Statistical method for testing the neutral mutation hypothesis by DNA polymorphism.

Recent advances in sequencing technology make it possible to comprehensively catalogue genetic variation in population samples, creating a foundation for understanding human disease, ancestry and evolution. The amounts of raw data produced are prodigious and many computational steps are required to translate this output into high-quality variant calls. We present a unified analytic framework to discover and genotype variation among multiple samples simultaneously that achieves sensitive and specific results across five sequencing technologies and three distinct, canonical experimental designs. Our process includes (1) initial read mapping; (2) local realignment around indels; (3) base quality score recalibration; (4) SNP discovery and genotyping to find all potential variants; and (5) machine learning to separate true segregating variation from machine artifacts common to next-generation sequencing technologies. We discuss the application of these tools, instantiated in the Genome Analysis Toolkit (GATK), to deep whole-genome, whole-exome capture, and multi-sample low-pass (~4×) 1000 Genomes Project datasets.

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A framework for variation discovery and genotyping using next-generation DNA sequencing data

Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes.

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Analysis of protein-coding genetic variation in 60,706 humans

The UK Biobank project is a prospective cohort study with deep genetic and phenotypic data collected on approximately 500,000 individuals from across the United Kingdom, aged between 40 and 69 at recruitment. The open resource is unique in its size and scope. A rich variety of phenotypic and health-related information is available on each participant, including biological measurements, lifestyle indicators, biomarkers in blood and urine, and imaging of the body and brain. Follow-up information is provided by linking health and medical records. Genome-wide genotype data have been collected on all participants, providing many opportunities for the discovery of new genetic associations and the genetic bases of complex traits. Here we describe the centralized analysis of the genetic data, including genotype quality, properties of population structure and relatedness of the genetic data, and efficient phasing and genotype imputation that increases the number of testable variants to around 96 million. Classical allelic variation at 11 human leukocyte antigen genes was imputed, resulting in the recovery of signals with known associations between human leukocyte antigen alleles and many diseases.

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The UK Biobank resource with deep phenotyping and genomic data

Trillions of microbes inhabit the human intestine, forming a complex ecological community that influences normal physiology and susceptibility to disease through its collective metabolic activities and host interactions. Understanding the factors that underlie changes in the composition and function of the gut microbiota will aid in the design of therapies that target it. This goal is formidable. The gut microbiota is immensely diverse, varies between individuals and can fluctuate over time — especially during disease and early development. Viewing the microbiota from an ecological perspective could provide insight into how to promote health by targeting this microbial community in clinical treatments.

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Diversity, stability and resilience of the human gut microbiota

Objective To determine frequencies of genetic polymorphisms of coagulation factor Ⅶ (F Ⅶ),coagulation factor F Ⅻ (F Ⅻ ),fibrinogen (FBG) and 9p21 in ethnic Han Chinese from Yunnan province,and to assess the association between such polymorphisms and onset of myocardial infarction (MI).Methods One hundred and forty-two patients with MI and 192 healthy controls were analyzed.Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and pyrosequencing were used to determine the genotypes of FⅦ,FⅫ,FBG and 9p21.Results No significant difference was found between in the frequencies of R353Q,5′F7,C46T,-148C/T,rs1333049 and rs4977574 loci between the two groups (P＞0.05).However,the frequencies of AA of -455G/A,T and TT of rs1333040,T and TT of rs10116277 and G and GG of rs2383207 were significantly higher in MI group compared with the controls (P＜0.05),whilst the frequencies of CT of rs1333040 and GT of rs10116277 were significantly lower in MI group compared with the controls (P＜0.05).Conclusion Polymorphisms of FⅦ,FⅫ,-148C/T of FBG and rs1333049 of 9p21 were not associated with myocardial infarction.Polymorphisms of -455G/A of FBG and rs1333040,rs10116277 and rs2383207 of 9p21 may be associated with MI in ethnic Han Chinese from Yunnan province.

Key words: 
Myocardial infarction; Gene; Polymorphism; Genetic association

Association between gene polymorphisms and myocardial infarction in Han Chinese of Yunnan province

Objective To assess the association between single nucleotide polymorphisms (SNPs) of PSMB8,PSMB9 and TAP2 genes and rheumatoid arthritis (RA) in ethnic Han Chinese from Yunnan.Methods A case-control study was carried out using 177 RA patients and 288 healthy controls.Genotypes of rs2071543,rs55745125 and rs138635403 loci of PSMB8 gene,and rs17587 locus of PSMB9 gene were determined with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).And polymerase chain reaction amplification refractory mutation system (ARMS-PCR) was used for typing rs2228396 locus of TAP2 gene.Genotypic and allelic frequencies were calculated.An Epi Info 7 software was used to calculate the Odds Ratio (OR) of above SNPs between the two groups.Results Allelic and genotypic frequencies of rs138635403 and rs17587 loci have differed significantly between the two groups (P ＜0.05).The frequency of GG genotype for rs17587 locus was also higher in the RA group (0.672) compared with control group (0.524) (OR =1.862,95％ CI:1.261-2.749).Conclusion Genetic polymorphisms of rs17587 appeared to be associated with RA in ethnic Han Chinese from Yunnan.

Key words: 
Rheumatoid Arthritis;  Genetic polymorphism;  PSMB gene;  TAP gene

[Association between polymorphisms of PSMB8, PSMB9 and TAP2 genes with rheumatoid arthritis in ethnic Han Chinese from Yunnan].

Objective To explore the relationship between genetic polyrnorphisms of 3 single nucleotide polymorphisms (SNPs) in the elastin microfibril interfacer 1 (EMILIN1)gene and essential hypertension. Methods A case-control study was conducted in which 201 hypertensive patients and 202 healthy controls in Mongolian population were enrolled, and the genotypes of rs3754734, rs2011616 and rs2304682 loci were analyzed using polymerase chain reaction-restriction fragment length polyrnorphism (PCR-RFLP) and direct sequencing techniques. Results There were significant differences in the frequencies of alleles and genotypes for the rs2304682 between the hypertensives and normotensives in the population(P＜0. 05). The frequency of the G-G haplotype established by rs3754734 and rs2304682 was significantly higher in the hypertensive patients (P＜0. 05). The frequencies of alleles and genotypes for the rs2304682 also had significant differences between the group with high diastolic blood pressure and normal diastolic blood pressure (P＜0.05). There were no significant differences in the frequencies of alleles and genotypes for the 3 SNPs between the group with high systolic blood pressure and normal systolic blood pressure (P＞0.05). Conclusion The rs2304682 locus in the EMILIN1 gene, as well as the haplotypes G-G constructed using rs3754734 and rs2304682, may associate with the susceptibility of essential hypertension in the Mongolian population. Also, rs2304682 may associate with the level of the diastolic blood pressure.

Key words: 
Mongolian;  essential hypertension;  EMILIN1 gene;  genetic polymorphism

Association of EMILIN1 gene polymorphism with essential hypertension in Mongolian

Mitochondrial DNA (mtDNA) differs from nuclear genome in many aspects such as lack of recombination, thus the investigation of mtDNA plays an essential role in human evolutionary history. We compared different sequences (approximately 2 kb) of ATP6, ATP8 and Cyt b genes in mtDNA among Tibetans in three different zones and found that the whole mtDNA sequences of the three genes, ATP6 and ATP 8 genes deviate gradually from neutral model with the increase of altitudes, yet no differences were observed. Also we found that the effect of purifying selection on Cyt b gene was elevated with the decrease of altitudes. Meanwhile, there was a possibility for the adaptive selection in ATP6 gene, which had an enhanced trend with the increase of altitudes. Thus, the geographic environment is the main determinant for selection, namely, different geographic environment has direct effect on selection.

[Comparison on mitochondrial ATP6, ATP8 and Cyt b genes between Chinese Tibetans in three different zones: detecting the signature of natural selection on mitochondrial genome].

Background: The clinical consequences and significance of many unstable hemoglobins interacting with other hemoglobinopathies remain unrecognized. Here we first explore molecular and hematological ...

https://tandfonline.com/doi/pdf/10.1080/16078454.2019.1621020

Jiayou Chu

Papers

Association between gene polymorphisms and myocardial infarction in Han Chinese of Yunnan province

[Association between polymorphisms of PSMB8, PSMB9 and TAP2 genes with rheumatoid arthritis in ethnic Han Chinese from Yunnan].

Association of EMILIN1 gene polymorphism with essential hypertension in Mongolian

[Comparison on mitochondrial ATP6, ATP8 and Cyt b genes between Chinese Tibetans in three different zones: detecting the signature of natural selection on mitochondrial genome].

Interactions of unstable hemoglobin Rush with thalassemia and hemoglobin E result in thalassemia intermedia.