The prevalence and distribution of the amyloidogenic transthyretin (TTR) V122I allele in Africa

Transthyretin (TTR) pV142I (rs76992529-A) is one of the 113 variants in the human TTR gene associated with systemic amyloidosis. It results from a G to A transition at a CG dinucleotide in the codon for amino acid 122 of the mature protein (TTR V122I). The allele frequency is 0.0173 in African Americans

Polymorphisms in genes of interleukin 12 and its receptors and their association with protection against severe malarial anaemia in children in western Kenya

Abstract Background: Malarial anaemia is characterized by destruction of malaria infected red blood cells and suppression of erythropoiesis. Interleukin 12 (IL12) significantly boosts erythropoietic responses in murine models of malarial anaemia and decreased IL12 levels are associated with severe malarial anaemia (SMA) in children. Based on the biological relevance of IL12 in malaria anaemia, the relationship between genetic polymorphisms of IL12 and its receptors and SMA was examined. Methods: Fifty-five tagging single nucleotide polymorphisms covering genes encoding two IL12 subunits, IL12A and IL12B, and its receptors, IL12RB1 and IL12RB2, were examined in a cohort of 913 children residing in Asembo Bay region of western Kenya. Results: An increasing copy number of minor variant (C) in IL12A (rs2243140) was significantly associated with a decreased risk of SMA (P = 0.006; risk ratio, 0.52 for carrying one copy of allele C and 0.28 for two copies). Individuals possessing two copies of a rare variant (C) in IL12RB1 (rs429774) also appeared to be strongly protective against SMA (P = 0.00005; risk ratio, 0.18). In addition, children homozygous for another rare allele (T) in IL12A (rs22431348) were associated with reduced risk of severe anaemia (SA) (P = 0.004; risk ratio, 0.69) and of severe anaemia with any parasitaemia (SAP) (P = 0.004; risk ratio, 0.66). In contrast, AG genotype for another variant in IL12RB1 (rs383483) was associated with susceptibility to high-density parasitaemia (HDP) (P = 0.003; risk ratio, 1.21). Conclusions: This study has shown strong associations between polymorphisms in the genes of IL12A and IL12RB1 and protection from SMA in Kenyan children, suggesting that human genetic variants of IL12 related genes may significantly contribute to the development of anaemia in malaria patients

The episode of genetic drift defining the migration of humans out of Africa is derived from a large east African population size.

Human genetic variation particularly in Africa is still poorly understood. This is despite a consensus on the large African effective population size compared to populations from other continents. Based on sequencing of the mitochondrial Cytochrome C Oxidase subunit II (MT-CO2), and genome wide microsatellite data we observe evidence suggesting the effective size (Ne) of humans to be larger than the current estimates, with a foci of increased genetic diversity in east Africa, and a population size of east Africans being at least 2-6 fold larger than other populations. Both phylogenetic and network analysis indicate that east Africans possess more ancestral lineages in comparison to various continental populations placing them at the root of the human evolutionary tree. Our results also affirm east Africa as the likely spot from which migration towards Asia has taken place. The study reflects the spectacular level of sequence variation within east Africans in comparison to the global sample, and appeals for further studies that may contribute towards filling the existing gaps in the database. The implication of these data to current genomic research, as well as the need to carry out defined studies of human genetic variation that includes more African populations; particularly east Africans is paramount

Line Plot. Line plot of the effective size (lower), expected census size (middle line) and actual census size (upper) of the continental populations and some east African populations.

<p>Each point represents the log of actual values of the census, expected census and effective size of these populations. The expected census is obtained by calculating the current <i>Ne</i> by 10.</p

Current effective population sizes for all continental populations and selected African groups were calculated from the theta value generated by LAMARC version 2.1.8 by employing a Bayesian approach.

<p>Archaic theta was calculated using the formula: theta (at time t) = theta (now)EXP(−gt).</p><p><i>Ne</i> is calculated at different generations (in bracket) in the past using mutation rate of 9.2×10⁻⁷ substitutions/site/generation.</p><p>The archaic <i>Ne</i> at different time (in generations) interval in the past was calculated subsequently after the archaic theta was calculated from the current theta using a formula: theta (t) = theta (now)*EXP (growth rate*t*mutation rate).</p

Median joining (MJ) Network tree.

<p>MJ tree based on MT-CO2 gene sequences of world populations. Black points indicate, root; Blue, East Africans; Red, Africans; Orange, Australians; Green, Asians; Pink, Americans; Purple, Europeans. Branch lengths are not representative of evolutionary distance. The background colors outline possible demographic events in east Africa, and early episodes of evolution possibly towards the Rift Valley.</p

Values of <i>Ne</i> calculated using a maximum likelihood estimate (MLE) of theta value generated by LAMARC version 2.1.8 for all continental populations and selected African groups.

a<p>Mutation rate calculated from observed variations in MT-CO2 this work, ^bJazin <i>et al</i>., 1998 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0097674#pone.0097674-Jazin1" target="_blank">[17]</a>, ^cMishmar <i>et al</i>., 2003 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0097674#pone.0097674-Mishmar1" target="_blank">[14]</a>, ^dZhivotosksy <i>et al</i>., 2000 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0097674#pone.0097674-Zhivotovsky2" target="_blank">[56]</a>, ^eErikson and Monica 2011 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0097674#pone.0097674-Eriksson1" target="_blank">[19]</a>, ^ffor comparison.</p><p>Theta values are based on analysis of mtDNA sequences and microsatellite alleles.</p

Bayesian Skyline Plot (BSP). BSP based on 543 base pairs of mitochondrial DNA MT-CO2 region.

<p>The graph was constructed merging all populations as global population. The plot displays changes in world female effective population size (<i>Nef</i>) through time, a 25 year generation time, and a 9.2×10⁻⁷ sub/site/generation mutation rate. Present day is on the left on the x-axis. An increase in world female population observed at around 50, 000YBP and around 10, 000–20,000YBP (the periods are highlighted).</p

Number of sequences sampled, population parameters and selective neutrality test (Tajima's D) based on MT-CO2 variation of all continental groups, mean values and test of significance for the obtained values.

<p>Number of sequences sampled, population parameters and selective neutrality test (Tajima's D) based on MT-CO2 variation of all continental groups, mean values and test of significance for the obtained values.</p

The association of DNA sequence variation at the MAOA genetic locus with quantitative behavioural traits in normal males

Monoamine oxidase A (MAOA) catalyses the oxidative deamination of biogenic amines including neurotransmitters, mainly norepinephrine and serotonin in the brain and peripheral tissues. A nonsense mutation in the gene was shown to be involved in a rare X-linked behavioural syndrome, which includes impaired impulse control, aggression and borderline mental retardation (Brunner syndrome). Several recent studies have shown the association of genetic variation of a VNTR in the gene promoter with various pathological behavioural traits. In the present study the association of MAOA genetic variation with a large set of quantitative behavioural traits in normal individuals has been examined. DNA samples from 421 unrelated males were genotyped for 14 SNPs and for the promoter VNTR at the MAOA locus. An additional 16 SNPs were genotyped at apparently neutral loci across the X chromosome to serve as a genomic control for possible false positive associations due to population structure. Behavioural traits were measured using the NEO psychometric questionnaire, which is based on a 5-axis model of personality, and consists of 30 different quantitative traits. There was a robust association of the A2 ("straightforwardness") facet with common allelic variants at the promoter VNTR. Most of the tested traits were not associated with the VNTR despite reasonable power, thus demonstrating that the VNTR influence on quantitative behavioural traits in normal males may be very specific. In contrast, several traits of the C ("conscientiousness") axis were associated with less common SNP-defined haplotypes. Hence, it appears that common genetic variation at the VNTR contributes to the behavioural attribute of "straightforwardness", while rare haplotypes defined by SNPs downstream of the transcription start site may contribute to "conscientiousness". This study is used to address the validation, interpretation and limitation of genetic association studies of quantitative behavioural traits