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.

/pdf/a-framework-for-variation-discovery-and-genotyping-using-1mhes6klgp.pdf

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.

/pdf/analysis-of-protein-coding-genetic-variation-in-60-706-43wjw7d23z.pdf

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

Summary

Recently, a 14-bp insertion/deletion polymorphism (+14 bp/−14 bp) in exon 8 of the Human leucocyte antigen-G (HLA-G) gene has been studied extensively because this polymorphism has been associated with HLA-G mRNA stability and could influence HLA-G mRNA expression. We investigated the distribution of the 14-bp insertion/deletion polymorphism in six different Chinese ethnic groups (Bulang, Wa, Hani, Jinuo, Maonan and Zhuang), which originated from three major ancient tribes (Di-Qiang, Baipu and Baiyue) in China. Comparison of the 14-bp insertion frequency in the six groups with other Chinese groups showed marked variation among the three ancient tribes, Di-Qing (0.490–0.534), Baipu (0.470–0.609) and Baiyue (0.280–0.344). Furthermore, the frequencies of the 14-bp insertion were similar in groups that came from the same ancient tribe, which indicated that the individuals who share the 14-bp insertion have the most probably inherited the 14-bp element from a common ancestor. In addition, an intra-tribal comparison of the 14-bp insertion/deletion frequencies between the descendants of the ancient ancestral tribes suggests that population histories or some environmental effects, such as founder effect or isolation, might also influence the distribution.

Distribution of HLA-G 14-bp insertion/deletion polymorphism in six Chinese ethnic groups.

129 samples of Han population in Yunnan province were detected by polymerase chain reaction and microtitre plate hybridization (PCR-MPH). The samples of DR*15 subgroup being detected by PCR-MPH were further analyzed by Single-Strand Conformation Polymorphism (SSCP). By first polymerase chain reaction and microtitre plate hybridization (PCR-MPH), all of the 129 samples were divided into the following subgroups, viz. DR*01,DR*03,DR*04,DR*0701,DR*08,DR*09012,DR*1001,DR*11,DR*12,DR*13,DR*14,DR*15, DR*1602 and DR*1604. The samples of DR*04, DR*08/12, DR*03/11/13/14 were further detected by second PCR-MPH and the ones of DR*15 by SSCP. 36 kinds of alleles on HLA-DRB1 were detected in these samples. Among them, DRB1*1501(0.1240),DRB1*09012(0.0969), DRB1*08032(0.0930),DRB1*1202(0.0891),DRB1*1201(0.0814), DRB1 *1401(0.0775),DRB1 *0701(0.0620),are the most frequent. The chi(2) test of HLA-DRB1 alleles was done between Yunnan Han and the other 9 Han populations. In detail, comparing with Yunnan Han on the chi(2) test, the chi(2) values of few alleles in the few Han populations was more than 10, they were Xian Han(DR8,chi(2)=13.9712), Shanghai Han(DR4,chi(2)=10.1632), Guangdong Han(DR9,chi(2)=12.6121)and Nanjing Han(DR4,chi(2)=10.5796). Comparing with 9 Han populations, the genetic distance between Yunnan Han and Liaoning Han was the nearest(0.0541),Guangdong Han was the farthest(0.1851). In the 9 Han populations, the genetic distance between Shanghai Han and Nanjing Han was the nearest(0.0122),and the one between Tianjin Han and Shanxi Han was also nearer(0.0219). Based on above analysis, the conclusion may be deduced that the resource of Yunnan Han may be close to Liaoning Han and it was not a typical southern Han population though Yunnan Han are resident in the South. Some gene flow may be exit between Yunnan Han and the local minorities and made Yunnan Han become a special population.

[Polymorphism of HLA-DRB1 in Han population in Yunnan and comparison with 9 Han populations].

Human genomics is witnessing an ongoing paradigm shift from a single reference sequence to a pangenome form, but populations of Asian ancestry are underrepresented. Here we present data from the first phase of the Chinese Pangenome Consortium, including a collection of 116 high-quality and haplotype-phased de novo assemblies based on 58 core samples representing 36 minority Chinese ethnic groups. With an average 30.65× high-fidelity long-read sequence coverage, an average contiguity N50 of more than 35.63 megabases and an average total size of 3.01 gigabases, the CPC core assemblies add 189 million base pairs of euchromatic polymorphic sequences and 1,367 protein-coding gene duplications to GRCh38. We identified 15.9 million small variants and 78,072 structural variants, of which 5.9 million small variants and 34,223 structural variants were not reported in a recently released pangenome reference1. The Chinese Pangenome Consortium data demonstrate a remarkable increase in the discovery of novel and missing sequences when individuals are included from underrepresented minority ethnic groups. The missing reference sequences were enriched with archaic-derived alleles and genes that confer essential functions related to keratinization, response to ultraviolet radiation, DNA repair, immunological responses and lifespan, implying great potential for shedding new light on human evolution and recovering missing heritability in complex disease mapping. 

/pdf/a-pangenome-reference-of-36-chinese-populations-180mdrbu.pdf

A pangenome reference of 36 Chinese populations

BACKGROUND TOR1A has been proposed as an important genetic factor in early-onset isolated dystonia. Variants located in the 3' untranslated region of TOR1A are of particular importance because they may influence gene expression, although related studies are limited. The objectives of the present study focused on variants in the TOR1A 3' untranslated region. METHODS The last exon of TOR1A was sequenced in 229 cases with isolated dystonia and in 210 controls. In addition, 471 controls were tested to determine the frequency of the variants in the 3' untranslated region. RESULTS Except for c.904_906delGAG, 3 rare sequence variants (NM_000113.2:c.*454T>A, NM_000113.2:c.860C>A [rs766483672], and NM_000113.2:c.*302T>A [rs563498119]) were found only in the patients. The c.*302T>A variant was located in the conserved region of the human microRNA (hsa-miR-494) binding site. A luciferase reporter assay showed that c.*302T>A significantly altered gene expression. CONCLUSIONS Population frequencies, computational analyses, and function experiments in this study implied that c.*302T>A is associated with dystonia. © 2017 International Parkinson and Movement Disorder Society.

A rare variant in TOR1A exon 5 associated with isolated dystonia in southwestern Chinese.

Human natural killer cells express killer cell immunoglobulin-like receptors (KIRs), which interact with human leukocyte antigen (HLA) class I molecules. KIR/HLA combinations play an important role in innate and adaptive immunity. In the current study, 16 KIR genes were analyzed in an isolated Han group living in the Fengyandong (FYDH) region in the Yunnan province of southwest China. The framework KIR genes 3DL2, 3DL3, 3DP1, and 2DL4 were found in all individuals. A total of 22 distinct KIR genotypes were observed, four of which were unknown previously. Genotype 1 (N = 52, 55.9%) was the predominant genotype. Analysis of inhibitory and activating KIR and HLA-C ligands showed that all individuals displayed at least one inhibitory or activating KIR/HLA-C pair. One KIR/HLA-C pair was the most frequent (67/93), followed by two pairs (21/93), and three pairs (6/93). The comparison of KIR and HLA frequencies between FYDH and a local Han population showed that the two populations showed similar frequencies for the KIR genes. In contrast, the distribution of HLA alleles and haplotypes showed significant differences between them.

Jiayou Chu

Papers

Distribution of HLA-G 14-bp insertion/deletion polymorphism in six Chinese ethnic groups.

[Polymorphism of HLA-DRB1 in Han population in Yunnan and comparison with 9 Han populations].

A pangenome reference of 36 Chinese populations

A rare variant in TOR1A exon 5 associated with isolated dystonia in southwestern Chinese.

Distribution of killer cell immunoglobulin-like receptor genes and combinations with HLA-C ligands in an isolated Han population in southwest China.