Paola Flórez de Sessions

Genome Institute of Singapore

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Martin L. Hibberd

London School of Hygiene & Tropical Medicine

Collins Wenhan Chu

Genome Institute of Singapore

Eliza Xin Pei Ho

Agency for Science, Technology and Research

Niranjan Nagarajan

Genome Institute of Singapore

Christophe Lay

National University of Singapore

Jan Knol

Nutricia Research (Netherlands)

Surasith Chaithongwongwatthana

Chulalongkorn University

Guus Roeselers

Nutricia Research (Netherlands)

Rajeshwar Rao

KK Women's and Children's Hospital

Shuwen Chen

Anhui Medical University

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National University of Singapore

217

Agency for Science, Technology and Research

141

National University Health System

Cornell University

Duke-NUS Medical School

Nanyang Technological University

Genome Institute of Singapore

Weill Cornell Medicine

London School of Hygiene & Tropical Medicine

National University Hospital

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Additional file 7 of A synbiotic intervention modulates meta-omics signatures of gut redox potential and acidity in elective caesarean born infants

Figshare (2021)

Christophe Lay Collins Wenhan Chu Rikky W. Purbojati Enzo Acerbi Daniela I. Drautz‐Moses

Additional file 7: Supplementary Table 6. 16S rRNA Species data (Mean and SD) per group and time point.

Omics

10.6084/m9.figshare.14850788

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Additional file 2 of A synbiotic intervention modulates meta-omics signatures of gut redox potential and acidity in elective caesarean born infants

Figshare (2021)

Christophe Lay Collins Wenhan Chu Rikky W. Purbojati Enzo Acerbi Daniela I. Drautz‐Moses

Additional file 2: Supplementary Table 1. Number of subjects per group and number of 16S rRNA samples per group and time point.

Omics

10.6084/m9.figshare.14850773

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Global genetic diversity of var2csa in Plasmodium falciparum with implications for malaria in pregnancy and vaccine development

Scientific Reports (2018)

Ernest Diez Benavente Damilola R. Oresegun Paola Flórez de Sessions Eloise M. Walker Cally Roper

Malaria infection during pregnancy, caused by the sequestering of Plasmodium falciparum parasites in the placenta, leads to high infant mortality and maternal morbidity. The parasite-placenta adherence mechanism is mediated by the VAR2CSA protein, a target for natural occurring immunity. Currently, vaccine development is based on its ID1-DBL2Xb domain however little is known about the global genetic diversity of the encoding var2csa gene, which could influence vaccine efficacy. In a comprehensive analysis of the var2csa gene in >2,000 P. falciparum field isolates across 23 countries, we found that var2csa is duplicated in high prevalence (>25%), African and Oceanian populations harbour a much higher diversity than other regions, and that insertions/deletions are abundant leading to an underestimation of the diversity of the locus. Further, ID1-DBL2Xb haplotypes associated with adverse birth outcomes are present globally, and African-specific haplotypes exist, which should be incorporated into vaccine design.

10.1038/s41598-018-33767-3

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Structure mapping of dengue and Zika viruses reveals functional long-range interactions

Nature Communications (2019)

Roland G. Huber Xin Ni Lim Wy Ching Ng Adelene Y. L. Sim Hui Xian Poh

Abstract Dengue (DENV) and Zika (ZIKV) viruses are clinically important members of the Flaviviridae family with an 11 kb positive strand RNA genome that folds to enable virus function. Here, we perform structure and interaction mapping on four DENV and ZIKV strains inside virions and in infected cells. Comparative analysis of SHAPE reactivities across serotypes nominates potentially functional regions that are highly structured, conserved, and contain low synonymous mutation rates. Interaction mapping by SPLASH identifies many pair-wise interactions, 40% of which form alternative structures, suggesting extensive structural heterogeneity. Analysis of shared interactions between serotypes reveals a conserved macro-organization whereby interactions can be preserved at physical locations beyond sequence identities. We further observe that longer-range interactions are preferentially disrupted inside cells, and show the importance of new interactions in virus fitness. These findings deepen our understanding of Flavivirus genome organization and serve as a resource for designing therapeutics in targeting RNA viruses.

Zika Virus

Flavivirus

10.1038/s41467-019-09391-8

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Citations (130)

ISID0888 - FLG allelic and mutation phasing with nanopore sequencing to study phenotypic variability in ichthyosis vulgaris

Colin Wong John Common Paola Flórez de Sessions Cheng Yong Tham Lin Yang

Ichthyosis vulgaris

10.26226/m.641999f95cbd02001a87db69

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Comparative genomics of Leishmania donovani progeny from genetic crosses in two sand fly species and impact on the diversity of diagnostic and vaccine candidates

PLoS neglected tropical diseases (2024)

Jovana Sádlová Matthew Yeo David Mateus Jody Phelan Le Hai

Sand fly transmitted Leishmania species are responsible for severe, wide ranging, visceral and cutaneous leishmaniases. Genetic exchange can occur among natural Leishmania populations and hybrids can now be produced experimentally, with limitations. Feeding Phlebotomus orientalis or Phlebotomus argentipes on two strains of Leishmania donovani yielded hybrid progeny, selected using double drug resistance and fluorescence markers. Fluorescence activated cell sorting of cultured clones derived from these hybrids indicated diploid progeny. Multilocus sequence typing of the clones showed hybridisation and nuclear heterozygosity, although with inheritance of single haplotypes in a kinetoplastid target. Comparative genomics showed diversity of clonal progeny between single chromosomes, and extraordinary heterozygosity across all 36 chromosomes. Diversity between progeny was seen for the HASPB antigen, which has been noted previously as having implications for design of a therapeutic vaccine. Genomic diversity seen among Leishmania strains and hybrid progeny is of great importance in understanding the epidemiology and control of leishmaniasis. As an outcome of this study we strongly recommend that wider biological archives of different Leishmania species from endemic regions should be established and made available for comparative genomics. However, in parallel, performance of genetic crosses and genomic comparisons should give fundamental insight into the specificity, diversity and limitations of candidate diagnostics, vaccines and drugs, for targeted control of leishmaniasis.

10.1371/journal.pntd.0011920

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An integrated whole genome analysis of Mycobacterium tuberculosis reveals insights into relationship between its genome, transcriptome and methylome

Scientific Reports (2019)

Paula Josefina Gómez Núria Andreu Jody Phelan Paola Flórez de Sessions Judith R. Glynn

Abstract Human tuberculosis disease (TB), caused by Mycobacterium tuberculosis ( Mtb) , is a complex disease, with a spectrum of outcomes. Genomic, transcriptomic and methylation studies have revealed differences between Mtb lineages, likely to impact on transmission, virulence and drug resistance. However, so far no studies have integrated sequence-based genomic, transcriptomic and methylation characterisation across a common set of samples, which is critical to understand how DNA sequence and methylation affect RNA expression and, ultimately, Mtb pathogenesis. Here we perform such an integrated analysis across 22 M. tuberculosis clinical isolates, representing ancient (lineage 1) and modern (lineages 2 and 4) strains. The results confirm the presence of lineage-specific differential gene expression, linked to specific SNP-based expression quantitative trait loci: with 10 eQTLs involving SNPs in promoter regions or transcriptional start sites; and 12 involving potential functional impairment of transcriptional regulators. Methylation status was also found to have a role in transcription, with evidence of differential expression in 50 genes across lineage 4 samples. Lack of methylation was associated with three novel variants in mamA , likely to cause loss of function of this enzyme. Overall, our work shows the relationship of DNA sequence and methylation to RNA expression, and differences between ancient and modern lineages. Further studies are needed to verify the functional consequences of the identified mechanisms of gene expression regulation.

10.1038/s41598-019-41692-2

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Primary macrophages and J774 cells respond differently to infection with Mycobacterium tuberculosis

Scientific Reports (2017)

Núria Andreu Jody Phelan Paola Flórez de Sessions Jacqueline M. Cliff Taane G. Clark

Abstract Macrophages play an essential role in the early immune response to Mycobacterium tuberculosis and are the cell type preferentially infected in vivo . Primary macrophages and macrophage-like cell lines are commonly used as infection models, although the physiological relevance of cell lines, particularly for host-pathogen interaction studies, is debatable. Here we use high-throughput RNA-sequencing to analyse transcriptome dynamics of two macrophage models in response to M. tuberculosis infection. Specifically, we study the early response of bone marrow-derived mouse macrophages and cell line J774 to infection with live and γ-irradiated (killed) M. tuberculosis . We show that infection with live bacilli specifically alters the expression of host genes such as Rsad2, Ifit1/2/3 and Rig-I , whose potential roles in resistance to M. tuberculosis infection have not yet been investigated. In addition, the response of primary macrophages is faster and more intense than that of J774 cells in terms of number of differentially expressed genes and magnitude of induction/repression. Our results point to potentially novel processes leading to immune containment early during M. tuberculosis infection, and support the idea that important differences exist between primary macrophages and cell lines, which should be taken into account when choosing a macrophage model to study host-pathogen interactions.

Primary (astronomy)

10.1038/srep42225

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Citations (99)

Correction: Deciphering the Growth Behaviour of Mycobacterium africanum

PLoS neglected tropical diseases (2013)

Florian Gehre Jacob Otu Kathryn DeRiemer Paola Flórez de Sessions Martin L. Hibberd

Background: Human tuberculosis (TB) in West Africa is not only caused by M. tuberculosis but also by bacteria of the two lineages of M. africanum.For instance, in The Gambia, 40% of TB is due to infections with M. africanum West African 2. This bacterial lineage is associated with HIV infection, reduced ESAT-6 immunogenicity and slower progression to active disease.Although these characteristics suggest an attenuated phenotype of M. africanum, no underlying mechanism has been described.From the first descriptions of M. africanum in the literature in 1969, the time to a positive culture of M. africanum on solid medium was known to be longer than the time to a positive culture of M. tuberculosis.However, the delayed growth of M. africanum, which may correlate with the less virulent phenotype in the human host, has not previously been studied in detail.Methodology/Principal Findings: We compared the growth rates of M. tuberculosis and M. africanum isolates from The Gambia in two liquid culture systems.M. africanum grows significantly slower than M. tuberculosis, not only when grown directly from sputa, but also in growth experiments under defined laboratory conditions.We also sequenced four M. africanum isolates and compared their whole genomes with the published M. tuberculosis H37Rv genome.M. africanum strains have several non-synonymous SNPs or frameshift mutations in genes that were previously associated with growthattenuation.M. africanum strains also have a higher mutation frequency in genes crucial for transport of sulphur, ions and lipids/fatty acids across the cell membrane into the bacterial cell.Surprisingly, 5 of 7 operons, recently described as essential for intracellular survival of H37Rv in the host macrophage, showed at least one non-synonymously mutated gene in M. africanum.Conclusions/Significance: The altered growth behaviour of M. africanum might indicate a different survival strategy within host cells.

Correct name

10.1371/annotation/fb002e1b-e345-4832-a793-d2f4988de308

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Citations (7)

Clinical application of targeted long read sequencing in prenatal beta‐thalassemia testing and genetic counseling

Molecular Genetics & Genomic Medicine (2023)

Hui‐Lin Chin Miles C. Benton Lin Yang Kok‐Siong Poon Karen Tan

Abstract Background Beta thalassemia, related to HBB mutation and associated with elevated hemoglobin A2 (HbA2), is an important genetic hemoglobinopathy with high incidences of disease and carrier rates in Singapore. Carrier screening is essential to facilitate prenatal counseling and testing. However, when individuals with elevated HbA2 do not have an identifiable HBB disease‐associated variant, there is ambiguity on risk to their offspring. Methods We describe a case report of a proband with elevated HbA2, no identifiable HBB disease‐associated variant, whose partner was a beta thalassemia carrier. Through clinical HBB gene sequencing, multiplex ligation‐dependent probe amplification (MLPA) analysis, as well as targeted Nanopore long read sequencing of selected genes, we performed a complete analysis of HBB including the promoter region, 5′UTR and coding gene sequence, as well as evaluation for potential modifier variants and other rare structural variants. Results This process identified that the proband was heterozygous for KLF1 :c.544T>C (p.Phe182Leu), a potential functional polymorphism previously known to be associated with benign elevated HbA2 levels. The presence of disease variants in the HBB locus was excluded. Conclusion This finding provided clarity and enabled family planning for the proband and her family.

Proband

Hemoglobin A2

Sanger sequencing

Carrier testing

Beta thalassemia

Alpha-thalassemia

10.1002/mgg3.2285

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Citations (1)