Marlo Möller

Activating KIRs alter susceptibility to pulmonary tuberculosis in a South African population

We investigate the role of killer immunoglobulin-like receptor (KIR) genes and human leukocyte antigen class-I (HLA) variants in susceptibility to tuberculosis in a South African population. In a sample set comprising 408xa0TB cases and 351 healthy controls, we show that the KIR3DS1 gene and KIR genotypes with five or more activating KIRs, and the presence of 3DS1, protect against developing active TB in the South African Coloured population. Several HLA class-I alleles were identified as susceptibility factors for TB disease. However, none of the KIR-HLA compound genotypes were found to be associated with TB. Our data suggests that the KIR genes may play an important role in TB disease.

The complete genome sequence of the African buffalo (Syncerus caffer)

BackgroundThe African buffalo (Syncerus caffer) is an important role player in the savannah ecosystem. It has become a species of relevance because of its role as a wildlife maintenance host for an array of infectious and zoonotic diseases some of which include corridor disease, foot-and-mouth disease and bovine tuberculosis. To date, no complete genome sequence for S. caffer had been available for study and the genomes of other species such as the domestic cow (Bos taurus) had been used as a proxy for any genetics analysis conducted on this species. Here, the high coverage genome sequence of the African buffalo (S. caffer) is presented.ResultsA total of 19,765 genes were predicted and 19,296 genes could be successfully annotated to S. caffer while 469 genes remained unannotated. Moreover, in order to extend a detailed annotation of S. caffer, gene clusters were constructed using twelve additional mammalian genomes. The S. caffer genome contains 10,988 gene clusters, of which 62 are shared exclusively between B. taurus and S. caffer.ConclusionsThis study provides a unique genomic perspective for the S. caffer, allowing for the identification of novel variants that may play a role in the natural history and physiological adaptations.

The role of human host genetics in tuberculosis resistance

ABSTRACT Introduction: Tuberculosis (TB) remains a public health problem: the latest estimate of new incident cases per year is a staggering 10.4 million. Despite this overwhelming number, the majority of the immunocompetent population can control infection with Mycobacterium tuberculosis. The human genome underlies the immune response and contributes to the outcome of TB infection. Areas covered: Investigations of TB resistance in the general population have closely mirrored those of other infectious diseases and initially involved epidemiological observations. Linkage and association studies, including studies of VDR, SLC11A1 and HLA-DRB1 followed. Genome-wide association studies of common variants, not necessarily sufficient for disease, became possible after technological advancements. Other approaches involved the identification of those individuals with rare disease-causing mutations that strongly predispose to TB, epistasis and the role of ethnicity in disease. Despite these efforts, infection outcome, on an individual basis, cannot yet be predicted. Expert commentary: The early identification of future disease progressors is necessary to stem the TB epidemic. Human genetics may contribute to this endeavour and could in future suggest pathways to target for disease prevention. This will however require concerted efforts to establish large, well-phenotyped cohorts from different ethnicities, improved genomic resources and a better understanding of the human genome architecture.

Exome sequencing identifies a novel TTC37 mutation in the first reported case of Trichohepatoenteric syndrome (THE-S) in South Africa

BackgroundTrichohepatoenteric syndrome (THE-S) or phenotypic diarrhoea of infancy is a rare autosomal recessive disorder characterised by severe infantile diarrhoea, facial dysmorphism, immunodeficiency and woolly hair. It was first described in 1982 in two infants with intractable diarrhoea, liver cirrhosis and abnormal hair structure on microscopy. We report on two siblings from a consanguineous family of Somali descent who, despite extensive clinical investigation, remained undiagnosed until their demise. The index patient died of fulminant cytomegalovirus pneumonitis at 3xa0months of age.MethodsWhole exome sequencing (WES) was performed on a premortem DNA sample from the index case. Variants in a homozygous recessive state or compound heterozygous state were prioritized as potential candidate variants using TAPER™. Sanger sequencing was done to genotype the parents, unaffected sibling and a deceased sibling for the variant of interest.ResultsExome sequencing identified a novel homozygous mutation (c.4507Cu2009>u2009T, rs200067423) in TTC37 which was confirmed by Sanger sequencing in the index case. The identification of this mutation led to the diagnosis of THE-S in the proband and the same homozygous variant was confirmed in a male sibling who died 4xa0years earlier with severe chronic diarrhoea of infancy. The unaffected parents and sister were heterozygous for the identified variant.ConclusionsWES permitted definitive genetic diagnosis despite an atypical presentation in the index case and suggests that severe infection, likely secondary to immunodeficiency, may be a presenting feature. In addition definitive molecular diagnosis allows for genetic counseling and future prenatal diagnosis, and demonstrates the value of WES for post-mortem diagnosis of disorders with a non-specific clinical presentation in which a Mendelian cause is suspected.

A new tool for prioritization of sequence variants from whole exome sequencing data.

BackgroundWhole exome sequencing (WES) has provided a means for researchers to gain access to a highly enriched subset of the human genome in which to search for variants that are likely to be pathogenic and possibly provide important insights into disease mechanisms. In developing countries, bioinformatics capacity and expertise is severely limited and wet bench scientists are required to take on the challenging task of understanding and implementing the barrage of bioinformatics tools that are available to them.ResultsWe designed a novel method for the filtration of WES data called TAPER™ (Tool for Automated selection and Prioritization for Efficient Retrieval of sequence variants).ConclusionsTAPER™ implements a set of logical steps by which to prioritize candidate variants that could be associated with disease and this is aimed for implementation in biomedical laboratories with limited bioinformatics capacity. TAPER™ is free, can be setup on a Windows operating system (from Windows 7 and above) and does not require any programming knowledge. In summary, we have developed a freely available tool that simplifies variant prioritization from WES data in order to facilitate discovery of disease-causing genes.