Frequency of EGFR Mutations in 907 Lung Adenocarcioma Patients of Indian Ethnicity

Background

During the past decade, the incidence of EGFR mutation has been shown to vary across different ethnicities. It occurs at the rate of 10–15% in North Americans and Europeans, 19% in African-Americans, 20–30% in various East Asian series including Chinese, Koreans, and Japanese. Frequency of EGFR mutations in India however remains sparsely explored.

Methodology/Principal Findings

We report 23% incidence of Epidermal growth factor receptor (EGFR) mutations in 907 Non small cell lung cancer (NSCLC) patients of Indian ethnicity, in contrast to 10–15% known in Caucasians and 27–62% among East Asians. In this study, EGFR mutations were found to be more common in never-smokers 29.4% as compared to smokers 15.3%. Consistent with other populations, mutation rates among adenocarcinoma-males were predominantly lower than females with 32% incidence. However unlike Caucasians, EGFR mutation rate among adenocarcinoma-never-smoker females were comparable to males suggesting lack of gender bias among never smokers likely to benefit from EGFR targeted therapy.

Conclusions/Significance

This study has an overall implication for establishing relevance for routine EGFR mutation diagnostics for NSCLC patients in clinics and emphasizes effectiveness for adoption of EGFR inhibitors as the first line treatment among Indian population. The intermediate frequency of EGFR mutation among Indian population compared to Caucasians and East Asians is reminiscent of an ancestral admixture of genetic influence from Middle Easterners, Central Asians, and Europeans on modern- Indian population that may confer differential susceptibility to somatic mutations in EGFR.     

Association of Codon 16 and Codon 27 β2‐Adrenergic Receptor Gene Polymorphisms with Obesity: A Meta‐analysis

Objective: To search for an association between the Glu27Gln (rs1042714; B27) and the Arg16Gly (rs1042713; B16) polymorphisms of the β2‐adrenergic receptor (ADRB2) gene and obesity. Methods: Meta‐analysis of published studies, included if subjects were genotyped at either codon 27 (“B27”) or codon 16 (“B16”) of the ADRB2 gene and both obese and nonobese subjects were selected, based on a reported cutoff BMI limit. Initial selection included 14,444 subjects genotyped at B27 (rs1042714) and 6,825 genotyped at B16 (rs1042713). After testing each control group for Hardy‐Weinberg equilibrium, the final selection included 10,404 subjects and 4,328 subjects, respectively. Studies were published before 18 August 2006. Results: The frequency of Glu27 allele carriers, either homozygous or heterozygous, ranged from 6.71% in Aymara American Indians to 78.29% in a Dutch population. The frequency of Arg16 allele carriers varied from 51.4 to 64.6% in Europeans and from 71.1 to 85.6% in East Asians. The summary odds ratio (OR) from overall analyses showed no association between either rs1042714 or rs1042713 and obesity. In race groups with low Glu27 allele frequency (Asians, Pacific Islanders, and American Indians), ORs revealed a significant obesity risk associated with rs1042714. These results were not found in East Asians for rs1042713. Discussion: The presence of the Glu27 allele in the ADRB2 gene appears to be a significant risk factor for obesity in Asians, Pacific Islanders, and American Indians, but not in Europeans. Obesity does not appear to be associated with the Arg16 allele.     

Genetic evidence in support of a shared Eurasian-North African dairying origin

The process by which pastoralism and agriculture spread from the Fertile Crescent over the past 10,000 years has been the subject of intense investigation by geneticists, linguists and archaeologists. However, no consensus has been reached as to whether this Neolithic transition is best characterized by a demic diffusion (with a significant genetic input from migrating farmers) or a cultural diffusion (without substantial migration of farmers). Milk consumption and thus lactose tolerance are assumed to have spread with pastoralism and we propose that by looking at the relevant mutations in and around the lactase gene in human populations, we can gain insight into the origin(s) and spread of dairying. We genotyped the putatively causal allele for lactose tolerance (–13910T) and constructed haplotypes from several polymorphisms in and around the lactase gene (LCT) in three North African Berber populations and compared our results with previously published data. We found that the frequency of the –13910T allele predicts the frequency of lactose tolerance in several Eurasian and North African Berber populations but not in most sub-Saharan African populations. Our analyses suggest that contemporary Berber populations possess the genetic signature of a past migration of pastoralists from the Middle East and that they share a dairying origin with Europeans and Asians, but not with sub-Saharan Africans.     

Heterogeneity of coronary heart disease risk factors in Indian,Pakistani, Bangladeshi,and European origin populations: cross sectional study

ObjectiveTo compare coronary risk factors and disease prevalence among Indians, Pakistanis, and Bangladeshis, and in all South Asians (these three groups together) with Europeans.DesignCross sectional survey.SettingNewcastle upon Tyne.Participants259 Indian, 305 Pakistani, 120 Bangladeshi, and 825 European men and women aged 25-74 years.ResultsThere were differences in social and economic circumstances, lifestyles, anthropometric measures and disease both between Indians, Pakistanis, and Bangladeshis and between all South Asians and Europeans. Bangladeshis and Pakistanis were the poorest groups. For most risk factors, the Bangladeshis (particularly men) fared the worst: smoking was most common (57%) in that group, and Bangladeshis had the highest concentrations of triglycerides (2.04 mmol/l) and fasting blood glucose (6.6 mmol/l) and the lowest concentration of high density lipoprotein cholesterol (0.97 mmol/l). Blood pressure, however, was lowest in Bangladeshis. Bangladeshis were the shortest (men 164 cm tall v 170 cm for Indians and 174 cm for Europeans). A higher proportion of Pakistani and Bangladeshi men had diabetes (22.4% and 26.6% respectively) than Indians (15.2%). Comparisons of all South Asians with Europeans hid some important differences, but South Asians were still disadvantaged in a wide range of risk factors. Findings in women were similar.ConclusionRisk of coronary heart disease is not uniform among South Asians, and there are important differences between Indians, Pakistanis, and Bangladeshis for many coronary risk factors. The belief that, except for insulin resistance, South Asians have lower levels of coronary risk factors than Europeans is incorrect, and may have arisen from combining ethnic subgroups and examining a narrow range of factors.

Key messages

• South Asians have more coronary heart disease than Europeans despite apparently lower levels of risk factors
• This study shows that Indians, Pakistanis and Bangladeshis differ in a wide range of coronary risk factors and combining their data is misleading
• Among South Asians, Indians were least and Bangladeshis most disadvantaged in a range of coronary risk factors. South Asians were disadvantaged in comparison with Europeans
• Future research and prevention strategies for coronary heart disease in South Asians should acknowledge a broad range of risk factors, the heterogeneity of these populations, linguistic and cultural needs, and environmental factors

     

Natural selection at genomic regions associated with obesity and type-2 diabetes: East Asians and sub-Saharan Africans exhibit high levels of differentiation at type-2 diabetes regions

Different populations suffer from different rates of obesity and type-2 diabetes (T2D). Little is known about the genetic or adaptive component, if any, that underlies these differences. Given the cultural, geographic, and dietary variation that accumulated among humans over the last 60,000 years, we examined whether loci identified by genome-wide association studies for these traits have been subject to recent selection pressures. Using genome-wide SNP data on 938 individuals in 53 populations from the Human Genome Diversity Panel, we compare population differentiation and haplotype patterns at these loci to the rest of the genome. Using an “expanding window” approach (100–1,600 kb) for the individual loci as well as the loci as ensembles, we find a high degree of differentiation for the ensemble of T2D loci. This differentiation is most pronounced for East Asians and sub-Saharan Africans, suggesting that these groups experienced natural selection at loci associated with T2D. Haplotype analysis suggests an excess of obesity loci with evidence of recent positive selection among South Asians and Europeans, compared to sub-Saharan Africans and Native Americans. We also identify individual loci that may have been subjected to natural selection, such as the T2D locus, HHEX, which displays both elevated differentiation and extended haplotype homozygosity in comparisons of East Asians with other groups. Our findings suggest that there is an evolutionary genetic basis for population differences in these traits, and we have identified potential group-specific genetic risk factors.     

Distribution of Two Asian-Related Coding SNPs in the MC1R and OCA2 Genes

Very little is known about the genes and mechanisms affecting skin lightening in Asian populations. In this study, two coding SNPs, c.G1129A (R163Q) at the MC1R (melanocortin 1 receptor) gene and c.A1962G (H615R) at the OCA2 (oculocutaneous albinism type II) gene, were investigated in a total of 1,809 individuals in 16 populations from various areas. The Q163 and R615 alleles prevailed almost exclusively in East and Southeast Asian populations. Wright’s F _ST was 0.445 for R163Q and 0.385 for H615R among the 16 populations. The frequency of the Q163 allele was higher in Northeast Asians than in Southeast Asians. The frequency of the R615 allele was highest in South China and unlikely to be associated with levels of ultraviolet radiation. This allele may be a good marker to study the genetic affinity among East Asians because of its restricted distribution and marked difference in allele frequency.     

The investigation of allele and genotype frequencies of <Emphasis Type="Italic">CYP3A5 (1*/3*)</Emphasis> and <Emphasis Type="Italic">P2Y12</Emphasis> (T744C) in Iran

Research on the frequency of the highly functional mutations of genes coding required for metabolizing enzymes has shown significant ethnic variations. However, few studies, if any, have examined the frequency distribution of major allelic variations in the context of Iran. In this regard, the present study focused on the genotype profile of Southern Iranians in order to compare allele frequencies of their CYP3A5 and P2Y12 (T744C) which have been shown to have roles in metabolizing clopidogrel, with those of other populations. Therefore, genotyping was carried out on 112 unrelated individuals by PCR–RFLP. The CYP3A5*3 allele was found in 185 persons with allelic frequency 0.82, which is the most common allele among Caucasians (90–95%). The frequency of 82% is different from other Caucasians (90–94%), Indians (67%), Vietnam (67%) and Africans (15%). but lower than frequency in Chinese populations (74%) and Korean (76%). The allele frequency of the −744T (4%) is different from frequencies of Caucasian, American, Chinese, Korean, and Subsahara population. This study confirmed significant inter-ethnic differences in CYP3A5 and P2Y12 frequencies between Iranians and other ethnic groups. The results of this study will be useful for clinical pharmacokinetic investigations and drug dosage recommendations especially antiplatelet drugs such as Clopidogrel, for Iranians.     

Stability or variation? Patterns of lactase gene and its enhancer region distributions in Brazilian Amerindians

Lactase persistence (LP) is the phenotypic trait in which lactase secretion is maintained during adulthood. LP is due to mutations in the LCT enhancer region, located 14‐kb upstream of the gene. In Europeans, the ?13910*T allele is associated with LP. In Africans this allele is rare while other mutations in this same region were related to LP. The LCT is highly polymorphic in human populations, but so far Brazilian Amerindians had not been investigated for these polymorphisms or for the presence of LP mutations. We describe the genetic diversity of the LCT region and the presence of LP enhancer mutations in four native Brazilian populations (Guarani‐Kaiowá, Guarani–Ñandeva, Kaingang, and Xavante). Twelve polymorphisms were genotyped by PCR‐based methods. The ?13910*T allele varied from 0.5% in the Xavante to 7.6% in the Guarani–Ñandeva. These frequencies probably derive from European sources and they correlate with non‐native admixture proportions previously estimated for these groups. But since admixture is virtually absent in the Xavante, we suggest that the presence of the LP allele could have been determined by a de novo mutation. No other mutations in the ?14 kb enhancer region were found. The LCT was highly polymorphic in the present sample showing 15 haplotypes with a heterogeneous distribution among the four Amerindian populations. This diversity could be due to drift, as indicated by the neutrality test performed. Am J Phys Anthropol, 2012. © 2012 Wiley Periodicals, Inc.     

Arylsulfatase A: Relationship of genotype to variant electrophoretic properties

Previous work has shown that specific electrophoretic variants of arylsulfatase A occur more frequently among alcoholic patients than among psychiatric and normal controls. The present study sequenced the gene for two of these electrophoretic variants, IIIa and IIIb. Both contain an A-to-G transition corresponding to substitution of Asn₃₅₀ by Ser, with the resulting loss of anN -glycosylation site. The difference in electrophoretic mobility of their gene products is due to a mutation in the IIIb gene resulting in the replacement of Arg₄₉₆ by His. Evidence is presented that individuals possessing either of two other electrophoretic variants, Va and Vb, are heterozygous for a normal ASA allele and either a IIIa or IIIb allele, respectively. Thus, the relationship between the phenotype of the electrophoretic banding patterns, IIIa, IIIb, Va, and Vb, and their corresponding genotypes has been elucidated.     

Common BMI and diabetes-related genetic variants: A pilot study among indigenous people in the Brazilian Amazon

This study was carried out to investigate the frequency of genetic variants related to body mass index (BMI) and type 2 diabetes (T2D) and evaluating the potential impact of risk alleles on susceptibility to these disorders in six indigenous peoples from Brazilian Amazon region. The majority of Fst values for pairwise population comparisons among the indigenous groups are low or moderate. The indigenous people show high values of differentiation with Africans, Europeans and Southeast Asians and moderate values with East Asian and American populations, as expected. The allelic frequencies among indigenous indicate that the majority of associations observed with T2D in continental populations can be replicated in native Amazonians. The genetic risk scores calculated for T2D in indigenous are high and similar to those calculated for Americans and East Asians, while the estimates obtained for obesity are low, probably due to the low frequencies of the risk allele of the FTO gene found in our samples. ADRB3-rs4994 and ABCC8-rs1799854 genes showed a significant association with BMI and waist circumference, and the KCNJ11-rs5219 gene with hyperglycemia. These results emphasize the importance of knowing the genetic variability underlying complex genetic diseases in indigenous peoples and the search for particular or rare variants. Keywords: T2D, BMI, SNP, Amerindians, Brazilian     

The Light Skin Allele of SLC24A5 in South Asians and Europeans Shares Identity by Descent

Skin pigmentation is one of the most variable phenotypic traits in humans. A non-synonymous substitution (rs1426654) in the third exon of SLC24A5 accounts for lighter skin in Europeans but not in East Asians. A previous genome-wide association study carried out in a heterogeneous sample of UK immigrants of South Asian descent suggested that this gene also contributes significantly to skin pigmentation variation among South Asians. In the present study, we have quantitatively assessed skin pigmentation for a largely homogeneous cohort of 1228 individuals from the Southern region of the Indian subcontinent. Our data confirm significant association of rs1426654 SNP with skin pigmentation, explaining about 27% of total phenotypic variation in the cohort studied. Our extensive survey of the polymorphism in 1573 individuals from 54 ethnic populations across the Indian subcontinent reveals wide presence of the derived-A allele, although the frequencies vary substantially among populations. We also show that the geospatial pattern of this allele is complex, but most importantly, reflects strong influence of language, geography and demographic history of the populations. Sequencing 11.74 kb of SLC24A5 in 95 individuals worldwide reveals that the rs1426654-A alleles in South Asian and West Eurasian populations are monophyletic and occur on the background of a common haplotype that is characterized by low genetic diversity. We date the coalescence of the light skin associated allele at 22–28 KYA. Both our sequence and genome-wide genotype data confirm that this gene has been a target for positive selection among Europeans. However, the latter also shows additional evidence of selection in populations of the Middle East, Central Asia, Pakistan and North India but not in South India.     

The association between the mannose-binding lectin codon 54 polymorphism and systemic lupus erythematosus: a meta-analysis update

The aim of this study was to determine whether the functional mannose-binding lectin (MBL2) exon 1 codon 54 polymorphism (rs1800450) confers susceptibility to systemic lupus erythematosus (SLE) in ethnically different populations. A meta-analysis was conducted on the MBL2 codon 54 polymorphism across 21 comparative studies. Meta-analysis showed an association between the MBL2 codon 54 B allele and SLE in all study subjects [odds ratio (OR) = 1.298, 95% confidence interval (CI) = 1.154–1.459, P = 1.4 × 10⁻⁵]. Analysis after stratification by ethnicity indicated that the MBL2 codon 54 B allele is significantly associated with SLE in Europeans, Asian, and Africans (OR = 1.246, 95% CI = 1.062–1.462, P = 0.007; OR = 1.268, 95% CI = 1.049–1.532, P = 0.014; OR = 1.939, 95% CI = 1.269–2.962, P = 0.002, respectively). However, African Americans had a much lower prevalence of the T allele (5.8%) than any other populations studied, whereas Asians had the highest prevalence (16.2%). This meta-analysis confirms that the MBL2 codon 54 polymorphism is associated with SLE susceptibility in different ethnic groups, and that its prevalence is ethnicity dependent.     

Y-chromosome specific alleles and haplotypes in European and Asian populations: Linkage disequilibrium and geographic diversity

Variation on the Y chromosome may permit our understanding the evolution of the human paternal lineage and male gene flow. This study reports upon the distribution and non random association of alleles at four Y-chromosome specific loci in four populations, three Caucasoid (Italian, Greek and Slav) and one Asian. The markers include insertion/deletion (p12f), point mutation (92R7 and pYαI), and repeat sequence (p21A1) polymorphisms. Our data confirm that the p12f/TaqI 8 kb allele is a Caucasoid marker and that Asians are monomorphic at three of the loci (p12f, 92R7, and pYαI). The alleles at 92R7 and pYαI were found to be in complete disequilibrium in Europeans. Y-haplotype diversity was highly significant between Asians and all three European groups (P < 0.001), but the Greeks and Italians were also significantly different with respect to some alleles and haplotypes (P < 0.02). We find strong evidence that the p12f/TaqI 8 kb allele may have arisen only once, as a deletion event, and, additionally, that the present-day frequency distribution of Y chromosomes carrying the p12f/8 kb allele suggests that it may have been spread by colonising sea-faring peoples from the Near East, possibly the Phoenicians, rather than by expansion of Neolithic farmers into continental Europe. The p12f deletion is the key marker of a unique Y chromosome, found only in Caucasians to date, labelled ‘Mediterranean’ and this further increases the level of Y-chromosome diversity seen among Caucasoids when compared to the other major population groups. Am J Phys Anthropol 104:167–176, 1997. © 1997 Wiley-Liss, Inc.     

Association between Common Polymorphism near the MC4R Gene and Obesity Risk: A Systematic Review and Meta-Analysis

Background

Genome-wide association studies on Europeans have shown that two polymorphisms (rs17782313, rs12970134) near the melanocortin 4 receptor (MC4R) gene were associated with increased risk of obesity. Subsequently studies among different ethnic populations have shown mixed results with some confirming and others showing inconsistent results, especially among East Asians and Africans. We performed a comprehensive meta-analysis of various studies from different ethnic populations to assess the association of the MC4R polymorphism with obesity risk.

Methods

We retrieved all published literature that investigated association of MC4R variants with obesity from PubMed and Embase. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using fixed- or random-effects model.

Results

A total of 61 studies (80,957 cases/220,223 controls) for rs17782313 polymorphism (or proxy) were included in the meta-analysis. The results suggested that rs17782313 polymorphism was significantly associated with obesity risk (OR = 1.18, 95%CI = 1.15–1.21, p<0.001). Similar trends were observed among subgroups of Europeans and East Asians, adults and children, studies with high quality score, and for each five MC4R polymorphisms independently.

Conclusions

The present meta-analysis confirms the significant association of MC4R polymorphism with risk of obesity. Further studies should be conducted to identify the causal variant and the underlying mechanisms of the identified association.     

GSTT1 and GSTM1 gene polymorphisms in European and African populations

Glutathione S-transferases (GSTs) are a superfamily of detoxificant enzymes. Pharmacogenomic studies have revealed interethnic differences in GST allelic frequencies. This study is focused on GSTT1 (gene deletion, rs17850155, rs2234953, and rs11550605) and GSTM1 (gene deletion) gene frequency distributions in two population samples of Europe origin (Italy, n = 120; Spain, n = 94) and two population samples of Africa origin (Cameroon, n = 126; Ethiopia, n = 153). Detection of GSTT1 and GSTM1 null genotypes was performed by multiplex PCR analysis, while the other GSTT1 gene polymorphisms were detected using allele specific PCR and sequencing. GSTT1 and GSTM1 null frequencies in the samples analyzed fit with the variability range observed in European and African populations, respectively. The SNP analysis in GSTT1 gene did not highlight any nucleotide substitution in 493 individuals analyzed. The comparisons among GSTM1 and GSTT1 null phenotype frequencies in worldwide populations show different patterns between Asians, Africans, and Europeans. Important insights into the effects of GSTM1 and GSTT1 gene deletions on the pathogenesis of human diseases have been hypothesized. Detailed studies on the geography of GST variants could therefore increase knowledge about the relationship between ethnicity and the prevalence of certain diseases.     

CTLA-4 and TNF-α promoter-308 A/G polymorphisms and ANCA-associated vasculitis susceptibility: a meta-analysis

The aim of this study was to explore whether the cytotoxic T lymphocyte associated antigen-4 (CTLA-4) or tumor necrosis factor-α (TNF-α) polymorphisms contribute to anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) susceptibility. The authors conducted a meta-analysis on associations between polymorphisms of the 3′ untranslated region (UTR) microsatellite at exon 3, exon 4 CT60 (A/G), exon 1 +49 (A/G), and promoter -318 (C/T) of CTLA-4, and TNF-α promoter-308 (A/G) and AAV susceptibility as determined using; (1) allelic contrast and (2) homozygote contrast, (3) recessive, and (4) dominant models. A total of 11 comparisons were considered in this meta-analysis. These studies encompassed 7 CTLA-4 studies and 4 TNF-α studies in 10 European populations and 1 Asian population. The (AT)_n repeat polymorphisms of CTLA-4 were found to be significantly associated with AAV in European populations (OR of 86 vs. xx allele = 0.402, 95% CI = 0.184–0.875, P = 0.022). The one study conducted on this polymorphism in Asians showed no significant association with AAV. Meta-analysis of the 86/86 (recessive effect), 86/86 and 86/xx (dominant effect), and 86/86 vs. xx/xx (homozygote contrast) of the (AT)_n repeat revealed a significant association with AAV in Europeans. Both the CTLA-4 CT60 and +49 polymorphisms were found to be significantly associated with AAV in European populations, and allele and genotype-based analyses showed a significant association between the CTLA-4 CT60 and +49 polymorphisms with AAV in Europeans (OR of the A allele of CT60 = 0.769, 95% CI = 0.619–0.017, P = 0.035; OR of the T allele of +49 = 1.382, 95% CI = 1.147–1.664, P = 0.001, respectively). Meta-analysis of the CTLA-4 -318 polymorphism failed to identify any association with AAV. Furthermore, meta-analysis of the AA genotype, the AA and AG genotypes, and the A allele of TNF-α failed to reveal any association with Wegener’s granulomatosis (WG). This meta-analysis demonstrates that the CTLA-4 polymorphisms confer susceptibility to AAV in Europeans. In contrast, no association was found between the TNF-α-308 polymorphism and susceptibility to WG in Europeans.     

A Point Mutation Creating an ExtraN-Glycosylation Site in Fibrillin-1 Results in Neonatal Marfan Syndrome

Fibrillin-1 is a large cysteine-rich glycoprotein of the 10-nm microfibrils in the extracellular matrix. A spectrum of mutations in the fibrillin-1 gene (FBN1) have been identified in patients with Marfan syndrome (MFS), and the majority of mutations resulting in the neonatal and often lethal form of MFS have been identified in the restricted region of exons 24–32 of theFBN1gene. Here we report a novel point mutation in exon 25 of theFBN1gene in a patient with lethal MFS. The mutation resulted in a molecular defect rarely encountered in human diseases, the creation of an extra consensus sequence forN-glycosylation. Metabolic labeling of the patient fibroblast culture andin vitroexpression of the mutagenized cDNA construct suggest that this novelN-glycosylation site is actually utilized. Immunohistochemical and ultrastructural analyses of the fibroblast cultures of the patient show that this excessiveN-glycosylation severely affects microfibril formationin vitro;this finding emphasizes the importance of correct posttranslational modifications of fibrillin molecules for correct aggregation into microfibrillar structures.     

Three Novel Mutant Arylsulfatase A Alleles Causing Metachromatic Leukodystrophy

Metachromatic leukodystrophy is a lysosomal storage disorder caused by the deficiency of arylsulfatase A. This leads to the accumulation of 3-O-sulfogalactosylceramide, which results in severe demyelination. Here we describe a novel non-sense mutation W124ter and two disease-causing missense mutations E382Q and C500F in arylsulfatase A gene. Another so far unknown allele harbors three sequence alterations: two polymorphisms (N350S, R496H) and a missense mutation (R288H). The R288H substitution and the N350S polymorphism have previously been found on one allele together with a polymorphism in a polyadenylation signal characteristic for the arylsulfatase A pseudodeficiency allele. The R496H has been shown to occur on another allele. The presence of the R288H, N350S, and R496H substitution on one allele in the absence of the polyadenylation site polymorphism shows that this allele has probably arisen by recombination between the nucleotides of codon 350 and 496.     

Effect of mutation on helper T-cells and viral population: A computer simulation model for HIV

Summary A Monte Carlo simulation is proposed to study the dynamics of helper T-cells (N _H) and viral (N _V) populations in an immune response model relevant to HIV. Cellular states are binary variables and the interactions are described by logical expressions. Viral population shows a nonmonotonic growth before reaching a constant value while helper T-cells grow to a constant after a relaxation/reaction time. Initially, the population of helper cells grows with time with a power-law, N _H ∼t ^β, before reaching the steady-state; the growth exponent β increases systematically (β ≈ 1 – 2) with the mutation rate (P _mut≈0.1–0.4). The critical recovery time (t _c) increases exponentially with the viral mutation, t _c≈Ae ^αP _mut , with α=4.52±0.29 in low mutation regime and α=15.21±1.41 in high mutation regime. The equilibrium population of helper T-cell declines slowly with P _mut and collapses at ∼ 0.40; the viral population exhibits a reverse trend, i.e., a slow increase before the burst around the same mutation regime.     

Population stratification of a common APOBEC gene deletion polymorphism

The APOBEC3 gene family plays a role in innate cellular immunity inhibiting retroviral infection, hepatitis B virus propagation, and the retrotransposition of endogenous elements. We present a detailed sequence and population genetic analysis of a 29.5-kb common human deletion polymorphism that removes the APOBEC3B gene. We developed a PCR-based genotyping assay, characterized 1,277 human diversity samples, and found that the frequency of the deletion allele varies significantly among major continental groups (global F_ST = 0.2843). The deletion is rare in Africans and Europeans (frequency of 0.9% and 6%), more common in East Asians and Amerindians (36.9% and 57.7%), and almost fixed in Oceanic populations (92.9%). Despite a worldwide frequency of 22.5%, analysis of data from the International HapMap Project reveals that no single existing tag single nucleotide polymorphism may serve as a surrogate for the deletion variant, emphasizing that without careful analysis its phenotypic impact may be overlooked in association studies. Application of haplotype-based tests for selection revealed potential pitfalls in the direct application of existing methods to the analysis of genomic structural variation. These data emphasize the importance of directly genotyping structural variation in association studies and of accurately resolving variant breakpoints before proceeding with more detailed population-genetic analysis.