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Background: Genetic susceptibility to type 2 diabetes (T2D) is multifactorial. A growing number of genes have been identified as risk factors for T2D across multiple ethnicities in trans-ancestry meta-analysis of large-scale genome-wide association studies. Few studies have looked at these genes in Sub-Saharan African populations. This study was undertaken to look for associations between T2D and single nucleotide polymorphisms (SNPs) in a number of the top candidate genes in a selected Sudanese population. Methods: A total 240 T2D cases and 128 unrelated healthy control subjects were included in this study. Age, sex, weight and height were recorded, blood pressure and biochemical profiles of glucose and lipids were analysed. Single nucleotide polymorphism (SNP) genotyping was performed using the Sequenom MassARRAY® system. Fourteen SNPs were selected across 7 genes: CAPN10 (rs2975760 and rs5030952), PPARG (rs17036314 and rs1801282), IGF2BP2 (rs4402960 and rs1470579), CDKAL1 (rs9465871), HHEX (rs1111875), TCF7L2 (rs7903146, rs11196205 and rs12255372), and KCNJ11 (rs5215, rs1800467 and rs5219). Allelic and haplotype association analyses were performed under additive models in PLINK. P ≤ 0.007 (=0.05/7 genes) was the P-value required to achieve correction for multiple testing. Results: A significant genetic association between the SNPs rs7903146 (odds ratio 1.69, 95 % confidence interval 1.21-2.38, P = 0.002) and rs12255372 (odds ratio 1.70, 95 % confidence interval 1.20-2.41, P = 0.003) at TCF7L2 and T2D was found in Sudanese population. These associations were retained after adjusting for age, sex and BMI (e.g. rs7903146: odds ratio 1.70, Padj:age/sex/BMI = 0.005). The strongest haplotype association (odds ratio 2.24; Padj:age/sex/BMI = 0.0003) comprised the two point haplotype T_C across rs7903146 and rs11196205. Stepwise logistic regression demonstrated that SNP rs7903146 added significant main effects to rs11196205 or rs12255372, whereas the reverse was not true, indicating that the main effect for association with T2D in this population is most strongly tagged by SNP rs7903146. Adjusted analyses also provided support for protection from T2D associated with minor alleles at SNPs rs2975760 at CAPN10 (odds ratio 0.44, 95 % confidence interval 0.20-0.97, Padj:age/sex/BMI = 0.042) and rs1111876 at HHEX (odds ratio 0.60, 95 % confidence interval 0.39-0.93, Padj:age/sex/BMI = 0.022). Conclusions: Multiethnic associations between T2D and SNPs at TCF7L2, CAPN10 and HHEX extend to Sub-Saharan Africa, specifically Sudan. [ABSTRACT FROM AUTHOR]

Background The Erythrocyte Binding Antigen (EBA) 175 has been considered as one of the most important Plasmodium falciparum (P. falciparum) merozoite ligands that mediate invasion of the erythrocytes through their sialated receptor: Glycophorin A (GPA). The effect of the EBA 175 dimorphic alleles (F and C) on the severity of the disease is not yet fully understood. Therefore this study was designed to assess the distribution of the divergent dimorphic alleles of P. falciparum EBA-175 (F and C) in three different geographical areas in Sudan and the possible association of this dimorphism with the severity of the disease. Methods A sum of 339 field isolates of P. falciparum obtained from patients in three different geographical areas in Sudan were screened for the dimorphic alleles (F, C) of the EBA-175 using nested PCR. Results The percentage of F, C, and mixed F/C alleles were; 41%, 51%, and 8% respectively. F and C alleles showed significantly different distributions in the various geographic areas (p = 0.00). There was no significant association between malaria clinical manifestation and P. falciparum EBA-175 F and C alleles frequencies Conclusions This study showed a significant differential distribution of F and C alleles in different geographical malaria endemic areas. No significant association was observed between F and C alleles and different malaria phenotypes. [ABSTRACT FROM AUTHOR]

Intratumoral evolution produces extensive genetic heterogeneity in clinical cancers. This is generally attributed to an increased mutation rate that continually produces new genetically defined clonal lineages. Equally important are the interactions between the heritable traits of cancer cells and their microenvironment that produces natural selection favoring some clonal 'species' over others. That is, while mutations produce the heritable variation, environmental selection and cellular adaptation govern the strategies (and genotypes) that can proliferate within the tumor ecosystem. Here we ask: What are the dominant evolutionary forces in the cancer ecosystem? We propose that the tumor vascular network is a common and primary cause of intratumoral heterogeneity. Specifically, variations in blood flow result in variability in substrate, such as oxygen, and metabolites, such as acid, that serve as critical, but predictable, environmental selection forces. We examine the evolutionary and ecological consequences of variable blood flow by drawing an analogy to riparian habitats within desert landscapes. We propose that the phenotypic properties of cancer cells will exhibit predictable spatial variation within tumor phenotypes as a result of proximity to blood flow. Just as rivers in the desert create an abrupt shift from the lush, mesic riparian vegetation along the banks to sparser, xeric and dry-adapted plant species in the adjacent drylands, we expect blood vessels within tumors to promote similarly distinct communities of cancer cells that change abruptly with distance from the blood vessel. We propose vascular density and blood flow within a tumor as a primary evolutionary force governing variations in the phenotypic properties of cancer cells thus providing a unifying ecological framework for understanding intratumoral heterogeneity. [ABSTRACT FROM AUTHOR]

Haplogroup J1 is a prevalent Y-chromosome lineage within the Near East. We report the frequency and YSTR diversity data for its major sub-clade (J1e). The overall expansion time estimated from 453 chromosomes is 10 000 years. Moreover, the previously described J1 (DYS388=13) chromosomes, frequently found in the Caucasus and eastern Anatolian populations, were ancestral to J1e and displayed an expansion time of 9000 years. For J1e, the Zagros/Taurus mountain region displays the highest haplotype diversity, although the J1e frequency increases toward the peripheral Arabian Peninsula. The southerly pattern of decreasing expansion time estimates is consistent with the serial drift and founder effect processes. The first such migration is predicted to have occurred at the onset of the Neolithic, and accordingly J1e parallels the establishment of rain-fed agriculture and semi-nomadic herders throughout the Fertile Crescent. Subsequently, J1e lineages might have been involved in episodes of the expansion of pastoralists into arid habitats coinciding with the spread of Arabic and other Semitic-speaking populations. [ABSTRACT FROM AUTHOR]

Background: Infantile neuroaxonal dystrophy (INAD) is a rare hereditary neurological disorder caused by mutations in PLA2G6. The disease commonly affects children below 3 years of age and presents with delay in motor skills, optic atrophy and progressive spastic tetraparesis. Studies of INAD in Africa are extremely rare, and genetic studies from Sub Saharan Africa are almost non-existent. Case presentation: Two Sudanese siblings presented, at ages 18 and 24 months, with regression in both motor milestones and speech development and hyper-reflexia. Brain MRI showed bilateral and symmetrical T2/FLAIR hyperintense signal changes in periventricular areas and basal ganglia and mild cerebellar atrophy. Whole exome sequencing with confirmatory Sanger sequencing were performed for the two patients and healthy family members. A novel variant (NM_003560.2 c.1427 + 2 T > C) acting on a splice donor site and predicted to lead to skipping of exon 10 was found in PLA2G6. It was found in a homozygous state in the two patients and homozygous reference or heterozygous in five healthy family members. Conclusion: This variant has one very strong (loss of function mutation) and three supporting evidences for its pathogenicity (segregation with the disease, multiple computational evidence and specific patients' phenotype). Therefore this variant can be currently annotated as "pathogenic". This is the first study to report mutations in PLA2G6 gene in patients from Sudan. [ABSTRACT FROM AUTHOR]

Visceral leishmaniasis appears in the form of notoriously devastating epidemics and as an endemic disease of sporadic nature. In an attempt to understand the nature of this difference and its underlying causes, and to identify possible mechanisms for the instigation of outbreaks, the current status of the characterization of the parasite, its taxonomy, host immunity and genetics, are reviewed with the main focus on eastern Africa, one of the places where the dichotomous epidemiology of the disease is most pronounced. The new molecular tools offer various insights into the understanding of the complex epidemiology of visceral leishmaniasis and the interplay between parasite and host factors. Further insights are also provided on the parts played by demography, genetic history and geography in shaping the overall global portrait of the disease. [Copyright &y& Elsevier]

Mucosal leishmaniasis, which is a sporadic disease in the Sudan, was shown by isoenzyme characterization and PCR to be caused by Leishmania donovani. However, it was not clear if the parasite was exactly the same strain as that causing visceral leishmaniasis (VL), or of a different strain. We utilized a new generation of molecular DNA markers, minisatellites and kinetoplast DNA, for rapid characterization of the parasite. The results show that the genotypes of some of the parasites causing VL are different from those causing mucosal leishmaniasis. The L. donovani isolates causing visceral disease, as well as post-kala-azar mucosal leishmaniasis (PKML), have been shown to possess characteristic haplotypes. However, sequencing of a portion of the cytochrome oxidase II (COII) gene indicates that the parasite that invades the oral mucosa is divergent from other parasites causing VL. It appears to possess features of a more ancestral parasite with pronounced sequence homology to L. major. This agrees with earlier studies where isolates of mucosal leishmaniasis have been shown to possess an isoenzyme profile distinct from L. donovani and a different geographical distribution, albeit often overlapping with that of L. donovani. [Copyright &y& Elsevier]

Epidemiological studies indicate that infections by certain types of human papillomaviruses (HPVs) are causally linked to the development of cervical cancer. It is also known that HPV infections alone do not cause progression to cervical cancer, as additional genetic changes such as loss of distinct chromosomal regions, inactivation of tumor-suppressor genes and activation of oncogenes must also occur in order for malignant transformation to take place. In the present study, 78 patients diagnosed with cervical cancer and 36 cervical cancer-free cases (control) were analyzed for high-risk HPV genotypes (16 and 18) by polymerase chain reaction (PCR). Loss of heterozygosity (LOH) of the retinoblastoma gene (Rb) at two polymorphic intronic sites (intron 1 and 17) and the p53 polymorphism in codon 72 were detected by RFLP and allele-specific PCR, respectively. HPV 16 and 18 were found at frequencies of 93.6 and 8.3% in the cervical cancer and control samples, respectively. LOH was detected in 63% of patients in intron 1 and/or intron 17. p53 allele frequency for Arg/Arg was 43.6% (34/78), for Arg/Pro 37.2% (29/78) and for Pro/Pro 19.2% (15/78). The relative risk (RR) of LOH and Arg/Arg alone was 1.7 and 1.1, respectively, while the combined RR for Rb LOH and p53 Arg/Arg was 2.5. The present study showed a significant association of the chromosomal allelic loss of Rb in Sudanese cervical cancer patients, while no such association was observed with other parameters, such as clinical stage and degree of differentiation; hence, it cannot be a determinant of tumor behavior in cervical carcinoma. Although the p53 arginine allele is itself an important risk factor for cervical cancer, the combined risk with LOH of Rb, which appears to be greater, might indicate a possible epistatic effect of the two genes/polymorphisms.

We are reporting here, the cloning and characterization of the first cyclin from Leishmania mexicana. We have identified a cyclin-like motif from the L. major genome sequencing project. A cyclin homologue was cloned and sequenced from L. mexicana genome and it showed 96.1% amino acid identity with the putative L. major cyclin. It has also sequence identity to mitotic cyclins from other organisms. Southern analysis showed that it is present as a single copy gene. CYCa has been over-expressed in E. coli as a histidine fusion and western blot has confirmed the immunoreactive property of the recombinant cyclin, which then used to reconstitute active recombinant L. mexicana CRK3. No phosphorylation of histone HI was detected by both wild type and mutated CRK3 on the activation assays suggesting that phosphorylation status and cyclin binding are important for reconstituting protein kinase activity. The results confirm that we have isolated a cyclin molecule from L. mexicana (LmCYCa) which may play an important role in the regulation of the parasite cell cycle.

Background: Probably the best example of the rise and maintenance of balancing selection as an evolutionary trend is the role of S-haemoglobin (HbS - rs334) in protecting from malaria. Yet, the dynamics of such a process remains poorly understood, particularly in relation to different malaria transmission rates and the genetic background of the affected populations., Methods: We investigated the association of haemoglobin HbS in protection from clinical episodes of malaria in two populations/villages where malaria is endemic, but mostly presenting in mild clinical forms. Five-hundred and forty-six individuals comprising 65 and 82 families from the Hausa and Massalit villages respectively were genotyped for HbS. Allele and genotype frequencies as well as departure from Hardy-Weinberg Equilibrium were estimated from four-hundred and seventy independent genotypes across different age groups. Age-group frequencies were used to calculate the coefficient-of-fitness and to simulate the expected frequencies in future generations., Results: Genotype frequencies were within Hardy-Weinberg expectations in Hausa and Massalit in the total sample set but not within the different age groups. There was a trend for a decrease of the HbS allele frequency in Hausa and an increase of frequency in Massalit. Although the HbS allele was able to confer significant protection from the clinical episodes of malaria in the two populations, as suggested by the odds ratios, the overall relative fitness of the HbS allele seems to have declined in Hausa., Conclusions: Such loss of balancing selection could be due to a combined effect of preponderance of non-clinical malaria in Hausa, and the deleterious effect of the homozygous HbS under circumstances of endogamy.