scholarly journals High-Resolution Characterization of KIR Genes in a Large North American Cohort Reveals Novel Details of Structural and Sequence Diversity

2021 ◽  
Vol 12 ◽  
Author(s):  
Leonardo M. Amorim ◽  
Danillo G. Augusto ◽  
Neda Nemat-Gorgani ◽  
Gonzalo Montero-Martin ◽  
Wesley M. Marin ◽  
...  
Keyword(s):  
High Resolution ◽  
Copy Number ◽  
Structural Variation ◽  
High Throughput Sequencing ◽  
Full Range ◽  
Large Population ◽  
Killer Cell ◽  
Population Sample ◽  
Haplotype Diversity ◽  
Gene Copy

The KIR (killer-cell immunoglobulin-like receptor) region is characterized by structural variation and high sequence similarity among genes, imposing technical difficulties for analysis. We undertook the most comprehensive study to date of KIR genetic diversity in a large population sample, applying next-generation sequencing in 2,130 United States European-descendant individuals. Data were analyzed using our custom bioinformatics pipeline specifically designed to address technical obstacles in determining KIR genotypes. Precise gene copy number determination allowed us to identify a set of uncommon gene-content KIR haplotypes accounting for 5.2% of structural variation. In this cohort, KIR2DL4 is the framework gene that most varies in copy number (6.5% of all individuals). We identified phased high-resolution alleles in large multi-locus insertions and also likely founder haplotypes from which they were deleted. Additionally, we observed 250 alleles at 5-digit resolution, of which 90 have frequencies ≥1%. We found sequence patterns that were consistent with the presence of novel alleles in 398 (18.7%) individuals and contextualized multiple orphan dbSNPs within the KIR complex. We also identified a novel KIR2DL1 variant, Pro151Arg, and demonstrated by molecular dynamics that this substitution is predicted to affect interaction with HLA-C. No previous studies have fully explored the full range of structural and sequence variation of KIR as we present here. We demonstrate that pairing high-throughput sequencing with state-of-art computational tools in a large cohort permits exploration of all aspects of KIR variation including determination of population-level haplotype diversity, improving understanding of the KIR system, and providing an important reference for future studies.

scholarly journals High-throughput Interpretation of Killer-cell Immunoglobulin-like Receptor Short-read Sequencing Data with PING

2021 ◽  
Author(s):  
Wesley Marin ◽  
Ravi Dandekar ◽  
Danillo G. Augusto ◽  
Tasneem Yusufali ◽  
Bianca Heyn ◽  
...  
Keyword(s):  
High Resolution ◽  
High Throughput ◽  
Copy Number ◽  
Killer Cell ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Sequencing Data ◽  
Short Read ◽  
Short Read Sequencing ◽  
Kir Genes

The killer-cell immunoglobulin-like receptor ( KIR) complex on chromosome 19 encodes receptors that modulate the activity of natural killer cells, and variation in these genes has been linked to infectious and autoimmune disease, as well as having bearing on pregnancy and transplant outcomes. The medical relevance and high variability of KIR genes makes short-read sequencing an attractive technology for interrogating the region, providing a high-throughput, high-fidelity sequencing method that is cost-effective. However, because this gene complex is characterized by extensive nucleotide polymorphism, structural variation including gene fusions and deletions, and a high level of homology between genes, its interrogation at high resolution has been thwarted by bioinformatic challenges, with most studies limited to examining presence or absence of specific genes. Here, we present the PING (Pushing Immunogenetics to the Next Generation) pipeline, which incorporates empirical data, novel alignment strategies and a custom alignment processing workflow to enable high-throughput KIR sequence analysis from short-read data. PING provides KIR gene copy number classification functionality for all KIR genes through use of a comprehensive alignment reference. The gene copy number determined per individual enables an innovative genotype determination workflow using genotype-matched references. Together, these methods address the challenges imposed by the structural complexity and overall homology of the KIR complex. To determine copy number and genotype determination accuracy, we applied PING to European and African validation cohorts and a synthetic dataset. PING demonstrated exceptional copy number determination performance across all datasets and robust genotype determination performance. Finally, an investigation into discordant genotypes for the synthetic dataset provides insight into misaligned reads, advancing our understanding in interpretation of short-read sequencing data in complex genomic regions. PING promises to support a new era of studies of KIR polymorphism, delivering high-resolution KIR genotypes that are highly accurate, enabling high-quality, high-throughput KIR genotyping for disease and population studies.

scholarly journals High-throughput Interpretation of Killer-cell Immunoglobulin-like Receptor Short-read Sequencing Data with PING

2021 ◽  
Vol 17 (8) ◽  
pp. e1008904
Author(s):  
Wesley M. Marin ◽  
Ravi Dandekar ◽  
Danillo G. Augusto ◽  
Tasneem Yusufali ◽  
Bianca Heyn ◽  
...  
Keyword(s):  
High Resolution ◽  
High Throughput ◽  
Copy Number ◽  
Killer Cell ◽  
Gene Copy Number ◽  
Synthetic Dataset ◽  
Gene Copy ◽  
Sequencing Data ◽  
Short Read ◽  
Short Read Sequencing

The killer-cell immunoglobulin-like receptor (KIR) complex on chromosome 19 encodes receptors that modulate the activity of natural killer cells, and variation in these genes has been linked to infectious and autoimmune disease, as well as having bearing on pregnancy and transplant outcomes. The medical relevance and high variability of KIR genes makes short-read sequencing an attractive technology for interrogating the region, providing a high-throughput, high-fidelity sequencing method that is cost-effective. However, because this gene complex is characterized by extensive nucleotide polymorphism, structural variation including gene fusions and deletions, and a high level of homology between genes, its interrogation at high resolution has been thwarted by bioinformatic challenges, with most studies limited to examining presence or absence of specific genes. Here, we present the PING (Pushing Immunogenetics to the Next Generation) pipeline, which incorporates empirical data, novel alignment strategies and a custom alignment processing workflow to enable high-throughput KIR sequence analysis from short-read data. PING provides KIR gene copy number classification functionality for all KIR genes through use of a comprehensive alignment reference. The gene copy number determined per individual enables an innovative genotype determination workflow using genotype-matched references. Together, these methods address the challenges imposed by the structural complexity and overall homology of the KIR complex. To determine copy number and genotype determination accuracy, we applied PING to European and African validation cohorts and a synthetic dataset. PING demonstrated exceptional copy number determination performance across all datasets and robust genotype determination performance. Finally, an investigation into discordant genotypes for the synthetic dataset provides insight into misaligned reads, advancing our understanding in interpretation of short-read sequencing data in complex genomic regions. PING promises to support a new era of studies of KIR polymorphism, delivering high-resolution KIR genotypes that are highly accurate, enabling high-quality, high-throughput KIR genotyping for disease and population studies.

scholarly journals Cognitive Abilities in the Wild: Population-scale game-based cognitive assessment

2021 ◽  
Author(s):  
Mads Kock Pedersen ◽  
Carlos Mauricio Castaño Díaz ◽  
Mario Alejandro Alba-Marrugo ◽  
Ali Amidi ◽  
Rajiv Vaid Basaiwmoit ◽  
...  
Keyword(s):  
Cognitive Abilities ◽  
Wild Population ◽  
Full Range ◽  
Large Population ◽  
Population Sample ◽  
The Social ◽  
In The Wild ◽  
Large Population Sample ◽  
Key Questions ◽  
Unique Dataset

Psychology and the social sciences are undergoing a revolution: It has become increasingly clear that traditional lab-based experiments fail to capture the full range of differences in cognitive abilities and behaviours across the general population. Some progress has been made toward devising measures that can be applied at scale across individuals and populations. What has been missing is a broad battery of validated tasks that can be easily deployed, used across different age ranges and social backgrounds, and employed in practical, clinical, and research contexts. Here, we present Skill Lab, a game-based approach allowing the efficient assessment of a suite of cognitive abilities. Skill Lab has been validated outside the lab in a crowdsourced population-size sample recruited in collaboration with the Danish Broadcast Company (Danmarks Radio, DR). Our game-based measures are five times faster to complete than the equivalent traditional measures and replicate previous findings on the decline of cognitive abilities with age in a large population sample. Furthermore, by combining the game data with an in-game survey, we demonstrate that this unique dataset has implication for key questions in social science, challenging the Jack-of-all-Trades theory of entrepreneurship and provide evidence for risk preference being independent of executive functioning.

scholarly journals Influence of KIR gene copy number on natural killer cell education

Blood ◽  
2013 ◽  
Vol 121 (23) ◽  
pp. 4703-4707 ◽  
Author(s):  
Vivien Béziat ◽  
James A. Traherne ◽  
Lisa L. Liu ◽  
Jyothi Jayaraman ◽  
Monika Enqvist ◽  
...  
Keyword(s):  
Copy Number ◽  
Nk Cell ◽  
Killer Cell ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Linear Effect ◽  
Gene Copy Number Variation ◽  
Key Points ◽  
Number Variation ◽  
Kir Gene

Key Points KIR gene copy number variation influences NK cell education at the repertoire level due to a linear effect on KIR expression. No effect of KIR gene dose on NK cell education at the single cell level.

scholarly journals High-Resolution Analysis Identifies High Frequency of KIR-A Haplotypes and Inhibitory Interactions of KIR With HLA Class I in Zhejiang Han

2021 ◽  
Vol 12 ◽  
Author(s):  
Sudan Tao ◽  
Yanmin He ◽  
Katherine M. Kichula ◽  
Jielin Wang ◽  
Ji He ◽  
...  
Keyword(s):  
High Resolution ◽  
High Frequency ◽  
Killer Cell ◽  
Hla Class I ◽  
Class I ◽  
Gene Copy ◽  
Human Populations ◽  
Telomeric Region ◽  
Cell Functions ◽  
Hla Class I Molecules

Killer cell immunoglobulin-like receptors (KIR) interact with human leukocyte antigen (HLA) class I molecules, modulating critical NK cell functions in the maintenance of human health. Characterizing the distribution and characteristics of KIR and HLA allotype diversity across defined human populations is thus essential for understanding the multiple associations with disease, and for directing therapies. In this study of 176 Zhejiang Han individuals from Southeastern China, we describe diversity of the highly polymorphic KIR and HLA class I genes at high resolution. KIR-A haplotypes, which carry four inhibitory receptors specific for HLA-A, B or C, are known to associate with protection from infection and some cancers. We show the Chinese Southern Han from Zhejiang are characterized by a high frequency of KIR-A haplotypes and a high frequency of C1 KIR ligands. Accordingly, interactions of inhibitory KIR2DL3 with C1+HLA are more frequent in Zhejiang Han than populations outside East Asia. Zhejiang Han exhibit greater diversity of inhibitory than activating KIR, with three-domain inhibitory KIR exhibiting the greatest degree of polymorphism. As distinguished by gene copy number and allele content, 54 centromeric and 37 telomeric haplotypes were observed. We observed 6% of the population to have KIR haplotypes containing large-scale duplications or deletions that include complete genes. A unique truncated haplotype containing only KIR2DL4 in the telomeric region was also identified. An additional feature is the high frequency of HLA-B*46:01, which may have arisen due to selection pressure from infectious disease. This study will provide further insight into the role of KIR and HLA polymorphism in disease susceptibility of Zhejiang Chinese.

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