Browsing by Author "Möller, Marlo"

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    Determining ancestry proportions in complex admixture scenarios in South Africa using a novel proxy ancestry selection method
    (PLoS, 2013-09) Chimusa, Emile R.; Daya, Michelle; Möller, Marlo; Ramesar, Raj; Henn, Brenna M.; Van Helden, Paul D.; Mulder, Nicola J.; Hoal, Eileen G.
    Admixed populations can make an important contribution to the discovery of disease susceptibility genes if the parental populations exhibit substantial variation in susceptibility. Admixture mapping has been used successfully, but is not designed to cope with populations that have more than two or three ancestral populations. The inference of admixture proportions and local ancestry and the imputation of missing genotypes in admixed populations are crucial in both understanding variation in disease and identifying novel disease loci. These inferences make use of reference populations, and accuracy depends on the choice of ancestral populations. Using an insufficient or inaccurate ancestral panel can result in erroneously inferred ancestry and affect the detection power of GWAS and meta-analysis when using imputation. Current algorithms are inadequate for multi-way admixed populations. To address these challenges we developed PROXYANC, an approach to select the best proxy ancestral populations. From the simulation of a multi-way admixed population we demonstrate the capability and accuracy of PROXYANC and illustrate the importance of the choice of ancestry in both estimating admixture proportions and imputing missing genotypes. We applied this approach to a complex, uniquely admixed South African population. Using genome-wide SNP data from over 764 individuals, we accurately estimate the genetic contributions from the best ancestral populations: isiXhosa (33%±0:226), {Khomani SAN (31%±0:195), European (16%±0:118), Indian (13%±0:094), and Chinese (7%±0:0488). We also demonstrate that the ancestral allele frequency differences correlate with increased linkage disequilibrium in the South African population, which originates from admixture events rather than population bottlenecks.
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    Identification of a novel WAS mutation in a South African patient presenting with atypical Wiskott-Aldrich syndrome : a case report
    (BioMed Central, 2020-06-05) Glanzmann, Brigitte; Möller, Marlo; Schoeman, Mardelle; Urban, Michael; Van Helden, Paul D.; Frigati, Lisa; Grewal, Ravnit; Pieters, Hermanus; Loos, Ben; Hoal, Eileen G.; Glashoff, Richard H.; Cornelissen, Helena; Rabie, Helena; Esser, Monika M.; Kinnear, Craig J.
    Background: The X-linked recessive primary immunodeficiency disease (PIDD) Wiskott-Aldrich syndrome (WAS) is identified by an extreme susceptibility to infections, eczema and thrombocytopenia with microplatelets. The syndrome, the result of mutations in the WAS gene which encodes the Wiskott-Aldrich protein (WASp), has wide clinical phenotype variation, ranging from classical WAS to X-linked thrombocytopaenia and X-linked neutropaenia. In many cases, the diagnosis of WAS in first affected males is delayed, because patients may not present with the classic signs and symptoms, which may intersect with other thrombocytopenia causes. Case presentation: Here, we describe a three-year-old HIV negative boy presenting with recurrent infections, skin rashes, features of autoimmunity and atopy. However, platelets were initially reported as normal in numbers and morphology as were baseline immune investigations. An older male sibling had died in infancy from suspected immunodeficiency. Uncertainty of diagnosis and suspected severe PIDD prompted urgent further molecular investigation. Whole exome sequencing identified c. 397 G > A as a novel hemizygous missense mutation located in exon 4 of WAS. Conclusion: With definitive molecular diagnosis, we could target treatment and offer genetic counselling and prenatal diagnostic testing to the family. The identification of novel variants is important to confirm phenotype variations of a syndrome.
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    A panel of ancestry informative markers for the complex five-way admixed South African Coloured population
    (PLoS, 2013-12) Daya, Michelle; Van der Merwe, Lize; Ushma Galal; Möller, Marlo; Salie, Muneeb; Chimusa, Emile R.; Galanter, Joshua M.; Van Helden, Paul D.; Henn, Brenna M.; Gignoux, Chris R.; Hoal, Eileen
    Admixture is a well known confounder in genetic association studies. If genome-wide data is not available, as would be the case for candidate gene studies, ancestry informative markers (AIMs) are required in order to adjust for admixture. The predominant population group in the Western Cape, South Africa, is the admixed group known as the South African Coloured (SAC). A small set of AIMs that is optimized to distinguish between the five source populations of this population (African San, African non-San, European, South Asian, and East Asian) will enable researchers to cost-effectively reduce falsepositive findings resulting from ignoring admixture in genetic association studies of the population. Using genome-wide data to find SNPs with large allele frequency differences between the source populations of the SAC, as quantified by Rosenberg et. al’s In-statistic, we developed a panel of AIMs by experimenting with various selection strategies. Subsets of different sizes were evaluated by measuring the correlation between ancestry proportions estimated by each AIM subset with ancestry proportions estimated using genome-wide data. We show that a panel of 96 AIMs can be used to assess ancestry proportions and to adjust for the confounding effect of the complex five-way admixture that occurred in the South African Coloured population.