was mainly linked to cell proliferation and regulated by ER, whereas the signature of ESR1-negative tumours was mainly linked to the immune response and possibly regulated by transcription factors of the REL/NFκB family. These signatures were then verified in an independent series of familial and sporadic breast tumours, which revealed a possible prognostic value for each subclass. Over-expression of immune response genes seems to be a common feature of ER-negative sporadic and familial breast cancer and may be associated with good prognosis. Interestingly, the ESR1-negative tumours were substratified into two groups presenting slight differences in the magnitude of the expression of immune response transcripts and REL/NFκB transcription factors, which could be dependent on the type of BRCA1 germline mutation. Conclusion: This study reveals the molecular complexity of BRCA1 breast tumours, which are found to display similarities to sporadic tumours, and suggests possible prognostic implications. PMID:19826428

  3. Initial assessment of a model relating intratumoral genetic heterogeneity to radiological morphology

    PubMed Central

    Noterdaeme, O; Kelly, M; Friend, P; Soonowalla, Z; Steers, G; Brady, M

    2010-01-01

    Tumour heterogeneity has major implications for tumour development and response to therapy. Tumour heterogeneity results from mutations in the genes responsible for mismatch repair or maintenance of chromosomal stability. Cells with different genetic properties may grow at different rates and exhibit different resistance to therapeutic interventions. To date, there exists no approach to non-invasively assess tumour heterogeneity. Here we present a biologically inspired model of tumour growth, which relates intratumoral genetic heterogeneity to gross morphology visible on radiological images. The model represents the development of a tumour as a set of expanding spheres, each sphere representing a distinct clonal centre, with the sprouting of new spheres corresponding to new clonal centres. Each clonal centre may possess different characteristics relating to genetic composition, growth rate and response to treatment. We present a clinical example for which the model accurately tracks tumour growth and shows the correspondence to genetic variation (as determined by array comparative genomic hybridisation). One clinical implication of our work is that the assessment of heterogeneous tumours using Response Evaluation Criteria In Solid Tumours (RECIST) or volume measurements may not accurately reflect tumour growth, stability or the response to treatment. We believe that this is the first model linking the macro-scale appearance of tumours to their genetic composition. We anticipate that our model will provide a more informative way to assess the response of heterogeneous tumours to treatment, which is of increasing importance with the development of novel targeted anti-cancer treatments. PMID:19690073

  4. Unexpected allelic heterogeneity and spectrum of mutations in Fowler syndrome revealed by next-generation exome sequencing.

    PubMed

    Lalonde, Emilie; Albrecht, Steffen; Ha, Kevin C H; Jacob, Karine; Bolduc, Nathalie; Polychronakos, Constantin; Dechelotte, Pierre; Majewski, Jacek; Jabado, Nada

    2010-08-01

    Protein coding genes constitute approximately 1% of the human genome but harbor 85% of the mutations with large effects on disease-related traits. Therefore, efficient strategies for selectively sequencing complete coding regions (i.e., "whole exome") have the potential to contribute our understanding of human diseases. We used a method for whole-exome sequencing coupling Agilent whole-exome capture to the Illumina DNA-sequencing platform, and investigated two unrelated fetuses from nonconsanguineous families with Fowler Syndrome (FS), a stereotyped phenotype lethal disease. We report novel germline mutations in feline leukemia virus subgroup C cellular-receptor-family member 2, FLVCR2, which has recently been shown to cause FS. Using this technology, we identified three types of genetic abnormalities: point-mutations, insertions-deletions, and intronic splice-site changes (first pathogenic report using this technology), in the fetuses who both were compound heterozygotes for the disease. Although revealing a high level of allelic heterogeneity and mutational spectrum in FS, this study further illustrates the successful application of whole-exome sequencing to uncover genetic defects in rare Mendelian disorders. Of importance, we show that we can identify genes underlying rare, monogenic and recessive diseases using a limited number of patients (n=2), in the absence of shared genetic heritage and in the presence of allelic heterogeneity. PMID:20518025

  5. Genetic heterogeneity of polycystic kidney disease in Bulgaria

    SciTech Connect

    Bogdanova, N. |; Dragova, D.; Kalaydiieva, L.

    1994-09-01

    Autosomal dominant polycystic kidney disease (PKD) is a common genetic disorder whose frequency in Bulgaria has been estimated at 1 in 950. One gene (PKD1) causing this disease has been mapped to the short arm of chromosome 16 in 1985. Linkage analysis showed that in a considerable proportion of PKD families (approximately 14% in Europe) the disease is not linked to this locus, suggesting the existance of mutations in additional genes. In 1993 a PKD2-gene has been mapped to the long arm of chromosome 4. Here we report data of the first extensive investigation of PKD in Bulgaria. Initially 35 families with 341 individuals (178 affected, 89 unaffected family members, 74 spouses) were included in the study. Clinical diagnosis, mainly based on ultrasonographic examination of the kidneys, has been performed for all individuals. Linkage analysis was performed on 22 large pedigrees with microsatellites 16SC2.5 (D16S291) and SM7 (D16S283), which are closely linked to the PKD1 locus, as well as microsatellites D4S392, D4S400, D4S231 (proximal to the PDK2 locus) and D4S423, D4S414, D4S411 (distal to PKD2 locus). The study showed that the disease is caused in 14 families by mutations within the PKD1 gene and was clearly linked to the PDK2 locus in 5 families. In 3 families no clear conclusions about the linkage could be reached and analysis of additional markers from this region is in progress. The investigation has revealed the highest proportion of PKD2 families reported so far in Europe (23%). In addition, comparison of the severity of the clinical course of PKD1 and PKD2 families failed to confirm statistically significant differences which have been reported.

  6. A Comprehensive Genomic Analysis Reveals the Genetic Landscape of Mitochondrial Respiratory Chain Complex Deficiencies.

    PubMed

    Kohda, Masakazu; Tokuzawa, Yoshimi; Kishita, Yoshihito; Nyuzuki, Hiromi; Moriyama, Yohsuke; Mizuno, Yosuke; Hirata, Tomoko; Yatsuka, Yukiko; Yamashita-Sugahara, Yzumi; Nakachi, Yutaka; Kato, Hidemasa; Okuda, Akihiko; Tamaru, Shunsuke; Borna, Nurun Nahar; Banshoya, Kengo; Aigaki, Toshiro; Sato-Miyata, Yukiko; Ohnuma, Kohei; Suzuki, Tsutomu; Nagao, Asuteka; Maehata, Hazuki; Matsuda, Fumihiko; Higasa, Koichiro; Nagasaki, Masao; Yasuda, Jun; Yamamoto, Masayuki; Fushimi, Takuya; Shimura, Masaru; Kaiho-Ichimoto, Keiko; Harashima, Hiroko; Yamazaki, Taro; Mori, Masato; Murayama, Kei; Ohtake, Akira; Okazaki, Yasushi

    2016-01-01

    Mitochondrial disorders have the highest incidence among congenital metabolic disorders characterized by biochemical respiratory chain complex deficiencies. It occurs at a rate of 1 in 5,000 births, and has phenotypic and genetic heterogeneity. Mutations in about 1,500 nuclear encoded mitochondrial proteins may cause mitochondrial dysfunction of energy production and mitochondrial disorders. More than 250 genes that cause mitochondrial disorders have been reported to date. However exact genetic diagnosis for patients still remained largely unknown. To reveal this heterogeneity, we performed comprehensive genomic analyses for 142 patients with childhood-onset mitochondrial respiratory chain complex deficiencies. The approach includes whole mtDNA and exome analyses using high-throughput sequencing, and chromosomal aberration analyses using high-density oligonucleotide arrays. We identified 37 novel mutations in known mitochondrial disease genes and 3 mitochondria-related genes (MRPS23, QRSL1, and PNPLA4) as novel causative genes. We also identified 2 genes known to cause monogenic diseases (MECP2 and TNNI3) and 3 chromosomal aberrations (6q24.3-q25.1, 17p12, and 22q11.21) as causes in this cohort. Our approaches enhance the ability to identify pathogenic gene mutations in patients with biochemically defined mitochondrial respiratory chain complex deficiencies in clinical settings. They also underscore clinical and genetic heterogeneity and will improve patient care of this complex disorder. PMID:26741492

  7. A Comprehensive Genomic Analysis Reveals the Genetic Landscape of Mitochondrial Respiratory Chain Complex Deficiencies

    PubMed Central

    Nyuzuki, Hiromi; Moriyama, Yohsuke; Mizuno, Yosuke; Hirata, Tomoko; Yatsuka, Yukiko; Yamashita-Sugahara, Yzumi; Nakachi, Yutaka; Kato, Hidemasa; Okuda, Akihiko; Tamaru, Shunsuke; Borna, Nurun Nahar; Banshoya, Kengo; Aigaki, Toshiro; Sato-Miyata, Yukiko; Ohnuma, Kohei; Suzuki, Tsutomu; Nagao, Asuteka; Maehata, Hazuki; Matsuda, Fumihiko; Higasa, Koichiro; Nagasaki, Masao; Yasuda, Jun; Yamamoto, Masayuki; Fushimi, Takuya; Shimura, Masaru; Kaiho-Ichimoto, Keiko; Harashima, Hiroko; Yamazaki, Taro; Mori, Masato; Murayama, Kei; Ohtake, Akira; Okazaki, Yasushi

    2016-01-01

    Mitochondrial disorders have the highest incidence among congenital metabolic disorders characterized by biochemical respiratory chain complex deficiencies. It occurs at a rate of 1 in 5,000 births, and has phenotypic and genetic heterogeneity. Mutations in about 1,500 nuclear encoded mitochondrial proteins may cause mitochondrial dysfunction of energy production and mitochondrial disorders. More than 250 genes that cause mitochondrial disorders have been reported to date. However exact genetic diagnosis for patients still remained largely unknown. To reveal this heterogeneity, we performed comprehensive genomic analyses for 142 patients with childhood-onset mitochondrial respiratory chain complex deficiencies. The approach includes whole mtDNA and exome analyses using high-throughput sequencing, and chromosomal aberration analyses using high-density oligonucleotide arrays. We identified 37 novel mutations in known mitochondrial disease genes and 3 mitochondria-related genes (MRPS23, QRSL1, and PNPLA4) as novel causative genes. We also identified 2 genes known to cause monogenic diseases (MECP2 and TNNI3) and 3 chromosomal aberrations (6q24.3-q25.1, 17p12, and 22q11.21) as causes in this cohort. Our approaches enhance the ability to identify pathogenic gene mutations in patients with biochemically defined mitochondrial respiratory chain complex deficiencies in clinical settings. They also underscore clinical and genetic heterogeneity and will improve patient care of this complex disorder. PMID:26741492

  8. Novel Genetic and Phenotypic Heterogeneity in Bordetella bronchiseptica Pertactin

    PubMed Central

    Register, Karen B.

    2001-01-01

    The Bordetella bronchiseptica outer membrane protein pertactin is believed to function as an adhesin and is an important protective immunogen. Previous sequence analysis of the pertactin gene identified two regions predicted to encode amino acid repeat motifs. Recent studies have documented DNA sequence heterogeneity in both regions. The present study describes additional variants in these regions, which form the basis for six novel pertactin types. Immunoblotting demonstrated phenotypic heterogeneity in pertactin consistent with the predicted combined sizes of the repeat regions. A revised system for classifying B. bronchiseptica pertactin variants is proposed. PMID:11179374

  9. Genetic heterogeneity of RPMI-8402, a T-acute lymphoblastic leukemia cell line

    PubMed Central

    STOCZYNSKA-FIDELUS, EWELINA; PIASKOWSKI, SYLWESTER; PAWLOWSKA, ROZA; SZYBKA, MALGORZATA; PECIAK, JOANNA; HULAS-BIGOSZEWSKA, KRYSTYNA; WINIECKA-KLIMEK, MARTA; RIESKE, PIOTR

    2016-01-01

    Thorough examination of genetic heterogeneity of cell lines is uncommon. In order to address this issue, the present study analyzed the genetic heterogeneity of RPMI-8402, a T-acute lymphoblastic leukemia (T-ALL) cell line. For this purpose, traditional techniques such as fluorescence in situ hybridization and immunocytochemistry were used, in addition to more advanced techniques, including cell sorting, Sanger sequencing and massive parallel sequencing. The results indicated that the RPMI-8402 cell line consists of several genetically different cell subpopulations. Furthermore, massive parallel sequencing of RPMI-8402 provided insight into the evolution of T-ALL carcinogenesis, since this cell line exhibited the genetic heterogeneity typical of T-ALL. Therefore, the use of cell lines for drug testing in future studies may aid the progress of anticancer drug research. PMID:26870252

  10. Genetic heterogeneity in autism: From single gene to a pathway perspective.

    PubMed

    An, Joon Yong; Claudianos, Charles

    2016-09-01

    The extreme genetic heterogeneity of autism spectrum disorder (ASD) represents a major challenge. Recent advances in genetic screening and systems biology approaches have extended our knowledge of the genetic etiology of ASD. In this review, we discuss the paradigm shift from a single gene causation model to pathway perturbation model as a guide to better understand the pathophysiology of ASD. We discuss recent genetic findings obtained through next-generation sequencing (NGS) and examine various integrative analyses using systems biology and complex networks approaches that identify convergent patterns of genetic elements associated with ASD. PMID:27317861

  11. Does Genetic Variation Maintained by Environmental Heterogeneity Facilitate Adaptation to Novel Selection?

    PubMed

    Huang, Yuheng; Tran, Ivan; Agrawal, Aneil F

    2016-07-01

    Environmental heterogeneity helps maintain genetic variation in fitness. Therefore, one might predict that populations living in heterogeneous environments have higher adaptive potential than populations living in homogeneous environments. Such a prediction could be useful in guiding conservation priorities without requiring detailed genetic studies. However, this prediction will be true only if the additional genetic variation maintained by environmental heterogeneity can be used to respond to novel selection. Here we examine the effect of environmental heterogeneity on future adaptability using replicated experimental Drosophila melanogaster populations that had previously evolved for ∼100 generations under one of four selective regimes: constant salt-enriched larvae medium, constant cadmium-enriched larvae medium, and two heterogeneous regimes that vary either temporally or spatially between the two media. Replicates of these experimental populations were subjected to a novel heat stress while being maintained in their original larval diet selection regimes. Adaptation to increased temperature was measured with respect to female productivity and male siring success after ∼20 generations. For female productivity, there was evidence of adaptation overall and heterogeneous populations had a larger adaptive response than homogeneous populations. There was less evidence of adaptation overall for male siring success and no support for faster adaptation in heterogeneous populations. PMID:27322119

  12. Clinical and genetic heterogeneity in hereditary spastic paraplegias: from SPG1 to SPG72 and still counting.

    PubMed

    Klebe, S; Stevanin, G; Depienne, C

    2015-01-01

    Hereditary spastic paraplegias (HSPs) are genetically determined neurodegenerative disorders characterized by progressive weakness and spasticity of lower limbs, and are among the most clinically and genetically heterogeneous human diseases. All modes of inheritance have been described, and the recent technological revolution in molecular genetics has led to the identification of 76 different spastic gait disease-loci with 59 corresponding spastic paraplegia genes. Autosomal recessive HSP are usually associated with diverse additional features (referred to as complicated forms), contrary to autosomal dominant HSP, which are mostly pure. However, the identification of additional mutations and families has considerably enlarged the clinical spectra, and has revealed a huge clinical variability for almost all HSP; complicated forms have also been described for primary pure HSP subtypes, adding further complexity to the genotype-phenotype correlations. In addition, the introduction of next generation sequencing in clinical practice has revealed a genetic and phenotypic overlap with other neurodegenerative disorders (amyotrophic lateral sclerosis, neuropathies, cerebellar ataxias, etc.) and neurodevelopmental disorders, including intellectual disability. This review aims to describe the most recent advances in the field and to provide genotype-phenotype correlations that could help clinical diagnoses of this heterogeneous group of disorders. PMID:26008818

  13. Environmental heterogeneity explains the genetic structure of Continental and Mediterranean populations of Fraxinus angustifolia Vahl.

    PubMed

    Temunović, Martina; Franjić, Jozo; Satovic, Zlatko; Grgurev, Marin; Frascaria-Lacoste, Nathalie; Fernández-Manjarrés, Juan F

    2012-01-01

    Tree species with wide distributions often exhibit different levels of genetic structuring correlated to their environment. However, understanding how environmental heterogeneity influences genetic variation is difficult because the effects of gene flow, drift and selection are confounded. We investigated the genetic variation and its ecological correlates in a wind-pollinated Mediterranean tree species, Fraxinus angustifolia Vahl, within a recognised glacial refugium in Croatia. We sampled 11 populations from environmentally divergent habitats within the Continental and Mediterranean biogeographical regions. We combined genetic data analyses based on nuclear microsatellite loci, multivariate statistics on environmental data and ecological niche modelling (ENM). We identified a geographic structure with a high genetic diversity and low differentiation in the Continental region, which contrasted with the significantly lower genetic diversity and higher population divergence in the Mediterranean region. The positive and significant correlation between environmental and genetic distances after controlling for geographic distance suggests an important influence of ecological divergence of the sites in shaping genetic variation. The ENM provided support for niche differentiation between the populations from the Continental and Mediterranean regions, suggesting that contemporary populations may represent two divergent ecotypes. Ecotype differentiation was also supported by multivariate environmental and genetic distance analyses. Our results suggest that despite extensive gene flow in continental areas, long-term stability of heterogeneous environments have likely promoted genetic divergence of ashes in this region and can explain the present-day genetic variation patterns of these ancient populations. PMID:22905171

  14. Environmental Heterogeneity Explains the Genetic Structure of Continental and Mediterranean Populations of Fraxinus angustifolia Vahl

    PubMed Central

    Temunović, Martina; Franjić, Jozo; Satovic, Zlatko; Grgurev, Marin; Frascaria-Lacoste, Nathalie; Fernández-Manjarrés, Juan F.

    2012-01-01

    Tree species with wide distributions often exhibit different levels of genetic structuring correlated to their environment. However, understanding how environmental heterogeneity influences genetic variation is difficult because the effects of gene flow, drift and selection are confounded. We investigated the genetic variation and its ecological correlates in a wind-pollinated Mediterranean tree species, Fraxinus angustifolia Vahl, within a recognised glacial refugium in Croatia. We sampled 11 populations from environmentally divergent habitats within the Continental and Mediterranean biogeographical regions. We combined genetic data analyses based on nuclear microsatellite loci, multivariate statistics on environmental data and ecological niche modelling (ENM). We identified a geographic structure with a high genetic diversity and low differentiation in the Continental region, which contrasted with the significantly lower genetic diversity and higher population divergence in the Mediterranean region. The positive and significant correlation between environmental and genetic distances after controlling for geographic distance suggests an important influence of ecological divergence of the sites in shaping genetic variation. The ENM provided support for niche differentiation between the populations from the Continental and Mediterranean regions, suggesting that contemporary populations may represent two divergent ecotypes. Ecotype differentiation was also supported by multivariate environmental and genetic distance analyses. Our results suggest that despite extensive gene flow in continental areas, long-term stability of heterogeneous environments have likely promoted genetic divergence of ashes in this region and can explain the present-day genetic variation patterns of these ancient populations. PMID:22905171

  15. Endogenous molecular network reveals two mechanisms of heterogeneity within gastric cancer

    PubMed Central

    Li, Site; Zhu, Xiaomei; Liu, Bingya; Wang, Gaowei; Ao, Ping

    2015-01-01

    Intratumor heterogeneity is a common phenomenon and impedes cancer therapy and research. Gastric cancer (GC) cells have generally been classified into two heterogeneous cellular phenotypes, the gastric and intestinal types, yet the mechanisms of maintaining two phenotypes and controlling phenotypic transition are largely unknown. A qualitative systematic framework, the endogenous molecular network hypothesis, has recently been proposed to understand cancer genesis and progression. Here, a minimal network corresponding to such framework was found for GC and was quantified via a stochastic nonlinear dynamical system. We then further extended the framework to address the important question of intratumor heterogeneity quantitatively. The working network characterized main known features of normal gastric epithelial and GC cell phenotypes. Our results demonstrated that four positive feedback loops in the network are critical for GC cell phenotypes. Moreover, two mechanisms that contribute to GC cell heterogeneity were identified: particular positive feedback loops are responsible for the maintenance of intestinal and gastric phenotypes; GC cell progression routes that were revealed by the dynamical behaviors of individual key components are heterogeneous. In this work, we constructed an endogenous molecular network of GC that can be expanded in the future and would broaden the known mechanisms of intratumor heterogeneity. PMID:25962957

  16. Environmental and genetic perturbations reveal different networks of metabolic regulation

    PubMed Central

    Greenberg, Anthony J; Hackett, Sean R; Harshman, Lawrence G; Clark, Andrew G

    2011-01-01

    Progress in systems biology depends on accurate descriptions of biological networks. Connections in a regulatory network are identified as correlations of gene expression across a set of environmental or genetic perturbations. To use this information to predict system behavior, we must test how the nature of perturbations affects topologies of networks they reveal. To probe this question, we focused on metabolism of Drosophila melanogaster. Our source of perturbations is a set of crosses among 92 wild-derived lines from five populations, replicated in a manner permitting separate assessment of the effects of genetic variation and environmental fluctuation. We directly assayed activities of enzymes and levels of metabolites. Using a multivariate Bayesian model, we estimated covariance among metabolic parameters and built fine-grained probabilistic models of network topology. The environmental and genetic co-regulation networks are substantially the same among five populations. However, genetic and environmental perturbations reveal qualitative differences in metabolic regulation, suggesting that environmental shifts, such as diet modifications, produce different systemic effects than genetic changes, even if the primary targets are the same. PMID:22186737

  17. A genomewide association study of autism using the Simons Simplex Collection: Does reducing phenotypic heterogeneity in autism increase genetic homogeneity?

    PubMed Central

    Chaste, Pauline; Klei, Lambertus; Sanders, Stephan J.; Hus, Vanessa; Murtha, Michael T.; Lowe, Jennifer K.; Willsey, A. Jeremy; Moreno-De-Luca, Daniel; Yu, Timothy W.; Fombonne, Eric; Geschwind, Daniel; Grice, Dorothy E.; Ledbetter, David H.; Mane, Shrikant M.; Martin, Donna M.; Morrow, Eric M.; Walsh, Christopher A.; Sutcliffe, James S.; Martin, Christa Lese; Beaudet, Arthur L.; Lord, Catherine; State, Matthew W.; Cook, Edwin H.; Devlin, Bernie

    2014-01-01

    Background Phenotypic heterogeneity in autism has long been conjectured to be a major hindrance to the discovery of genetic risk factors, leading to numerous attempts to stratify children based on phenotype to increase power of discovery studies. This approach, however, is based on the hypothesis that phenotypic heterogeneity closely maps to genetic variation, which has not been tested. Our study examines the impact of sub-phenotyping of a well-characterized ASD sample on genetic homogeneity and the ability to discover common genetic variants conferring liability to ASD. Methods Genome-wide genotypic data of 2576 families from the Simons Simplex Collection (SSC) were analyzed in the overall sample and phenotypic subgroups defined on the basis of diagnosis, IQ, and symptom profiles. We conducted a family-based association study as well as estimating heritability and evaluating allele scores for each phenotypic subgroup. Results Association analyses revealed no genome-wide significant association signal. Sub-phenotyping did not increase power substantially. Moreover, allele scores built from the most associated SNPs, based on the odds ratio in the full sample, predicted case status in subsets of the sample equally well and heritability estimates were very similar for all subgroups. Conclusions In genome-wide association analysis of the SSC sample, reducing phenotypic heterogeneity had at most a modest impact on genetic homogeneity. Our results are based on a relatively small sample, one with greater homogeneity than the entire population; if they apply more broadly, they imply that analysis of sub-phenotypes is not a productive path forward for discovering genetic risk variants in ASD. PMID:25534755

  18. Global Population Genetic Structure of Caenorhabditis remanei Reveals Incipient Speciation

    PubMed Central

    Dey, Alivia; Jeon, Yong; Wang, Guo-Xiu; Cutter, Asher D.

    2012-01-01

    Mating system transitions dramatically alter the evolutionary trajectories of genomes that can be revealed by contrasts of species with disparate modes of reproduction. For such transitions in Caenorhabditis nematodes, some major causes of genome variation in selfing species have been discerned. And yet, we have only limited understanding of species-wide population genetic processes for their outcrossing relatives, which represent the reproductive state of the progenitors of selfing species. Multilocus–multipopulation sequence polymorphism data provide a powerful means to uncover the historical demography and evolutionary processes that shape genomes. Here we survey nucleotide polymorphism across the X chromosome for three populations of the outcrossing nematode Caenorhabditis remanei and demonstrate its divergence from a fourth population describing a closely related new species from China, C. sp. 23. We find high genetic variation globally and within each local population sample. Despite geographic barriers and moderate genetic differentiation between Europe and North America, considerable gene flow connects C. remanei populations. We discovered C. sp. 23 while investigating C. remanei, observing strong genetic differentiation characteristic of reproductive isolation that was confirmed by substantial F2 hybrid breakdown in interspecific crosses. That C. sp. 23 represents a distinct biological species provides a cautionary example of how standard practice can fail for mating tests of species identity in this group. This species pair permits full application of divergence population genetic methods to obligately outcrossing species of Caenorhabditis and also presents a new focus for interrogation of the genetics and evolution of speciation with the Caenorhabditis model system. PMID:22649079

  19. Detecting spatial genetic signatures of local adaptation in heterogeneous landscapes.

    PubMed

    Forester, Brenna R; Jones, Matthew R; Joost, Stéphane; Landguth, Erin L; Lasky, Jesse R

    2016-01-01

    The spatial structure of the environment (e.g. the configuration of habitat patches) may play an important role in determining the strength of local adaptation. However, previous studies of habitat heterogeneity and local adaptation have largely been limited to simple landscapes, which poorly represent the multiscale habitat structure common in nature. Here, we use simulations to pursue two goals: (i) we explore how landscape heterogeneity, dispersal ability and selection affect the strength of local adaptation, and (ii) we evaluate the performance of several genotype-environment association (GEA) methods for detecting loci involved in local adaptation. We found that the strength of local adaptation increased in spatially aggregated selection regimes, but remained strong in patchy landscapes when selection was moderate to strong. Weak selection resulted in weak local adaptation that was relatively unaffected by landscape heterogeneity. In general, the power of detection methods closely reflected levels of local adaptation. False-positive rates (FPRs), however, showed distinct differences across GEA methods based on levels of population structure. The univariate GEA approach had high FPRs (up to 55%) under limited dispersal scenarios, due to strong isolation by distance. By contrast, multivariate, ordination-based methods had uniformly low FPRs (0-2%), suggesting these approaches can effectively control for population structure. Specifically, constrained ordinations had the best balance of high detection and low FPRs and will be a useful addition to the GEA toolkit. Our results provide both theoretical and practical insights into the conditions that shape local adaptation and how these conditions impact our ability to detect selection. PMID:26576498

  20. Multiregion Whole-Exome Sequencing Uncovers the Genetic Evolution and Mutational Heterogeneity of Early-Stage Metastatic Melanoma.

    PubMed

    Harbst, Katja; Lauss, Martin; Cirenajwis, Helena; Isaksson, Karolin; Rosengren, Frida; Törngren, Therese; Kvist, Anders; Johansson, Maria C; Vallon-Christersson, Johan; Baldetorp, Bo; Borg, Åke; Olsson, Håkan; Ingvar, Christian; Carneiro, Ana; Jönsson, Göran

    2016-08-15

    Cancer genome sequencing has shed light on the underlying genetic aberrations that drive tumorigenesis. However, current sequencing-based strategies, which focus on a single tumor biopsy, fail to take into account intratumoral heterogeneity. To address this challenge and elucidate the evolutionary history of melanoma, we performed whole-exome and transcriptome sequencing of 41 multiple melanoma biopsies from eight individual tumors. This approach revealed heterogeneous somatic mutations in the range of 3%-38% in individual tumors. Known mutations in melanoma drivers BRAF and NRAS were always ubiquitous events. Using RNA sequencing, we found that the majority of mutations were not expressed or were expressed at very low levels, and preferential expression of a particular mutated allele did not occur frequently. In addition, we found that the proportion of ultraviolet B (UVB) radiation-induced C>T transitions differed significantly (P < 0.001) between early and late mutation acquisition, suggesting that different mutational processes operate during the evolution of metastatic melanoma. Finally, clinical history reports revealed that patients harboring a high degree of mutational heterogeneity were associated with more aggressive disease progression. In conclusion, our multiregion tumor-sequencing approach highlights the genetic evolution and non-UVB mutational signatures associated with melanoma development and progression, and may provide a more comprehensive perspective of patient outcome. Cancer Res; 76(16); 4765-74. ©2016 AACR. PMID:27216186

  1. Heterogeneity of Mesp1+ mesoderm revealed by single-cell RNA-seq.

    PubMed

    Chan, Sunny Sun-Kin; Chan, Howe H W; Kyba, Michael

    2016-06-01

    Mesp1 is a transcription factor that promotes differentiation of pluripotent cells into different mesoderm lineages including hematopoietic, cardiac and skeletal myogenic. This occurs via at least two transient cell populations: a common hematopoietic/cardiac progenitor population and a common cardiac/skeletal myogenic progenitor population. It is not established whether Mesp1-induced mesoderm cells are intrinsically heterogeneous, or are simply capable of multiple lineage decisions. In the current study, we applied single-cell RNA-seq to analyze Mesp1+ mesoderm. Initial whole transcriptome analysis showed a surprising homogeneity among Mesp1-induced mesoderm cells. However, this apparent global homogeneity masked an intrinsic heterogeneity revealed by interrogating a panel of early mesoderm patterning factors. This approach enabled discovery of subpopulations primed for hematopoietic or cardiac development. These studies demonstrate the heterogeneic nature of Mesp1+ mesoderm. PMID:27131741

  2. Cellular heterogeneity profiling by hyaluronan probes reveals an invasive but slow-growing breast tumor subset

    PubMed Central

    Veiseh, Mandana; Kwon, Daniel H.; Borowsky, Alexander D.; Tolg, Cornelia; Leong, Hon S.; Lewis, John D.; Turley, Eva A.; Bissell, Mina J.

    2014-01-01

    Tumor heterogeneity confounds cancer diagnosis and the outcome of therapy, necessitating analysis of tumor cell subsets within the tumor mass. Elevated expression of hyaluronan (HA) and HA receptors, receptor for HA-mediated motility (RHAMM)/HA-mediated motility receptor and cluster designation 44 (CD44), in breast tumors correlates with poor outcome. We hypothesized that a probe for detecting HA–HA receptor interactions may reveal breast cancer (BCa) cell heterogeneity relevant to tumor progression. A fluorescent HA (F-HA) probe containing a mixture of polymer sizes typical of tumor microenvironments (10–480 kDa), multiplexed profiling, and flow cytometry were used to monitor HA binding to BCa cell lines of different molecular subtypes. Formulae were developed to quantify binding heterogeneity and to measure invasion in vivo. Two subsets exhibiting differential binding (HA−/low vs. HAhigh) were isolated and characterized for morphology, growth, and invasion in culture and as xenografts in vivo. F-HA–binding amounts and degree of heterogeneity varied with BCa subtype, were highest in the malignant basal-like cell lines, and decreased upon reversion to a nonmalignant phenotype. Binding amounts correlated with CD44 and RHAMM displayed but binding heterogeneity appeared to arise from a differential ability of HA receptor-positive subpopulations to interact with F-HA. HAhigh subpopulations exhibited significantly higher local invasion and lung micrometastases but, unexpectedly, lower proliferation than either unsorted parental cells or the HA−/low subpopulation. Querying F-HA binding to aggressive tumor cells reveals a previously undetected form of heterogeneity that predicts invasive/metastatic behavior and that may aid both early identification of cancer patients susceptible to metastasis, and detection/therapy of invasive BCa subpopulations. PMID:24733940

  3. Genetic Heterogeneity in the rRNA Gene Locus of Trichophyton tonsurans

    PubMed Central

    Gaedigk, Andrea; Gaedigk, Roger; Abdel-Rahman, Susan M.

    2003-01-01

    Trichophyton tonsurans is the major pediatric pathogen in tinea capitis, causing disparate disease presentations. Little is known about genetic variation, which may ultimately be linked to divergent disease status. This investigation was aimed at identifying genetic variants of T. tonsurans by methods that can facilitate strain discrimination in population-based studies. Ninety-two isolates were acquired from six U.S. microbiology laboratories, and genomic DNA was isolated from mature colonies. The nontranscribed spacer (NTS) was amplified by PCR, and products from isolates with various amplicon sizes were fully sequenced. Nested amplification, targeting a variable internal repeat (VIR) region, allowed assignment of variant type by fragment size. Subvariant type was assigned by a combination of PCR-restriction fragment length polymorphism-based assays. Five variants differing in size (348 to 700 bp) and sequence were identified within the VIR region comprised of several large repeats (104, 140, and 194 bp) arranged in tandem. Seven single-nucleotide polymorphisms (SNPs) were detected across the NTS, with five occurring in the constant regions flanking the VIR region and two occurring in the VIR region. Additionally, a 10-bp insertion and a 14-bp deletion were identified upstream of the VIR region. The combination of SNPs revealed seven haplotype patterns which were stable upon serial passage over 1 year. No sequence variations were identified within the internal transcribed spacer regions. Unique NTS sequences were utilized to develop a duplex PCR assay that discriminated T. tonsurans from other dermatophytes. Of the 92 isolates evaluated, this genotyping scheme distinguished 12 distinct strains, providing evidence of genetic heterogeneity in T. tonsurans. PMID:14662928

  4. Genetic heterogeneity and population structure of Gond-related tribes in the Vidarbha region of Maharashtra.

    PubMed

    Rao, V R; Sathe, M S; Gorakshakar, A C; Vasantha, K

    1992-12-01

    Genetic heterogeneity in nine polymorphic loci is observed among Gond-related tribes in the Vidarbha region of Maharashtra. Pardhans, with their high ABO*A2 gene frequency (4.01%), low m gene frequency (57%), high P*1 gene frequency (42.7%), and high HbS trait (31.58%), differ significantly from other tribes. Per locus average heterozygosity among the studied tribes ranged from 36.24% to 40.37%, with Pardhans being more heterozygous. Analysis by FST and the empirical relationship between average allele frequencies and the ratio of within-gene to total gene diversity show that the tribes are isolated and that differentiation among them is at an early stage and approximately in conformity with expected differentiation under genetic drift. However, distances and principal components analysis reveal that Pardhans are far removed from the other tribes and from other central Dravidian tribes. Furthermore, of the various demographic parameters estimated, the high average heterozygosity in Pardhans is significantly correlated with mean marital distance (MMD), regression of MMD on wife's age, and effective population size. There is congruence between genetic and demographic data, showing that Pardhans are distinct. This conforms with Haimendorf's (1979) contention based on cultural traits that Pardhans are Gonds by historical accident and are later migrants to the Gond area from the north. The most significant and practical observation of the present study is that migration from an originally nontribal (Pardhan) to a tribal (Gond) area and admixture lead to severe disease course, differential selection pressure, and hence highly elevated HbS trait frequency. PMID:1427746

  5. Extensive genetic heterogeneity in the neuroblastoma cell line NB(TU)1.

    PubMed

    Inoue, A; Yokomori, K; Tanabe, H; Mizusawa, H; Sofuni, T; Hayashi, Y; Tsuchida, Y; Shimatake, H

    1997-09-17

    A neuroblastoma cell line displaying genetically unique features was established from a stage III case of a 20-month-old girl. Southern blotting by the probe pTNB6, which contains exon 1 of the N-myc gene, showed that the primary tumor had in total 4 aberrant bands beside the normal amplified band. The established cell line NB(TU)1 had an aberrant N-myc band (9.0 kb) in addition to the normal band (2.9 kb). Cytogenetic analysis revealed that NB(TU)1 has a composite karyotype composed of at least 7 related karyotypes, which are pseudo-diploid and contain complex chromosomal abnormalities, including translocations, deletions and homogeneously staining regions (HSRs). Such extensive abnormalities were considered to be prominent among known neuroblastoma cell lines, and it was suggested that NB(TU)1 had acquired a certain type of genetic instability. Analysis of N-myc bands in 11 clones of NB(TU)1 showed that the intensity ratio of the normal-sized band (2.9 kb) and the aberrant one (9.0 kb) markedly varied among clones. Moreover, 3 clones showed an additional band with the size of 3.7 kb, which was detectable neither in the parent NB(TU)1 nor in the primary tumor. Thus, NB(TU)1 was shown to be composed of heterogeneous cell components. To further detect such ongoing chromosomal instability, we examined micronuclei formation. NB(TU)1 yielded a larger number of micronuclei than 5 other neuroblastoma cell lines. We conclude that NB(TU)1 has acquired genetic instability detectable by both Southern blotting and cytogenetic analysis. PMID:9378542

  6. Heterogeneity in Genetic Admixture across Different Regions of Argentina

    PubMed Central

    Avena, Sergio; Via, Marc; Ziv, Elad; Pérez-Stable, Eliseo J.; Gignoux, Christopher R.; Dejean, Cristina; Huntsman, Scott; Torres-Mejía, Gabriela; Dutil, Julie; Matta, Jaime L.; Beckman, Kenneth; Burchard, Esteban González; Parolin, María Laura; Goicoechea, Alicia; Acreche, Noemí; Boquet, Mariel; Ríos Part, María Del Carmen; Fernández, Vanesa; Rey, Jorge; Stern, Mariana C.; Carnese, Raúl F.; Fejerman, Laura

    2012-01-01

    The population of Argentina is the result of the intermixing between several groups, including Indigenous American, European and African populations. Despite the commonly held idea that the population of Argentina is of mostly European origin, multiple studies have shown that this process of admixture had an impact in the entire Argentine population. In the present study we characterized the distribution of Indigenous American, European and African ancestry among individuals from different regions of Argentina and evaluated the level of discrepancy between self-reported grandparental origin and genetic ancestry estimates. A set of 99 autosomal ancestry informative markers (AIMs) was genotyped in a sample of 441 Argentine individuals to estimate genetic ancestry. We used non-parametric tests to evaluate statistical significance. The average ancestry for the Argentine sample overall was 65% European (95%CI: 63–68%), 31% Indigenous American (28–33%) and 4% African (3–4%). We observed statistically significant differences in European ancestry across Argentine regions [Buenos Aires province (BA) 76%, 95%CI: 73–79%; Northeast (NEA) 54%, 95%CI: 49–58%; Northwest (NWA) 33%, 95%CI: 21–41%; South 54%, 95%CI: 49–59%; p<0.0001] as well as between the capital and immediate suburbs of Buenos Aires city compared to more distant suburbs [80% (95%CI: 75–86%) versus 68% (95%CI: 58–77%), p = 0.01]. European ancestry among individuals that declared all grandparents born in Europe was 91% (95%CI: 88–94%) compared to 54% (95%CI: 51–57%) among those with no European grandparents (p<0.001). Our results demonstrate the range of variation in genetic ancestry among Argentine individuals from different regions in the country, highlighting the importance of taking this variation into account in genetic association and admixture mapping studies in this population. PMID:22506044

  7. Heterogeneity in genetic admixture across different regions of Argentina.

    PubMed

    Avena, Sergio; Via, Marc; Ziv, Elad; Pérez-Stable, Eliseo J; Gignoux, Christopher R; Dejean, Cristina; Huntsman, Scott; Torres-Mejía, Gabriela; Dutil, Julie; Matta, Jaime L; Beckman, Kenneth; Burchard, Esteban González; Parolin, María Laura; Goicoechea, Alicia; Acreche, Noemí; Boquet, Mariel; Ríos Part, María Del Carmen; Fernández, Vanesa; Rey, Jorge; Stern, Mariana C; Carnese, Raúl F; Fejerman, Laura

    2012-01-01

    The population of Argentina is the result of the intermixing between several groups, including Indigenous American, European and African populations. Despite the commonly held idea that the population of Argentina is of mostly European origin, multiple studies have shown that this process of admixture had an impact in the entire Argentine population. In the present study we characterized the distribution of Indigenous American, European and African ancestry among individuals from different regions of Argentina and evaluated the level of discrepancy between self-reported grandparental origin and genetic ancestry estimates. A set of 99 autosomal ancestry informative markers (AIMs) was genotyped in a sample of 441 Argentine individuals to estimate genetic ancestry. We used non-parametric tests to evaluate statistical significance. The average ancestry for the Argentine sample overall was 65% European (95%CI: 63-68%), 31% Indigenous American (28-33%) and 4% African (3-4%). We observed statistically significant differences in European ancestry across Argentine regions [Buenos Aires province (BA) 76%, 95%CI: 73-79%; Northeast (NEA) 54%, 95%CI: 49-58%; Northwest (NWA) 33%, 95%CI: 21-41%; South 54%, 95%CI: 49-59%; p<0.0001] as well as between the capital and immediate suburbs of Buenos Aires city compared to more distant suburbs [80% (95%CI: 75-86%) versus 68% (95%CI: 58-77%), p = 0.01]. European ancestry among individuals that declared all grandparents born in Europe was 91% (95%CI: 88-94%) compared to 54% (95%CI: 51-57%) among those with no European grandparents (p<0.001). Our results demonstrate the range of variation in genetic ancestry among Argentine individuals from different regions in the country, highlighting the importance of taking this variation into account in genetic association and admixture mapping studies in this population. PMID:22506044

  8. Minireview: Genetic basis of heterogeneity and severity in sickle cell disease.

    PubMed

    Habara, Alawi; Steinberg, Martin H

    2016-04-01

    Sickle cell disease, a common single gene disorder, has a complex pathophysiology that at its root is initiated by the polymerization of deoxy sickle hemoglobin. Sickle vasoocclusion and hemolytic anemia drive the development of disease complications. In this review, we focus on the genetic modifiers of disease heterogeneity. The phenotypic heterogeneity of disease is only partially explained by genetic variability of fetal hemoglobin gene expression and co-inheritance of α thalassemia. Given the complexity of pathophysiology, many different definitions of severity are possible complicating a full understanding of its genetic foundation. The pathophysiological complexity and the interlocking nature of the biological processes underpinning disease severity are becoming better understood. Nevertheless, useful genetic signatures of severity, regardless of how this is defined, are insufficiently developed to be used for treatment decisions and for counseling. PMID:26936084

  9. Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy.

    PubMed

    Lohr, Jens G; Stojanov, Petar; Carter, Scott L; Cruz-Gordillo, Peter; Lawrence, Michael S; Auclair, Daniel; Sougnez, Carrie; Knoechel, Birgit; Gould, Joshua; Saksena, Gordon; Cibulskis, Kristian; McKenna, Aaron; Chapman, Michael A; Straussman, Ravid; Levy, Joan; Perkins, Louise M; Keats, Jonathan J; Schumacher, Steven E; Rosenberg, Mara; Getz, Gad; Golub, Todd R

    2014-01-13

    We performed massively parallel sequencing of paired tumor/normal samples from 203 multiple myeloma (MM) patients and identified significantly mutated genes and copy number alterations and discovered putative tumor suppressor genes by determining homozygous deletions and loss of heterozygosity. We observed frequent mutations in KRAS (particularly in previously treated patients), NRAS, BRAF, FAM46C, TP53, and DIS3 (particularly in nonhyperdiploid MM). Mutations were often present in subclonal populations, and multiple mutations within the same pathway (e.g., KRAS, NRAS, and BRAF) were observed in the same patient. In vitro modeling predicts only partial treatment efficacy of targeting subclonal mutations, and even growth promotion of nonmutated subclones in some cases. These results emphasize the importance of heterogeneity analysis for treatment decisions. PMID:24434212

  10. Targeted exome sequencing resolves allelic and the genetic heterogeneity in the genetic diagnosis of nephronophthisis-related ciliopathy

    PubMed Central

    Kang, Hee Gyung; Lee, Hyun Kyung; Ahn, Yo Han; Joung, Je-Gun; Nam, Jaeyong; Kim, Nayoung K D; Ko, Jung Min; Cho, Min Hyun; Shin, Jae Il; Kim, Joon; Park, Hye Won; Park, Young Seo; Ha, Il-Soo; Chung, Woo Yeong; Lee, Dae-Yeol; Kim, Su Young; Park, Woong Yang; Cheong, Hae Il

    2016-01-01

    Nephronophthisis-related ciliopathy (NPHP-RC) is a common genetic cause of end-stage renal failure during childhood and adolescence and exhibits an autosomal recessive pattern of inheritance. Genetic diagnosis is quite limited owing to genetic heterogeneity in NPHP-RC. We designed a novel approach involving the step-wise screening of Sanger sequencing and targeted exome sequencing for the genetic diagnosis of 55 patients with NPHP-RC. First, five NPHP-RC genes were analyzed by Sanger sequencing in phenotypically classified patients. Known pathogenic mutations were identified in 12 patients (21.8%); homozygous deletions of NPHP1 in 4 juvenile nephronophthisis patients, IQCB1/NPHP5 mutations in 3 Senior–Løken syndrome patients, a CEP290/NPHP6 mutation in 1 Joubert syndrome patient, and TMEM67/MKS3 mutations in 4 Joubert syndrome patients with liver involvement. In the remaining undiagnosed patients, we applied targeted exome sequencing of 34 ciliopathy-related genes to detect known pathogenic mutations in 7 (16.3%) of 43 patients. Another 18 likely damaging heterozygous variants were identified in 13 NPHP-RC genes in 18 patients. In this study, we report a variety of pathogenic and candidate mutations identified in 55 patients with NPHP-RC in Korea using a step-wise application of two genetic tests. These results support the clinical utility of targeted exome sequencing to resolve the issue of allelic and genetic heterogeneity in NPHP-RC. PMID:27491411

  11. Targeted exome sequencing resolves allelic and the genetic heterogeneity in the genetic diagnosis of nephronophthisis-related ciliopathy.

    PubMed

    Kang, Hee Gyung; Lee, Hyun Kyung; Ahn, Yo Han; Joung, Je-Gun; Nam, Jaeyong; Kim, Nayoung K D; Ko, Jung Min; Cho, Min Hyun; Shin, Jae Il; Kim, Joon; Park, Hye Won; Park, Young Seo; Ha, Il-Soo; Chung, Woo Yeong; Lee, Dae-Yeol; Kim, Su Young; Park, Woong Yang; Cheong, Hae Il

    2016-01-01

    Nephronophthisis-related ciliopathy (NPHP-RC) is a common genetic cause of end-stage renal failure during childhood and adolescence and exhibits an autosomal recessive pattern of inheritance. Genetic diagnosis is quite limited owing to genetic heterogeneity in NPHP-RC. We designed a novel approach involving the step-wise screening of Sanger sequencing and targeted exome sequencing for the genetic diagnosis of 55 patients with NPHP-RC. First, five NPHP-RC genes were analyzed by Sanger sequencing in phenotypically classified patients. Known pathogenic mutations were identified in 12 patients (21.8%); homozygous deletions of NPHP1 in 4 juvenile nephronophthisis patients, IQCB1/NPHP5 mutations in 3 Senior-Løken syndrome patients, a CEP290/NPHP6 mutation in 1 Joubert syndrome patient, and TMEM67/MKS3 mutations in 4 Joubert syndrome patients with liver involvement. In the remaining undiagnosed patients, we applied targeted exome sequencing of 34 ciliopathy-related genes to detect known pathogenic mutations in 7 (16.3%) of 43 patients. Another 18 likely damaging heterozygous variants were identified in 13 NPHP-RC genes in 18 patients. In this study, we report a variety of pathogenic and candidate mutations identified in 55 patients with NPHP-RC in Korea using a step-wise application of two genetic tests. These results support the clinical utility of targeted exome sequencing to resolve the issue of allelic and genetic heterogeneity in NPHP-RC. PMID:27491411

  12. Behavioral idiosyncrasy reveals genetic control of phenotypic variability

    PubMed Central

    Ayroles, Julien F.; Buchanan, Sean M.; O’Leary, Chelsea; Skutt-Kakaria, Kyobi; Grenier, Jennifer K.; Clark, Andrew G.; Hartl, Daniel L.; de Bivort, Benjamin L.

    2015-01-01

    Quantitative genetics has primarily focused on describing genetic effects on trait means and largely ignored the effect of alternative alleles on trait variability, potentially missing an important axis of genetic variation contributing to phenotypic differences among individuals. To study the genetic effects on individual-to-individual phenotypic variability (or intragenotypic variability), we used Drosophila inbred lines and measured the spontaneous locomotor behavior of flies walking individually in Y-shaped mazes, focusing on variability in locomotor handedness, an assay optimized to measure variability. We discovered that some lines had consistently high levels of intragenotypic variability among individuals, whereas lines with low variability behaved as although they tossed a coin at each left/right turn decision. We demonstrate that the degree of variability is itself heritable. Using a genome-wide association study (GWAS) for the degree of intragenotypic variability as the phenotype across lines, we identified several genes expressed in the brain that affect variability in handedness without affecting the mean. One of these genes, Ten-a, implicates a neuropil in the central complex of the fly brain as influencing the magnitude of behavioral variability, a brain region involved in sensory integration and locomotor coordination. We validated these results using genetic deficiencies, null alleles, and inducible RNAi transgenes. Our study reveals the constellation of phenotypes that can arise from a single genotype and shows that different genetic backgrounds differ dramatically in their propensity for phenotypic variabililty. Because traditional mean-focused GWASs ignore the contribution of variability to overall phenotypic variation, current methods may miss important links between genotype and phenotype. PMID:25953335

  13. Network‐Informed Gene Ranking Tackles Genetic Heterogeneity in Exome‐Sequencing Studies of Monogenic Disease

    PubMed Central

    Schulz, Reiner; Weale, Michael E.; Southgate, Laura; Oakey, Rebecca J.; Simpson, Michael A.; Schlitt, Thomas

    2015-01-01

    ABSTRACT Genetic heterogeneity presents a significant challenge for the identification of monogenic disease genes. Whole‐exome sequencing generates a large number of candidate disease‐causing variants and typical analyses rely on deleterious variants being observed in the same gene across several unrelated affected individuals. This is less likely to occur for genetically heterogeneous diseases, making more advanced analysis methods necessary. To address this need, we present HetRank, a flexible gene‐ranking method that incorporates interaction network data. We first show that different genes underlying the same monogenic disease are frequently connected in protein interaction networks. This motivates the central premise of HetRank: those genes carrying potentially pathogenic variants and whose network neighbors do so in other affected individuals are strong candidates for follow‐up study. By simulating 1,000 exome sequencing studies (20,000 exomes in total), we model varying degrees of genetic heterogeneity and show that HetRank consistently prioritizes more disease‐causing genes than existing analysis methods. We also demonstrate a proof‐of‐principle application of the method to prioritize genes causing Adams‐Oliver syndrome, a genetically heterogeneous rare disease. An implementation of HetRank in R is available via the Website http://sourceforge.net/p/hetrank/. PMID:26394720

  14. Noninvasive genetic sampling reveals intrasex territoriality in wolverines.

    PubMed

    Bischof, Richard; Gregersen, Espen R; Brøseth, Henrik; Ellegren, Hans; Flagstad, Øystein

    2016-03-01

    Due to its conspicuous manifestations and its capacity to shape the configuration and dynamics of wild populations, territorial behavior has long intrigued ecologists. Territoriality and other animal interactions in situ have traditionally been studied via direct observations and telemetry. Here, we explore whether noninvasive genetic sampling, which is increasingly supplementing traditional field methods in ecological research, can reveal territorial behavior in an elusive carnivore, the wolverine (Gulo gulo). Using the locations of genotyped wolverine scat samples collected annually over a period of 12 years in central Norway, we test three predictions: (1) male home ranges constructed from noninvasive genetic sampling data are larger than those of females, (2) individuals avoid areas used by other conspecifics of the same sex (intrasexual territoriality), and (3) avoidance of same-sex territories diminishes or disappears after the territory owner's death. Each of these predictions is substantiated by our results: sex-specific differences in home range size and intrasexual territoriality in wolverine are patently reflected in the spatial and temporal configuration of noninvasively collected genetic samples. Our study confirms that wildlife monitoring programs can utilize the spatial information in noninvasive genetic sampling data to detect and quantify home ranges and social organization. PMID:27087927

  15. Genome-wide detection of intervals of genetic heterogeneity associated with complex traits

    PubMed Central

    Llinares-López, Felipe; Grimm, Dominik G.; Bodenham, Dean A.; Gieraths, Udo; Sugiyama, Mahito; Rowan, Beth; Borgwardt, Karsten

    2015-01-01

    Motivation: Genetic heterogeneity, the fact that several sequence variants give rise to the same phenotype, is a phenomenon that is of the utmost interest in the analysis of complex phenotypes. Current approaches for finding regions in the genome that exhibit genetic heterogeneity suffer from at least one of two shortcomings: (i) they require the definition of an exact interval in the genome that is to be tested for genetic heterogeneity, potentially missing intervals of high relevance, or (ii) they suffer from an enormous multiple hypothesis testing problem due to the large number of potential candidate intervals being tested, which results in either many false positives or a lack of power to detect true intervals. Results: Here, we present an approach that overcomes both problems: it allows one to automatically find all contiguous sequences of single nucleotide polymorphisms in the genome that are jointly associated with the phenotype. It also solves both the inherent computational efficiency problem and the statistical problem of multiple hypothesis testing, which are both caused by the huge number of candidate intervals. We demonstrate on Arabidopsis thaliana genome-wide association study data that our approach can discover regions that exhibit genetic heterogeneity and would be missed by single-locus mapping. Conclusions: Our novel approach can contribute to the genome-wide discovery of intervals that are involved in the genetic heterogeneity underlying complex phenotypes. Availability and implementation: The code can be obtained at: http://www.bsse.ethz.ch/mlcb/research/bioinformatics-and-computational-biology/sis.html. Contact: felipe.llinares@bsse.ethz.ch Supplementary information: Supplementary data are available at Bioinformatics online. PMID:26072488

  16. Revealing the dynamic heterogeneity of PMMA/PVDF blends: from microscopic dynamics to macroscopic properties.

    PubMed

    Lu, Bo; Lamnawar, Khalid; Maazouz, Abderrahim; Zhang, Huagui

    2016-04-01

    An effort was made to demonstrate the dynamic heterogeneity of poly(methyl methacrylate) (PMMA)/poly(vinylidene fluoride) (PVDF) blends, where its composition dependence and the role of interphase were probed. Firstly, the composition dependence of thermorheological complexity of PMMA/PVDF blends in the melt was revealed. The molecular entanglement state involving intra- and interchain entanglements was found to govern the scenario of thermorheological complexity. Intriguingly, local heterogeneity was further demonstrated to exist in the melt-state blends with intermediate compositions, and its origin was depicted to be the interphase. The interphase, coupled with unfavourable interchain entanglements in those blends, could explain the reduced viscosity and speed-up relaxations, contributing to the overall thermorheological complexity. Besides, two experimental glass transition temperatures of blends were resolved in view of segment motions in the miscible phase and the crystal-amorphous interphase, and further assessed via the "self-concentration" concept. The presence of a crystal-amorphous interphase, likely leading to three distinct dynamics of segments in blends, was supposed to contribute to the dynamic heterogeneity in segment relaxations for PMMA/PVDF blends in the solid state. Lastly, effects of dynamic heterogeneity on dynamic mechanical properties were also evaluated. PMID:26932245

  17. Genetic and environmental heterogeneity of residual variance of weight traits in Nellore beef cattle

    PubMed Central

    2012-01-01

    Background Many studies have provided evidence of the existence of genetic heterogeneity of environmental variance, suggesting that it could be exploited to improve robustness and uniformity of livestock by selection. However, little is known about the perspectives of such a selection strategy in beef cattle. Methods A two-step approach was applied to study the genetic heterogeneity of residual variance of weight gain from birth to weaning and long-yearling weight in a Nellore beef cattle population. First, an animal model was fitted to the data and second, the influence of additive and environmental effects on the residual variance of these traits was investigated with different models, in which the log squared estimated residuals for each phenotypic record were analyzed using the restricted maximum likelihood method. Monte Carlo simulation was performed to assess the reliability of variance component estimates from the second step and the accuracy of estimated breeding values for residual variation. Results The results suggest that both genetic and environmental factors have an effect on the residual variance of weight gain from birth to weaning and long-yearling in Nellore beef cattle and that uniformity of these traits could be improved by selecting for lower residual variance, when considering a large amount of information to predict genetic merit for this criterion. Simulations suggested that using the two-step approach would lead to biased estimates of variance components, such that more adequate methods are needed to study the genetic heterogeneity of residual variance in beef cattle. PMID:22672564

  18. Genetic heterogeneity among uterine leiomyomata: insights into malignant progression.

    PubMed

    Hodge, Jennelle C; Morton, Cynthia C

    2007-04-15

    Uterine leiomyomata (UL), also known as fibroids, are the most common pelvic tumors in women of reproductive age and are the primary indication for hysterectomy in the USA. Many lines of evidence indicate a strong genetic component to the development of these tumors. In fact, approximately 40% of UL have non-random, tumor-specific chromosome abnormalities which have allowed classification into well-defined subgroups (deletion of portions of 7q, trisomy 12 or rearrangements of 12q15, 6p21 or 10q22) as well as identification of candidate genes for UL predisposition. Although benign, UL have been linked to malignancy through two genomic regions on chromosome 1. Mutation of fumarate hydratase (FH) at 1q43 is known to cause the Mendelian syndromes of multiple cutaneous and uterine leiomyomata (MCL) and hereditary leiomyomatosis and renal cell cancer (HLRCC), and recently, FH mutations have been detected in some non-syndromic UL. In addition, transcriptional profiling suggests that loss of the short arm of chromosome 1 in cellular leiomyomata, an uncommon histological variant of UL, may account in part for the presumed yet rare malignant transformation of UL to uterine leiomyosarcoma. PMID:17613550

  19. Evidence for genetic heterogeneity in male pseudohermaphroditism due to Leydig cell hypoplasia.

    PubMed

    Zenteno, J C; Canto, P; Kofman-Alfaro, S; Mendez, J P

    1999-10-01

    Leydig cell aplasia or hypoplasia is a rare form of male pseudohermaphroditism resulting from inadequate fetal testicular Leydig cell differentiation. Affected individuals presented a wide phenotypic spectrum, ranging from complete female external genitalia to males with micropenis. Recessive mutations in the LH receptor gene have been identified as responsible for the condition. The majority of these mutations are point mutations and have been located in exon 11 of the gene. In this study, we report the molecular characterization of the LH receptor gene in three siblings with Leydig cell hypoplasia. After sequencing the 11 exons of the gene, no deleterious mutations were detected in any patient. However, we identified a previously described polymorphism in exon 11. In patients 1 and 3 DNA sequencing revealed a C to T substitution at nucleotide 1065; both patients were homozygous GAT/GAT at codon 355. In contrast, patient 2 was homozygous GAC/GAC, whereas the father and one unaffected sister were heterozygous GAC/GAT at this polymorphic site. These results exclude that Leydig cell hypoplasia in this family is due to a mutation in the LH receptor gene and provide evidence that defects in other loci may also result in failure of Leydig cell differentiation, demonstrating, for the first time, that Leydig cell hypoplasia is a genetically heterogeneous condition. PMID:10523033

  20. Molecular and Cytogenetic Characterization of Plexiform Leiomyomata Provide Further Evidence for Genetic Heterogeneity Underlying Uterine Fibroids

    PubMed Central

    Hodge, Jennelle C.; Quade, Bradley J.; Rubin, Mark A.; Stewart, Elizabeth A.; Dal Cin, Paola; Morton, Cynthia C.

    2008-01-01

    The plexiform variant of uterine leiomyomata (UL) is named for its ribbons or nests of smooth muscle cells that have a rounded, epithelioid shape caused by their entrapment in abundant extracellular matrix. Plexiform UL are currently classified as epithelioid smooth muscle tumors alongside the less predictable, “true” epithelioid tumors (ie, leiomyoblastomas). Karyotypes of six plexiform UL cases were studied, and their abnormalities were found to differ from those of leiomyoblastomas. Analyses using real-time polymerase chain reaction, immunohistochemistry, and fluorescence in situ hybridization demonstrated elevated mRNA and protein levels of the architectural factor HMGA2 and, in some cases, increased DNA copy number. Four of these plexiform UL were profiled with Affymetrix human U133 plus 2.0 expression arrays. Cluster analysis using genes previously shown to discriminate benign and malignant uterine smooth muscle tissues revealed that the plexiform tumors form an isolated group in the benign branch. This is in contrast to an earlier finding in which another variant, cellular UL characterized by loss of a portion of the short arm of chromosome 1, clustered with malignant leiomyosarcomas. These results provide additional evidence of genetic heterogeneity underlying UL of various histological types. We further suggest that plexiform UL should be classified among tumors with extensive hyalinization rather than with “true” epithelioid smooth muscle neoplasms. PMID:18403592

  1. Spatial Heterogeneity as a Genetic Mixing Mechanism in Highly Philopatric Colonial Seabirds

    PubMed Central

    Cristofari, Robin; Trucchi, Emiliano; Whittington, Jason D.; Vigetta, Stéphanie; Gachot-Neveu, Hélène; Stenseth, Nils Christian; Le Maho, Yvon; Le Bohec, Céline

    2015-01-01

    How genetic diversity is maintained in philopatric colonial systems remains unclear, and understanding the dynamic balance of philopatry and dispersal at all spatial scales is essential to the study of the evolution of coloniality. In the King penguin, Aptenodytes patagonicus, return rates of post-fledging chicks to their natal sub-colony are remarkably high. Empirical studies have shown that adults return year after year to their previous breeding territories within a radius of a few meters. Yet, little reliable data are available on intra- and inter-colonial dispersal in this species. Here, we present the first fine-scale study of the genetic structure in a king penguin colony in the Crozet Archipelago. Samples were collected from individual chicks and analysed at 8 microsatellite loci. Precise geolocation data of hatching sites and selective pressures associated with habitat features were recorded for all sampling locations. We found that despite strong natal and breeding site fidelity, king penguins retain a high degree of panmixia and genetic diversity. Yet, genetic structure appears markedly heterogeneous across the colony, with higher-than-expected inbreeding levels, and local inbreeding and relatedness hotspots that overlap predicted higher-quality nesting locations. This points towards heterogeneous population structure at the sub-colony level, in which fine-scale environmental features drive local philopatric behaviour, while lower-quality patches may act as genetic mixing mechanisms at the colony level. These findings show how a lack of global genetic structuring can emerge from small-scale heterogeneity in ecological parameters, as opposed to the classical model of homogeneous dispersal. Our results also emphasize the importance of sampling design for estimation of population parameters in colonial seabirds, as at high spatial resolution, basic genetic features are shown to be location-dependent. Finally, this study stresses the importance of

  2. Comparative RNA sequencing reveals substantial genetic variation in endangered primates

    PubMed Central

    Perry, George H.; Melsted, Páll; Marioni, John C.; Wang, Ying; Bainer, Russell; Pickrell, Joseph K.; Michelini, Katelyn; Zehr, Sarah; Yoder, Anne D.; Stephens, Matthew; Pritchard, Jonathan K.; Gilad, Yoav

    2012-01-01

    Comparative genomic studies in primates have yielded important insights into the evolutionary forces that shape genetic diversity and revealed the likely genetic basis for certain species-specific adaptations. To date, however, these studies have focused on only a small number of species. For the majority of nonhuman primates, including some of the most critically endangered, genome-level data are not yet available. In this study, we have taken the first steps toward addressing this gap by sequencing RNA from the livers of multiple individuals from each of 16 mammalian species, including humans and 11 nonhuman primates. Of the nonhuman primate species, five are lemurs and two are lorisoids, for which little or no genomic data were previously available. To analyze these data, we developed a method for de novo assembly and alignment of orthologous gene sequences across species. We assembled an average of 5721 gene sequences per species and characterized diversity and divergence of both gene sequences and gene expression levels. We identified patterns of variation that are consistent with the action of positive or directional selection, including an 18-fold enrichment of peroxisomal genes among genes whose regulation likely evolved under directional selection in the ancestral primate lineage. Importantly, we found no relationship between genetic diversity and endangered status, with the two most endangered species in our study, the black and white ruffed lemur and the Coquerel's sifaka, having the highest genetic diversity among all primates. Our observations imply that many endangered lemur populations still harbor considerable genetic variation. Timely efforts to conserve these species alongside their habitats have, therefore, strong potential to achieve long-term success. PMID:22207615

  3. A fifth major genetic group among honeybees revealed in Syria

    PubMed Central

    2013-01-01

    Background Apiculture has been practiced in North Africa and the Middle-East from antiquity. Several thousand years of selective breeding have left a mosaic of Apis mellifera subspecies in the Middle-East, many uniquely adapted and survived to local environmental conditions. In this study we explore the genetic diversity of A. mellifera from Syria (n = 1258), Lebanon (n = 169) and Iraq (n = 35) based on 14 short tandem repeat (STR) loci in the context of reference populations from throughout the Old World (n = 732). Results Our data suggest that the Syrian honeybee Apis mellifera syriaca occurs in both Syrian and Lebanese territories, with no significant genetic variability between respective populations from Syria and Lebanon. All studied populations clustered within a new fifth independent nuclear cluster, congruent with an mtDNA Z haplotype identified in a previous study. Syrian honeybee populations are not associated with Oriental lineage O, except for sporadic introgression into some populations close to the Turkish and Iraqi borders. Southern Syrian and Lebanese populations demonstrated high levels of genetic diversity compared to the northern populations. Conclusion This study revealed the effects of foreign queen importations on Syrian bee populations, especially for the region of Tartus, where extensive introgression of A. m. anatolica and/or A. m. caucasica alleles were identified. The policy of creating genetic conservation centers for the Syrian subspecies should take into consideration the influence of the oriental lineage O from the northern Syrian border and the large population of genetically divergent indigenous honeybees located in southern Syria. PMID:24314104

  4. The clinical and genetic heterogeneity of paroxysmal dyskinesias.

    PubMed

    Gardiner, Alice R; Jaffer, Fatima; Dale, Russell C; Labrum, Robyn; Erro, Roberto; Meyer, Esther; Xiromerisiou, Georgia; Stamelou, Maria; Walker, Matthew; Kullmann, Dimitri; Warner, Tom; Jarman, Paul; Hanna, Mike; Kurian, Manju A; Bhatia, Kailash P; Houlden, Henry

    2015-12-01

    Paroxysmal dyskinesia can be subdivided into three clinical syndromes: paroxysmal kinesigenic dyskinesia or choreoathetosis, paroxysmal exercise-induced dyskinesia, and paroxysmal non-kinesigenic dyskinesia. Each subtype is associated with the known causative genes PRRT2, SLC2A1 and PNKD, respectively. Although separate screening studies have been carried out on each of the paroxysmal dyskinesia genes, to date there has been no large study across all genes in these disorders and little is known about the pathogenic mechanisms. We analysed all three genes (the whole coding regions of SLC2A1 and PRRT2 and exons one and two of PNKD) in a series of 145 families with paroxysmal dyskinesias as well as in a series of 53 patients with familial episodic ataxia and hemiplegic migraine to investigate the mutation frequency and type and the genetic and phenotypic spectrum. We examined the mRNA expression in brain regions to investigate how selective vulnerability could help explain the phenotypes and analysed the effect of mutations on patient-derived mRNA. Mutations in the PRRT2, SLC2A1 and PNKD genes were identified in 72 families in the entire study. In patients with paroxysmal movement disorders 68 families had mutations (47%) out of 145 patients. PRRT2 mutations were identified in 35% of patients, SLC2A1 mutations in 10%, PNKD in 2%. Two PRRT2 mutations were in familial hemiplegic migraine or episodic ataxia, one SLC2A1 family had episodic ataxia and one PNKD family had familial hemiplegic migraine alone. Several previously unreported mutations were identified. The phenotypes associated with PRRT2 mutations included a high frequency of migraine and hemiplegic migraine. SLC2A1 mutations were associated with variable phenotypes including paroxysmal kinesigenic dyskinesia, paroxysmal non-kinesigenic dyskinesia, episodic ataxia and myotonia and we identified a novel PNKD gene deletion in familial hemiplegic migraine. We found that some PRRT2 loss-of-function mutations cause

  5. The clinical and genetic heterogeneity of paroxysmal dyskinesias

    PubMed Central

    Gardiner, Alice R.; Jaffer, Fatima; Dale, Russell C.; Labrum, Robyn; Erro, Roberto; Meyer, Esther; Xiromerisiou, Georgia; Stamelou, Maria; Walker, Matthew; Kullmann, Dimitri; Warner, Tom; Jarman, Paul; Hanna, Mike; Kurian, Manju A.; Bhatia, Kailash P.

    2015-01-01

    Paroxysmal dyskinesia can be subdivided into three clinical syndromes: paroxysmal kinesigenic dyskinesia or choreoathetosis, paroxysmal exercise-induced dyskinesia, and paroxysmal non-kinesigenic dyskinesia. Each subtype is associated with the known causative genes PRRT2, SLC2A1 and PNKD, respectively. Although separate screening studies have been carried out on each of the paroxysmal dyskinesia genes, to date there has been no large study across all genes in these disorders and little is known about the pathogenic mechanisms. We analysed all three genes (the whole coding regions of SLC2A1 and PRRT2 and exons one and two of PNKD) in a series of 145 families with paroxysmal dyskinesias as well as in a series of 53 patients with familial episodic ataxia and hemiplegic migraine to investigate the mutation frequency and type and the genetic and phenotypic spectrum. We examined the mRNA expression in brain regions to investigate how selective vulnerability could help explain the phenotypes and analysed the effect of mutations on patient-derived mRNA. Mutations in the PRRT2, SLC2A1 and PNKD genes were identified in 72 families in the entire study. In patients with paroxysmal movement disorders 68 families had mutations (47%) out of 145 patients. PRRT2 mutations were identified in 35% of patients, SLC2A1 mutations in 10%, PNKD in 2%. Two PRRT2 mutations were in familial hemiplegic migraine or episodic ataxia, one SLC2A1 family had episodic ataxia and one PNKD family had familial hemiplegic migraine alone. Several previously unreported mutations were identified. The phenotypes associated with PRRT2 mutations included a high frequency of migraine and hemiplegic migraine. SLC2A1 mutations were associated with variable phenotypes including paroxysmal kinesigenic dyskinesia, paroxysmal non-kinesigenic dyskinesia, episodic ataxia and myotonia and we identified a novel PNKD gene deletion in familial hemiplegic migraine. We found that some PRRT2 loss-of-function mutations cause

  6. Clinical, genetic and pathological heterogeneity of frontotemporal dementia: a review.

    PubMed

    Seelaar, Harro; Rohrer, Jonathan D; Pijnenburg, Yolande A L; Fox, Nick C; van Swieten, John C

    2011-05-01

    Frontotemporal dementia (FTD) is the second most common young-onset dementia and is clinically characterised by progressive behavioural change, executive dysfunction and language difficulties. Three clinical syndromes, behavioural variant FTD, semantic dementia and progressive non-fluent aphasia, form part of a clinicopathological spectrum named frontotemporal lobar degeneration (FTLD). The classical neuropsychological phenotype of FTD has been enriched by tests exploring Theory of Mind, social cognition and emotional processing. Imaging studies have detailed the patterns of atrophy associated with different clinical and pathological subtypes. These patterns offer some diagnostic utility, while measures of progression of atrophy may be of use in future trials. 30-50% of FTD is familial, and mutations in two genes, microtubule associated protein tau and Progranulin (GRN), account for about half of these cases. Rare defects in VCP, CHMP2B, TARDP and FUS genes have been found in a small number of families. Linkage to chromosome 9p13.2-21.3 has been established in familial FTD with motor neuron disease, although the causative gene is yet to be identified. Recent developments in the immunohistochemistry of FTLD, and also in amyotrophic lateral sclerosis (ALS), have led to a new pathological nomenclature. The two major groups are those with tau-positive inclusions (FTLD-tau) and those with ubiquitin-positive and TAR DNA-binding protein of 43 kDa (TDP-43) positive inclusions (FTLD-TDP). Recently, a new protein involved in familial ALS, fused in sarcoma (FUS), has been found in FTLD patients with ubiquitin-positive and TDP-43-negative inclusions. In this review, the authors discuss recent clinical, neuropsychological, imaging, genetic and pathological developments that have changed our understanding of FTD, its classification and criteria. The potential to establish an early diagnosis, predict underlying pathology during life and quantify disease progression will

  7. Multiple genetic factors in the heterogeneity of thyroid hormone resistance

    SciTech Connect

    Weiss, R.E.; Refetoff, S. ); Marcocci, C.; Bruno-Bossio, G. )

    1993-01-01

    Generalized resistance to thyroid hormone (GRTH), a syndrome of inherited tissue hyposensitivity to thyroid hormone, is linked to thyroid hormone receptor (TR) mutations. A typical feature of GRTH is variable severity of organ involvement among families that, surprisingly, does not correlate with the degree of T[sub 3]-binding impairment of the corresponding in vitro synthesized mutant TRs. Furthermore, variations in the clinical severity among family members harboring identical TR[beta] mutations have been reported. The authors compared serum levels of thyroid hormones that maintained a normal TSH in members of a large family with GRTH divided in three groups: Group A, 8 affected subjects with a mutation replacing arginine-320 with a histidine in the T[sub 3]-binding domain of TR[beta]; Group B, 11 first degree relatives (sibs and children of affected subjects) with no TR[beta] mutation; Group C, 16 controls related by marriage. TSH values were not different among the three groups. As expected, total and free T[sub 4] and T[sub 3], and rT[sub 3] levels were significantly higher in Group A vs Groups B and C. However, with the exception of T[sub 3], the same tests were also significantly higher in Group B vs Group C. The latter differences are not due to thyroid hormone transport in serum since TBG concentrations were not different. It is postulated that genetic variability of factors that contribute to the action of thyroid hormone modulate the phenotype of GRTH associated with TR[beta] mutations. 23 refs., 2 figs., 1 tab.

  8. Distinct evolution and dynamics of epigenetic and genetic heterogeneity in acute myeloid leukemia.

    PubMed

    Li, Sheng; Garrett-Bakelman, Francine E; Chung, Stephen S; Sanders, Mathijs A; Hricik, Todd; Rapaport, Franck; Patel, Jay; Dillon, Richard; Vijay, Priyanka; Brown, Anna L; Perl, Alexander E; Cannon, Joy; Bullinger, Lars; Luger, Selina; Becker, Michael; Lewis, Ian D; To, Luen Bik; Delwel, Ruud; Löwenberg, Bob; Döhner, Hartmut; Döhner, Konstanze; Guzman, Monica L; Hassane, Duane C; Roboz, Gail J; Grimwade, David; Valk, Peter J M; D'Andrea, Richard J; Carroll, Martin; Park, Christopher Y; Neuberg, Donna; Levine, Ross; Melnick, Ari M; Mason, Christopher E

    2016-07-01

    Genetic heterogeneity contributes to clinical outcome and progression of most tumors, but little is known about allelic diversity for epigenetic compartments, and almost no data exist for acute myeloid leukemia (AML). We examined epigenetic heterogeneity as assessed by cytosine methylation within defined genomic loci with four CpGs (epialleles), somatic mutations, and transcriptomes of AML patient samples at serial time points. We observed that epigenetic allele burden is linked to inferior outcome and varies considerably during disease progression. Epigenetic and genetic allelic burden and patterning followed different patterns and kinetics during disease progression. We observed a subset of AMLs with high epiallele and low somatic mutation burden at diagnosis, a subset with high somatic mutation and lower epiallele burdens at diagnosis, and a subset with a mixed profile, suggesting distinct modes of tumor heterogeneity. Genes linked to promoter-associated epiallele shifts during tumor progression showed increased single-cell transcriptional variance and differential expression, suggesting functional impact on gene regulation. Thus, genetic and epigenetic heterogeneity can occur with distinct kinetics likely to affect the biological and clinical features of tumors. PMID:27322744

  9. "Polyhybrid heterogeneous bastards": promoting medical genetics in America in the 1930s and 1940s.

    PubMed

    Comfort, Nathaniel

    2006-10-01

    I examine three American researchers in the 1930s and 1940s who populate the no-man's-land of medical genetics, between the heyday of "mainline" eugenics and the medical turn in human genetics in the 1950s. In scientists' narratives, William Allan, Madge Macklin, and Laurence Snyder appear as pioneers of medical genetics and genetic education. Allan was a country doctor with an interest in heredity. Snyder, a Harvard-trained geneticist, entered medical genetics through population-genetic studies of human blood groups. Macklin came from a background in academic medicine. Allan, Snyder, and Macklin believed in a genetic approach to medicine well before genetics offered clinical benefits. Although hereditary diseases had begun to overtake infectious diseases as causes of death and illness, formal genetics offered medicine little more than a few explanatory principles. These researchers made their case by a) listing mostly hopeful potential applications of genetics to disease; b) blurring the distinction between genetics and heredity; and c) engaging in preventive genetic medicine, that is, eugenics. Examining their careers reveals some of the texture of eugenic thought in American medicine as well as the continuities between the early eugenic phase of human genetics and the professional medical genetics that today's practitioners take as the origin of their field. PMID:16762994

  10. Large-scale replication and heterogeneity in Parkinson disease genetic loci

    PubMed Central

    Ioannidis, John P.A.; Aasly, Jan O.; Annesi, Grazia; Brice, Alexis; Van Broeckhoven, Christine; Bertram, Lars; Bozi, Maria; Crosiers, David; Clarke, Carl; Facheris, Maurizio; Farrer, Matthew; Garraux, Gaetan; Gispert, Suzana; Auburger, Georg; Vilariño-Güell, Carles; Hadjigeorgiou, Georgios M.; Hicks, Andrew A.; Hattori, Nobutaka; Jeon, Beom; Lesage, Suzanne; Lill, Christina M.; Lin, Juei-Jueng; Lynch, Timothy; Lichtner, Peter; Lang, Anthony E.; Mok, Vincent; Jasinska-Myga, Barbara; Mellick, George D.; Morrison, Karen E.; Opala, Grzegorz; Pramstaller, Peter P.; Pichler, Irene; Park, Sung Sup; Quattrone, Aldo; Rogaeva, Ekaterina; Ross, Owen A.; Stefanis, Leonidas; Stockton, Joanne D.; Satake, Wataru; Silburn, Peter A.; Theuns, Jessie; Tan, Eng-King; Toda, Tatsushi; Tomiyama, Hiroyuki; Uitti, Ryan J.; Wirdefeldt, Karin; Wszolek, Zbigniew; Xiromerisiou, Georgia; Yueh, Kuo-Chu; Zhao, Yi; Gasser, Thomas; Maraganore, Demetrius; Krüger, Rejko

    2012-01-01

    Objective: Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown. Methods: Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry. Results: In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78–0.87 (LAMP3, BST1, and MAPT) and susceptibility per-allele odds ratios of 1.14–1.43 (STK39, GAK, SNCA, LRRK2, SYT11, and HIP1R). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (I2 estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA, LRRK2, LAMP3, HIP1R, and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD. Conclusion: Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity. Neurology® 2012;79:659–667 PMID:22786590

  11. Mitochondrial DNA from El Mirador Cave (Atapuerca, Spain) Reveals the Heterogeneity of Chalcolithic Populations

    PubMed Central

    Pierini, Federica; Matas-Lalueza, Laura; Gigli, Elena; Lari, Martina; Civit, Sergi; Lozano, Marina; Vergès, Josep Maria; Caramelli, David; Ramírez, Oscar; Lalueza-Fox, Carles

    2014-01-01

    Previous mitochondrial DNA analyses on ancient European remains have suggested that the current distribution of haplogroup H was modeled by the expansion of the Bell Beaker culture (ca 4,500–4,050 years BP) out of Iberia during the Chalcolithic period. However, little is known on the genetic composition of contemporaneous Iberian populations that do not carry the archaeological tool kit defining this culture. Here we have retrieved mitochondrial DNA (mtDNA) sequences from 19 individuals from a Chalcolithic sample from El Mirador cave in Spain, dated to 4,760–4,200 years BP and we have analyzed the haplogroup composition in the context of modern and ancient populations. Regarding extant African, Asian and European populations, El Mirador shows affinities with Near Eastern groups. In different analyses with other ancient samples, El Mirador clusters with Middle and Late Neolithic populations from Germany, belonging to the Rössen, the Salzmünde and the Baalberge archaeological cultures but not with contemporaneous Bell Beakers. Our analyses support the existence of a common genetic signal between Western and Central Europe during the Middle and Late Neolithic and points to a heterogeneous genetic landscape among Chalcolithic groups. PMID:25116044

  12. Genetic structure of Tunisian ethnic groups revealed by paternal lineages.

    PubMed

    Fadhlaoui-Zid, Karima; Martinez-Cruz, Begoña; Khodjet-el-khil, Houssein; Mendizabal, Isabel; Benammar-Elgaaied, Amel; Comas, David

    2011-10-01

    Tunisia has experienced a variety of human migrations that have modeled the myriad cultural groups inhabiting the area. Both Arabic and Berber-speaking populations live in Tunisia. Berbers are commonly considered as in situ descendants of peoples who settled roughly in Palaeolithic times, and posterior demographic events such as the arrival of the Neolithic, the Arab migrations, and the expulsion of the "Moors" from Spain, had a strong cultural influence. Nonetheless, the genetic structure and the population relationships of the ethnic groups living in Tunisia have been poorly assessed. In order to gain insight into the paternal genetic landscape and population structure, more than 40 Y-chromosome single nucleotide polymorphisms and 17 short tandem repeats were analyzed in five Tunisian ethnic groups (three Berber-speaking isolates, one Andalusian, and one Cosmopolitan Arab). The most common lineage was the North African haplogroup E-M81 (71%), being fixed in two Berber samples (Chenini-Douiret and Jradou), suggesting isolation and genetic drift. Differential levels of paternal gene flow from the Near East were detected in the Tunisian samples (J-M267 lineage over 30%); however, no major sub-Saharan African or European influence was found. This result contrasts with the high amount of sub-Saharan and Eurasian maternal lineages previously described in Tunisia. Overall, our results reveal a certain genetic inter-population diversity, especially among Berber groups, and sexual asymmetry, paternal lineages being mostly of autochthonous origin. In addition, Andalusians, who are supposed to be migrants from southern Spain, do not exhibit any substantial contribution of European lineages, suggesting a North African origin for this ethnic group. PMID:21915847

  13. Adolescent non-adherence reveals a genetic cause for diabetes

    PubMed Central

    Carmody, D.; Lindauer, K. L.; Naylor, R. N.

    2015-01-01

    Background GCK-MODY is a form of monogenic diabetes characterized by mildly elevated fasting blood sugars and HbA1c typically ranging from 38 to 60 mmol/mol (5.6–7.6%). It is frequently unrecognized or misdiagnosed as Type 1 or Type 2 diabetes, resulting in unnecessary pharmacologic therapy. Case report Two brothers were initially diagnosed with Type 1 diabetes mellitus. The brothers were maintained on a total daily insulin dose of 0.3–0.5 units/kg/day and had HbA1c values of 40–51 mmol/mol (5.8–6.8%) throughout childhood. After over 10 years of insulin treatment, the younger brother chose to discontinue his insulin therapy without informing his family or his clinician. Following cessation of insulin treatment, he did not experience any change in overall glycaemic control. Subsequent research-based genetic testing revealed a deleterious mutation in GCK in both brothers (p.Val182Met). The older brother subsequently discontinued insulin therapy and both have remained off all pharmacological therapy with good glycaemic control (HbA1c < 53 mmol/mol, < 7%) and no adverse complications. The family was advised to seek confirmatory genetic testing in the father and other relatives with hyperglycaemia. Conclusion The family described above exemplifies the rationale behind considering a genetic cause when evaluating every person with new-onset hyperglycaemia or those with atypical diabetes. The cost of genetic testing for the most common maturity-onset diabetes of the young (MODY)-causing genes may be offset by savings made in therapeutic costs. It is important that all clinicians supervising diabetes care recognize the cardinal features that distinguish GCK-MODY from other forms of diabetes. PMID:25494859

  14. Diagnostic and prognostic significance of genetic regional heterogeneity in meningiomas1

    PubMed Central

    Pfisterer, Wolfgang K.; Hank, Nicole C.; Preul, Mark C.; Hendricks, William P.; Pueschel, Jeanette; Coons, Stephen W.; Scheck, Adrienne C.

    2004-01-01

    We analyzed the frequency and regional distribution of cells with genetic abnormalities of chromosomes 1, 14, and 22 in meningiomas. This data was evaluated for correlation to the clinical outcome of the patients. Eight defined areas of each of 77 paraffin-embedded meningioma samples (59 grade I, 13 grade II, and 5 grade III) were analyzed by fluorescent in situ hybridization using bacterial artificial chromosome probes localized to chromosomes 1p36.32, 1q25.3, 14q13.3, 14q32.12, 22q11.2, and 22q12.1-3. Chromosome deletion was considered to be regionally heterogeneous if <7 regions showed cells with chromosome deletions. Deletion of 1p occurred in 35% of the grade I tumors. Distribution of cells with 1p deletion was regionally heterogeneous in 25% and homogeneous in 10% of grade I tumors. Distribution of cells with deletion of 1p was regionally heterogeneous in 23% and homogeneous in 69% of the grade II tumors. All grade III meningiomas had homogeneous distribution of cells with deletion of chromosome 1p. Distribution of cells with deletion of 14q was regionally heterogeneous in 27% and homogeneous in 2% of the grade I meningiomas, heterogeneous in 31% and homogeneous in 62% of the grade II tumors, and heterogeneous in 40% and homogeneous in 60% of the grade III meningiomas. Distribution of cells with deletion of 22q was regionally heterogeneous in 15% and homogeneous in 3% of the grade I tumors, heterogeneous in 15% and homogeneous in 31% of grade II tumors, and homogeneous in 20% of the grade III meningiomas. Distribution of cells with trisomy 22q was regionally heterogeneous in 10% of grade I tumors, heterogeneous in 23% of grade II, and homogeneous in 80% of grade III meningiomas. The proportion of patients with a deletion of 22q (either homogeneous or heterogeneous) who had recurrence was greater than the proportion of those without 22q deletion who had recurrence, and deletion of 22q was significantly associated with radiologically detected recurrence (P < 0

  15. An analysis toolbox to explore mesenchymal migration heterogeneity reveals adaptive switching between distinct modes

    PubMed Central

    Shafqat-Abbasi, Hamdah; Kowalewski, Jacob M; Kiss, Alexa; Gong, Xiaowei; Hernandez-Varas, Pablo; Berge, Ulrich; Jafari-Mamaghani, Mehrdad; Lock, John G; Strömblad, Staffan

    2016-01-01

    Mesenchymal (lamellipodial) migration is heterogeneous, although whether this reflects progressive variability or discrete, 'switchable' migration modalities, remains unclear. We present an analytical toolbox, based on quantitative single-cell imaging data, to interrogate this heterogeneity. Integrating supervised behavioral classification with multivariate analyses of cell motion, membrane dynamics, cell-matrix adhesion status and F-actin organization, this toolbox here enables the detection and characterization of two quantitatively distinct mesenchymal migration modes, termed 'Continuous' and 'Discontinuous'. Quantitative mode comparisons reveal differences in cell motion, spatiotemporal coordination of membrane protrusion/retraction, and how cells within each mode reorganize with changed cell speed. These modes thus represent distinctive migratory strategies. Additional analyses illuminate the macromolecular- and cellular-scale effects of molecular targeting (fibronectin, talin, ROCK), including 'adaptive switching' between Continuous (favored at high adhesion/full contraction) and Discontinuous (low adhesion/inhibited contraction) modes. Overall, this analytical toolbox now facilitates the exploration of both spontaneous and adaptive heterogeneity in mesenchymal migration. DOI: http://dx.doi.org/10.7554/eLife.11384.001 PMID:26821527

  16. Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD

    PubMed Central

    Cortez, Eliane; Gladh, Hanna; Braun, Sebastian; Bocci, Matteo; Cordero, Eugenia; Björkström, Niklas K.; Miyazaki, Hideki; Michael, Iacovos P.; Eriksson, Ulf; Folestad, Erika; Pietras, Kristian

    2016-01-01

    Intratumoral heterogeneity is an inherent feature of most human cancers and has profound implications for cancer therapy. As a result, there is an emergent need to explore previously unmapped mechanisms regulating distinct subpopulations of tumor cells and to understand their contribution to tumor progression and treatment response. Aberrant platelet-derived growth factor receptor beta (PDGFRβ) signaling in cancer has motivated the development of several antagonists currently in clinical use, including imatinib, sunitinib, and sorafenib. The discovery of a novel ligand for PDGFRβ, platelet-derived growth factor (PDGF)-DD, opened the possibility of a previously unidentified signaling pathway involved in tumor development. However, the precise function of PDGF-DD in tumor growth and invasion remains elusive. Here, making use of a newly generated Pdgfd knockout mouse, we reveal a functionally important malignant cell heterogeneity modulated by PDGF-DD signaling in pancreatic neuroendocrine tumors (PanNET). Our analyses demonstrate that tumor growth was delayed in the absence of signaling by PDGF-DD. Surprisingly, ablation of PDGF-DD did not affect the vasculature or stroma of PanNET; instead, we found that PDGF-DD stimulated bulk tumor cell proliferation by induction of paracrine mitogenic signaling between heterogeneous malignant cell clones, some of which expressed PDGFRβ. The presence of a subclonal population of tumor cells characterized by PDGFRβ expression was further validated in a cohort of human PanNET. In conclusion, we demonstrate a previously unrecognized heterogeneity in PanNET characterized by signaling through the PDGF-DD/PDGFRβ axis. PMID:26831065

  17. Genetic heterogeneity in psoriasis vulgaris based on linkage analyses of a large family material

    SciTech Connect

    Wahlstroem, J.; Swanbeck, G.; Inerot, A.

    1994-09-01

    Information on psoriasis among parents and siblings in 14,008 families has been collected. On the basis of this material, evidence for monogenetic autosomal recessive inheritance of psoriasis has recently been presented. Indications from more than one type of non-pustular psoriasis has been obtained from the population genetic data. Molecular genetic linkage analysis of psoriasis to a number of polymorphic genetic markers for a large number of families has been made. It is apparent that there is genetic heterogeneity in a psoriasis population with regard to psoriasis genes. Using the computer program Linkage 5.0 and a formula for heterogeneity, a lodscore over 3.0 for one locus has been obtained. This locus has further been confirmed by several other markers in the vicinity. The locus found is linked to slightly over half of the families, indicating that there are more genetically independent types of psoriasis. The age at onset of those families that are apparently linked to this locus have a slightly higher age at onset than those not linked to that locus but with a considerable overlap. In spite of close coverage of the whole chromosomes number 6 and 17, no linkage has been found in this regions. This indicates that neither the HLA region nor the region earlier found to be involved in one family with psoriasis are primarily involved in our families.

  18. Evidence for a susceptibility gene for autism on chromosome 2 and for genetic heterogeneity.

    PubMed

    Buxbaum, J D; Silverman, J M; Smith, C J; Kilifarski, M; Reichert, J; Hollander, E; Lawlor, B A; Fitzgerald, M; Greenberg, D A; Davis, K L

    2001-06-01

    Although there is considerable evidence for a strong genetic component to idiopathic autism, several genomewide screens for susceptibility genes have been performed with limited concordance of linked loci, reflecting either numerous genes of weak effect and/or sample heterogeneity. Because decreasing sample heterogeneity would increase the power to identify genes, the effect on evidence for linkage of restricting a sample of autism-affected relative pairs to those with delayed onset (at age >36 mo) of phrase speech (PSD, for phrase speech delay) was studied. In the second stage of a two-stage genome screen for susceptibility loci involving 95 families with two or more individuals with autism or related disorders, a maximal multipoint heterogeneity LOD score (HLOD) of 1.96 and a maximal multipoint nonparametric linkage (NPL) score of 2.39 was seen on chromosome 2q. Restricting the analysis to the subset of families (n=49) with two or more individuals having a narrow diagnosis of autism and PSD generated a maximal multipoint HLOD score of 2.99 and an NPL score of 3.32. The increased scores in the restricted sample, together with evidence for heterogeneity in the entire sample, indicate that the restricted sample comprises a population that is more genetically homogeneous, which could therefore increase the likelihood of positional cloning of susceptibility loci. PMID:11353400

  19. Metabolomics reveals the heterogeneous secretome of two entomopathogenic fungi to ex vivo cultured insect tissues.

    PubMed

    de Bekker, Charissa; Smith, Philip B; Patterson, Andrew D; Hughes, David P

    2013-01-01

    Fungal entomopathogens rely on cellular heterogeneity during the different stages of insect host infection. Their pathogenicity is exhibited through the secretion of secondary metabolites, which implies that the infection life history of this group of environmentally important fungi can be revealed using metabolomics. Here metabolomic analysis in combination with ex vivo insect tissue culturing shows that two generalist isolates of the genus Metarhizium and Beauveria, commonly used as biological pesticides, employ significantly different arrays of secondary metabolites during infectious and saprophytic growth. It also reveals that both fungi exhibit tissue specific strategies by a distinguishable metabolite secretion on the insect tissues tested in this study. In addition to showing the important heterogeneous nature of these two entomopathogens, this study also resulted in the discovery of several novel destruxins and beauverolides that have not been described before, most likely because previous surveys did not use insect tissues as a culturing system. While Beauveria secreted these cyclic depsipeptides when encountering live insect tissues, Metarhizium employed them primarily on dead tissue. This implies that, while these fungi employ comparable strategies when it comes to entomopathogenesis, there are most certainly significant differences at the molecular level that deserve to be studied. PMID:23940603

  20. Metabolomics Reveals the Heterogeneous Secretome of Two Entomopathogenic Fungi to Ex Vivo Cultured Insect Tissues

    PubMed Central

    de Bekker, Charissa; Smith, Philip B.; Patterson, Andrew D.; Hughes, David P.

    2013-01-01

    Fungal entomopathogens rely on cellular heterogeneity during the different stages of insect host infection. Their pathogenicity is exhibited through the secretion of secondary metabolites, which implies that the infection life history of this group of environmentally important fungi can be revealed using metabolomics. Here metabolomic analysis in combination with ex vivo insect tissue culturing shows that two generalist isolates of the genus Metarhizium and Beauveria, commonly used as biological pesticides, employ significantly different arrays of secondary metabolites during infectious and saprophytic growth. It also reveals that both fungi exhibit tissue specific strategies by a distinguishable metabolite secretion on the insect tissues tested in this study. In addition to showing the important heterogeneous nature of these two entomopathogens, this study also resulted in the discovery of several novel destruxins and beauverolides that have not been described before, most likely because previous surveys did not use insect tissues as a culturing system. While Beauveria secreted these cyclic depsipeptides when encountering live insect tissues, Metarhizium employed them primarily on dead tissue. This implies that, while these fungi employ comparable strategies when it comes to entomopathogenesis, there are most certainly significant differences at the molecular level that deserve to be studied. PMID:23940603

  1. Individual olfactory perception reveals meaningful nonolfactory genetic information

    PubMed Central

    Secundo, Lavi; Snitz, Kobi; Weissler, Kineret; Pinchover, Liron; Shoenfeld, Yehuda; Loewenthal, Ron; Agmon-Levin, Nancy; Frumin, Idan; Bar-Zvi, Dana; Shushan, Sagit; Sobel, Noam

    2015-01-01

    Each person expresses a potentially unique subset of ∼400 different olfactory receptor subtypes. Given that the receptors we express partially determine the odors we smell, it follows that each person may have a unique nose; to capture this, we devised a sensitive test of olfactory perception we termed the “olfactory fingerprint.” Olfactory fingerprints relied on matrices of perceived odorant similarity derived from descriptors applied to the odorants. We initially fingerprinted 89 individuals using 28 odors and 54 descriptors. We found that each person had a unique olfactory fingerprint (P < 10−10), which was odor specific but descriptor independent. We could identify individuals from this pool using randomly selected sets of 7 odors and 11 descriptors alone. Extrapolating from this data, we determined that using 34 odors and 35 descriptors we could individually identify each of the 7 billion people on earth. Olfactory perception, however, fluctuates over time, calling into question our proposed perceptual readout of presumably stable genetic makeup. To test whether fingerprints remain informative despite this temporal fluctuation, building on the linkage between olfactory receptors and HLA, we hypothesized that olfactory perception may relate to HLA. We obtained olfactory fingerprints and HLA typing for 130 individuals, and found that olfactory fingerprint matching using only four odorants was significantly related to HLA matching (P < 10−4), such that olfactory fingerprints can save 32% of HLA tests in a population screen (P < 10−6). In conclusion, a precise measure of olfactory perception reveals meaningful nonolfactory genetic information. PMID:26100865

  2. Genomic View of Bipolar Disorder Revealed by Whole Genome Sequencing in a Genetic Isolate

    PubMed Central

    Georgi, Benjamin; Craig, David; Kember, Rachel L.; Liu, Wencheng; Lindquist, Ingrid; Nasser, Sara; Brown, Christopher; Egeland, Janice A.; Paul, Steven M.; Bućan, Maja

    2014-01-01

    Bipolar disorder is a common, heritable mental illness characterized by recurrent episodes of mania and depression. Despite considerable effort to elucidate the genetic underpinnings of bipolar disorder, causative genetic risk factors remain elusive. We conducted a comprehensive genomic analysis of bipolar disorder in a large Old Order Amish pedigree. Microsatellite genotypes and high-density SNP-array genotypes of 388 family members were combined with whole genome sequence data for 50 of these subjects, comprising 18 parent-child trios. This study design permitted evaluation of candidate variants within the context of haplotype structure by resolving the phase in sequenced parent-child trios and by imputation of variants into multiple unsequenced siblings. Non-parametric and parametric linkage analysis of the entire pedigree as well as on smaller clusters of families identified several nominally significant linkage peaks, each of which included dozens of predicted deleterious variants. Close inspection of exonic and regulatory variants in genes under the linkage peaks using family-based association tests revealed additional credible candidate genes for functional studies and further replication in population-based cohorts. However, despite the in-depth genomic characterization of this unique, large and multigenerational pedigree from a genetic isolate, there was no convergence of evidence implicating a particular set of risk loci or common pathways. The striking haplotype and locus heterogeneity we observed has profound implications for the design of studies of bipolar and other related disorders. PMID:24625924

  3. Evidence of intermetastatic heterogeneity for pathological response and genetic mutations within colorectal liver metastases following preoperative chemotherapy

    PubMed Central

    Sebagh, Mylène; Allard, Marc-Antoine; Bosselut, Nelly; Dao, Myriam; Vibert, Eric; Lewin, Maïté; Lemoine, Antoinette; Cherqui, Daniel; Adam, René; Cunha, Antonio Sa

    2016-01-01

    Background In patients receiving preoperative chemotherapy, colorectal liver metastases (CLM) are expected to demonstrate a similar behaviour because of similar organ microenvironment and tumour cell chemosensitivity. We focused on the occurrence of pathological and genetic heterogeneity within CLM. Methods Patients resected for multiple CLM between 2004 and 2011 after > three cycles of chemotherapy were included. Pathological heterogeneity was arbitrarily defined as a > 50% difference in the percentage of remaining tumour cells between individual CLM. In patients with pathological heterogeneity, the mutational genotyping (KRAS, NRAS, BRAF and PIK3CA) was determined from the most heterogeneous CLM. Results Pathological heterogeneity was observed in 31 of 157 patients with multiple CLM (median = 4, range, 2–32) (19.7%). In 72.4% of them, we found a concordance of the mutation status between the paired CLM: both wild-type in 55%, and both mutated in 17.2%. We observed a discordance of the mutation status of 27.6% between CLM: one mutated and the other wild-type. The mutated CLM was the less florid one in 75% of patients with genetic heterogeneity. Conclusions Pathological heterogeneity is present in 19.7% of patients with multiple CLM. Genetic heterogeneity is present in 27.6% of patients with pathological heterogeneity. Heterogeneity could refine guide management for tissue sampling. PMID:26943031

  4. Unexpected genetic heterogeneity in a large consanguineous Brazilian pedigree presenting deafness.

    PubMed

    Lezirovitz, Karina; Pardono, Eliete; de Mello Auricchio, Maria T B; de Carvalho E Silva, Fernando L; Lopes, Juliana J; Abreu-Silva, Ronaldo S; Romanos, Jihane; Batissoco, Ana C; Mingroni-Netto, Regina C

    2008-01-01

    Nonsyndromic autosomal recessive deafness accounts for 80% of hereditary deafness. To date, 52 loci responsible for autosomal recessive deafness have been mapped and 24 genes identified. Here, we report a large inbred Brazilian pedigree with 26 subjects affected by prelingual deafness. Given the extensive consanguinity found in this pedigree, the most probable pattern of inheritance is autosomal recessive. However, our linkage and mutational analysis revealed, instead of an expected homozygous mutation in a single gene, two different mutant alleles and a possible third undetected mutant allele in the MYO15A gene (DFNB3 locus), as well as evidence for other causes for deafness in the same pedigree. Among the 26 affected subjects, 15 were homozygous for the novel c.10573delA mutation in the MYO15A gene, 5 were compound heterozygous for the mutation c.10573delA and the novel deletion c.9957_9960delTGAC and one inherited only a single c.10573delA mutant allele, while the other one could not be identified. Given the extensive consanguinity of the pedigree, there might be at least one more deafness locus segregating to explain the condition in some of the subjects whose deafness is not clearly associated with MYO15A mutations, although overlooked environmental causes could not be ruled out. Our findings illustrate a high level of etiological heterogeneity for deafness in the family and highlight some of the pitfalls of genetic analysis of large genes in extended pedigrees, when homozygosity for a single mutant allele is expected. PMID:17851452

  5. PHENOTYPIC AND GENETIC HETEROGENEITY AMONG SUBJECTS WITH MILD AIRFLOW OBSTRUCTION IN COPDGENE

    PubMed Central

    Lee, Jin Hwa; Cho, Michael H.; McDonald, Merry-Lynn N.; Hersh, Craig P.; Castaldi, Peter J.; Crapo, James D.; Wan, Emily S.; Dy, Jennifer G.; Chang, Yale; Regan, Elizabeth A.; Hardin, Megan; DeMeo, Dawn L.; Silverman, Edwin K.

    2014-01-01

    Background Chronic obstructive pulmonary disease (COPD) is characterized by marked phenotypic heterogeneity. Most previous studies have focused on COPD subjects with FEV1 < 80% predicted. We investigated the clinical and genetic heterogeneity in subjects with mild airflow limitation in spirometry grade 1 defined by the Global Initiative for chronic Obstructive Lung Disease (GOLD 1). Methods Data from current and former smokers participating in the COPDGene Study (NCT00608764) were analyzed. K-means clustering was performed to explore subtypes within 794 GOLD 1 subjects. For all subjects with GOLD 1 and with each cluster, a genome-wide association study and candidate gene testing were performed using smokers with normal lung function as a control group. Combinations of COPD genome-wide significant single nucleotide polymorphisms (SNPs) were tested for association with FEV1 (% predicted) in GOLD 1 and in a combined group of GOLD1 and smoking control subjects. Results K-means clustering of GOLD 1 subjects identified putative “near-normal”, “airway-predominant”, “emphysema-predominant” and “lowest FEV1 % predicted” subtypes. In non-Hispanic whites, the only SNP nominally associated with GOLD 1 status relative to smoking controls was rs7671167 (FAM13A) in logistic regression models with adjustment for age, sex, pack-years of smoking, and genetic ancestry. The emphysema-predominant GOLD 1 cluster was nominally associated with rs7671167 (FAM13A) and rs161976 (BICD1). The lowest FEV1 % predicted cluster was nominally associated with rs1980057 (HHIP) and rs1051730 (CHRNA3). Combinations of COPD genome-wide significant SNPs were associated with FEV1 (% predicted) in a combined group of GOLD 1 and smoking control subjects. Conclusions Our results indicate that GOLD 1 subjects show substantial clinical heterogeneity, which is at least partially related to genetic heterogeneity. PMID:25154699

  6. Temporal fate mapping reveals age-linked heterogeneity in naive T lymphocytes in mice

    PubMed Central

    Hogan, Thea; Gossel, Graeme; Yates, Andrew J.; Seddon, Benedict

    2015-01-01

    Understanding how our T-cell compartments are maintained requires knowledge of their population dynamics, which are typically quantified over days to weeks using the administration of labels incorporated into the DNA of dividing cells. These studies present snapshots of homeostatic dynamics and have suggested that lymphocyte populations are heterogeneous with respect to rates of division and/or death, although resolving the details of such heterogeneity is problematic. Here we present a method of studying the population dynamics of T cells in mice over timescales of months to years that reveals heterogeneity in rates of division and death with respect to the age of the host at the time of thymic export. We use the transplant conditioning drug busulfan to ablate hematopoetic stem cells in young mice but leave the peripheral lymphocyte compartments intact. Following their reconstitution with congenically labeled (donor) bone marrow, we followed the dilution of peripheral host T cells by donor-derived lymphocytes for a year after treatment. Describing these kinetics with mathematical models, we estimate rates of thymic production, division and death of naive CD4 and CD8 T cells. Population-averaged estimates of mean lifetimes are consistent with earlier studies, but we find the strongest support for a model in which both naive T-cell pools contain kinetically distinct subpopulations of older host-derived cells with self-renewing capacity that are resistant to displacement by naive donor lymphocytes. We speculate that these incumbent cells are conditioned or selected for increased fitness through homeostatic expansion into the lymphopenic neonatal environment. PMID:26607449

  7. Temporal fate mapping reveals age-linked heterogeneity in naive T lymphocytes in mice.

    PubMed

    Hogan, Thea; Gossel, Graeme; Yates, Andrew J; Seddon, Benedict

    2015-12-15

    Understanding how our T-cell compartments are maintained requires knowledge of their population dynamics, which are typically quantified over days to weeks using the administration of labels incorporated into the DNA of dividing cells. These studies present snapshots of homeostatic dynamics and have suggested that lymphocyte populations are heterogeneous with respect to rates of division and/or death, although resolving the details of such heterogeneity is problematic. Here we present a method of studying the population dynamics of T cells in mice over timescales of months to years that reveals heterogeneity in rates of division and death with respect to the age of the host at the time of thymic export. We use the transplant conditioning drug busulfan to ablate hematopoetic stem cells in young mice but leave the peripheral lymphocyte compartments intact. Following their reconstitution with congenically labeled (donor) bone marrow, we followed the dilution of peripheral host T cells by donor-derived lymphocytes for a year after treatment. Describing these kinetics with mathematical models, we estimate rates of thymic production, division and death of naive CD4 and CD8 T cells. Population-averaged estimates of mean lifetimes are consistent with earlier studies, but we find the strongest support for a model in which both naive T-cell pools contain kinetically distinct subpopulations of older host-derived cells with self-renewing capacity that are resistant to displacement by naive donor lymphocytes. We speculate that these incumbent cells are conditioned or selected for increased fitness through homeostatic expansion into the lymphopenic neonatal environment. PMID:26607449

  8. CRISPR-Barcoding for Intratumor Genetic Heterogeneity Modeling and Functional Analysis of Oncogenic Driver Mutations.

    PubMed

    Guernet, Alexis; Mungamuri, Sathish Kumar; Cartier, Dorthe; Sachidanandam, Ravi; Jayaprakash, Anitha; Adriouch, Sahil; Vezain, Myriam; Charbonnier, Françoise; Rohkin, Guy; Coutant, Sophie; Yao, Shen; Ainani, Hassan; Alexandre, David; Tournier, Isabelle; Boyer, Olivier; Aaronson, Stuart A; Anouar, Youssef; Grumolato, Luca

    2016-08-01

    Intratumor genetic heterogeneity underlies the ability of tumors to evolve and adapt to different environmental conditions. Using CRISPR/Cas9 technology and specific DNA barcodes, we devised a strategy to recapitulate and trace the emergence of subpopulations of cancer cells containing a mutation of interest. We used this approach to model different mechanisms of lung cancer cell resistance to EGFR inhibitors and to assess effects of combined drug therapies. By overcoming intrinsic limitations of current approaches, CRISPR-barcoding also enables investigation of most types of genetic modifications, including repair of oncogenic driver mutations. Finally, we used highly complex barcodes inserted at a specific genome location as a means of simultaneously tracing the fates of many thousands of genetically labeled cancer cells. CRISPR-barcoding is a straightforward and highly flexible method that should greatly facilitate the functional investigation of specific mutations, in a context that closely mimics the complexity of cancer. PMID:27453044

  9. Hydrogeophysics and geochemistry reveal heterogeneity and water quality improvements in aquifer recharge and recovery (ARR) (Invited)

    NASA Astrophysics Data System (ADS)

    Parsekian, A.; Regnery, J.; Wing, A.; Knight, R. J.; Drewes, J. E.

    2013-12-01

    Aquifer recharge and recover (ARR) is the process of infiltrating water into the ground for storage and withdrawal through wells at a later time. Two significant challenges faced during the design of ARR systems are 1) evaluating aquifer heterogeneity and 2) understanding the rock fluid interactions; these knowledge gaps may have profound impacts on the volume of recoverable water and the improvement in water quality in comparison with the source-water. Our objective in this research is to leverage the advantages of hydrogeophysical measurements and geochemical sampling to reveal the properties of an aquifer through which ARR water travels with the goal of informing current operations and future design decisions. Combined geophysical and geochemical investigations reveal subsurface heterogeneity, indicate possible flow paths though the aquifer and quantify specific reductions in contaminant concentrations. Ground penetrating radar (GPR), electromagnetic induction (EMI) and electrical resistivity tomography (ERT) were used to image the subsurface throughout two key infiltration/extraction areas of an ARR site in Colorado, USA. The most valuable results came from 2.5D ERT revealing the structural patterns and suggesting the distribution of textural composition of unconsolidated sediments. Geochemical measurements on transects intersecting the geophysical measurements resolved bulk parameters (i.e. total organic carbon, cations, anions) and trace organic contaminants (e.g. trace organic compounds) and were also used to estimate mixing and water travel times and assess the performance of the ARR site regarding water quality and quantity. Our results indicate that the subsurface is highly heterogeneous at our study site and that the coarse-grained sedimentary units, acting as the best conduit for transporting water, are likely discontinuous. The electrical resistivity measurements indicate certain areas of the infiltration basins may have good hydraulic connections to

  10. Trace incorporation of heavy water reveals slow and heterogeneous pathogen growth rates in cystic fibrosis sputum

    NASA Astrophysics Data System (ADS)

    Kopf, Sebastian H.; Sessions, Alex L.; Cowley, Elise S.; Reyes, Carmen; Van Sambeek, Lindsey; Hu, Yang; Orphan, Victoria J.; Kato, Roberta; Newman, Dianne K.

    2016-01-01

    Effective treatment for chronic infections is undermined by a significant gap in understanding of the physiological state of pathogens at the site of infection. Chronic pulmonary infections are responsible for the morbidity and mortality of millions of immunocompromised individuals worldwide, yet drugs that are successful in laboratory culture are far less effective against pathogen populations persisting in vivo. Laboratory models, upon which preclinical development of new drugs is based, can only replicate host conditions when we understand the metabolic state of the pathogens and the degree of heterogeneity within the population. In this study, we measured the anabolic activity of the pathogen Staphylococcus aureus directly in the sputum of pediatric patients with cystic fibrosis (CF), by combining the high sensitivity of isotope ratio mass spectrometry with a heavy water labeling approach to capture the full range of in situ growth rates. Our results reveal S. aureus generation times with a median of 2.1 d, with extensive growth rate heterogeneity at the single-cell level. These growth rates are far below the detection limit of previous estimates of CF pathogen growth rates, and the rates are slowest in acutely sick patients undergoing pulmonary exacerbations; nevertheless, they are accessible to experimental replication within laboratory models. Treatment regimens that include specific antibiotics (vancomycin, piperacillin/tazobactam, tobramycin) further appear to correlate with slow growth of S. aureus on average, but follow-up longitudinal studies must be performed to determine whether this effect holds for individual patients.

  11. Trace incorporation of heavy water reveals slow and heterogeneous pathogen growth rates in cystic fibrosis sputum

    PubMed Central

    Kopf, Sebastian H.; Sessions, Alex L.; Cowley, Elise S.; Reyes, Carmen; Van Sambeek, Lindsey; Hu, Yang; Orphan, Victoria J.; Kato, Roberta; Newman, Dianne K.

    2016-01-01

    Effective treatment for chronic infections is undermined by a significant gap in understanding of the physiological state of pathogens at the site of infection. Chronic pulmonary infections are responsible for the morbidity and mortality of millions of immunocompromised individuals worldwide, yet drugs that are successful in laboratory culture are far less effective against pathogen populations persisting in vivo. Laboratory models, upon which preclinical development of new drugs is based, can only replicate host conditions when we understand the metabolic state of the pathogens and the degree of heterogeneity within the population. In this study, we measured the anabolic activity of the pathogen Staphylococcus aureus directly in the sputum of pediatric patients with cystic fibrosis (CF), by combining the high sensitivity of isotope ratio mass spectrometry with a heavy water labeling approach to capture the full range of in situ growth rates. Our results reveal S. aureus generation times with a median of 2.1 d, with extensive growth rate heterogeneity at the single-cell level. These growth rates are far below the detection limit of previous estimates of CF pathogen growth rates, and the rates are slowest in acutely sick patients undergoing pulmonary exacerbations; nevertheless, they are accessible to experimental replication within laboratory models. Treatment regimens that include specific antibiotics (vancomycin, piperacillin/tazobactam, tobramycin) further appear to correlate with slow growth of S. aureus on average, but follow-up longitudinal studies must be performed to determine whether this effect holds for individual patients. PMID:26715741

  12. Multilocus genotypic data reveal high genetic diversity and low population genetic structure of Iranian indigenous sheep.

    PubMed

    Vahidi, S M F; Faruque, M O; Falahati Anbaran, M; Afraz, F; Mousavi, S M; Boettcher, P; Joost, S; Han, J L; Colli, L; Periasamy, K; Negrini, R; Ajmone-Marsan, P

    2016-08-01

    Iranian livestock diversity is still largely unexplored, in spite of the interest in the populations historically reared in this country located near the Fertile Crescent, a major livestock domestication centre. In this investigation, the genetic diversity and differentiation of 10 Iranian indigenous fat-tailed sheep breeds were investigated using 18 microsatellite markers. Iranian breeds were found to host a high level of diversity. This conclusion is substantiated by the large number of alleles observed across loci (average 13.83, range 7-22) and by the high within-breed expected heterozygosity (average 0.75, range 0.72-0.76). Iranian sheep have a low level of genetic differentiation, as indicated by the analysis of molecular variance, which allocated a very small proportion (1.67%) of total variation to the between-population component, and by the small fixation index (FST  = 0.02). Both Bayesian clustering and principal coordinates analysis revealed the absence of a detectable genetic structure. Also, no isolation by distance was observed through comparison of genetic and geographical distances. In spite of high within-breed variation, signatures of inbreeding were detected by the FIS indices, which were positive in all and statistically significant in three breeds. Possible factors explaining the patterns observed, such as considerable gene flow and inbreeding probably due to anthropogenic activities in the light of population management and conservation programmes, are discussed. PMID:26953226

  13. Ideal probe single-molecule experiments reveal the intrinsic dynamic heterogeneity of a supercooled liquid

    PubMed Central

    Paeng, Keewook; Park, Heungman; Hoang, Dat Tien; Kaufman, Laura J.

    2015-01-01

    The concept of dynamic heterogeneity and the picture of the supercooled liquid as a mosaic of environments with distinct dynamics that interchange in time have been invoked to explain the nonexponential relaxations measured in these systems. The spatial extent and temporal persistence of these regions of distinct dynamics have remained challenging to identify. Here, single-molecule fluorescence measurements using a probe similar in size and mobility to the host o-terphenyl unambiguously reveal exponential relaxations distributed in time and space and directly demonstrate ergodicity of the system down to the glass transition temperature. In the temperature range probed, at least 200 times the structural relaxation time of the host is required to recover ensemble-averaged relaxation at every spatial region in the system. PMID:25825739

  14. Evidence of Heterogeneity by Race/Ethnicity in Genetic Determinants of QT Interval

    PubMed Central

    Seyerle, Amanda A.; Young, Alicia M.; Jeff, Janina M.; Melton, Phillip E.; Jorgensen, Neal W.; Lin, Yi; Carty, Cara L.; Deelman, Ewa; Heckbert, Susan R.; Hindorff, Lucia A.; Jackson, Rebecca D.; Martin, Lisa W.; Okin, Peter M; Perez, Marco V.; Psaty, Bruce M.; Soliman, Elsayed Z.; Whitsel, Eric A.; North, Kari E; Laston, Sandra; Kooperberg, Charles; Avery, Christy L.

    2015-01-01

    Background QT-interval (QT) prolongation is an established risk factor for ventricular tachyarrhythmia and sudden cardiac death. Previous genome-wide association studies in populations of the European descent have identified multiple genetic loci that influence QT, but few have examined these loci in ethnically diverse populations. Methods Here, we examine the direction, magnitude, and precision of effect sizes for 21 previously reported SNPs from 12 QT loci, in populations of European (n=16,398), African (n=5,437), American Indian (n=5,032), Hispanic (n=1,143), and Asian (n=932) descent as part of the Population Architecture using Genomics and Epidemiology (PAGE) study. Estimates obtained from linear regression models stratified by race/ethnicity were combined using inverse-variance weighted meta-analysis. Heterogeneity was evaluated using Cochran's Q test. Results Of 21 SNPs, seven showed consistent direction of effect across all five populations, and an additional nine had estimated effects that were consistent across four populations. Despite consistent direction of effect, nine of 16 SNPs had evidence (P < 0.05) of heterogeneity by race/ethnicity. For these 9 SNPs, linkage disequilibrium plots often indicated substantial variation in linkage disequilibrium patterns among the various racial/ethnic groups, as well as possible allelic heterogeneity. Conclusions These results emphasize the importance of analyzing racial/ethnic groups separately in genetic studies. Furthermore, they underscore the possible utility of trans-ethnic studies to pinpoint underlying casual variants influencing heritable traits such as QT. PMID:25166880

  15. Genetic diversity and structure in Leishmania infantum populations from southeastern Europe revealed by microsatellite analysis

    PubMed Central

    2013-01-01

    Background The dynamic re-emergence of visceral leishmaniasis (VL) in south Europe and the northward shift to Leishmania-free European countries are well-documented. However, the epidemiology of VL due to Leishmania infantum in southeastern (SE) Europe and the Balkans is inadequately examined. Herein, we aim to re-evaluate and compare the population structure of L. infantum in SE and southwestern (SW) Europe. Methods Leishmania strains collected from humans and canines in Turkey, Cyprus, Bulgaria, Greece, Albania and Croatia, were characterized by the K26-PCR assay and multilocus enzyme electrophoresis (MLEE). Genetic diversity was assessed by multilocus microsatellite typing (MLMT) and MLM Types were analyzed by model- and distance- based algorithms to infer the population structure of 128 L. infantum strains. Results L. infantum MON-1 was found predominant in SE Europe, whilst 16.8% of strains were MON-98. Distinct genetic populations revealed clear differentiation between SE and SW European strains. Interestingly, Cypriot canine isolates were genetically isolated and formed a monophyletic group, suggesting the constitution of a clonal MON-1 population circulating among dogs. In contrast, two highly heterogeneous populations enclosed all MON-1 and MON-98 strains from the other SE European countries. Structure sub-clustering, phylogenetic and Splitstree analysis also revealed two distinct Croatian subpopulations. A mosaic of evolutionary effects resulted in consecutive sub-structuring, which indicated substantial differentiation and gene flow among strains of both zymodemes. Conclusions This is the first population genetic study of L. infantum in SE Europe and the Balkans. Our findings demonstrate the differentiation between SE and SW European strains; revealing the partition of Croatian strains between these populations and the genetic isolation of Cypriot strains. This mirrors the geographic position of Croatia located in central Europe and the natural

  16. The number of candidate variants in exome sequencing for Mendelian disease under no genetic heterogeneity.

    PubMed

    Nishino, Jo; Mano, Shuhei

    2013-01-01

    There has been recent success in identifying disease-causing variants in Mendelian disorders by exome sequencing followed by simple filtering techniques. Studies generally assume complete or high penetrance. However, there are likely many failed and unpublished studies due in part to incomplete penetrance or phenocopy. In this study, the expected number of candidate single-nucleotide variants (SNVs) in exome data for autosomal dominant or recessive Mendelian disorders was investigated under the assumption of "no genetic heterogeneity." All variants were assumed to be under the "null model," and sample allele frequencies were modeled using a standard population genetics theory. To investigate the properties of pedigree data, full-sibs were considered in addition to unrelated individuals. In both cases, particularly regarding full-sibs, the number of SNVs remained very high without controls. The high efficacy of controls was also confirmed. When controls were used with a relatively large total sample size (e.g., N = 20, 50), filtering incorporating of incomplete penetrance and phenocopy efficiently reduced the number of candidate SNVs. This suggests that filtering is useful when an assumption of no "genetic heterogeneity" is appropriate and could provide general guidelines for sample size determination. PMID:23762180

  17. The Genetic Relationship between Leishmania aethiopica and Leishmania tropica Revealed by Comparing Microsatellite Profiles

    PubMed Central

    Krayter, Lena; Schnur, Lionel F.; Schönian, Gabriele

    2015-01-01

    Background Leishmania (Leishmania) aethiopica and L. (L.) tropica cause cutaneous leishmaniases and appear to be related. L. aethiopica is geographically restricted to Ethiopia and Kenya; L. tropica is widely dispersed from the Eastern Mediterranean, through the Middle East into eastern India and in north, east and south Africa. Their phylogenetic inter-relationship is only partially revealed. Some studies indicate a close relationship. Here, eight strains of L. aethiopica were characterized genetically and compared with 156 strains of L. tropica from most of the latter species' geographical range to discern the closeness. Methodology/Principal Findings Twelve unlinked microsatellite markers previously used to genotype strains of L. tropica were successfully applied to the eight strains of L. aethiopica and their microsatellite profiles were compared to those of 156 strains of L. tropica from various geographical locations that were isolated from human cases of cutaneous and visceral leishmaniasis, hyraxes and sand fly vectors. All the microsatellite profiles were subjected to various analytical algorithms: Bayesian statistics, distance-based and factorial correspondence analysis, revealing: (i) the species L. aethiopica, though geographically restricted, is genetically very heterogeneous; (ii) the strains of L. aethiopica formed a distinct genetic cluster; and (iii) strains of L. aethiopica are closely related to strains of L. tropica and more so to the African ones, although, by factorial correspondence analysis, clearly separate from them. Conclusions/Significance The successful application of the 12 microsatellite markers, originally considered species-specific for the species L. tropica, to strains of L. aethiopica confirmed the close relationship between these two species. The Bayesian and distance-based methods clustered the strains of L. aethiopica among African strains of L. tropica, while the factorial correspondence analysis indicated a clear separation

  18. Candida milleri species reveals intraspecific genetic and metabolic polymorphisms.

    PubMed

    Vigentini, Ileana; Antoniani, Davide; Roscini, Luca; Comasio, Andrea; Galafassi, Silvia; Picozzi, Claudia; Corte, Laura; Compagno, Concetta; Dal Bello, Fabio; Cardinali, Gianluigi; Foschino, Roberto

    2014-09-01

    Candida milleri, together with Candida humilis, is the most representative yeast species found in type I sourdough ecosystems. In this work, comparison of the ITS region and the D1/D2 domain of 26S rDNA gene partial sequences, karyotyping, mtDNA-RFLP analysis, Intron Splice Site dispersion (ISS-PCR) and (GTG)5 microsatellite analyses, assimilation test of different carbohydrates, and metabolome assessment by FT-IR analysis, were investigated in seventeen strains isolated from four different companies as well as in type strains CBS6897(T) and CBS5658(T). Most isolates were ascribed to C. milleri, even if a strong relatedness was confirmed with C. humilis as well, particularly for three strains. Genetic characterization showed a high degree of intraspecific polymorphism since 12 different genotypes were discriminated. The number of chromosomes varied from 9 to 13 and their size ranged from less than 0.3 to over 2 Mbp. Phenotypic traits let to recognize 9 different profiles of carbon sources assimilation. FT-IR spectra from yeast cells cultivated in different media and collected at different growth phases revealed a diversity of behaviour among strains in accordance with the results of PCR-based fingerprinting. A clear evidence of the polymorphic status of C. milleri species is provided thus representing an important feature for the development of technological applications in bakery industries. PMID:24929720

  19. Genetically engineered immunoglobulins reveal structural features controlling segmental flexibility.

    PubMed Central

    Schneider, W P; Wensel, T G; Stryer, L; Oi, V T

    1988-01-01

    We have carried out nanosecond fluorescence polarization studies of genetically engineered immunoglobulins to determine the structural features controlling their segmental flexibility. The proteins studied were hybrids of a relatively rigid isotype (mouse IgG1) and a relatively flexible one (mouse IgG2a). They have identical light chains and heavy chain variable regions and have the same combining sites for epsilon-dansyl-L-lysine, a fluorescent hapten. The fluorescence of the bound dansyl chromophore was excited at 348 nm with subnanosecond laser pulses, and the emission in the nanosecond time range was measured with a single-photon-counting apparatus. The emission anisotropy kinetics of the hybrid antibodies revealed that segmental flexibility is controlled by the heavy chain constant region 1 (CH1) as well as by the hinge. In contrast, the CH2 and CH3 domains did not influence segmental flexibility. The hinge and CH1 domains must be properly matched to allow facile movement of the Fab units. Studies of hybrids of IgG1 and IgG2a within CH1 showed that the loop formed by residues 131-139 is important in controlling segmental flexibility. X-ray crystallographic studies by others of human IgG1 have shown that this loop makes several van der Waals contacts with the hinge. Images PMID:3128789

  20. Genetic heterogeneity in five Italian regions: analysis of PAH mutations and minihaplotypes.

    PubMed

    Giannattasio, S; Dianzani, I; Lattanzio, P; Spada, M; Romano, V; Calì, F; Andria, G; Ponzone, A; Marra, E; Piazza, A

    2001-01-01

    Molecular analysis of 289 chromosomes has been performed in a cohort of phenylketonuria (PKU) patients whose ancestors lived in five Italian regions, Calabria, Campania, Piemonte, Puglia/Basilicata and Sicilia. Phenylalaninehydroxylase (PAH) gene mutations and minihaplotypes (combinations of PAH gene STR and VNTR systems) have been determined for 78.5 and 64%, respectively, of the chromosomes studied. 21 different minihaplotypes and 24 PKU mutations were found. Heterogeneity tests carried out for the frequencies of mutations and minihaplotypes show that the distribution of eight mutations and four minihaplotypes is statistically heterogeneous in the five Italian regions. Although the evolutionary rate of microsatellites or the age of these mutations is difficult to estimate with accuracy, our findings taken together show a genetic stratification of the Italian population. These results rule out allelic homogeneity of PKU at the molecular level between regions of Italy, yet minihaplotype data may be of practical use for a multistep approach to PAH gene genotyping. PMID:11588399

  1. Assignment of a gene for autosomal recessive retinitis pigmentosa (RP12) to chromosome 1q31-q32.1 in an inbred and genetically heterogeneous disease population

    SciTech Connect

    Van Soest, S.; Ingeborgh Van Den Born, L.; Bergen, A.A.B.

    1994-08-01

    Linkage analysis was carried out in a large family segregating for autosomal recessive retinitis pigmentosa (arRP), originating from a genetically isolated population in The Netherlands. Within the family, clinical heterogeneity was observed, with a major section of the family segregating arRP with characteristic para-arteriolar preservation of the retinal pigment epithelium (PPRPE). In the remainder of the arRP patients no PPRPE was found. Initially, all branches of the family were analyzed jointly, and linkage was found between the marker F13B, located at 1q31-q32.1, and RP12 ({Zeta}{sub max} = 4.99 at 8% recombination). Analysis of linkage heterogeneity between five branches of the family yielded significant evidence for nonallelic genetic heterogeneity within this family, coinciding with the observed clinical differences. Multipoint analysis, carried out in the branches that showed linkage, favored the locus order 1cen-D1S158-(F13B, RP12)-D1S53-1qter ({Zeta}{sub max} = 9.17). The finding of a single founder allele associated with the disease phenotype supports this localization. This study reveals that even in a large family, apparently segregating for a single disease entity, genetic heterogeneity can be detected and resolved successfully. 35 refs., 5 figs.

  2. Modelling the dispersal of the two main hosts of the raccoon rabies variant in heterogeneous environments with landscape genetics.

    PubMed

    Rioux Paquette, Sébastien; Talbot, Benoit; Garant, Dany; Mainguy, Julien; Pelletier, Fanie

    2014-08-01

    Predicting the geographic spread of wildlife epidemics requires knowledge about the movement patterns of disease hosts or vectors. The field of landscape genetics provides valuable approaches to study dispersal indirectly, which in turn may be used to understand patterns of disease spread. Here, we applied landscape genetic analyses and spatially explicit models to identify the potential path of raccoon rabies spread in a mesocarnivore community. We used relatedness estimates derived from microsatellite genotypes of raccoons and striped skunks to investigate their dispersal patterns in a heterogeneous landscape composed predominantly of agricultural, forested and residential areas. Samples were collected in an area covering 22 000 km(2) in southern Québec, where the raccoon rabies variant (RRV) was first detected in 2006. Multiple regressions on distance matrices revealed that genetic distance among male raccoons was strictly a function of geographic distance, while dispersal in female raccoons was significantly reduced by the presence of agricultural fields. In skunks, our results suggested that dispersal is increased in edge habitats between fields and forest fragments in both males and females. Resistance modelling allowed us to identify likely dispersal corridors used by these two rabies hosts, which may prove especially helpful for surveillance and control (e.g. oral vaccination) activities. PMID:25469156

  3. Modelling the dispersal of the two main hosts of the raccoon rabies variant in heterogeneous environments with landscape genetics

    PubMed Central

    Rioux Paquette, Sébastien; Talbot, Benoit; Garant, Dany; Mainguy, Julien; Pelletier, Fanie

    2014-01-01

    Predicting the geographic spread of wildlife epidemics requires knowledge about the movement patterns of disease hosts or vectors. The field of landscape genetics provides valuable approaches to study dispersal indirectly, which in turn may be used to understand patterns of disease spread. Here, we applied landscape genetic analyses and spatially explicit models to identify the potential path of raccoon rabies spread in a mesocarnivore community. We used relatedness estimates derived from microsatellite genotypes of raccoons and striped skunks to investigate their dispersal patterns in a heterogeneous landscape composed predominantly of agricultural, forested and residential areas. Samples were collected in an area covering 22 000 km2 in southern Québec, where the raccoon rabies variant (RRV) was first detected in 2006. Multiple regressions on distance matrices revealed that genetic distance among male raccoons was strictly a function of geographic distance, while dispersal in female raccoons was significantly reduced by the presence of agricultural fields. In skunks, our results suggested that dispersal is increased in edge habitats between fields and forest fragments in both males and females. Resistance modelling allowed us to identify likely dispersal corridors used by these two rabies hosts, which may prove especially helpful for surveillance and control (e.g. oral vaccination) activities. PMID:25469156

  4. Deep sequencing identifies genetic heterogeneity and recurrent convergent evolution in chronic lymphocytic leukemia

    PubMed Central

    Ojha, Juhi; Ayres, Jackline; Secreto, Charla; Tschumper, Renee; Rabe, Kari; Van Dyke, Daniel; Slager, Susan; Shanafelt, Tait; Fonseca, Rafael; Kay, Neil E.

    2015-01-01

    Recent high-throughput sequencing and microarray studies have characterized the genetic landscape and clonal complexity of chronic lymphocytic leukemia (CLL). Here, we performed a longitudinal study in a homogeneously treated cohort of 12 patients, with sequential samples obtained at comparable stages of disease. We identified clonal competition between 2 or more genetic subclones in 70% of the patients with relapse, and stable clonal dynamics in the remaining 30%. By deep sequencing, we identified a high reservoir of genetic heterogeneity in the form of several driver genes mutated in small subclones underlying the disease course. Furthermore, in 2 patients, we identified convergent evolution, characterized by the combination of genetic lesions affecting the same genes or copy number abnormality in different subclones. The phenomenon affects multiple CLL putative driver abnormalities, including mutations in NOTCH1, SF3B1, DDX3X, and del(11q23). This is the first report documenting convergent evolution as a recurrent event in the CLL genome. Furthermore, this finding suggests the selective advantage of specific combinations of genetic lesions for CLL pathogenesis in a subset of patients. PMID:25377784

  5. Genome-wide mutational spectra analysis reveals significant cancer-specific heterogeneity

    PubMed Central

    Tan, Hua; Bao, Jiguang; Zhou, Xiaobo

    2015-01-01

    Cancer is widely recognized as a genetic disease in which somatic mutations are sequentially accumulated to drive tumor progression. Although genomic landscape studies are informative for individual cancer types, a comprehensive comparative study of tumorigenic mutations across cancer types based on integrative data sources is still a pressing need. We systematically analyzed ~106 non-synonymous mutations extracted from COSMIC, involving ~8000 genome-wide screened samples across 23 major human cancers at both the amino acid and gene levels. Our analysis identified cancer-specific heterogeneity that traditional nucleotide variation analysis alone usually overlooked. Particularly, the amino acid arginine (R) turns out to be the most favorable target of amino acid alteration in most cancer types studied (P < 10−9, binomial test), reflecting its important role in cellular physiology. The tumor suppressor gene TP53 is mutated exclusively with the HYDIN, KRAS, and PTEN genes in large intestine, lung, and endometrial cancers respectively, indicating that TP53 takes part in different signaling pathways in different cancers. While some of our analyses corroborated previous observations, others indicated relevant candidates with high priority for further experimental validation. Our findings have many ramifications in understanding the etiology of cancer and the underlying molecular mechanisms in particular cancers. PMID:26212640

  6. New Genetic Susceptibility Factors for Sjögren's Syndrome Revealed

    MedlinePlus

    ... 1999 Spotlight on Research 2014 March 2014 (historical) New Genetic Susceptibility Factors for Sjögren’s Syndrome Revealed By ... the journal Nature Genetics, could help researchers develop new strategies to diagnose and treat the condition. In ...

  7. Spatial heterogeneity in a deep artificial lake plankton community revealed by PCR-DGGE fingerprinting

    NASA Astrophysics Data System (ADS)

    Li, Qiang; Zhao, Yue; Zhang, Xu; Wei, Yuquan; Qiu, Linlin; Wei, Zimin; Li, Fuheng

    2015-05-01

    To explore the spatial heterogeneity of plankton communities in a deep artificial lake (Songhua Lake, China), samples were collected at seven sites. Samples were investigated by denaturing gradient gel electrophoresis (DGGE) analysis of the PCR-amplified 16S and 18S rRNA genes and specific bands were sequenced. Cluster analysis of the DGGE profiles revealed that all of the samples grouped into two distinct clusters, in accordance with sampling site; while in each cluster, the divergence of sub-clusters correlated with sampling depth. Sequence analysis of selected dominant DGGE bands revealed that most sequenced phylotypes (84%) exhibited ≥97% similarity to the closest sequences in GenBank, and were affiliated with ten common freshwater plankton phyla ( Proteobacteria, Actinobacteria, Bacteroidetes, Cyanobacteria, Bacillariophyta, Pyrrophyta, Cryptophyta, Ciliophora, Stramenopiles, and Rotifera). Several of these groups are also found worldwide, indicating the cosmopolitan distribution of the phylotypes. The relationships between DGGE patterns and environmental factors were analyzed by redundancy analysis (RDA). The results suggested that, total nitrogen, nitrate, nitrite, ammonia, and CODMn concentrations, and water temperature were strongly correlated with the variation in plankton composition.

  8. Single-cell gene expression profiling reveals functional heterogeneity of undifferentiated human epidermal cells

    PubMed Central

    Tan, David W. M.; Jensen, Kim B.; Trotter, Matthew W. B.; Connelly, John T.; Broad, Simon; Watt, Fiona M.

    2013-01-01

    Human epidermal stem cells express high levels of β1 integrins, delta-like 1 (DLL1) and the EGFR antagonist LRIG1. However, there is cell-to-cell variation in the relative abundance of DLL1 and LRIG1 mRNA transcripts. Single-cell global gene expression profiling showed that undifferentiated cells fell into two clusters delineated by expression of DLL1 and its binding partner syntenin. The DLL1+ cluster had elevated expression of genes associated with endocytosis, integrin-mediated adhesion and receptor tyrosine kinase signalling. Differentially expressed genes were not independently regulated, as overexpression of DLL1 alone or together with LRIG1 led to the upregulation of other genes in the DLL1+ cluster. Overexpression of DLL1 and LRIG1 resulted in enhanced extracellular matrix adhesion and increased caveolin-dependent EGFR endocytosis. Further characterisation of CD46, one of the genes upregulated in the DLL1+ cluster, revealed it to be a novel cell surface marker of human epidermal stem cells. Cells with high endogenous levels of CD46 expressed high levels of β1 integrin and DLL1 and were highly adhesive and clonogenic. Knockdown of CD46 decreased proliferative potential and β1 integrin-mediated adhesion. Thus, the previously unknown heterogeneity revealed by our studies results in differences in the interaction of undifferentiated basal keratinocytes with their environment. PMID:23482486

  9. Fatal familial insomnia: clinical and pathologic heterogeneity in genetic half brothers.

    PubMed

    Johnson, M D; Vnencak-Jones, C L; McLean, M J

    1998-12-01

    We describe clinical and pathologic features of a patient with fatal familial insomnia (FFI) whose prion (PrP) genotype is D178N coupled with methionine at codon 129 on his mutant allele and valine at codon 129 on his normal allele. A cousin (genetic half brother) with identical PrP genotypes exhibited strikingly different clinical and pathologic changes. Comparison of these cousins shows the phenotypic heterogeneity of FFI and suggests that the phenotypic expression of D178N is influenced by multiple factors. PMID:9855529

  10. Characterization of FGFR1 Locus in sqNSCLC Reveals a Broad and Heterogeneous Amplicon

    PubMed Central

    Rooney, Claire; Geh, Catherine; Williams, Victoria; Heuckmann, Johannes M.; Menon, Roopika; Schneider, Petra; Al-Kadhimi, Katherine; Dymond, Michael; Smith, Neil R.; Baker, Dawn; French, Tim; Smith, Paul D.; Harrington, Elizabeth A.; Barrett, J. Carl; Kilgour, Elaine

    2016-01-01

    FGFR1 amplification occurs in ~20% of sqNSCLC and trials with FGFR inhibitors have selected FGFR1 amplified patients by FISH. Lung cancer cell lines were profiled for sensitivity to AZD4547, a potent, selective inhibitor of FGFRs 1–3. Sensitivity to FGFR inhibition was associated with but not wholly predicted by increased FGFR1 gene copy number. Additional biomarker assays evaluating expression of FGFRs and correlation between amplification and expression in clinical tissues are therefore warranted. We validated nanoString for mRNA expression analysis of 194 genes, including FGFRs, from clinical tumour tissue. In a panel of sqNSCLC tumours 14.4% (13/90) were FGFR1 amplified by FISH. Although mean FGFR1 expression was significantly higher in amplified samples, there was significant overlap in the range of expression levels between the amplified and non-amplified cohorts with several non-amplified samples expressing FGFR1 to levels equivalent to amplified samples. Statistical analysis revealed increased expression of FGFR1 neighboring genes on the 8p12 amplicon (BAG4, LSM1 and WHSC1L1) in FGFR1 amplified tumours, suggesting a broad rather than focal amplicon and raises the potential for codependencies. High resolution aCGH analysis of pre-clinical and clinical samples supported the presence of a broad and heterogeneous amplicon around the FGFR1 locus. In conclusion, the range of FGFR1 expression levels in both FGFR1 amplified and non-amplified NSCLC tissues, together with the breadth and intra-patient heterogeneity of the 8p amplicon highlights the need for gene expression analysis of clinical samples to inform the understanding of determinants of response to FGFR inhibitors. In this respect the nanoString platform provides an attractive option for RNA analysis of FFPE clinical samples. PMID:26905262

  11. Genetic heterogeneity in wild isolates of cellular slime mold social groups.

    PubMed

    Sathe, Santosh; Kaushik, Sonia; Lalremruata, Albert; Aggarwal, Ramesh K; Cavender, James C; Nanjundiah, Vidyanand

    2010-07-01

    This study addresses the issues of spatial distribution, dispersal, and genetic heterogeneity in social groups of the cellular slime molds (CSMs). The CSMs are soil amoebae with an unusual life cycle that consists of alternating solitary and social phases. Because the social phase involves division of labor with what appears to be an extreme form of "altruism", the CSMs raise interesting evolutionary questions regarding the origin and maintenance of sociality. Knowledge of the genetic structure of social groups in the wild is necessary for answering these questions. We confirm that CSMs are widespread in undisturbed forest soil from South India. They are dispersed over long distances via the dung of a variety of large mammals. Consistent with this mode of dispersal, most social groups in the two species examined for detailed study, Dictyostelium giganteum and Dictyostelium purpureum, are multi-clonal. PMID:20179919

  12. Gene expression in amygdala as a function of differential trait anxiety levels in genetically heterogeneous NIH-HS rats.

    PubMed

    Díaz-Morán, Sira; Palència, Marta; Mont-Cardona, Carme; Cañete, Toni; Blázquez, Gloria; Martínez-Membrives, Esther; López-Aumatell, Regina; Sabariego, Marta; Donaire, Rocío; Morón, Ignacio; Torres, Carmen; Martínez-Conejero, José Antonio; Tobeña, Adolf; Esteban, Francisco José; Fernández-Teruel, Alberto

    2013-09-01

    To identify genes involved in anxiety/fear traits, we analyzed the gene expression profile in the amygdala of genetically heterogeneous NIH-HS rats. The NIH-HS rat stock has revealed to be a unique genetic resource for the fine mapping of Quantitative Trait Loci (QTLs) to very small genomic regions, due to the high amount of genetic recombinants accumulated along more than 50 breeding generations, and for the same reason it can be expected that those genetically heterogeneous rats should be especially useful for studying differential gene expression as a function of anxiety-(or other)-related traits. We selected high- and low-anxious NIH-HS rats differing in their number of avoidances in a single 50-trial session of the two-way active avoidance task. Rats were also tested in unconditioned anxiety tests (e.g., elevated zero-maze). Three weeks after behavioural testing, the amygdala was dissected and prepared for the microarray study. There appeared 6 significantly down-regulated and 28 up-regulated genes (fold-change >|2|, FDR<0.05) between the low- and high-anxious groups, with central nervous system-related functions. Regression analyses (stepwise) revealed that differential expression of some genes could be predictive of anxiety/fear responses. Among those genes for which the present results suggest a link with individual differences in trait anxiety, six relevant genes were examined with qRT-PCR, four of which (Ucn3, Tacr3, H2-M9 and Arr3) were validated. Remarkably, some of them are characterized by sharing known functions related with hormonal HPA-axis responses to (and/or modulation of) stress, anxiety or fear, and putative involvement in related neurobehavioural functions. The results confirm the usefulness of NIH-HS rats as a good animal model for research on the neurogenetic basis of anxiety and fear, while suggesting the involvement of some neuropeptide/neuroendocrine pathways on the development of differential anxiety profiles. PMID:23777796

  13. Genetic Underpinnings of White Matter ‘Connectivity’: Heritability, Risk, and Heterogeneity in Schizophrenia

    PubMed Central

    Voineskos, Aristotle N.

    2014-01-01

    Schizophrenia is a highly heritable disorder. Thus, the combination of genetics and brain imaging may be a useful strategy to investigate the effects of risk genes on anatomical connectivity, and for gene discovery, i.e. discovering the genetic correlates of white matter phenotypes. Following a database search, I review evidence for heritability of white matter phenotypes. I also review candidate gene investigations, examining association of putative risk variants with white matter phenotypes, as well as the recent flurry of research exploring relationships of genome-wide significant risk loci with white matter phenotypes. Finally, I review multivariate and polygene approaches, which constitute a new wave of imaging-genetics research, including large collaborative initiatives aiming to discover new genes that may predict aspects of white matter microstructure. The literature supports the heritability of white matter phenotypes. Loci in genes intimately implicated in oligodendrocyte and myelin development, growth and maintenance, and neurotrophic systems are associated with white matter microstructure. GWAS variants have not yet sufficiently been explored using DTI-based evaluation of white matter to draw conclusions, although micro-RNA 137 is promising due to its potential regulation of other GWAS schizophrenia genes. Many imaging-genetic studies only include healthy participants, which, while helping control for certain confounds, cannot address questions related to disease heterogeneity or symptom expression, and thus more studies should include participants with schizophrenia. With sufficiently large sample sizes, the future of this field lies in polygene strategies aimed at risk prediction and heterogeneity dissection of schizophrenia that can translate to personalized interventions. PMID:24893906

  14. Revealing core-mantle boundary temperature and corresponding lower mantle heterogeneities by numerical simulations

    NASA Astrophysics Data System (ADS)

    Fomin, Ilya; Tackley, Paul

    2016-04-01

    Koker et al., 2013], [Beuchert & Schmeling, 2013]). Melt migration downwards causes iron and other components extraction and accumulation around CMB. This process can produce layer of refractory material above partialy molten rocks at CMB. Our calculations show, that at 3900K mantle is totally solid. If we do not take into account melt segregation processes, molten layer will exceed 60 km already at 4100K. Darcy filtration causes drastical thinning of this layer, so it does not exceed 40 km even at 4500K. In that case a layer of iron depleted solid material forms above core-mantle boundary. This seems to be a natural way of mantle heterogeneity production. We conclude, that revealing of the Lower Mantle structure is a complex question, which cannot be solved by static models; chemical differentiation and melt buoyancy require long-term dynamic simulation. Partial melting may produce chemically heterogeneous mantle consisting depleted and fertilized counterparts. Our preliminary results agree with moderate estimates of CMB temperature [Buffett, 2012].

  15. Extreme Heterogeneity in Parasitism Despite Low Population Genetic Structure among Monarch Butterflies Inhabiting the Hawaiian Islands

    PubMed Central

    Pierce, Amanda A.; de Roode, Jacobus C.; Altizer, Sonia; Bartel, Rebecca A.

    2014-01-01

    Host movement and spatial structure can strongly influence the ecology and evolution of infectious diseases, with limited host movement potentially leading to high spatial heterogeneity in infection. Monarch butterflies (Danaus plexippus) are best known for undertaking a spectacular long-distance migration in eastern North America; however, they also form non-migratory populations that breed year-round in milder climates such as Hawaii and other tropical locations. Prior work showed an inverse relationship between monarch migratory propensity and the prevalence of the protozoan parasite, Ophryocystis elektroscirrha. Here, we sampled monarchs from replicate sites within each of four Hawaiian Islands to ask whether these populations show consistently high prevalence of the protozoan parasite as seen for monarchs from several other non-migratory populations. Counter to our predictions, we observed striking spatial heterogeneity in parasite prevalence, with infection rates per site ranging from 4–85%. We next used microsatellite markers to ask whether the observed variation in infection might be explained by limited host movement and spatial sub-structuring among sites. Our results showed that monarchs across the Hawaiian Islands form one admixed population, supporting high gene flow among sites. Moreover, measures of individual-level genetic diversity did not predict host infection status, as might be expected if more inbred hosts harbored higher parasite loads. These results suggest that other factors such as landscape-level environmental variation or colonization-extinction processes might instead cause the extreme heterogeneity in monarch butterfly infection observed here. PMID:24926796

  16. Extreme heterogeneity in parasitism despite low population genetic structure among monarch butterflies inhabiting the Hawaiian Islands.

    PubMed

    Pierce, Amanda A; de Roode, Jacobus C; Altizer, Sonia; Bartel, Rebecca A

    2014-01-01

    Host movement and spatial structure can strongly influence the ecology and evolution of infectious diseases, with limited host movement potentially leading to high spatial heterogeneity in infection. Monarch butterflies (Danaus plexippus) are best known for undertaking a spectacular long-distance migration in eastern North America; however, they also form non-migratory populations that breed year-round in milder climates such as Hawaii and other tropical locations. Prior work showed an inverse relationship between monarch migratory propensity and the prevalence of the protozoan parasite, Ophryocystis elektroscirrha. Here, we sampled monarchs from replicate sites within each of four Hawaiian Islands to ask whether these populations show consistently high prevalence of the protozoan parasite as seen for monarchs from several other non-migratory populations. Counter to our predictions, we observed striking spatial heterogeneity in parasite prevalence, with infection rates per site ranging from 4-85%. We next used microsatellite markers to ask whether the observed variation in infection might be explained by limited host movement and spatial sub-structuring among sites. Our results showed that monarchs across the Hawaiian Islands form one admixed population, supporting high gene flow among sites. Moreover, measures of individual-level genetic diversity did not predict host infection status, as might be expected if more inbred hosts harbored higher parasite loads. These results suggest that other factors such as landscape-level environmental variation or colonization-extinction processes might instead cause the extreme heterogeneity in monarch butterfly infection observed here. PMID:24926796

  17. Intra-Tumor Genetic Heterogeneity in Wilms Tumor: Clonal Evolution and Clinical Implications.

    PubMed

    Cresswell, George D; Apps, John R; Chagtai, Tasnim; Mifsud, Borbala; Bentley, Christopher C; Maschietto, Mariana; Popov, Sergey D; Weeks, Mark E; Olsen, Øystein E; Sebire, Neil J; Pritchard-Jones, Kathy; Luscombe, Nicholas M; Williams, Richard D; Mifsud, William

    2016-07-01

    The evolution of pediatric solid tumors is poorly understood. There is conflicting evidence of intra-tumor genetic homogeneity vs. heterogeneity (ITGH) in a small number of studies in pediatric solid tumors. A number of copy number aberrations (CNA) are proposed as prognostic biomarkers to stratify patients, for example 1q+ in Wilms tumor (WT); current clinical trials use only one sample per tumor to profile this genetic biomarker. We multisampled 20 WT cases and assessed genome-wide allele-specific CNA and loss of heterozygosity, and inferred tumor evolution, using Illumina CytoSNP12v2.1 arrays, a custom analysis pipeline, and the MEDICC algorithm. We found remarkable diversity of ITGH and evolutionary trajectories in WT. 1q+ is heterogeneous in the majority of tumors with this change, with variable evolutionary timing. We estimate that at least three samples per tumor are needed to detect >95% of cases with 1q+. In contrast, somatic 11p15 LOH is uniformly an early event in WT development. We find evidence of two separate tumor origins in unilateral disease with divergent histology, and in bilateral WT. We also show subclonal changes related to differential response to chemotherapy. Rational trial design to include biomarkers in risk stratification requires tumor multisampling and reliable delineation of ITGH and tumor evolution. PMID:27333041

  18. Genetic heterogeneity of limb-girdle muscular dystrophy in Amish populations

    SciTech Connect

    Beckmann, J.S.; Allamand, V.; Broux, O.

    1994-09-01

    The autosomal recessive form of limb-girdle muscular dystrophy (LGMD2) is characterized by onset in childhood, progressive weakness predominantly of shoulder, pelvic and trunk muscles with sparing of facial muscles. A gene for LGMD2 was localized to chromosome 15q by Beckmann et al. in 1991 in Isle La Reunion families, subsequently confirmed in Amish families and in Brazilian families where genetic heterogeneity has been demonstrated. Analysis of LGM2 families for recombination events permitted the gene region to be restricted to an interval of about 7 cM defined by flanking markers D15S129 and D15S143. Extended haplotypes were established in the families on the basis of the segregation of multiple markers within this interval. Although the nine northern Indiana Amish families showed linkage of the gene to chromosome 15 markers (maximum lod score of 7.58 at {theta}=0.06 for D15S129 and 12.57 at {theta}=0.046 for D15S143), six large southern Indiana families with LGMD2, clinically indistinguishable from the LGMD2 in northern Indiana, were found to have a disease neither linked to chromosome 15 nor to chromosome 2 where a second localization has been reported. Although these two Indiana Amish LGMD2 kindreds contain some common ancestors and are clinically similar, the LGMD2 appears to be genetically heterogeneous.

  19. Study of Integrated Heterogeneous Data Reveals Prognostic Power of Gene Expression for Breast Cancer Survival

    PubMed Central

    Neapolitan, Richard E.; Jiang, Xia

    2015-01-01

    Background Studies show that thousands of genes are associated with prognosis of breast cancer. Towards utilizing available genetic data, efforts have been made to predict outcomes using gene expression data, and a number of commercial products have been developed. These products have the following shortcomings: 1) They use the Cox model for prediction. However, the RSF model has been shown to significantly outperform the Cox model. 2) Testing was not done to see if a complete set of clinical predictors could predict as well as the gene expression signatures. Methodology/Findings We address these shortcomings. The METABRIC data set concerns 1981 breast cancer tumors. Features include 21 clinical features, expression levels for 16,384 genes, and survival. We compare the survival prediction performance of the Cox model and the RSF model using the clinical data and the gene expression data to their performance using only the clinical data. We obtain significantly better results when we used both clinical data and gene expression data for 5 year, 10 year, and 15 year survival prediction. When we replace the gene expression data by PAM50 subtype, our results are significant only for 5 year and 15 year prediction. We obtain significantly better results using the RSF model over the Cox model. Finally, our results indicate that gene expression data alone may predict long-term survival. Conclusions/Significance Our results indicate that we can obtain improved survival prediction using clinical data and gene expression data compared to prediction using only clinical data. We further conclude that we can obtain improved survival prediction using the RSF model instead of the Cox model. These results are significant because by incorporating more gene expression data with clinical features and using the RSF model, we could develop decision support systems that better utilize heterogeneous information to improve outcome prediction and decision making. PMID:25723490

  20. Glycogen distribution in the microwave-fixed mouse brain reveals heterogeneous astrocytic patterns.

    PubMed

    Oe, Yuki; Baba, Otto; Ashida, Hitoshi; Nakamura, Kouichi C; Hirase, Hajime

    2016-09-01

    In the brain, glycogen metabolism has been implied in synaptic plasticity and learning, yet the distribution of this molecule has not been fully described. We investigated cerebral glycogen of the mouse by immunohistochemistry (IHC) using two monoclonal antibodies that have different affinities depending on the glycogen size. The use of focused microwave irradiation yielded well-defined glycogen immunoreactive signals compared with the conventional periodic acid-Schiff method. The IHC signals displayed a punctate distribution localized predominantly in astrocytic processes. Glycogen immunoreactivity (IR) was high in the hippocampus, striatum, cortex, and cerebellar molecular layer, whereas it was low in the white matter and most of the subcortical structures. Additionally, glycogen distribution in the hippocampal CA3-CA1 and striatum had a 'patchy' appearance with glycogen-rich and glycogen-poor astrocytes appearing in alternation. The glycogen patches were more evident with large-molecule glycogen in young adult mice but they were hardly observable in aged mice (1-2 years old). Our results reveal brain region-dependent glycogen accumulation and possibly metabolic heterogeneity of astrocytes. GLIA 2016;64:1532-1545. PMID:27353480

  1. Population Genomics Reveals Chromosome-Scale Heterogeneous Evolution in a Protoploid Yeast

    PubMed Central

    Friedrich, Anne; Jung, Paul; Reisser, Cyrielle; Fischer, Gilles; Schacherer, Joseph

    2015-01-01

    Yeast species represent an ideal model system for population genomic studies but large-scale polymorphism surveys have only been reported for species of the Saccharomyces genus so far. Hence, little is known about intraspecific diversity and evolution in yeast. To obtain a new insight into the evolutionary forces shaping natural populations, we sequenced the genomes of an expansive worldwide collection of isolates from a species distantly related to Saccharomyces cerevisiae: Lachancea kluyveri (formerly S. kluyveri). We identified 6.5 million single nucleotide polymorphisms and showed that a large introgression event of 1 Mb of GC-rich sequence in the chromosomal arm probably occurred in the last common ancestor of all L. kluyveri strains. Our population genomic data clearly revealed that this 1-Mb region underwent a molecular evolution pattern very different from the rest of the genome. It is characterized by a higher recombination rate, with a dramatically elevated A:T → G:C substitution rate, which is the signature of an increased GC-biased gene conversion. In addition, the predicted base composition at equilibrium demonstrates that the chromosome-scale compositional heterogeneity will persist after the genome has reached mutational equilibrium. Altogether, the data presented herein clearly show that distinct recombination and substitution regimes can coexist and lead to different evolutionary patterns within a single genome. PMID:25349286

  2. Population genomics reveals chromosome-scale heterogeneous evolution in a protoploid yeast.

    PubMed

    Friedrich, Anne; Jung, Paul; Reisser, Cyrielle; Fischer, Gilles; Schacherer, Joseph

    2015-01-01

    Yeast species represent an ideal model system for population genomic studies but large-scale polymorphism surveys have only been reported for species of the Saccharomyces genus so far. Hence, little is known about intraspecific diversity and evolution in yeast. To obtain a new insight into the evolutionary forces shaping natural populations, we sequenced the genomes of an expansive worldwide collection of isolates from a species distantly related to Saccharomyces cerevisiae: Lachancea kluyveri (formerly S. kluyveri). We identified 6.5 million single nucleotide polymorphisms and showed that a large introgression event of 1 Mb of GC-rich sequence in the chromosomal arm probably occurred in the last common ancestor of all L. kluyveri strains. Our population genomic data clearly revealed that this 1-Mb region underwent a molecular evolution pattern very different from the rest of the genome. It is characterized by a higher recombination rate, with a dramatically elevated A:T → G:C substitution rate, which is the signature of an increased GC-biased gene conversion. In addition, the predicted base composition at equilibrium demonstrates that the chromosome-scale compositional heterogeneity will persist after the genome has reached mutational equilibrium. Altogether, the data presented herein clearly show that distinct recombination and substitution regimes can coexist and lead to different evolutionary patterns within a single genome. PMID:25349286

  3. The impact of genetic heterogeneity on biomarker development in kidney cancer assessed by multiregional sampling.

    PubMed

    Sankin, Alexander; Hakimi, Abraham A; Mikkilineni, Nina; Ostrovnaya, Irina; Silk, Mikhail T; Liang, Yupu; Mano, Roy; Chevinsky, Michael; Motzer, Robert J; Solomon, Stephen B; Cheng, Emily H; Durack, Jeremy C; Coleman, Jonathan A; Russo, Paul; Hsieh, James J

    2014-12-01

    Primary clear cell renal cell carcinoma (ccRCC) genetic heterogeneity may lead to an underestimation of the mutational burden detected from a single site evaluation. We sought to characterize the extent of clonal branching involving key tumor suppressor mutations in primary ccRCC and determine if genetic heterogeneity could limit the mutation profiling from a single region assessment. Ex vivo core needle biopsies were obtained from three to five different regions of resected renal tumors at a single institution from 2012 to 2013. DNA was extracted and targeted sequencing was performed on five genes associated with ccRCC (von-Hippel Lindau [VHL], PBRM1, SETD2, BAP1, and KDM5C). We constructed phylogenetic trees by inferring clonal evolution based on the mutations present within each core and estimated the predictive power of detecting a mutation for each successive tumor region sampled. We obtained 47 ex vivo biopsy cores from 14 primary ccRCC's (median tumor size 4.5 cm, IQR 4.0-5.9 cm). Branching patterns of various complexities were observed in tumors with three or more mutations. A VHL mutation was detected in nine tumors (64%), each time being present ubiquitously throughout the tumor. Other genes had various degrees of regional mutational variation. Based on the mutations' prevalence we estimated that three different tumor regions should be sampled to detect mutations in PBRM1, SETD2, BAP1, and/or KDM5C with 90% certainty. The mutational burden of renal tumors varies by region sampled. Single site assessment of key tumor suppressor mutations in primary ccRCC may not adequately capture the genetic predictors of tumor behavior. PMID:25124064

  4. Whole-exome sequencing points to considerable genetic heterogeneity of cerebral palsy.

    PubMed

    McMichael, G; Bainbridge, M N; Haan, E; Corbett, M; Gardner, A; Thompson, S; van Bon, B W M; van Eyk, C L; Broadbent, J; Reynolds, C; O'Callaghan, M E; Nguyen, L S; Adelson, D L; Russo, R; Jhangiani, S; Doddapaneni, H; Muzny, D M; Gibbs, R A; Gecz, J; MacLennan, A H

    2015-02-01

    Cerebral palsy (CP) is a common, clinically heterogeneous group of disorders affecting movement and posture. Its prevalence has changed little in 50 years and the causes remain largely unknown. The genetic contribution to CP causation has been predicted to be ~2%. We performed whole-exome sequencing of 183 cases with CP including both parents (98 cases) or one parent (67 cases) and 18 singleton cases (no parental DNA). We identified and validated 61 de novo protein-altering variants in 43 out of 98 (44%) case-parent trios. Initial prioritization of variants for causality was by mutation type, whether they were known or predicted to be deleterious and whether they occurred in known disease genes whose clinical spectrum overlaps CP. Further, prioritization used two multidimensional frameworks-the Residual Variation Intolerance Score and the Combined Annotation-dependent Depletion score. Ten de novo mutations in three previously identified disease genes (TUBA1A (n=2), SCN8A (n=1) and KDM5C (n=1)) and in six novel candidate CP genes (AGAP1, JHDM1D, MAST1, NAA35, RFX2 and WIPI2) were predicted to be potentially pathogenic for CP. In addition, we identified four predicted pathogenic, hemizygous variants on chromosome X in two known disease genes, L1CAM and PAK3, and in two novel candidate CP genes, CD99L2 and TENM1. In total, 14% of CP cases, by strict criteria, had a potentially disease-causing gene variant. Half were in novel genes. The genetic heterogeneity highlights the complexity of the genetic contribution to CP. Function and pathway studies are required to establish the causative role of these putative pathogenic CP genes. PMID:25666757

  5. Genetic micro-heterogeneity of Leishmania major in emerging foci of zoonotic cutaneous leishmaniasis in Tunisia.

    PubMed

    Attia, Hanene; Sghaier, Rabiaa M; Gelanew, Tesfaye; Bali, Aymen; Schweynoch, Carola; Guerfali, Fatma Z; Mkannez, Ghada; Chlif, Sadok; Belhaj-Hamida, Nabil; Dellagi, Koussay; Schönian, Gabriele; Laouini, Dhafer

    2016-09-01

    Tunisia is endemic for zoonotic cutaneous leishmaniasis (ZCL), a parasitic disease caused by Leishmania (L.) major. ZCL displays a wide clinical polymorphism, with severe forms present more frequently in emerging foci where naive populations are dominant. In this study, we applied the multi-locus microsatellite typing (MLMT) using ten highly informative and discriminative markers to investigate the genetic structure of 35 Tunisian Leishmania (L.) major isolates collected from patients living in five different foci of Central Tunisia (two old and three emerging foci). Phylogenetic reconstructions based on genetic distances showed that nine of the ten tested loci were homogeneous in all isolates with homozygous alleles, whereas one locus (71AT) had a 58/64-bp bi-allelic profile with an allele linked to emerging foci. Promastigote-stage parasites with the 58-bp allele tend to be more resistant to in vitro complement lysis. These results, which stress the geographical dependence of the genetic micro-heterogeneity, may improve our understanding of the ZCL epidemiology and clinical outcome. PMID:27137082

  6. Genetic heterogeneity of prematurity and intrauterine growth retardation: clues from the Old Order Amish.

    PubMed

    Khoury, M J; Cohen, B H

    1987-08-01

    We studied differences in the role of genetic factors in prematurity and intrauterine growth retardation with the use of data on 312 Amish singleton live children ascertained from Amish records in Lancaster county, Pennsylvania, between 1969 and 1980. Birth and death certificates were obtained on all children, and inbreeding coefficients of child, mother, and father were computed by use of the path method of tracing common ancestors in a unique genealogic registry of Amish ancestors dating back to the 1700s. Multivariate analysis with linear and log linear models showed that a lower mean gestational age and a higher risk of prematurity (less than 37 weeks) and borderline maturity (37 to 38 weeks) were significantly associated with increased maternal inbreeding but not child or paternal inbreeding. On the other hand, a higher risk of intrauterine growth retardation (less than the tenth percentile in birth weight for gestational age) and mild intrauterine growth delay (tenth to twenty-fifth percentile) were associated with increased child inbreeding but not maternal or paternal inbreeding. The analysis suggests the presence of genetic heterogeneity in the etiology of prematurity and intrauterine growth retardation; while prematurity is mostly related to the maternal genotype, intrauterine growth retardation is related to the fetal genotype. The study reemphasizes the need for separating low birth weight into prematurity and intrauterine growth retardation in genetic and epidemiologic studies. PMID:3618690

  7. One size fits all? Direct evidence for the heterogeneity of genetic drift throughout the genome.

    PubMed

    Jiménez-Mena, Belén; Tataru, Paula; Brøndum, Rasmus F; Sahana, Goutam; Guldbrandtsen, Bernt; Bataillon, Thomas

    2016-07-01

    Effective population size (Ne) is a central parameter in population and conservation genetics. It measures the magnitude of genetic drift, rates of accumulation of inbreeding in a population, and it conditions the efficacy of selection. It is often assumed that a single Ne can account for the evolution of genomes. However, recent work provides indirect evidence for heterogeneity in Ne throughout the genome. We study this by examining genome-wide diversity in the Danish Holstein cattle breed. Using the differences in allele frequencies over a single generation, we directly estimated Ne among autosomes and smaller windows within autosomes. We found statistically significant variation in Ne at both scales. However, no correlation was found between the detected regional variability in Ne, and proxies for the intensity of linked selection (local recombination rate, gene density), or the presence of either past strong selection or current artificial selection on traits of economic value. Our findings call for further caution regarding the wide applicability of the Ne concept for understanding quantitatively processes such as genetic drift and accumulation of consanguinity in both natural and managed populations. PMID:27405384

  8. Multiple region whole-exome sequencing reveals dramatically evolving intratumor genomic heterogeneity in esophageal squamous cell carcinoma

    PubMed Central

    Cao, W; Wu, W; Yan, M; Tian, F; Ma, C; Zhang, Q; Li, X; Han, P; Liu, Z; Gu, J; Biddle, F G

    2015-01-01

    Cancer is a disease of genome instability and genomic alterations; now, genomic heterogeneity is rapidly emerging as a defining feature of cancer, both within and between tumors. Motivation for our pilot study of tumor heterogeneity in esophageal squamous cell carcinoma (ESCC) is that it is not well studied, but the highest incidences of esophageal cancers are found in China and ESCC is the most common type. We profiled the mutations and changes in copy number that were identified by whole-exome sequencing and array-based comparative genomic hybridization in multiple regions within an ESCC from two patients. The average mutational heterogeneity rate was 90% in all regions of the individual tumors in each patient; most somatic point mutations were nonsynonymous substitutions, small Indels occurred in untranslated regions of genes, and copy number alterations varied among multiple regions of a tumor. Independent Sanger sequencing technology confirmed selected gene mutations with more than 88% concordance. Phylogenetic analysis of the somatic mutation frequency demonstrated that multiple, genomically heterogeneous divergent clones evolve and co-exist within a primary ESCC and metastatic subclones result from the dispersal and adaptation of an initially non-metastatic parental clone. Therefore, a single-region sampling will not reflect the evolving architecture of a genomically heterogeneous landscape of mutations in ESCC tumors and the divergent complexity of this genomic heterogeneity among patients will complicate any promise of a simple genetic or epigenetic diagnostic signature in ESCC. We conclude that any potential for informative biomarker discovery in ESCC and targeted personalized therapies will require a deeper understanding of the functional biology of the ontogeny and phylogeny of the tumor heterogeneity. PMID:26619400

  9. qDNAmod: a statistical model-based tool to reveal intercellular heterogeneity of DNA modification from SMRT sequencing data

    PubMed Central

    Feng, Zhixing; Li, Jing; Zhang, Jing-Ren; Zhang, Xuegong

    2014-01-01

    In an isogenic cell population, phenotypic heterogeneity among individual cells is common and critical for survival of the population under different environment conditions. DNA modification is an important epigenetic factor that can regulate phenotypic heterogeneity. The single molecule real-time (SMRT) sequencing technology provides a unique platform for detecting a wide range of DNA modifications, including N6-methyladenine (6-mA), N4-methylcytosine (4-mC) and 5-methylcytosine (5-mC). Here we present qDNAmod, a novel bioinformatic tool for genome-wide quantitative profiling of intercellular heterogeneity of DNA modification from SMRT sequencing data. It is capable of estimating proportion of isogenic haploid cells, in which the same loci of the genome are differentially modified. We tested the reliability of qDNAmod with the SMRT sequencing data of Streptococcus pneumoniae strain ST556. qDNAmod detected extensive intercellular heterogeneity of DNA methylation (6-mA) in a clonal population of ST556. Subsequent biochemical analyses revealed that the recognition sequences of two type I restriction–modification (R-M) systems are responsible for the intercellular heterogeneity of DNA methylation initially identified by qDNAmod. qDNAmod thus represents a valuable tool for studying intercellular phenotypic heterogeneity from genome-wide DNA modification. PMID:25404133

  10. Solvatochromic Nile Red probes with FRET quencher reveal lipid order heterogeneity in living and apoptotic cells.

    PubMed

    Kreder, Rémy; Pyrshev, Kyrylo A; Darwich, Zeinab; Kucherak, Oleksandr A; Mély, Yves; Klymchenko, Andrey S

    2015-06-19

    Detecting and imaging lipid microdomains (rafts) in cell membranes remain a challenge despite intensive research in the field. Two types of fluorescent probes are used for this purpose: one specifically labels a given phase (liquid ordered, Lo, or liquid disordered, Ld), while the other, being environment-sensitive (solvatochromic), stains the two phases in different emission colors. Here, we combined the two approaches by designing a phase-sensitive probe of the Ld phase and a quencher of the Ld phase. The former is an analogue of the recently developed Nile Red-based probe NR12S, bearing a bulky hydrophobic chain (bNR10S), while the latter is based on Black Hole Quencher-2 designed as bNR10S (bQ10S). Fluorescence spectroscopy of large unilamellar vesicles and microscopy of giant vesicles showed that the bNR10S probe can partition specifically into the Ld phase, while bQ10S can specifically quench the NR12S probe in the Ld phase so that only its fraction in the Lo phase remains fluorescent. Thus, the toolkit of two probes with quencher can specifically target Ld and Lo phases and identify their lipid order from the emission color. Application of this toolkit in living cells (HeLa, CHO, and 293T cell lines) revealed heterogeneity in the cell plasma membranes, observed as distinct probe environments close to the Lo and Ld phases of model membranes. In HeLa cells undergoing apoptosis, our toolkit showed the formation of separate domains of the Ld-like phase in the form of blebs. The developed tools open new possibilities in lipid raft research. PMID:25710589

  11. Bovine Genetic Diversity Revealed By mtDNA Sequence Variation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Mitochondrial DNA single nucleotide polymorphism (SNP) data were used to determine genetic distance, nucleotide diversity, construction of haplotypes, estimation of information contents, and phylogenic relationships in bovine HapMap breeds. The Bovine International HapMap panel consists of 720 anima...

  12. Genetic Heterogeneity of Induced Pluripotent Stem Cells: Results from 24 Clones Derived from a Single C57BL/6 Mouse

    PubMed Central

    Li, Cheng; Klco, Jeffery M.; Helton, Nichole M.; George, Daniel R.; Mudd, Jacqueline L.; Miller, Christopher A.; Lu, Charles; Fulton, Robert; O'Laughlin, Michelle; Fronick, Catrina; Wilson, Richard K.; Ley, Timothy J.

    2015-01-01

    Induced pluripotent stem cells (iPSCs) have tremendous potential as a tool for disease modeling, drug testing, and other applications. Since the generation of iPSCs “captures” the genetic history of the individual cell that was reprogrammed, iPSC clones (even those derived from the same individual) would be expected to demonstrate genetic heterogeneity. To assess the degree of genetic heterogeneity, and to determine whether some cells are more genetically “fit” for reprogramming, we performed exome sequencing on 24 mouse iPSC clones derived from skin fibroblasts obtained from two different sites of the same 8-week-old C57BL/6J male mouse. While no differences in the coding regions were detected in the two parental fibroblast pools, each clone had a unique genetic signature with a wide range of heterogeneity observed among the individual clones: a total of 383 iPSC variants were validated for the 24 clones (mean 16.0/clone, range 0–45). Since these variants were all present in the vast majority of the cells in each clone (variant allele frequencies of 40–60% for heterozygous variants), they most likely preexisted in the individual cells that were reprogrammed, rather than being acquired during reprogramming or cell passaging. We then tested whether this genetic heterogeneity had functional consequences for hematopoietic development by generating hematopoietic progenitors in vitro and enumerating colony forming units (CFUs). While there was a range of hematopoietic potentials among the 24 clones, only one clone failed to differentiate into hematopoietic cells; however, it was able to form a teratoma, proving its pluripotent nature. Further, no specific association was found between the mutational spectrum and the hematopoietic potential of each iPSC clone. These data clearly highlight the genetic heterogeneity present within individual fibroblasts that is captured by iPSC generation, and suggest that most of the changes are random, and functionally benign

  13. Genetic heterogeneity in benign familial neonatal convulsions: Identification of a new locus on chromosome 8q

    SciTech Connect

    Lewis, T.B.; Leach, R.J.; O'Connell, P.; Ryan, S.G. ); Ward, K. )

    1993-09-01

    The syndrome of benign familial neonatal convulsions (BFNC) is a rare autosomal dominant disorder characterized by unprovoked seizures in the first weeks of life. One locus for BFNC has been mapped to chromosome 20 in several pedigrees, but the authors have excluded linkage to chromosome 20 in one large kindred. In order to identify this novel BFNC locus, dinucleotide repeat markers distributed throughout the genome were used to screen this family. Maximum pairwise LOD scores of 4.43 were obtained with markers D8S284 and D8S256 on chromosome 8q. Multipoint analysis placed the BFNC locus in the interval spanned by D8S198-D8S274. This study establishes the presence of a new BFNC locus and confirms genetic heterogeneity of this disorder. 26 refs., 3 figs., 1 tab.

  14. The impact of distance and a shifting temperature gradient on genetic connectivity across a heterogeneous landscape

    PubMed Central

    2011-01-01

    Background Inter-population distance and differences in breeding times are barriers to reproduction that can contribute to genotypic differentiation between populations. Temporal changes in environmental conditions and local selective processes can further contribute to the establishment of reproductive barriers. Telopea speciosissima (Proteaceae) is an excellent subject for studying the effect of geographic, edaphic and phenological heterogeneity on genotypic differentiation because previous studies show that these factors are correlated with morphological variation. Molecular, morphological and environmental datasets were combined to characterise the relative influence of these factors on inter-population differentiation, and Bayesian analyses were used to investigate current levels of admixture between differentiated genomes. Results A landscape genetic approach involving molecular and morphological analyses identified three endpoints of differentiated population groups: coastal, upland and southern. The southern populations, isolated from the other populations by an edaphic barrier, show low migration and no evidence of admixture with other populations. Amongst the northern populations, coastal and upland populations are connected along a skewed altitudinal gradient by genetically intermediate populations. The strong association between temperature and flowering time in Telopea speciosissima was shown to maintain a temporally unstable reproductive barrier between coastal and upland populations. Conclusions Substrate-mediated allopatry appears to be responsible for long-term genetic isolation of the southern populations. However, the temperature-dependent reproductive barrier between upland and coastal populations bears the genetic signature of temporal adjustments. The extreme climatic events of the last glacial maximum are likely to have caused more complete allochronic isolation between upland and coastal populations, as well as exerting increased selective

  15. Single nucleotide polymorphism analysis reveals heterogeneity within a seedling tree population of a polyembryonic mango cultivar.

    PubMed

    Winterhagen, Patrick; Wünsche, Jens-Norbert

    2016-05-01

    Within a polyembryonic mango seedling tree population, the genetic background of individuals should be identical because vigorous plants for cultivation are expected to develop from nucellar embryos representing maternal clones. Due to the fact that the mango cultivar 'Hôi' is assigned to the polyembryonic ecotype, an intra-cultivar variability of ethylene receptor genes was unexpected. Ethylene receptors in plants are conserved, but the number of receptors or receptor isoforms is variable regarding different plant species. However, it is shown here that the ethylene receptor MiETR1 is present in various isoforms within the mango cultivar 'Hôi'. The investigation of single nucleotide polymorphisms revealed that different MiETR1 isoforms can not be discriminated simply by individual single nucleotide exchanges but by the specific arrangement of single nucleotide polymorphisms at certain positions in the exons of MiETR1. Furthermore, an MiETR1 isoform devoid of introns in the genomic sequence was identified. The investigation demonstrates some limitations of high resolution melting and ScreenClust analysis and points out the necessity of sequencing to identify individual isoforms and to determine the variability within the tree population. PMID:27093244

  16. Prefrontal neuronal integrity predicts symptoms and cognition in schizophrenia and is sensitive to genetic heterogeneity.

    PubMed

    Malaspina, Dolores; Kranz, Thorsten M; Heguy, Adriana; Harroch, Sheila; Mazgaj, Robert; Rothman, Karen; Berns, Adam; Hasan, Sumya; Antonius, Daniel; Goetz, Raymond; Lazar, Mariana; Chao, Moses V; Gonen, Oded

    2016-04-01

    Schizophrenia is a genetically complex syndrome with substantial inter-subject variability in multiple domains. Person-specific measures to resolve its heterogeneity could focus on the variability in prefrontal integrity, which this study indexed as relative rostralization within the anterior cingulate cortex (ACC). Twenty-two schizophrenia cases and 11 controls underwent rigorous diagnostic procedures, symptom assessments (PANSS, Deficit Syndrome Scale) and intelligence testing. All underwent multivoxel MRSI at 3T to measure concentrations of the neuronal-specific biomarker N-acetylaspartate (NAA) in all of the voxels of the ACC. The concentrations of NAA were separately calculated and then compared across the rostral and caudal subregions to generate a rostralization ratio, which was examined with respect to the study measures and to which cases carried a missense coding polymorphism in PTPRG, SCL39A13, TGM5, NTRK1 or ARMS/KIDINS220. Rostralization significantly differed between cases and controls (χ(2)=18.40, p<.0001). In cases, it predicted verbal intelligence (r=.469, p=.043) and trait negative symptoms (diminished emotional range (r=-.624, p=.010); curbed interests, r=-.558, p=.025). Rostralization was similar to controls for missense coding variants in TGM5 and was significantly greater than controls for the PTPRG variant carrier. This is the first study examining the utility of MRS metrics in describing pathological features at both group and person-specific levels. Rostralization predicted core illness features and differed based on which signaling genes were disrupted. While future studies in larger populations are needed, ACC rostralization appears to be a promising measure to reduce the heterogeneity of schizophrenia for genetic research and selecting cases for treatment studies. PMID:26925801

  17. Heterogeneous Ensemble Combination Search Using Genetic Algorithm for Class Imbalanced Data Classification

    PubMed Central

    Haque, Mohammad Nazmul; Noman, Nasimul; Berretta, Regina; Moscato, Pablo

    2016-01-01

    Classification of datasets with imbalanced sample distributions has always been a challenge. In general, a popular approach for enhancing classification performance is the construction of an ensemble of classifiers. However, the performance of an ensemble is dependent on the choice of constituent base classifiers. Therefore, we propose a genetic algorithm-based search method for finding the optimum combination from a pool of base classifiers to form a heterogeneous ensemble. The algorithm, called GA-EoC, utilises 10 fold-cross validation on training data for evaluating the quality of each candidate ensembles. In order to combine the base classifiers decision into ensemble’s output, we used the simple and widely used majority voting approach. The proposed algorithm, along with the random sub-sampling approach to balance the class distribution, has been used for classifying class-imbalanced datasets. Additionally, if a feature set was not available, we used the (α, β) − k Feature Set method to select a better subset of features for classification. We have tested GA-EoC with three benchmarking datasets from the UCI-Machine Learning repository, one Alzheimer’s disease dataset and a subset of the PubFig database of Columbia University. In general, the performance of the proposed method on the chosen datasets is robust and better than that of the constituent base classifiers and many other well-known ensembles. Based on our empirical study we claim that a genetic algorithm is a superior and reliable approach to heterogeneous ensemble construction and we expect that the proposed GA-EoC would perform consistently in other cases. PMID:26764911

  18. Prefrontal neuronal integrity predicts symptoms and cognition in schizophrenia and is sensitive to genetic heterogeneity

    PubMed Central

    Malaspina, Dolores; Kranz, Thorsten M.; Heguy, Adriana; Harroch, Sheila; Mazgaj, Robert; Rothman, Karen; Berns, Adam; Hasan, Sumya; Antonius, Daniel; Goetz, Raymond; Lazar, Mariana; Chao, Moses V.; Gonen, Oded

    2016-01-01

    Schizophrenia is a genetically complex syndrome with substantial inter-subject variability in multiple domains. Person-specific measures to resolve its heterogeneity could focus on the variability in prefrontal integrity, which this study indexed as relative rostralization within the anterior cingulate cortex (ACC). Twenty-two schizophrenia cases and 11 controls underwent rigorous diagnostic procedures, symptom assessments (PANSS, Deficit Syndrome Scale) and intelligence testing. All underwent multivoxel MRSI at 3 T to measure concentrations of the neuronal-specific biomarker N-acetylaspartate (NAA) in all of the voxels of the ACC. The concentrations of NAA were separately calculated and then compared across the rostral and caudal subregions to generate a rostralization ratio, which was examined with respect to the study measures and to which cases carried a missense coding polymorphism in PTPRG, SCL39A13, TGM5, NTRK1 or ARMS/KIDINS220. Rostralization significantly differed between cases and controls (χ2 = 18.40, p < .0001). In cases, it predicted verbal intelligence (r = .469, p = .043) and trait negative symptoms (diminished emotional range (r = −.624, p = .010); curbed interests, r = −.558, p = .025). Rostralization was similar to controls for missense coding variants in TGM5 and was significantly greater than controls for the PTPRG variant carrier. This is the first study examining the utility of MRS metrics in describing pathological features at both group and person-specific levels. Rostralization predicted core illness features and differed based on which signaling genes were disrupted. While future studies in larger populations are needed, ACC rostralization appears to be a promising measure to reduce the heterogeneity of schizophrenia for genetic research and selecting cases for treatment studies. PMID:26925801

  19. Phenotypic heterogeneity and genetic modification of P102L inherited prion disease in an international series

    PubMed Central

    Webb, T. E. F.; Poulter, M.; Beck, J.; Uphill, J.; Adamson, G.; Campbell, T.; Linehan, J.; Powell, C.; Brandner, S.; Pal, S.; Siddique, D.; Wadsworth, J. D.; Joiner, S.; Alner, K.; Petersen, C.; Hampson, S.; Rhymes, C.; Treacy, C.; Storey, E.; Geschwind, M. D.; Nemeth, A. H.; Wroe, S.; Mead, S.

    2008-01-01

    The largest kindred with inherited prion disease P102L, historically Gerstmann-Sträussler-Scheinker syndrome, originates from central England, with émigrés now resident in various parts of the English-speaking world. We have collected data from 84 patients in the large UK kindred and numerous small unrelated pedigrees to investigate phenotypic heterogeneity and modifying factors. This collection represents by far the largest series of P102L patients so far reported. Microsatellite and genealogical analyses of eight separate European kindreds support multiple distinct mutational events at a cytosine-phosphate diester-guanidine dinucleotide mutation hot spot. All of the smaller P102L kindreds were linked to polymorphic human prion protein gene codon 129M and were not connected by genealogy or microsatellite haplotype background to the large kindred or each other. While many present with classical Gerstmann-Sträussler-Scheinker syndrome, a slowly progressive cerebellar ataxia with later onset cognitive impairment, there is remarkable heterogeneity. A subset of patients present with prominent cognitive and psychiatric features and some have met diagnostic criteria for sporadic Creutzfeldt-Jakob disease. We show that polymorphic human prion protein gene codon 129 modifies age at onset: the earliest eight clinical onsets were all MM homozygotes and overall age at onset was 7 years earlier for MM compared with MV heterozygotes (P = 0.02). Unexpectedly, apolipoprotein E4 carriers have a delayed age of onset by 10 years (P = 0.02). We found a preponderance of female patients compared with males (54 females versus 30 males, P = 0.01), which probably relates to ascertainment bias. However, these modifiers had no impact on a semi-quantitative pathological phenotype in 10 autopsied patients. These data allow an appreciation of the range of clinical phenotype, modern imaging and molecular investigation and should inform genetic counselling of at-risk individuals, with the

  20. Heme dynamics and trafficking factors revealed by genetically encoded fluorescent heme sensors.

    PubMed

    Hanna, David A; Harvey, Raven M; Martinez-Guzman, Osiris; Yuan, Xiaojing; Chandrasekharan, Bindu; Raju, Gheevarghese; Outten, F Wayne; Hamza, Iqbal; Reddi, Amit R

    2016-07-01

    Heme is an essential cofactor and signaling molecule. Heme acquisition by proteins and heme signaling are ultimately reliant on the ability to mobilize labile heme (LH). However, the properties of LH pools, including concentration, oxidation state, distribution, speciation, and dynamics, are poorly understood. Herein, we elucidate the nature and dynamics of LH using genetically encoded ratiometric fluorescent heme sensors in the unicellular eukaryote Saccharomyces cerevisiae We find that the subcellular distribution of LH is heterogeneous; the cytosol maintains LH at ∼20-40 nM, whereas the mitochondria and nucleus maintain it at concentrations below 2.5 nM. Further, we find that the signaling molecule nitric oxide can initiate the rapid mobilization of heme in the cytosol and nucleus from certain thiol-containing factors. We also find that the glycolytic enzyme glyceraldehyde phosphate dehydrogenase constitutes a major cellular heme buffer, and is responsible for maintaining the activity of the heme-dependent nuclear transcription factor heme activator protein (Hap1p). Altogether, we demonstrate that the heme sensors can be used to reveal fundamental aspects of heme trafficking and dynamics and can be used across multiple organisms, including Escherichia coli, yeast, and human cell lines. PMID:27247412

  1. Landscape Genetics Reveals Focal Transmission of a Human Macroparasite

    PubMed Central

    Criscione, Charles D.; Anderson, Joel D.; Sudimack, Dan; Subedi, Janardan; Upadhayay, Ram P.; Jha, Bharat; Williams, Kimberly D.; Williams-Blangero, Sarah; Anderson, Timothy J. C.

    2010-01-01

    Macroparasite infections (e.g., helminths) remain a major human health concern. However, assessing transmission dynamics is problematic because the direct observation of macroparasite dispersal among hosts is not possible. We used a novel landscape genetics approach to examine transmission of the human roundworm Ascaris lumbricoides in a small human population in Jiri, Nepal. Unexpectedly, we found significant genetic structuring of parasites, indicating the presence of multiple transmission foci within a small sampling area (∼14 km2). We analyzed several epidemiological variables, and found that transmission is spatially autocorrelated around households and that transmission foci are stable over time despite extensive human movement. These results would not have been obtainable via a traditional epidemiological study based on worm counts alone. Our data refute the assumption that a single host population corresponds to a single parasite transmission unit, an assumption implicit in many classic models of macroparasite transmission. Newer models have shown that the metapopulation-like pattern observed in our data can adversely affect targeted control strategies aimed at community-wide impacts. Furthermore, the observed metapopulation structure and local mating patterns generate an excess of homozygotes that can accelerate the spread of recessive traits such as drug resistance. Our study illustrates how molecular analyses complement traditional epidemiological information in providing a better understanding of parasite transmission. Similar landscape genetic approaches in other macroparasite systems will be warranted if an accurate depiction of the transmission process is to be used to inform effective control strategies. PMID:20421919

  2. Functional Heterogeneity of Embryonic Stem Cells Revealed through Translational Amplification of an Early Endodermal Transcript

    PubMed Central

    Canham, Maurice A.; Sharov, Alexei A.; Ko, Minoru S. H.; Brickman, Joshua M.

    2010-01-01

    ES cells are defined as self-renewing, pluripotent cell lines derived from early embryos. Cultures of ES cells are also characterized by the expression of certain markers thought to represent the pluripotent state. However, despite the widespread expression of key markers such as Oct4 and the appearance of a characteristic undifferentiated morphology, functional ES cells may represent only a small fraction of the cultures grown under self-renewing conditions. Thus phenotypically “undifferentiated” cells may consist of a heterogeneous population of functionally distinct cell types. Here we use a transgenic allele designed to detect low level transcription in the primitive endoderm lineage as a tool to identify an immediate early endoderm-like ES cell state. This reporter employs a tandem array of internal ribosomal entry sites to drive translation of an enhanced Yellow Fluorescent Protein (Venus) from the transcript that normally encodes for the early endodermal marker Hex. Expression of this Venus transgene reports on single cells with low Hex transcript levels and reveals the existence of distinct populations of Oct4 positive undifferentiated ES cells. One of these cells types, characterized by both the expression of the Venus transgene and the ES cells marker SSEA-1 (V+S+), appears to represent an early step in primitive endoderm specification. We show that the fraction of cells present within this state is influenced by factors that both promote and suppress primitive endoderm differentiation, but conditions that support ES cell self-renewal prevent their progression into differentiation and support an equilibrium between this state and at least one other that resembles the Nanog positive inner cell mass of the mammalian blastocysts. Interestingly, while these subpopulations are equivalently and clonally interconvertible under self-renewing conditions, when induced to differentiate both in vivo and in vitro they exhibit different behaviours. Most strikingly

  3. The loss of genetic diversity in Sichuan taimen as revealed by DNA fingerprinting.

    PubMed

    Wu, Xue-Chang

    2006-06-01

    Species endangerment often derives from the "endangerment" of genetic diversity, thus loss of genetic diversity is an important cause of species extinction. Since historical specimens were unavailable, previous studies mainly described the genetic diversity status in the current population rather than the loss of genetic variation over time. In this study, we collected samples during 1998-1999 and obtained historical specimens from 1957 to 1958. Based on the two sets of fish, we determined the changes in genetic diversity of Sichuan taimen using DNA fingerprinting. The differences in genetic parameters between the present samples and historical taimens revealed their loss of genetic variation. As a result, the existing populations have lower viability, and proper management has to be implemented to preserve genetic diversity. PMID:16944294

  4. Quantitative Genetic Interactions Reveal Layers of Biological Modularity

    PubMed Central

    Beltrao, Pedro; Cagney, Gerard; Krogan, Nevan J.

    2010-01-01

    In the past, biomedical research has embraced a reductionist approach, primarily focused on characterizing the individual components that comprise a system of interest. Recent technical developments have significantly increased the size and scope of data describing biological systems. At the same time, advances in the field of systems biology have evoked a broader view of how the underlying components are interconnected. In this essay, we discuss how quantitative genetic interaction mapping has enhanced our view of biological systems, allowing a deeper functional interrogation at different biological scales. PMID:20510918

  5. BAYESIAN METHODS FOR GENETIC ASSOCIATION ANALYSIS WITH HETEROGENEOUS SUBGROUPS: FROM META-ANALYSES TO GENE-ENVIRONMENT INTERACTIONS

    PubMed Central

    Wen, Xiaoquan; Stephens, Matthew

    2015-01-01

    Genetic association analyses often involve data from multiple potentially-heterogeneous subgroups. The expected amount of heterogeneity can vary from modest (e.g. a typical meta-analysis), to large (e.g. a strong gene-environment interaction). However, existing statistical tools are limited in their ability to address such heterogeneity. Indeed, most genetic association meta-analyses use a “fixed effects” analysis, which assumes no heterogeneity. Here we develop and apply Bayesian association methods to address this problem. These methods are easy to apply (in the simplest case, requiring only a point estimate for the genetic effect, and its standard error, from each subgroup), and effectively include standard frequentist meta-analysis methods, including the usual “fixed effects” analysis, as special cases. We apply these tools to two large genetic association studies: one a meta-analysis of genome-wide association studies from the Global Lipids consortium, and the second a cross-population analysis for expression quantitative trait loci (eQTLs). In the Global Lipids data we find, perhaps surprisingly, that effects are generally quite homogeneous across studies. In the eQTL study we find that eQTLs are generally shared among different continental groups, and discuss consequences of this for study design. PMID:26413181

  6. Comparative riverscape genetics reveals reservoirs of genetic diversity for conservation and restoration of Great Plains fishes

    PubMed Central

    Osborne, Megan J; Perkin, Joshuah S.; Gido, Keith B.; Turner, Thomas F.

    2014-01-01

    We used comparative landscape genetics to examine the relative roles of historical events, intrinsic traits, and landscape factors in determining the distribution of genetic diversity of river fishes across the North American Great Plains. Spatial patterns of diversity were overlaid on a patch-based graphical model, and then compared within and among three species that co-occurred across five Great Plains watersheds. Species differing in reproductive strategy (benthic vs. pelagic spawning) were hypothesized to have different patterns of genetic diversity, but the overriding factor shaping contemporary patterns of diversity was the signature of past climates and geological history. Allelic diversity was significantly higher at southern latitudes for Cyprinella lutrensis and Hybognathus placitus, consistent with northward expansion from southern Pleistocene refugia. Within the historical context, all species exhibited lowered occupancy and abundance in heavily fragmented and drier upstream reaches, particularly H. placitus; a pelagic-spawning species, suggesting rates of extirpation have outpaced losses of genetic diversity in this species. Within most basins, genetically diverse populations of each species persisted. Hence, reconnecting genetically diverse populations with those characterized by reduced diversity (regardless of their position within the riverine network) would provide populations with greater genetic and demographic resilience. We discuss cases where cross-basin transfer may be appropriate to enhance genetic diversity and mitigate negative effects of climate change. Overall, striking similarities in genetic patterns and response to fragmentation and dewatering suggest a common strategy for genetic resource management in this unique riverine fish assemblage. PMID:25327780

  7. Identification of Multilocus Genetic Heterogeneity in Anaplasma marginale subsp. centrale and Its Restriction following Tick-Borne Transmission

    PubMed Central

    Herndon, David R.; Ueti, Massaro W.; Reif, Kathryn E.; Noh, Susan M.; Brayton, Kelly A.; Agnes, Joseph T.

    2013-01-01

    Anaplasma marginale subsp. centrale was the first vaccine used to protect against a rickettsial disease and is still in widespread use a century later. As its use preceded development of either cryopreservation or cell culture, the vaccine strain was maintained for decades by sequential passage among donor animals, excluding the natural tick-borne transmission cycle that provides a selective pressure or population “bottleneck.” We demonstrated that the vaccine strain is genetically heterogeneous at 46 chromosomal loci and that heterogeneity was maintained upon inoculation into recipient animals. The number of variants per site ranged from 2 to 11 with a mean of 2.8/locus and a mode and median of 2/locus; variants included single-nucleotide polymorphisms, insertions/deletions, polynucleotide tracts, and different numbers of perfect repeats. The genetic heterogeneity is highly unlikely to be a result of strain contamination based on analysis using a panel of eight gene markers with a high power for strain discrimination. In contrast, heterogeneity appears to be a result of genetic drift in the absence of the restriction of tick passage. Heterogeneity could be reduced following tick passage, and the reduced heterogeneity could be maintained in sequential intravenous and tick-borne passages. The reduction in vaccine strain heterogeneity following tick passage did not confer an enhanced transmission phenotype, indicating that a stochastically determined population bottleneck was likely responsible as opposed to a positive selective pressure. These findings demonstrate the plasticity of an otherwise highly constrained genome and highlight the role of natural transmission cycles in shaping and maintaining the bacterial genome. PMID:23509140

  8. Identification of multilocus genetic heterogeneity in Anaplasma marginale subsp. centrale and its restriction following tick-borne transmission.

    PubMed

    Herndon, David R; Ueti, Massaro W; Reif, Kathryn E; Noh, Susan M; Brayton, Kelly A; Agnes, Joseph T; Palmer, Guy H

    2013-05-01

    Anaplasma marginale subsp. centrale was the first vaccine used to protect against a rickettsial disease and is still in widespread use a century later. As its use preceded development of either cryopreservation or cell culture, the vaccine strain was maintained for decades by sequential passage among donor animals, excluding the natural tick-borne transmission cycle that provides a selective pressure or population "bottleneck." We demonstrated that the vaccine strain is genetically heterogeneous at 46 chromosomal loci and that heterogeneity was maintained upon inoculation into recipient animals. The number of variants per site ranged from 2 to 11 with a mean of 2.8/locus and a mode and median of 2/locus; variants included single-nucleotide polymorphisms, insertions/deletions, polynucleotide tracts, and different numbers of perfect repeats. The genetic heterogeneity is highly unlikely to be a result of strain contamination based on analysis using a panel of eight gene markers with a high power for strain discrimination. In contrast, heterogeneity appears to be a result of genetic drift in the absence of the restriction of tick passage. Heterogeneity could be reduced following tick passage, and the reduced heterogeneity could be maintained in sequential intravenous and tick-borne passages. The reduction in vaccine strain heterogeneity following tick passage did not confer an enhanced transmission phenotype, indicating that a stochastically determined population bottleneck was likely responsible as opposed to a positive selective pressure. These findings demonstrate the plasticity of an otherwise highly constrained genome and highlight the role of natural transmission cycles in shaping and maintaining the bacterial genome. PMID:23509140

  9. STED-FLCS: An Advanced Tool to Reveal Spatiotemporal Heterogeneity of Molecular Membrane Dynamics

    PubMed Central

    2015-01-01

    Heterogeneous diffusion dynamics of molecules play an important role in many cellular signaling events, such as of lipids in plasma membrane bioactivity. However, these dynamics can often only be visualized by single-molecule and super-resolution optical microscopy techniques. Using fluorescence lifetime correlation spectroscopy (FLCS, an extension of fluorescence correlation spectroscopy, FCS) on a super-resolution stimulated emission depletion (STED) microscope, we here extend previous observations of nanoscale lipid dynamics in the plasma membrane of living mammalian cells. STED-FLCS allows an improved determination of spatiotemporal heterogeneity in molecular diffusion and interaction dynamics via a novel gated detection scheme, as demonstrated by a comparison between STED-FLCS and previous conventional STED-FCS recordings on fluorescent phosphoglycerolipid and sphingolipid analogues in the plasma membrane of live mammalian cells. The STED-FLCS data indicate that biophysical and biochemical parameters such as the affinity for molecular complexes strongly change over space and time within a few seconds. Drug treatment for cholesterol depletion or actin cytoskeleton depolymerization not only results in the already previously observed decreased affinity for molecular interactions but also in a slight reduction of the spatiotemporal heterogeneity. STED-FLCS specifically demonstrates a significant improvement over previous gated STED-FCS experiments and with its improved spatial and temporal resolution is a novel tool for investigating how heterogeneities of the cellular plasma membrane may regulate biofunctionality. PMID:26235350

  10. Computational analysis of stochastic heterogeneity in PCR amplification efficiency revealed by single molecule barcoding

    PubMed Central

    Best, Katharine; Oakes, Theres; Heather, James M.; Shawe-Taylor, John; Chain, Benny

    2015-01-01

    The polymerase chain reaction (PCR) is one of the most widely used techniques in molecular biology. In combination with High Throughput Sequencing (HTS), PCR is widely used to quantify transcript abundance for RNA-seq, and in the context of analysis of T and B cell receptor repertoires. In this study, we combine DNA barcoding with HTS to quantify PCR output from individual target molecules. We develop computational tools that simulate both the PCR branching process itself, and the subsequent subsampling which typically occurs during HTS sequencing. We explore the influence of different types of heterogeneity on sequencing output, and compare them to experimental results where the efficiency of amplification is measured by barcodes uniquely identifying each molecule of starting template. Our results demonstrate that the PCR process introduces substantial amplification heterogeneity, independent of primer sequence and bulk experimental conditions. This heterogeneity can be attributed both to inherited differences between different template DNA molecules, and the inherent stochasticity of the PCR process. The results demonstrate that PCR heterogeneity arises even when reaction and substrate conditions are kept as constant as possible, and therefore single molecule barcoding is essential in order to derive reproducible quantitative results from any protocol combining PCR with HTS. PMID:26459131

  11. STED-FLCS: An Advanced Tool to Reveal Spatiotemporal Heterogeneity of Molecular Membrane Dynamics.

    PubMed

    Vicidomini, Giuseppe; Ta, Haisen; Honigmann, Alf; Mueller, Veronika; Clausen, Mathias P; Waithe, Dominic; Galiani, Silvia; Sezgin, Erdinc; Diaspro, Alberto; Hell, Stefan W; Eggeling, Christian

    2015-09-01

    Heterogeneous diffusion dynamics of molecules play an important role in many cellular signaling events, such as of lipids in plasma membrane bioactivity. However, these dynamics can often only be visualized by single-molecule and super-resolution optical microscopy techniques. Using fluorescence lifetime correlation spectroscopy (FLCS, an extension of fluorescence correlation spectroscopy, FCS) on a super-resolution stimulated emission depletion (STED) microscope, we here extend previous observations of nanoscale lipid dynamics in the plasma membrane of living mammalian cells. STED-FLCS allows an improved determination of spatiotemporal heterogeneity in molecular diffusion and interaction dynamics via a novel gated detection scheme, as demonstrated by a comparison between STED-FLCS and previous conventional STED-FCS recordings on fluorescent phosphoglycerolipid and sphingolipid analogues in the plasma membrane of live mammalian cells. The STED-FLCS data indicate that biophysical and biochemical parameters such as the affinity for molecular complexes strongly change over space and time within a few seconds. Drug treatment for cholesterol depletion or actin cytoskeleton depolymerization not only results in the already previously observed decreased affinity for molecular interactions but also in a slight reduction of the spatiotemporal heterogeneity. STED-FLCS specifically demonstrates a significant improvement over previous gated STED-FCS experiments and with its improved spatial and temporal resolution is a novel tool for investigating how heterogeneities of the cellular plasma membrane may regulate biofunctionality. PMID:26235350

  12. Genetic heterogeneity in human T-cell leukemia/lymphoma virus type II.

    PubMed Central

    Dube, D K; Sherman, M P; Saksena, N K; Bryz-Gornia, V; Mendelson, J; Love, J; Arnold, C B; Spicer, T; Dube, S; Glaser, J B

    1993-01-01

    DNA from the peripheral blood mononuclear cells of 17 different individuals infected with human T-cell lymphoma/leukemia virus type II (HTLV-II) was successfully amplified by the polymerase chain reaction (PCR) with the primer pair SK110/SK111. This primer pair is conserved among the pol genes of all primate T-cell lymphoma viruses (PTLV) and flanks a 140-bp fragment of DNA which, when used in comparative analyses, reflects the relative degree of diversity among PTLV genomes. Cloning, sequencing, and phylogenetic comparisons of these amplified 140-bp pol fragments indicated that there are at least two distinct genetic substrains of HTLV-II in the Western Hemisphere. These data were confirmed for selected isolates by performing PCR, cloning, and sequencing with to 10 additional primer pair-probe sets specific for different regions throughout the PTLV genome. HTLV-II isolates from Seminole, Guaymi, and Tobas Indians belong in the new substrain of HTLV-II, while the prototype MoT isolate defines the original substrain. There was greater diversity among HTLV-II New World strains than among HTLV-I New World strains. In fact, the heterogeneity among HTLV-II strains from the Western Hemisphere was similar to that observed in HTLV-I and simian T-cell lymphoma/leukemia virus type I isolates from around the world, including Japan, Africa, and Papua New Guinea. Given these geographic and anthropological considerations and assuming similar mutation rates and selective forces among the PTLV, these data suggest either that HTLV-II has existed for a long time in the indigenous Amerindian population or that HTLV-II isolates introduced into the New World were more heterogeneous than the HTLV-I strains introduced into the New World. PMID:8437209

  13. Genetic Heterogeneity in a Large Cohort of Indian Type 3 von Willebrand Disease Patients

    PubMed Central

    Kasatkar, Priyanka; Shetty, Shrimati; Ghosh, Kanjaksha

    2014-01-01

    Background Though von Willebrand disease (VWD) is a common coagulation disorder, due to the complexity of the molecular analysis of von Willebrand factor gene (VWF), not many reports are available from this country. Large size of the gene, heterogeneous nature of mutations and presence of a highly homologous pseudogene region are the major impediments in the genetic diagnosis of VWD. The study is aimed at unravelling the molecular pathology in a large series of VWD patients from India using an effective strategy. Method We evaluated 85 unrelated Indian type 3 VWD families to identify the molecular defects using a combination of techniques i.e. PCR-RFLP, direct DNA sequencing and multiple ligation probe amplification (MLPA). Results Mutations could be characterized in 77 unrelated index cases (ICs). 59 different mutations i.e. nonsense 20 (33.9%), missense 13 (22%), splice site 4 (6.8%), gene conversions 6 (10.2%), insertions 2 (3.4%), duplication 1 (1.7%), small deletions 10 (17%) and large deletions 3 (5.1%) were identified, of which 34 were novel. Two common mutations i.e. p.R1779* and p.L970del were identified in our population with founder effect. Development of alloantibodies to VWF was seen in two patients, one with nonsense mutation (p.R2434*) and the other had a large deletion spanning exons 16–52. Conclusion The molecular pathology of a large cohort of Indian VWD patients could be identified using a combination of techniques. A wide heterogeneity was observed in the nature of mutations in Indian VWD patients. PMID:24675615

  14. X-linkage in bipolar affective illness. Perspectives on genetic heterogeneity, pedigree analysis and the X-chromosome map.

    PubMed

    Baron, M; Rainer, J D; Risch, N

    1981-06-01

    The search for genetic markers is a powerful strategy in psychiatric genetics. The present article examines four areas relevant to discrepancies among X-linkage studies in bipolar affective disorder. These are questions of ascertainment, analytic methods, the X-chromosome map and genetic heterogeneity. The following conclusions are reached: (a) Positive linkage findings cannot be attributed to ascertainment bias or association between affective illness and colorblindness. (b) The possibility that falsely positive linkage results were obtained by using inappropriate analytic methods is ruled out. (c) Reported linkages of bipolar illness to colorblind and G6PD loci are compatible with known map distances between X-chromosome loci. Linkage to the Xg antigen remains uncertain. (d) The discrepancy among the various data sets on affective illness and colorblindness is best explained by significant linkage heterogeneity among pedigrees informative for the two traits. PMID:6454708

  15. Intra-tumor Genetic Heterogeneity and Mortality in Head and Neck Cancer: Analysis of Data from The Cancer Genome Atlas

    PubMed Central

    Mroz, Edmund A.; Tward, Aaron M.; Hammon, Rebecca J.; Ren, Yin; Rocco, James W.

    2015-01-01

    Background Although the involvement of intra-tumor genetic heterogeneity in tumor progression, treatment resistance, and metastasis is established, genetic heterogeneity is seldom examined in clinical trials or practice. Many studies of heterogeneity have had prespecified markers for tumor subpopulations, limiting their generalizability, or have involved massive efforts such as separate analysis of hundreds of individual cells, limiting their clinical use. We recently developed a general measure of intra-tumor genetic heterogeneity based on whole-exome sequencing (WES) of bulk tumor DNA, called mutant-allele tumor heterogeneity (MATH). Here, we examine data collected as part of a large, multi-institutional study to validate this measure and determine whether intra-tumor heterogeneity is itself related to mortality. Methods and Findings Clinical and WES data were obtained from The Cancer Genome Atlas in October 2013 for 305 patients with head and neck squamous cell carcinoma (HNSCC), from 14 institutions. Initial pathologic diagnoses were between 1992 and 2011 (median, 2008). Median time to death for 131 deceased patients was 14 mo; median follow-up of living patients was 22 mo. Tumor MATH values were calculated from WES results. Despite the multiple head and neck tumor subsites and the variety of treatments, we found in this retrospective analysis a substantial relation of high MATH values to decreased overall survival (Cox proportional hazards analysis: hazard ratio for high/low heterogeneity, 2.2; 95% CI 1.4 to 3.3). This relation of intra-tumor heterogeneity to survival was not due to intra-tumor heterogeneity’s associations with other clinical or molecular characteristics, including age, human papillomavirus status, tumor grade and TP53 mutation, and N classification. MATH improved prognostication over that provided by traditional clinical and molecular characteristics, maintained a significant relation to survival in multivariate analyses, and distinguished

  16. Genotyping of ancient Mycobacterium tuberculosis strains reveals historic genetic diversity

    PubMed Central

    Müller, Romy; Roberts, Charlotte A.; Brown, Terence A.

    2014-01-01

    The evolutionary history of the Mycobacterium tuberculosis complex (MTBC) has previously been studied by analysis of sequence diversity in extant strains, but not addressed by direct examination of strain genotypes in archaeological remains. Here, we use ancient DNA sequencing to type 11 single nucleotide polymorphisms and two large sequence polymorphisms in the MTBC strains present in 10 archaeological samples from skeletons from Britain and Europe dating to the second–nineteenth centuries AD. The results enable us to assign the strains to groupings and lineages recognized in the extant MTBC. We show that at least during the eighteenth–nineteenth centuries AD, strains of M. tuberculosis belonging to different genetic groups were present in Britain at the same time, possibly even at a single location, and we present evidence for a mixed infection in at least one individual. Our study shows that ancient DNA typing applied to multiple samples can provide sufficiently detailed information to contribute to both archaeological and evolutionary knowledge of the history of tuberculosis. PMID:24573854

  17. Revealing heterogeneous nucleation of primary Si and eutectic Si by AlP in hypereutectic Al-Si alloys

    PubMed Central

    Li, Jiehua; Hage, Fredrik S.; Liu, Xiangfa; Ramasse, Quentin; Schumacher, Peter

    2016-01-01

    The heterogeneous nucleation of primary Si and eutectic Si can be attributed to the presence of AlP. Although P, in the form of AlP particles, is usually observed in the centre of primary Si, there is still a lack of detailed investigations on the distribution of P within primary Si and eutectic Si in hypereutectic Al-Si alloys at the atomic scale. Here, we report an atomic-scale experimental investigation on the distribution of P in hypereutectic Al-Si alloys. P, in the form of AlP particles, was observed in the centre of primary Si. However, no significant amount of P was detected within primary Si, eutectic Si and the Al matrix. Instead, P was observed at the interface between the Al matrix and eutectic Si, strongly indicating that P, in the form of AlP particles (or AlP ‘patch’ dependent on the P concentration), may have nucleated on the surface of the Al matrix and thereby enhanced the heterogeneous nucleation of eutectic Si. The present investigation reveals some novel insights into heterogeneous nucleation of primary Si and eutectic Si by AlP in hypereutectic Al-Si alloys and can be used to further develop heterogeneous nucleation mechanisms based on adsorption. PMID:27120994

  18. Revealing heterogeneous nucleation of primary Si and eutectic Si by AlP in hypereutectic Al-Si alloys.

    PubMed

    Li, Jiehua; Hage, Fredrik S; Liu, Xiangfa; Ramasse, Quentin; Schumacher, Peter

    2016-01-01

    The heterogeneous nucleation of primary Si and eutectic Si can be attributed to the presence of AlP. Although P, in the form of AlP particles, is usually observed in the centre of primary Si, there is still a lack of detailed investigations on the distribution of P within primary Si and eutectic Si in hypereutectic Al-Si alloys at the atomic scale. Here, we report an atomic-scale experimental investigation on the distribution of P in hypereutectic Al-Si alloys. P, in the form of AlP particles, was observed in the centre of primary Si. However, no significant amount of P was detected within primary Si, eutectic Si and the Al matrix. Instead, P was observed at the interface between the Al matrix and eutectic Si, strongly indicating that P, in the form of AlP particles (or AlP 'patch' dependent on the P concentration), may have nucleated on the surface of the Al matrix and thereby enhanced the heterogeneous nucleation of eutectic Si. The present investigation reveals some novel insights into heterogeneous nucleation of primary Si and eutectic Si by AlP in hypereutectic Al-Si alloys and can be used to further develop heterogeneous nucleation mechanisms based on adsorption. PMID:27120994

  19. Revealing heterogeneous nucleation of primary Si and eutectic Si by AlP in hypereutectic Al-Si alloys

    NASA Astrophysics Data System (ADS)

    Li, Jiehua; Hage, Fredrik S.; Liu, Xiangfa; Ramasse, Quentin; Schumacher, Peter

    2016-04-01

    The heterogeneous nucleation of primary Si and eutectic Si can be attributed to the presence of AlP. Although P, in the form of AlP particles, is usually observed in the centre of primary Si, there is still a lack of detailed investigations on the distribution of P within primary Si and eutectic Si in hypereutectic Al-Si alloys at the atomic scale. Here, we report an atomic-scale experimental investigation on the distribution of P in hypereutectic Al-Si alloys. P, in the form of AlP particles, was observed in the centre of primary Si. However, no significant amount of P was detected within primary Si, eutectic Si and the Al matrix. Instead, P was observed at the interface between the Al matrix and eutectic Si, strongly indicating that P, in the form of AlP particles (or AlP ‘patch’ dependent on the P concentration), may have nucleated on the surface of the Al matrix and thereby enhanced the heterogeneous nucleation of eutectic Si. The present investigation reveals some novel insights into heterogeneous nucleation of primary Si and eutectic Si by AlP in hypereutectic Al-Si alloys and can be used to further develop heterogeneous nucleation mechanisms based on adsorption.

  20. The integration of quantitative genetics, paleontology, and neontology reveals genetic underpinnings of primate dental evolution.

    PubMed

    Hlusko, Leslea J; Schmitt, Christopher A; Monson, Tesla A; Brasil, Marianne F; Mahaney, Michael C

    2016-08-16

    Developmental genetics research on mice provides a relatively sound understanding of the genes necessary and sufficient to make mammalian teeth. However, mouse dentitions are highly derived compared with human dentitions, complicating the application of these insights to human biology. We used quantitative genetic analyses of data from living nonhuman primates and extensive osteological and paleontological collections to refine our assessment of dental phenotypes so that they better represent how the underlying genetic mechanisms actually influence anatomical variation. We identify ratios that better characterize the output of two dental genetic patterning mechanisms for primate dentitions. These two newly defined phenotypes are heritable with no measurable pleiotropic effects. When we consider how these two phenotypes vary across neontological and paleontological datasets, we find that the major Middle Miocene taxonomic shift in primate diversity is characterized by a shift in these two genetic outputs. Our results build on the mouse model by combining quantitative genetics and paleontology, and thereby elucidate how genetic mechanisms likely underlie major events in primate evolution. PMID:27402751

  1. The integration of quantitative genetics, paleontology, and neontology reveals genetic underpinnings of primate dental evolution

    PubMed Central

    Hlusko, Leslea J.; Schmitt, Christopher A.; Monson, Tesla A.; Brasil, Marianne F.; Mahaney, Michael C.

    2016-01-01

    Developmental genetics research on mice provides a relatively sound understanding of the genes necessary and sufficient to make mammalian teeth. However, mouse dentitions are highly derived compared with human dentitions, complicating the application of these insights to human biology. We used quantitative genetic analyses of data from living nonhuman primates and extensive osteological and paleontological collections to refine our assessment of dental phenotypes so that they better represent how the underlying genetic mechanisms actually influence anatomical variation. We identify ratios that better characterize the output of two dental genetic patterning mechanisms for primate dentitions. These two newly defined phenotypes are heritable with no measurable pleiotropic effects. When we consider how these two phenotypes vary across neontological and paleontological datasets, we find that the major Middle Miocene taxonomic shift in primate diversity is characterized by a shift in these two genetic outputs. Our results build on the mouse model by combining quantitative genetics and paleontology, and thereby elucidate how genetic mechanisms likely underlie major events in primate evolution. PMID:27402751

  2. Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients

    PubMed Central

    Chabon, Jacob J.; Simmons, Andrew D.; Lovejoy, Alexander F.; Esfahani, Mohammad S.; Newman, Aaron M.; Haringsma, Henry J.; Kurtz, David M.; Stehr, Henning; Scherer, Florian; Karlovich, Chris A.; Harding, Thomas C.; Durkin, Kathleen A.; Otterson, Gregory A.; Purcell, W. Thomas; Camidge, D. Ross; Goldman, Jonathan W.; Sequist, Lecia V.; Piotrowska, Zofia; Wakelee, Heather A.; Neal, Joel W.; Alizadeh, Ash A.; Diehn, Maximilian

    2016-01-01

    Circulating tumour DNA (ctDNA) analysis facilitates studies of tumour heterogeneity. Here we employ CAPP-Seq ctDNA analysis to study resistance mechanisms in 43 non-small cell lung cancer (NSCLC) patients treated with the third-generation epidermal growth factor receptor (EGFR) inhibitor rociletinib. We observe multiple resistance mechanisms in 46% of patients after treatment with first-line inhibitors, indicating frequent intra-patient heterogeneity. Rociletinib resistance recurrently involves MET, EGFR, PIK3CA, ERRB2, KRAS and RB1. We describe a novel EGFR L798I mutation and find that EGFR C797S, which arises in ∼33% of patients after osimertinib treatment, occurs in <3% after rociletinib. Increased MET copy number is the most frequent rociletinib resistance mechanism in this cohort and patients with multiple pre-existing mechanisms (T790M and MET) experience inferior responses. Similarly, rociletinib-resistant xenografts develop MET amplification that can be overcome with the MET inhibitor crizotinib. These results underscore the importance of tumour heterogeneity in NSCLC and the utility of ctDNA-based resistance mechanism assessment. PMID:27283993

  3. Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients.

    PubMed

    Chabon, Jacob J; Simmons, Andrew D; Lovejoy, Alexander F; Esfahani, Mohammad S; Newman, Aaron M; Haringsma, Henry J; Kurtz, David M; Stehr, Henning; Scherer, Florian; Karlovich, Chris A; Harding, Thomas C; Durkin, Kathleen A; Otterson, Gregory A; Purcell, W Thomas; Camidge, D Ross; Goldman, Jonathan W; Sequist, Lecia V; Piotrowska, Zofia; Wakelee, Heather A; Neal, Joel W; Alizadeh, Ash A; Diehn, Maximilian

    2016-01-01

    Circulating tumour DNA (ctDNA) analysis facilitates studies of tumour heterogeneity. Here we employ CAPP-Seq ctDNA analysis to study resistance mechanisms in 43 non-small cell lung cancer (NSCLC) patients treated with the third-generation epidermal growth factor receptor (EGFR) inhibitor rociletinib. We observe multiple resistance mechanisms in 46% of patients after treatment with first-line inhibitors, indicating frequent intra-patient heterogeneity. Rociletinib resistance recurrently involves MET, EGFR, PIK3CA, ERRB2, KRAS and RB1. We describe a novel EGFR L798I mutation and find that EGFR C797S, which arises in ∼33% of patients after osimertinib treatment, occurs in <3% after rociletinib. Increased MET copy number is the most frequent rociletinib resistance mechanism in this cohort and patients with multiple pre-existing mechanisms (T790M and MET) experience inferior responses. Similarly, rociletinib-resistant xenografts develop MET amplification that can be overcome with the MET inhibitor crizotinib. These results underscore the importance of tumour heterogeneity in NSCLC and the utility of ctDNA-based resistance mechanism assessment. PMID:27283993

  4. Spatial heterogeneity in landscape structure influences dispersal and genetic structure: empirical evidence from a grasshopper in an agricultural landscape.

    PubMed

    Gauffre, Bertrand; Mallez, Sophie; Chapuis, Marie-Pierre; Leblois, Raphael; Litrico, Isabelle; Delaunay, Sabrina; Badenhausser, Isabelle

    2015-04-01

    Dispersal may be strongly influenced by landscape and habitat characteristics that could either enhance or restrict movements of organisms. Therefore, spatial heterogeneity in landscape structure could influence gene flow and the spatial structure of populations. In the past decades, agricultural intensification has led to the reduction in grassland surfaces, their fragmentation and intensification. As these changes are not homogeneously distributed in landscapes, they have resulted in spatial heterogeneity with generally less intensified hedged farmland areas remaining alongside streams and rivers. In this study, we assessed spatial pattern of abundance and population genetic structure of a flightless grasshopper species, Pezotettix giornae, based on the surveys of 363 grasslands in a 430-km² agricultural landscape of western France. Data were analysed using geostatistics and landscape genetics based on microsatellites markers and computer simulations. Results suggested that small-scale intense dispersal allows this species to survive in intensive agricultural landscapes. A complex spatial genetic structure related to landscape and habitat characteristics was also detected. Two P. giornae genetic clusters bisected by a linear hedged farmland were inferred from clustering analyses. This linear hedged farmland was characterized by high hedgerow and grassland density as well as higher grassland temporal stability that were suspected to slow down dispersal. Computer simulations demonstrated that a linear-shaped landscape feature limiting dispersal could be detected as a barrier to gene flow and generate the observed genetic pattern. This study illustrates the relevance of using computer simulations to test hypotheses in landscape genetics studies. PMID:25773398

  5. An evaluation of genetic heterogeneity in 145 breast-ovarian cancer families

    SciTech Connect

    Narod, S.A.; Ford, D.; Devilee, P.; Barkardottir, R.B.; Lynch, H.T.; Smith, S.A.; Ponder, B.A.J.; Weber, B.L.; Garber, J.E.; Birch, J.M.

    1995-01-01

    The breast-ovary cancer-family syndrome is a dominant predisposition to cancer of the breast and ovaries which has been mapped to chromosome region 17q12-q21. The majority, but not all, of breast-ovary cancer families show linkage to this susceptibility locus, designated BRCA1. We report the results of a linkage analysis of 145 families with both breast and ovarian cancer. These families contain either a total of three or more cases of early-onset (before age 60 years) breast cancer or ovarian cancer. All families contained at least one case of ovarian cancer. Overall, an estimated 76% of the 145 families are linked to the BRCA1 locus. None of the 13 families with cases of male breast cancer appear to be linked, but it is estimated that 92% (95% confidence interval 76%-100%) of families with no male breast cancer and with two or more ovarian cancers are linked to BRCA1. These data suggest that the breast-ovarian cancer-family syndrome is genetically heterogeneous. However, the large majority of families with early-onset breast cancer and with two or more cases of ovarian cancer are likely to be due to BRCA1 mutations. 39 refs., 6 figs., 3 tabs.

  6. Multilocus analysis reveals large genetic diversity in Kluyveromyces marxianus strains isolated from Parmigiano Reggiano and Pecorino di Farindola cheeses.

    PubMed

    Fasoli, Giuseppe; Barrio, Eladio; Tofalo, Rosanna; Suzzi, Giovanna; Belloch, Carmela

    2016-09-16

    In the present study, we have analysed the genetic diversity in Kluyveromyces marxianus isolated from Parmigiano Reggiano and Pecorino di Farindola cheesemaking environment. Molecular typing methods inter-RTL fingerprint and mtDNA RFLPs, as well as, sequence diversity and heterozygosity in the intergenic region between KmSSB1 and KmRIO2 genes and analysis of the mating locus were applied to 54 K. marxianus strains. Inter-RTL fingerprint revealed a large degree of genetic heterogeneity and clustering allowed differentiation of K. marxianus strains from different geographical origins. In general, inter-LTR profiles were more discriminating than RFLPs of mtDNA; however our results also indicate that both techniques could be complementary unveiling different degrees of genetic diversity. Sequence analysis of the intergenic region between KmSSB1 and KmRIO2 genes revealed 26 variable positions in which a double peak could be observed in the sequence chromatogram. Further analysis revealed the presence of heterozygous strains in the K. marxianus population isolated from Parmigiano Reggiano. On the other hand, all strains isolated from Pecorino di Farindola were homozygous. Two very different groups of haplotypes could be observed as well as mixtures between them. Phylogenetic reconstruction divided K. marxianus dairy strains into two separate populations. A few heterozygous strains in an intermediate position between them could also be observed. Mating type locus analysis revealed a large population of diploid strains containing both MATa and MATα alleles and few haploid strains, most of them presenting the MATα allele. Different scenarios explaining the presence and maintaining of homozygous and heterozygous diploids as well as hybrids between them in the Parmigiano Reggiano K. marxianus population are proposed. A principal component analysis supported the large differences between K. marxianus isolated from Parmigiano Reggiano and Pecorino di Farindola. PMID:27294555

  7. The genetic basis for ecological adaptation of the Atlantic herring revealed by genome sequencing

    PubMed Central

    Martinez Barrio, Alvaro; Lamichhaney, Sangeet; Fan, Guangyi; Rafati, Nima; Pettersson, Mats; Zhang, He; Dainat, Jacques; Ekman, Diana; Höppner, Marc; Jern, Patric; Martin, Marcel; Nystedt, Björn; Liu, Xin; Chen, Wenbin; Liang, Xinming; Shi, Chengcheng; Fu, Yuanyuan; Ma, Kailong; Zhan, Xiao; Feng, Chungang; Gustafson, Ulla; Rubin, Carl-Johan; Sällman Almén, Markus; Blass, Martina; Casini, Michele; Folkvord, Arild; Laikre, Linda; Ryman, Nils; Ming-Yuen Lee, Simon; Xu, Xun; Andersson, Leif

    2016-01-01

    Ecological adaptation is of major relevance to speciation and sustainable population management, but the underlying genetic factors are typically hard to study in natural populations due to genetic differentiation caused by natural selection being confounded with genetic drift in subdivided populations. Here, we use whole genome population sequencing of Atlantic and Baltic herring to reveal the underlying genetic architecture at an unprecedented detailed resolution for both adaptation to a new niche environment and timing of reproduction. We identify almost 500 independent loci associated with a recent niche expansion from marine (Atlantic Ocean) to brackish waters (Baltic Sea), and more than 100 independent loci showing genetic differentiation between spring- and autumn-spawning populations irrespective of geographic origin. Our results show that both coding and non-coding changes contribute to adaptation. Haplotype blocks, often spanning multiple genes and maintained by selection, are associated with genetic differentiation. DOI: http://dx.doi.org/10.7554/eLife.12081.001 PMID:27138043

  8. The intergenerational correlation in weight: How genetic resemblance reveals the social role of families*

    PubMed Central

    Martin, Molly A.

    2009-01-01

    According to behavioral genetics research, the intergenerational correlation in weight derives solely from shared genetic predispositions, but complete genetic determinism contradicts the scientific consensus that social and behavioral change underlies the modern obesity epidemic. To address this conundrum, this article utilizes sibling data from the National Longitudinal Study of Adolescent Health and extends structural equation sibling models to incorporate siblings’ genetic relationships to explore the role of families’ social characteristics for adolescent weight. The article is the first to demonstrate that the association between parents’ obesity and adolescent weight is both social and genetic. Furthermore, by incorporating genetic information, the shared and social origins of the correlation between inactivity and weight are better revealed. PMID:19569401

  9. The genetic basis for ecological adaptation of the Atlantic herring revealed by genome sequencing.

    PubMed

    Martinez Barrio, Alvaro; Lamichhaney, Sangeet; Fan, Guangyi; Rafati, Nima; Pettersson, Mats; Zhang, He; Dainat, Jacques; Ekman, Diana; Höppner, Marc; Jern, Patric; Martin, Marcel; Nystedt, Björn; Liu, Xin; Chen, Wenbin; Liang, Xinming; Shi, Chengcheng; Fu, Yuanyuan; Ma, Kailong; Zhan, Xiao; Feng, Chungang; Gustafson, Ulla; Rubin, Carl-Johan; Sällman Almén, Markus; Blass, Martina; Casini, Michele; Folkvord, Arild; Laikre, Linda; Ryman, Nils; Ming-Yuen Lee, Simon; Xu, Xun; Andersson, Leif

    2016-01-01

    Ecological adaptation is of major relevance to speciation and sustainable population management, but the underlying genetic factors are typically hard to study in natural populations due to genetic differentiation caused by natural selection being confounded with genetic drift in subdivided populations. Here, we use whole genome population sequencing of Atlantic and Baltic herring to reveal the underlying genetic architecture at an unprecedented detailed resolution for both adaptation to a new niche environment and timing of reproduction. We identify almost 500 independent loci associated with a recent niche expansion from marine (Atlantic Ocean) to brackish waters (Baltic Sea), and more than 100 independent loci showing genetic differentiation between spring- and autumn-spawning populations irrespective of geographic origin. Our results show that both coding and non-coding changes contribute to adaptation. Haplotype blocks, often spanning multiple genes and maintained by selection, are associated with genetic differentiation. PMID:27138043

  10. A Modularity-Based Method Reveals Mixed Modules from Chemical-Gene Heterogeneous Network

    PubMed Central

    Song, Jianglong; Tang, Shihuan; Liu, Xi; Gao, Yibo; Yang, Hongjun; Lu, Peng

    2015-01-01

    For a multicomponent therapy, molecular network is essential to uncover its specific mode of action from a holistic perspective. The molecular system of a Traditional Chinese Medicine (TCM) formula can be represented by a 2-class heterogeneous network (2-HN), which typically includes chemical similarities, chemical-target interactions and gene interactions. An important premise of uncovering the molecular mechanism is to identify mixed modules from complex chemical-gene heterogeneous network of a TCM formula. We thus proposed a novel method (MixMod) based on mixed modularity to detect accurate mixed modules from 2-HNs. At first, we compared MixMod with Clauset-Newman-Moore algorithm (CNM), Markov Cluster algorithm (MCL), Infomap and Louvain on benchmark 2-HNs with known module structure. Results showed that MixMod was superior to other methods when 2-HNs had promiscuous module structure. Then these methods were tested on a real drug-target network, in which 88 disease clusters were regarded as real modules. MixMod could identify the most accurate mixed modules from the drug-target 2-HN (normalized mutual information 0.62 and classification accuracy 0.4524). In the end, MixMod was applied to the 2-HN of Buchang naoxintong capsule (BNC) and detected 49 mixed modules. By using enrichment analysis, we investigated five mixed modules that contained primary constituents of BNC intestinal absorption liquid. As a matter of fact, the findings of in vitro experiments using BNC intestinal absorption liquid were found to highly accord with previous analysis. Therefore, MixMod is an effective method to detect accurate mixed modules from chemical-gene heterogeneous networks and further uncover the molecular mechanism of multicomponent therapies, especially TCM formulae. PMID:25927435

  11. Phylogeography of Pinus armandii and Its Relatives: Heterogeneous Contributions of Geography and Climate Changes to the Genetic Differentiation and Diversification of Chinese White Pines

    PubMed Central

    Liu, Liu; Hao, Zhen-Zhen; Liu, Yan-Yan; Wei, Xiao-Xin; Cun, Yu-Zhi; Wang, Xiao-Quan

    2014-01-01

    Geographic barriers and Quaternary climate changes are two major forces driving the evolution, speciation, and genetic structuring of extant organisms. In this study, we used Pinus armandii and eleven other Asian white pines (subsection Strobus, subgenus Pinus) to explore the influences of geographic factors and Pleistocene climatic oscillations on species in South China, a region known to be centers of plant endemism and biodiversity hotspots. Range-wide patterns of genetic variation were investigated using chloroplast and mitochondrial DNA markers, with extensive sampling throughout the entire range of P. armandii. Both cpDNA and mtDNA revealed that P. armandii exhibits high levels of genetic diversity and significant population differentiation. Three geographically distinct subdivisions corresponding to the Qinling-Daba Mountains (QDM), Himalaya-Hengduan Mountains (HHM) and Yungui Plateau (YGP) were revealed in mainland China by cpDNA. Their break zone was located in the southeastern margin of the Qinghai-Tibetan Plateau (QTP). A series of massive mountains, induced by the QTP uplift, imposed significant geographic barriers to genetic exchange. The disjunct distribution patterns of ancestral haplotypes suggest that a large continuous population of the white pines may have existed from southwest to subtropical China. Repeated range shifts in response to the Pleistocene glaciations led to the isolation and diversification of the subtropical species. The two Taiwanese white pines share a common ancestor with the species in mainland China and obtain their chloroplasts via long-distance pollen dispersal from North Asian pines. Distinct genetic patterns were detected in populations from the Qinling-Daba Mountains, Yungui Plateau, Himalaya-Hengduan Mountains, and subtropical China, indicating significant contributions of geographic factors to the genetic differentiation in white pines. Our study depicts a clear picture of the evolutionary history of Chinese white pines

  12. Single-Particle Spectroscopy Reveals Heterogeneity in Electrochemical Tuning of the Localized Surface Plasmon

    PubMed Central

    2015-01-01

    A hyperspectral imaging method was developed that allowed the identification of heterogeneous plasmon response from 50 nm diameter gold colloidal particles on a conducting substrate in a transparent three-electrode spectroelectrochemical cell under non-Faradaic conditions. At cathodic potentials, we identified three distinct behaviors from different nanoparticles within the same sample: irreversible chemical reactions, reversible chemical reactions, and reversible charge density tuning. The irreversible reactions in particular would be difficult to discern in alternate methodologies. Additional heterogeneity was observed when single nanoparticles demonstrating reversible charge density tuning in the cathodic regime were measured dynamically in anodic potential ranges. Some nanoparticles that showed charge density tuning in the cathodic range also showed signs of an additional chemical tuning mechanism in the anodic range. The expected changes in nanoparticle free-electron density were modeled using a charge density-modified Drude dielectric function and Mie theory, a commonly used model in colloidal spectroelectrochemistry. Inconsistencies between experimental results and predictions of this common physical model were identified and highlighted. The broad range of responses on even a simple sample highlights the rich experimental and theoretical playgrounds that hyperspectral single-particle electrochemistry opens. PMID:24971712

  13. Small angle neutron scattering contrast variation reveals heterogeneities of interactions in protein gels.

    PubMed

    Banc, A; Charbonneau, C; Dahesh, M; Appavou, M-S; Fu, Z; Morel, M-H; Ramos, L

    2016-06-28

    We propose a quantitative approach to probe the spatial heterogeneities of interactions in macromolecular gels, based on a combination of small angle X-ray (SAXS) and neutrons (SANS) scattering. We investigate the structure of model gluten protein gels and show that the gels display radically different SAXS and SANS profiles when the solvent is (at least partially) deuterated. The detailed analysis of the SANS signal as a function of the solvent deuteration demonstrates heterogeneities of sample deuteration at different length scales. The progressive exchange between the protons (H) of the proteins and the deuteriums (D) of the solvent is inhomogeneous and 60 nm large zones that are enriched in H are evidenced. In addition, at low protein concentration, in the sol state, solvent deuteration induces a liquid/liquid phase separation. Complementary biochemical and structure analyses show that the denser protein phase is more protonated and specifically enriched in glutenin, the polymeric fraction of gluten proteins. These findings suggest that the presence of H-rich zones in gluten gels would arise from the preferential interaction of glutenin polymers through a tight network of non-exchangeable intermolecular hydrogen bonds. PMID:27198847

  14. Fluorescence lifetime heterogeneity in aggregates of LHCII revealed by time-resolved microscopy.

    PubMed Central

    Barzda, V; de Grauw, C J; Vroom, J; Kleima, F J; van Grondelle, R; van Amerongen, H; Gerritsen, H C

    2001-01-01

    Two-photon excitation, time-resolved fluorescence microscopy was used to investigate the fluorescence quenching mechanisms in aggregates of light-harvesting chlorophyll a/b pigment protein complexes of photosystem II from green plants (LHCII). Time-gated microscopy images show the presence of large heterogeneity in fluorescence lifetimes not only for different LHCII aggregates, but also within a single aggregate. Thus, the fluorescence decay traces obtained from macroscopic measurements reflect an average over a large distribution of local fluorescence kinetics. This opens the possibility to resolve spatially different structural/functional units in chloroplasts and other heterogeneous photosynthetic systems in vivo, and gives the opportunity to investigate individually the excited states dynamics of each unit. We show that the lifetime distribution is sensitive to the concentration of quenchers contained in the system. Triplets, which are generated at high pulse repetition rates of excitation (>1 MHz), preferentially quench domains with initially shorter fluorescence lifetimes. This proves our previous prediction from singlet-singlet annihilation investigations (Barzda, V., V. Gulbinas, R. Kananavicius, V. Cervinskas, H. van Amerongen, R. van Grondelle, and L. Valkunas. 2001. Biophys. J. 80:2409-2421) that shorter fluorescence lifetimes originate from larger domains in LHCII aggregates. We found that singlet-singlet annihilation has a strong effect in time-resolved fluorescence microscopy of connective systems and has to be taken into consideration. Despite that, clear differences in fluorescence decays can be detected that can also qualitatively be understood. PMID:11423435

  15. Genomic profiling of malignant phyllodes tumors reveals aberrations in FGFR1 and PI-3 kinase/RAS signaling pathways and provides insights into intratumoral heterogeneity.

    PubMed

    Liu, Su-Yang; Joseph, Nancy M; Ravindranathan, Ajay; Stohr, Bradley A; Greenland, Nancy Y; Vohra, Poonam; Hosfield, Elizabeth; Yeh, Iwei; Talevich, Eric; Onodera, Courtney; Van Ziffle, Jessica A; Grenert, James P; Bastian, Boris C; Chen, Yunn-Yi; Krings, Gregor

    2016-09-01

    Malignant phyllodes tumors of the breast are poorly understood rare neoplasms with potential for aggressive behavior. Few efficacious treatment options exist for progressed or metastatic disease. The molecular features of malignant phyllodes tumors are poorly defined, and a deeper understanding of the genetics of these tumors may shed light on pathogenesis and progression and potentially identify novel treatment approaches. We sequenced 510 cancer-related genes in 10 malignant phyllodes tumors, including 5 tumors with liposarcomatous differentiation and 1 with myxoid chondrosarcoma-like differentiation. Intratumoral heterogeneity was assessed by sequencing two separate areas in 7 tumors, including non-heterologous and heterologous components of tumors with heterologous differentiation. Activating hotspot mutations in FGFR1 were identified in 2 tumors. Additional recurrently mutated genes included TERT promoter (6/10), TP53 (4/10), PIK3CA (3/10), MED12 (3/10), SETD2 (2/10) and KMT2D (2/10). Together, genomic aberrations in FGFR/EGFR PI-3 kinase and RAS pathways were identified in 8 (80%) tumors and included mutually exclusive and potentially actionable activating FGFR1, PIK3CA and BRAF V600E mutations, inactivating TSC2 mutation, EGFR amplification and PTEN loss. Seven (70%) malignant phyllodes tumors harbored TERT aberrations (six promoter mutations, one amplification). For comparison, TERT promoter mutations were identified by Sanger sequencing in 33% borderline (n=12) and no (0%, n=8) benign phyllodes tumors (P=0.391 and P=0.013 vs malignant tumors, respectively). Genetic features specific to liposarcoma, including CDK4/MDM2 amplification, were not identified. Copy number analysis revealed intratumoral heterogeneity and evidence for divergent tumor evolution in malignant phyllodes tumors with and without heterologous differentiation. Tumors with liposarcomatous differentiation revealed more chromosomal aberrations in non-heterologous components compared with

  16. Genetic analyses benefit from using less heterogeneous phenotypes: An illustration with the Hospital Anxiety and Depression Scale (HADS)

    PubMed Central

    Laurin, Charles A.; Hottenga, Jouke-Jan; Willemsen, Gonneke; Boomsma, Dorret I.; Lubke, Gitta H.

    2015-01-01

    Phenotypic heterogeneity of depression has been cited as one of causes of the limited success to detect genetic variants in genome-wide studies. The 7-item Hospital Anxiety and Depression Scale (HADS-D) was developed to detect depression in individuals with physical health problems. An initial psychometric analysis showed that a short version (“HADS-4”) is less heterogeneous and hence more reliable than the full scale, and correlates equally strong with a DSM-oriented depression scale. We compared the HADS-D and the HADS-4 to assess the benefits of using less heterogeneous phenotype measures in genetic analyses. We compared HADS-D and HADS-4 in three separate analyses: (1) twin- and family-based heritability estimation, (2) SNP-based heritability estimation using the software GCTA, and (3) a genome-wide association study (GWAS). The twin study resulted in heritability estimates between 18 and 25%, with additive genetic variance being the largest component. There was also evidence for assortative mating and a dominance component of genetic variance, with HADS-4 having slightly lower estimates of assortment. Importantly, when estimating heritability from SNPs, the HADS-D did not show a significant genetic variance component, while for the HADS-4, a statistically significant amount of heritability was estimated. Moreover, the HADS-4 had substantially more SNPs with small p-values in the GWAS analysis than did the HADS-D. Our results underline the benefits of using more homogeneous phenotypes in psychiatric genetic analyses. Homogeneity can be increased by focusing on core symptoms of disorders, thus reducing the noise in aggregate phenotypes caused by substantially different symptom profiles. PMID:25832296

  17. Heterogeneity in Genetic Diversity among Non-Coding Loci Fails to Fit Neutral Coalescent Models of Population History

    PubMed Central

    Peters, Jeffrey L.; Roberts, Trina E.; Winker, Kevin; McCracken, Kevin G.

    2012-01-01

    Inferring aspects of the population histories of species using coalescent analyses of non-coding nuclear DNA has grown in popularity. These inferences, such as divergence, gene flow, and changes in population size, assume that genetic data reflect simple population histories and neutral evolutionary processes. However, violating model assumptions can result in a poor fit between empirical data and the models. We sampled 22 nuclear intron sequences from at least 19 different chromosomes (a genomic transect) to test for deviations from selective neutrality in the gadwall (Anas strepera), a Holarctic duck. Nucleotide diversity among these loci varied by nearly two orders of magnitude (from 0.0004 to 0.029), and this heterogeneity could not be explained by differences in substitution rates alone. Using two different coalescent methods to infer models of population history and then simulating neutral genetic diversity under these models, we found that the observed among-locus heterogeneity in nucleotide diversity was significantly higher than expected for these simple models. Defining more complex models of population history demonstrated that a pre-divergence bottleneck was also unlikely to explain this heterogeneity. However, both selection and interspecific hybridization could account for the heterogeneity observed among loci. Regardless of the cause of the deviation, our results illustrate that violating key assumptions of coalescent models can mislead inferences of population history. PMID:22384117

  18. High Prevalence of Human Metapneumovirus Infection in Young Children and Genetic Heterogeneity of the Viral Isolates

    PubMed Central

    Viazov, S.; Ratjen, F.; Scheidhauer, R.; Fiedler, M.; Roggendorf, M.

    2003-01-01

    RNA of the newly identified human metapneumovirus (HMPV) was detected in nasopharyngeal aspirates of 11 of 63 (17.5%) young children with respiratory tract disease. Markers of infection caused by another member of the Pneumovirinae subfamily of the family Paramyxoviridae, respiratory syncytial virus (RSV), were identified in 15 of these patients (23.8%). Three patients were simultaneously infected with HMPV and RSV. Studies of the clinical characteristics of HMPV-infected children did not reveal any difference between HMPV-infected patients and a control population of RSV-infected patients with regard to disease severity, but the duration of symptoms was significantly shorter for HMPV-infected patients. Phylogenetic analysis of the amplified viral genome fragments confirmed the existence and simultaneous circulation within one epidemic season of HMPV isolates belonging to two genetic lineages. PMID:12843040

  19. The Pseudomonas aeruginosa Transcriptional Landscape Is Shaped by Environmental Heterogeneity and Genetic Variation

    PubMed Central

    Schniederjans, Monika; Khaledi, Ariane; Hornischer, Klaus; Schulz, Sebastian; Bielecka, Agata; Eckweiler, Denitsa; Pohl, Sarah; Häussler, Susanne

    2015-01-01

    ABSTRACT Phenotypic variability among bacteria depends on gene expression in response to different environments, and it also reflects differences in genomic structure. In this study, we analyzed transcriptome sequencing (RNA-seq) profiles of 151 Pseudomonas aeruginosa clinical isolates under standard laboratory conditions and of one P. aeruginosa type strain under 14 different environmental conditions. Our approach allowed dissection of the impact of the genetic background versus environmental cues on P. aeruginosa gene expression profiles and revealed that phenotypic variation was larger in response to changing environments than between genomically different isolates. We demonstrate that mutations within the global regulator LasR affect more than one trait (pleiotropy) and that the interaction between mutations (epistasis) shapes the P. aeruginosa phenotypic plasticity landscape. Because of pleiotropic and epistatic effects, average genotype and phenotype measures appeared to be uncorrelated in P. aeruginosa. PMID:26126853

  20. Genetic heterogeneity within the HLA region in three distinct clinical subgroups of myasthenia gravis.

    PubMed

    Saruhan-Direskeneli, Güher; Hughes, Travis; Yilmaz, Vuslat; Durmus, Hacer; Adler, Adam; Alahgholi-Hajibehzad, Mahdi; Aysal, Fikret; Yentür, Sibel P; Akalin, Mehmet Ali; Dogan, Oner; Marx, Alexander; Gülsen-Parman, Yesim; Oflazer, Piraye; Deymeer, Feza; Sawalha, Amr H

    2016-05-01

    This study aims to investigate genetic susceptibility to early-onset and late-onset anti-acetylcholine receptor antibody positive myasthenia gravis (EOMG and LOMG) and anti-muscle specific kinase antibody positive MG (MuSK-MG) at genome-wide level in a single population. Using a custom-designed array and imputing additional variants and the classical HLA alleles in 398 patients, we detected distinct associations. In EOMG, rs113519545 in the HLA class I region (OR=5.71 [3.77-8.66], P=2.24×10(-16)), HLA-B*08:01 (OR=7.04 [3.95-12.52], P=3.34×10(-11)) and HLA-C*07:01 (OR=2.74 [1.97-3.81], P=2.07(-9)), in LOMG, rs111256513 in the HLA class II region (OR=2.22 [1.59-3.09], P=2.48×10(-6)) and in MuSK-MG, an intronic variant within HLA-DQB1 (rs68081734, OR=5.86, P=2.25×10(-14)) and HLA-DQB1*05:02 (OR=8.56, P=6.88×10(-13)) revealed the most significant associations for genome-wide significance. Differential genetic susceptibility within the HLA to EOMG, LOMG and MuSK-MG has been established in a population from Turkey. PMID:27181991

  1. Time-Resolved Imaging Reveals Heterogeneous Landscapes of Nanomolar Ca(2+) in Neurons and Astroglia.

    PubMed

    Zheng, Kaiyu; Bard, Lucie; Reynolds, James P; King, Claire; Jensen, Thomas P; Gourine, Alexander V; Rusakov, Dmitri A

    2015-10-21

    Maintaining low intracellular calcium is essential to the functioning of brain cells, yet the phenomenology and mechanisms involved remain an enigma. We have advanced a two-photon excitation time-resolved imaging technique, which exploits high sensitivity of the OGB-1 fluorescence lifetime to nanomolar Ca(2+) concentration ([Ca(2+)]) and enables a high data acquisition rate in situ. The [Ca(2+)] readout is not affected by dye concentration, light scattering, photobleaching, micro-viscosity, temperature, or the main known concomitants of cellular activity. In quiescent tissue, standard whole-cell configuration has little effect on resting [Ca(2+)] inside neuronal dendrites or inside astroglia dye-filled via gap junctions. Mapping basal [Ca(2+)] in neurons and astrocytes with submicron resolution unveils heterogeneous concentration landscapes that depend on age and preceding activity. The rich information content represented by such landscapes in acute slices and in vivo promises to unveil the hitherto unexplored, potentially fundamental aspects of brain cell physiology. PMID:26494277

  2. Deep-sequencing of the peach latent mosaic viroid reveals new aspects of population heterogeneity.

    PubMed

    Glouzon, Jean-Pierre Sehi; Bolduc, François; Wang, Shengrui; Najmanovich, Rafael J; Perreault, Jean-Pierre

    2014-01-01

    Viroids are small circular single-stranded infectious RNAs characterized by a relatively high mutation level. Knowledge of their sequence heterogeneity remains largely elusive and previous studies, using Sanger sequencing, were based on a limited number of sequences. In an attempt to address sequence heterogeneity from a population dynamics perspective, a GF305-indicator peach tree was infected with a single variant of the Avsunviroidae family member Peach latent mosaic viroid (PLMVd). Six months post-inoculation, full-length circular conformers of PLMVd were isolated and deep-sequenced. We devised an original approach to the bioinformatics refinement of our sequence libraries involving important phenotypic data, based on the systematic analysis of hammerhead self-cleavage activity. Two distinct libraries yielded a total of 3,939 different PLMVd variants. Sequence variants exhibiting up to ∼17% of mutations relative to the inoculated viroid were retrieved, clearly illustrating the high level of divergence dynamics within a unique population. While we initially assumed that most positions of the viroid sequence would mutate, we were surprised to discover that ∼50% of positions remained perfectly conserved, including several small stretches as well as a small motif reminiscent of a GNRA tetraloop which are the result of various selective pressures. Using a hierarchical clustering algorithm, the different variants harvested were subdivided into 7 clusters. We found that most sequences contained an average of 4.6 to 6.4 mutations compared to the variant used to initially inoculate the plant. Interestingly, it was possible to reconstitute and compare the sequence evolution of each of these clusters. In doing so, we identified several key mutations. This study provides a reliable pipeline for the treatment of viroid deep-sequencing. It also sheds new light on the extent of sequence variation that a viroid population can sustain, and which may give rise to a

  3. Genomic profiling reveals extensive heterogeneity in somatic DNA copy number aberrations of canine hemangiosarcoma.

    PubMed

    Thomas, Rachael; Borst, Luke; Rotroff, Daniel; Motsinger-Reif, Alison; Lindblad-Toh, Kerstin; Modiano, Jaime F; Breen, Matthew

    2014-09-01

    Canine hemangiosarcoma is a highly aggressive vascular neoplasm associated with extensive clinical and anatomical heterogeneity and a grave prognosis. Comprehensive molecular characterization of hemangiosarcoma may identify novel therapeutic targets and advanced clinical management strategies, but there are no published reports of tumor-associated genome instability and disrupted gene dosage in this cancer. We performed genome-wide microarray-based somatic DNA copy number profiling of 75 primary intra-abdominal hemangiosarcomas from five popular dog breeds that are highly predisposed to this disease. The cohort exhibited limited global genomic instability, compared to other canine sarcomas studied to date, and DNA copy number aberrations (CNAs) were predominantly of low amplitude. Recurrent imbalances of several key cancer-associated genes were evident; however, the global penetrance of any single CNA was low and no distinct hallmark aberrations were evident. Copy number gains of dog chromosomes 13, 24, and 31, and loss of chromosome 16, were the most recurrent CNAs involving large chromosome regions, but their relative distribution within and between cases suggests they most likely represent passenger aberrations. CNAs involving CDKN2A, VEGFA, and the SKI oncogene were identified as potential driver aberrations of hemangiosarcoma development, highlighting potential targets for therapeutic modulation. CNA profiles were broadly conserved between the five breeds, although subregional variation was evident, including a near twofold lower incidence of VEGFA gain in Golden Retrievers versus other breeds (22 versus 40 %). These observations support prior transcriptional studies suggesting that the clinical heterogeneity of this cancer may reflect the existence of multiple, molecularly distinct subtypes of canine hemangiosarcoma. PMID:24599718

  4. Heterogeneity of tumor chemosensitivity in ovarian epithelial cancer revealed using the adenosine triphosphate-tumor chemosensitivity assay

    PubMed Central

    ZHANG, JIN; LI, HONGXIA

    2015-01-01

    Ovarian cancer has a poor prognosis, primarily due to the heterogeneity in chemosensitivity among patients. In the present study, this heterogeneity was evaluated in ovarian epithelial cancer (OEC) using an in vitro adenosine triphosphate tumor chemosensitivity assay (ATP-TCA). Specimens were collected from 80 patients who underwent cytoreductive surgery. Viable ovarian cancer cells obtained from malignant tissues were tested for sensitivity to paclitaxel (PTX), carboplatin (CBP), topotecan (TPT), gemcitabine (GEM), docetaxel (TXT), etoposide, bleomycin and 4-hydroperoxycyclophosphamide using ATP-TCA. The sensitivity, specificity, positive predictive value and negative predictive value for the clinical chemotherapy sensitivity of OEC were 88.6, 77.8, 83 and 84.8%, respectively. PTX demonstrated the highest sensitivity of all agents tested (82.5% in all specimens, 85.7% in recurrent specimens), followed by CBP (58.8 and 60.7%, respectively). The sensitivities to PTX and docetaxel (P<0.001) were correlated, in addition to those of CBP, TPT and GEM (P<0.001). Early-stage (I/II) and high- to mildly-differentiated OEC specimens revealed a lower chemosensitivity than advanced-stage (III) or low-differentiated specimens, respectively. The present study indicated that ATP-TCA is an effective method for guiding the choice of chemotherapy drugs. Notable heterogeneity of chemosensitivity was observed in the OEC specimens. PMID:26137074

  5. Single-cell analysis reveals gene-expression heterogeneity in syntrophic dual-culture of Desulfovibrio vulgaris with Methanosarcina barkeri

    NASA Astrophysics Data System (ADS)

    Qi, Zhenhua; Pei, Guangsheng; Chen, Lei; Zhang, Weiwen

    2014-12-01

    Microbial syntrophic metabolism has been well accepted as the heart of how methanogenic and other anaerobic microbial communities function. In this work, we applied a single-cell RT-qPCR approach to reveal gene-expression heterogeneity in a model syntrophic system of Desulfovibrio vulgaris and Methanosarcina barkeri, as compared with the D. vulgaris monoculture. Using the optimized primers and single-cell analytical protocol, we quantitatively determine gene-expression levels of 6 selected target genes in each of the 120 single cells of D. vulgaris isolated from its monoculture and dual-culture with M. barkeri. The results demonstrated very significant cell-to-cell gene-expression heterogeneity for the selected D. vulgaris genes in both the monoculture and the syntrophic dual-culture. Interestingly, no obvious increase in gene-expression heterogeneity for the selected genes was observed for the syntrophic dual-culture when compared with its monoculture, although the community structure and cell-cell interactions have become more complicated in the syntrophic dual-culture. In addition, the single-cell RT-qPCR analysis also provided further evidence that the gene cluster (DVU0148-DVU0150) may be involved syntrophic metabolism between D. vulgaris and M. barkeri. Finally, the study validated that single-cell RT-qPCR analysis could be a valuable tool in deciphering gene functions and metabolism in mixed-cultured microbial communities.

  6. Mechanisms of population genetic heterogeneity among molting common mergansers on Kodiak Island, Alaska: implications for assessments of migratory connectivity

    USGS Publications Warehouse

    Pearce, John M.; Zwiefelhofer, Denny; Maryanski, Nate

    2009-01-01

    Quantifying population genetic heterogeneity within nonbreeding aggregations can inform our understanding of patterns of site fidelity, migratory connectivity, and gene flow between breeding and nonbreeding areas. However, characterizing mechanisms that contribute to heterogeneity, such as migration and dispersal, is required before site fidelity and migratory connectivity can be assessed accurately. We studied nonbreeding groups of Common Mergansers (Mergus merganser) molting on Kodiak Island, Alaska, from 2005 to 2007, using banding data to assess rates of recapture, mitochondrial (mt) DNA to determine natal area, and nuclear microsatellite genotypes to assess dispersal. Using baseline information from differentiated mtDNA haplogroups across North America, we were able to assign individuals to natal regions and document population genetic heterogeneity within and among molting groups. Band-recovery and DNA data suggest that both migration from and dispersal among natal areas contribute to admixed groups of males molting on Kodiak Island. A lack of differentiation in the Common Merganser's nuclear, bi-parentally inherited DNA, observed across North America, implies that dispersal can mislead genetic assessments of migratory connectivity and assignments of nonbreeding individuals to breeding areas. Thus multiple and independent data types are required to account for such behaviors before accurate assessments of migratory connectivity can be made.

  7. Brachydactyly type B: linkage to chromosome 9q22 and evidence for genetic heterogeneity.

    PubMed Central

    Oldridge, M; Temple, I K; Santos, H G; Gibbons, R J; Mustafa, Z; Chapman, K E; Loughlin, J; Wilkie, A O

    1999-01-01

    Brachydactyly type B (BDB), an autosomal dominant disorder, is the most severe of the brachydactylies and is characterized by hypoplasia or absence of the terminal portions of the index to little fingers, usually with absence of the nails. The thumbs may be of normal length but are often flattened and occasionally are bifid. The feet are similarly but less severely affected. We have performed a genomewide linkage analysis of three families with BDB, two English and one Portugese. The two English families show linkage to the same region on chromosome 9 (combined multipoint maximum LOD score 8.69 with marker D9S257). The 16-cM disease interval is defined by recombinations with markers D9S1680 and D9S1786. These two families share an identical disease haplotype over 18 markers, inclusive of D9S278-D9S280. This provides strong evidence that the English families have the same ancestral mutation, which reduces the disease interval to <12.7 cM between markers D9S257 and D9S1851 in chromosome band 9q22. In the Portuguese family, we excluded linkage to this region, a result indicating that BDB is genetically heterogeneous. Reflecting this, there were atypical clinical features in this family, with shortening of the thumbs and absence or hypoplasia of the nails of the thumb and hallux. These results enable a refined classification of BDB and identify a novel locus for digit morphogenesis in 9q22. PMID:9973296

  8. The genetic tumor background is an important determinant for heterogeneous MYCN-amplified neuroblastoma.

    PubMed

    Bogen, Dominik; Brunner, Clemens; Walder, Diana; Ziegler, Andrea; Abbasi, Reza; Ladenstein, Ruth L; Noguera, Rosa; Martinsson, Tommy; Amann, Gabriele; Schilling, Freimut H; Ussowicz, Marek; Benesch, Martin; Ambros, Peter F; Ambros, Inge M

    2016-07-01

    Amplification of MYCN is the signature genetic aberration of 20-25% of neuroblastoma and a stratifying marker associated with aggressive tumor behavior. The detection of heterogeneous MYCN amplification (hetMNA) poses a diagnostic dilemma due to the uncertainty of its relevance to tumor behavior. Here, we aimed to shed light on the genomic background which permits hetMNA in neuroblastoma and tied the occurrence to other stratifying markers and disease outcome. We performed SNP analysis using Affymetrix Cytoscan HD arrays on 63 samples including constitutional DNA, tumor, bone marrow and relapse samples of 26 patients with confirmed hetMNA by MYCN-FISH. Tumors of patients ≤18m were mostly aneuploid with numeric chromosomal aberrations (NCAs), presented a prominent MNA subclone and carried none or a few segmental chromosomal aberrations (SCAs). In older patients, tumors were mostly di- or tetraploid, contained a lower number of MNA cells and displayed a multitude of SCAs including concomitant 11q deletions. These patients often suffered disease progression, tumor dissemination and relapse. Restricted to aneuploid tumors, we detected chromosomes with uniparental di- or trisomy (UPD/UPT) in almost every sample. UPD11 was exclusive to tumors of younger patients whereas older patients featured UPD14. In this study, the MNA subclone appears to be constraint by the tumor environment and thus less relevant for tumor behavior in aggressive tumors with a high genomic instability and many segmental aberrations. A more benign tumor background and lower tumor stage may favor an outgrowth of the MNA clone but tumors generally responded better to treatment. PMID:26910568

  9. Genetic evidence for heterogeneity in the etiology of CBAVD: Haplotype analysis in families

    SciTech Connect

    Kerem, B.; Rave-Harel, N.; Goshen, R.

    1994-09-01

    Male infertility due to congenital aplasia of the vas deference (CBAVD) is present in almost all CF male patients. It is also found in 1-2% of infertile otherwise healthy males. Several studies have found that about 10% of males with CBAVD carry 2 CF mutations, 40% carry one mutation and 50% have no mutations. These results indicate that in some males CBAVD is caused by two mutated CF alleles. However, in cases of males with one or no identified CF mutations, the association between CBAVD and CF is unclear. We therefore performed, in addition to CF mutation analysis, an extended haplotype analysis in 7 families of CBAVD males (2 had 2 brothers with CBAVD). Our results show that in 6 of the families, the infertile males inherited different CF alleles than their fertile brothers. However, in 2 families, in which no CF mutations were as of yet identified, different results were found. In one family, 2 infertile brothers differed in their haplotypes: both inherited from their mother the same CF allele, while from their father they inherited different alleles. Furthermore, their fertile brother inherited the same CF alleles as one of his fertile brothers. In another family, 2 brothers, one with CBAVD and the other fertile, inherited the same 2 CFTR alleles. These results provide genetic evidence for heterogeneity in the etiology of CBAVD. In some families the CBAVD is caused by 2 CF mutations, in others it is caused by other mechanism(s): heterozygosity for a CF mutation influenced by different threshold levels, mutations in other gene(s), or interaction between the two.

  10. Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice.

    PubMed

    Strong, Randy; Miller, Richard A; Astle, Clinton M; Floyd, Robert A; Flurkey, Kevin; Hensley, Kenneth L; Javors, Martin A; Leeuwenburgh, Christiaan; Nelson, James F; Ongini, Ennio; Nadon, Nancy L; Warner, Huber R; Harrison, David E

    2008-10-01

    The National Institute on Aging's Interventions Testing Program was established to evaluate agents that are purported to increase lifespan and delay the appearance of age-related disease in genetically heterogeneous mice. Up to five compounds are added to the study each year and each compound is tested at three test sites (The Jackson Laboratory, University of Michigan, and University of Texas Health Science Center at San Antonio). Mice in the first cohort were exposed to one of four agents: aspirin, nitroflurbiprofen, 4-OH-alpha-phenyl-N-tert-butyl nitrone, or nordihydroguaiaretic acid (NDGA). Sample size was sufficient to detect a 10% difference in lifespan in either sex,with 80% power, using data from two of the three sites. Pooling data from all three sites, a log-rank test showed that both NDGA (p=0.0006) and aspirin (p=0.01) led to increased lifespan of male mice. Comparison of the proportion of live mice at the age of 90% mortality was used as a surrogate for measurement of maximum lifespan;neither NDGA (p=0.12) nor aspirin (p=0.16) had a significant effect in this test. Measures of blood levels of NDGA or aspirin and its salicylic acid metabolite suggest that the observed lack of effects of NDGA or aspirin on life span in females could be related to gender differences in drug disposition or metabolism. Further studies are warranted to find whether NDGA or aspirin, over a range of doses,might prove to postpone death and various age-related outcomes reproducibly in mice. PMID:18631321