Positive selection in Europeans and East-Asians at the ABCA12 gene.
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ABSTRACT:
SUBMITTER: Sirica R
PROVIDER: S-EPMC6424970 | biostudies-literature | 2019 Mar
REPOSITORIES: biostudies-literature
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Project description:GDF5 is a member of the bone morphogenetic protein (BMP) gene family, and plays an important role in the development of the skeletal system. Variants of the gene are associated with osteoarthritis and height in some human populations. Here, we resequenced the gene in individuals from four geographically separated human populations, and found that the evolution of the promoter region deviated from neutral expectations, with the sequence evolution driven by positive selection in the East Asian population, especially the haplotypes carrying the derived alleles of 5' UTR SNPs rs143384 and rs143383. The derived alleles of rs143384 and rs143383, which are associated with a risk of osteoarthritis and decreased height, have high frequencies in non-Africans and show strong extended haplotype homozygosity and high population differentiation in East Asian. It is concluded that positive selection has driven the rapid evolution of the two osteoarthritis osteoarthritis-risk and decreased height associated variants of the human GDF5 gene, and supports the suggestion that the reduction in body size during the terminal Pleistocene and Holocene period might have been an adaptive process influenced by genetic factors.
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Project description:Genome-wide scans for positive selection in humans provide a promising approach to establish links between genetic variants and adaptive phenotypes. From this approach, lists of hundreds of candidate genomic regions for positive selection have been assembled. These candidate regions are expected to contain variants that contribute to adaptive phenotypes, but few of these regions have been associated with phenotypic effects. Here we present evidence that a derived nonsynonymous substitution (370A) in EDAR, a gene involved in ectodermal development, was driven to high frequency in East Asia by positive selection prior to 10,000 years ago. With an in vitro transfection assay, we demonstrate that 370A enhances NF-kappaB activity. Our results suggest that 370A is a positively selected functional genetic variant that underlies an adaptive human phenotype.
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Project description:To study the male and female lineages of East Asian and European humans, we have sequenced 25 short tandem repeat markers on 453 Y-chromosomes and collected sequences of 72 complete mitochondrial genomes to construct independent phylogenetic trees for male and female lineages. The results indicate that East Asian individuals fall into two clades, one that includes East Asian individuals only and a second that contains East Asian and European individuals. Surprisingly, the European individuals did not form an independent clade, but branched within in the East Asians. We then estimated the divergence time of the root of the European clade as ∼ 41,000 years ago. These data indicate that, contrary to traditional views, Europeans diverged from East Asians around that time. We also address the origin of the Ainu lineage in northern Japan.
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Project description:Body fat deposition and distribution differ between East Asians and Europeans, and for the same level of obesity, East Asians are at higher risks of Type 2 diabetes (T2D) and other metabolic disorders. This observation has prompted the reclassifications of body mass index thresholds for the definitions of "overweight" and "obese" in East Asians. However, the question remains over what evolutionary mechanisms have driven the differences in adiposity morphology between two population groups that shared a common ancestor less than 80,000 years ago. The Thrifty Gene hypothesis has been suggested as a possible explanation, where genetic factors that allowed for efficient food-energy conversion and storage are evolutionarily favoured by conferring increased chances of survival and fertility. Here, we leveraged on the existing findings from genome-wide association studies and large-scale surveys of positive natural selection to evaluate whether there is currently any evidence to support the Thrifty Gene hypothesis. We first assess whether the existing genetic associations with obesity and T2D are located in genomic regions that are reported to be under positive selection, and if so, whether the risk alleles sit on the extended haplotype forms. In addition, we interrogate whether these risk alleles are the derived forms that differ from the ancestral alleles, and whether there is significant evidence of population differentiation at these SNPs between East Asian and European populations. Our systematic survey did not yield conclusive evidence to support the Thrifty Gene hypothesis as a possible explanation for the differences observed between East Asians and Europeans.
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Project description:Large data sets on human genetic variation have been collected recently, but their usefulness for learning about history and natural selection has been limited by biases in the ways polymorphisms were chosen. We report large subsets of SNPs from the International HapMap Project that allow us to overcome these biases and to provide accurate measurement of a quantity of crucial importance for understanding genetic variation: the allele frequency spectrum. Our analysis shows that East Asian and northern European ancestors shared the same population bottleneck expanding out of Africa but that both also experienced more recent genetic drift, which was greater in East Asians.
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Project description:BackgroundThe pathogenesis and cardiovascular impact of type 2 diabetes (T2D) may be different in South Asians compared with other ethnic groups. The phenotypic characterization of diabetic cardiomyopathy remains debated and little is known regarding differences in T2D-related cardiovascular remodeling across ethnicities. We aimed to characterize the differences in left ventricular (LV) diastolic and systolic function, LV structure, myocardial tissue characteristics and aortic stiffness between T2D patients and controls and to assess the differences in T2D-related cardiovascular remodeling between South Asians and Europeans.MethodsT2D patients and controls of South Asian and European descent underwent 3 Tesla cardiovascular magnetic resonance imaging (CMR) and cardiac proton-magnetic resonance spectroscopy (1H-MRS). Differences in cardiovascular parameters between T2D patients and controls were examined using ANCOVA and were reported as mean (95% CI). Ethnic group comparisons in the association of T2D with cardiovascular remodeling were made by adding the interaction term between ethnicity and diabetes status to the model.ResultsA total of 131 individuals were included (54 South Asians [50.1 ± 8.7 years, 33% men, 33 patients vs. 21 controls) and 77 Europeans (58.8 ± 7.0 years, 56% men, 48 patients vs. 29 controls)]. The ratio of the transmitral early and late peak filling rate (E/A) was lower in T2D patients compared with controls, in South Asians [- 0.20 (- 0.36; - 0.03), P = 0.021] and Europeans [- 0.20 (- 0.36; - 0.04), P = 0.017], whereas global longitudinal strain and aortic pulse wave velocity were similar. South Asian T2D patients had a higher LV mass [+ 22 g (15; 30), P < 0.001] (P for interaction by ethnicity = 0.005) with a lower extracellular volume fraction [- 1.9% (- 3.4; - 0.4), P = 0.013] (P for interaction = 0.114), whilst European T2D patients had a higher myocardial triglyceride content [+ 0.59% (0.35; 0.84), P = 0.001] (P for interaction = 0.002) than their control group.ConclusionsDiabetic cardiomyopathy was characterized by impaired LV diastolic function in South Asians and Europeans. Increased LV mass was solely observed among South Asian T2D patients, whereas differences in myocardial triglyceride content between T2D patients and controls were only present in the European cohort. The diabetic cardiomyopathy phenotype may differ between subsets of T2D patients, for example across ethnicities, and tailored strategies for T2D management may be required.
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Project description:BackgroundObservational studies have revealed that type 2 diabetes (T2D) is associated with an increased risk of peripheral artery disease (PAD). However, whether the two diseases share a genetic basis and whether the relationship is causal remain unclear. It is also unclear as to whether these relationships differ between ethnic groups.MethodsBy leveraging large-scale genome-wide association study (GWAS) summary statistics of T2D (European-based: Ncase = 21,926, Ncontrol = 342,747; East Asian-based: Ncase = 36,614, Ncontrol = 155,150) and PAD (European-based: Ncase = 5673, Ncontrol = 359,551; East Asian-based: Ncase = 3593, Ncontrol = 208,860), we explored the genetic correlation and putative causal relationship between T2D and PAD in both Europeans and East Asians using linkage disequilibrium score regression and seven Mendelian randomization (MR) models. We also performed multi-trait analysis of GWAS and two gene-based analyses to reveal candidate variants and risk genes involved in the shared genetic basis between T2D and PAD.ResultsWe observed a strong genetic correlation (rg) between T2D and PAD in both Europeans (rg = 0.51; p-value = 9.34 × 10-15) and East Asians (rg = 0.46; p-value = 1.67 × 10-12). The MR analyses provided consistent evidence for a causal effect of T2D on PAD in both ethnicities (odds ratio [OR] = 1.05 to 1.28 for Europeans and 1.15 to 1.27 for East Asians) but not PAD on T2D. This putative causal effect was not influenced by total cholesterol, body mass index, systolic blood pressure, or smoking initiation according to multivariable MR analysis, and the genetic overlap between T2D and PAD was further explored employing an independent European sample through polygenic risk score regression. Multi-trait analysis of GWAS revealed two novel European-specific single nucleotide polymorphisms (rs927742 and rs1734409) associated with the shared genetic basis of T2D and PAD. Gene-based analyses consistently identified one gene ANKFY1 and gene-gene interactions (e.g., STARD10 [European-specific] to AP3S2 [East Asian-specific]; KCNJ11 [European-specific] to KCNQ1 [East Asian-specific]) associated with the trans-ethnic genetic overlap between T2D and PAD, reflecting a common genetic basis for the co-occurrence of T2D and PAD in both Europeans and East Asians.ConclusionsOur study provides the first evidence for a genetically causal effect of T2D on PAD in both Europeans and East Asians. Several candidate variants and risk genes were identified as being associated with this genetic overlap. Our findings emphasize the importance of monitoring PAD status in T2D patients and suggest new genetic biomarkers for screening PAD risk among patients with T2D.
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Project description:Running biomechanics and ethnicity can influence running economy (RE), which is a critical factor of running performance. Our aim was to compare RE of South East Asian (SEA) and non-South East Asian (non-SEA) runners at several endurance running speeds (10-14 km/h) matched for on-road racing performance and sex. Secondly, we explored anthropometric characteristics and relationships between RE and anthropometric and biomechanical variables. SEA were 6% less economical (p = 0.04) than non-SEA. SEA were lighter and shorter than non-SEA, and had lower body mass indexes and leg lengths (p ≤ 0.01). In terms of biomechanics, a higher prevalence of forefoot strikers in SEA than non-SEA was seen at each speed tested (p ≤ 0.04). Furthermore, SEA had a significantly higher step frequency (p = 0.02), shorter contact time (p = 0.04), smaller footstrike angle (p < 0.001), and less knee extension at toe-off (p = 0.03) than non-SEA. Amongst these variables, only mass was positively correlated to RE for both SEA (12 km/h) and non-SEA (all speeds); step frequency, negatively correlated to RE for both SEA (10 km/h) and non-SEA (12 km/h); and contact time, positively correlated to RE for SEA (12 km/h). Despite the observed anthropometric and biomechanical differences between cohorts, these data were limited in underpinning the observed RE differences at a group level. This exploratory study provides preliminary indications of potential differences between SEA and non-SEA runners warranting further consideration. Altogether, these findings suggest caution when generalizing from non-SEA running studies to SEA runners.
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