SVRare: discovering disease-causing structural variants in the 100K Genomes Project

Discovery of disease-causing structural variants (dcSV) from whole genome sequencing data is difficult due to high number of false positives and a lack of efficient way to estimate allele frequency. Here we introduce SVRare, an application that aggregates structural variants (SV) called by other tools, and efficiently annotates rare SVs to aid dcSVs discovery. Applied in the Genomics England (GEL) research environment to data from the 100K Genomes Project, SVRare aggregated 554,060,126 SVs called by Manta and Canvas in all the 71,408 participants in the rare-disease arm. From a pilot study of 4313 families, SVRare identified 36 novel protein-coding disrupting SVs on diagnostic grade genes that may explain proband's phenotype. It is estimated that SVRare can increase SV-based diagnosis yield by at least 4-fold. We also performed a genome-wide association study, and uncovered clusters of dcSVs in genes with known pathogenicity, such as PKD1/2 - cystic kidney diseases and LDLR - familial hypercholesterolaemia.

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A Nonsense Variant in Hephaestin Like 1 (HEPHL1) Is Responsible for Congenital Hypotrichosis in Belted Galloway Cattle

Genes ◽

10.3390/genes12050643 ◽

2021 ◽

Vol 12 (5) ◽

pp. 643

Author(s):

Thibaud Kuca ◽

Brandy M. Marron ◽

Joana G. P. Jacinto ◽

Julia M. Paris ◽

Christian Gerspach ◽

...

Keyword(s):

Genome Wide Association Study ◽

Homozygosity Mapping ◽

Mendelian Inheritance ◽

Large Animal Model ◽

Large Animal ◽

Loss Of Function ◽

Protein Coding ◽

Positional Candidate ◽

Genome Wide ◽

A Genome

Genodermatosis such as hair disorders mostly follow a monogenic mode of inheritance. Congenital hypotrichosis (HY) belong to this group of disorders and is characterized by abnormally reduced hair since birth. The purpose of this study was to characterize the clinical phenotype of a breed-specific non-syndromic form of HY in Belted Galloway cattle and to identify the causative genetic variant for this recessive disorder. An affected calf born in Switzerland presented with multiple small to large areas of alopecia on the limbs and on the dorsal part of the head, neck, and back. A genome-wide association study using Swiss and US Belted Galloway cattle encompassing 12 cases and 61 controls revealed an association signal on chromosome 29. Homozygosity mapping in a subset of cases refined the HY locus to a 1.5 Mb critical interval and subsequent Sanger sequencing of protein-coding exons of positional candidate genes revealed a stop gain variant in the HEPHL1 gene that encodes a multi-copper ferroxidase protein so-called hephaestin like 1 (c.1684A>T; p.Lys562*). A perfect concordance between the homozygous presence of this most likely pathogenic loss-of-function variant and the HY phenotype was found. Genotyping of more than 700 purebred Swiss and US Belted Galloway cattle showed the global spread of the mutation. This study provides a molecular test that will permit the avoidance of risk matings by systematic genotyping of relevant breeding animals. This rare recessive HEPHL1-related form of hypotrichosis provides a novel large animal model for similar human conditions. The results have been incorporated in the Online Mendelian Inheritance in Animals (OMIA) database (OMIA 002230-9913).

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TCF7L2 lncRNA: a link between bipolar disorder and body mass index through glucocorticoid signaling

Molecular Psychiatry ◽

10.1038/s41380-021-01274-z ◽

2021 ◽

Author(s):

Duan Liu ◽

Thanh Thanh Le Nguyen ◽

Huanyao Gao ◽

Huaizhi Huang ◽

Daniel C. Kim ◽

...

Keyword(s):

Body Mass Index ◽

Bipolar Disorder ◽

Body Mass ◽

Genome Wide Association Study ◽

Induced Pluripotent Stem Cell ◽

Sequencing Data ◽

Peripheral Tissues ◽

Genome Wide ◽

A Genome ◽

Trait Locus

AbstractBipolar disorder (BD) and obesity are highly comorbid. We previously performed a genome-wide association study (GWAS) for BD risk accounting for the effect of body mass index (BMI), which identified a genome-wide significant single-nucleotide polymorphism (SNP) in the gene encoding the transcription factor 7 like 2 (TCF7L2). However, the molecular function of TCF7L2 in the central nervous system (CNS) and its possible role in the BD and BMI interaction remained unclear. In the present study, we demonstrated by studying human induced pluripotent stem cell (hiPSC)-derived astrocytes, cells that highly express TCF7L2 in the CNS, that the BD-BMI GWAS risk SNP is associated with glucocorticoid-dependent repression of the expression of a previously uncharacterized TCF7L2 transcript variant. That transcript is a long non-coding RNA (lncRNA-TCF7L2) that is highly expressed in the CNS but not in peripheral tissues such as the liver and pancreas that are involved in metabolism. In astrocytes, knockdown of the lncRNA-TCF7L2 resulted in decreased expression of the parent gene, TCF7L2, as well as alterations in the expression of a series of genes involved in insulin signaling and diabetes. We also studied the function of TCF7L2 in hiPSC-derived astrocytes by integrating RNA sequencing data after TCF7L2 knockdown with TCF7L2 chromatin-immunoprecipitation sequencing (ChIP-seq) data. Those studies showed that TCF7L2 directly regulated a series of BD risk genes. In summary, these results support the existence of a CNS-based mechanism underlying BD-BMI genetic risk, a mechanism based on a glucocorticoid-dependent expression quantitative trait locus that regulates the expression of a novel TCF7L2 non-coding transcript.

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Genome-wide association study reveals 14 new SNPs and confirms two structural variants highly associated with the horned/polled phenotype in goats

BMC Genomics ◽

10.1186/s12864-021-08089-w ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Jiazhong Guo ◽

Rui Jiang ◽

Ayi Mao ◽

George E. Liu ◽

Siyuan Zhan ◽

...

Keyword(s):

Association Study ◽

Mixed Model ◽

Genome Wide Association Study ◽

Insertion Site ◽

Genome Wide Association ◽

Chromosome 1 ◽

Structural Variants ◽

Diagnostic Pcr ◽

Genome Wide ◽

A Genome

Abstract Background There is a long-term interest in investigating the genetic basis of the horned/polled phenotype in domestic goats. Here, we report a genome-wide association study (GWAS) to detect the genetic loci affecting the polled phenotype in goats. Results We obtained a total of 13,980,209 biallelic SNPs, using the genotyping-by-sequencing data from 45 Jintang Black (JT) goats, which included 32 female and nine male goats, and four individuals with the polled intersex syndrome (PIS). Using a mixed-model based GWAS, we identified two association signals, which were located at 150,334,857–150,817,260 bp (P = 5.15 × 10− 119) and 128,286,704–131,306,537 bp (P = 2.74 × 10− 15) on chromosome 1. The genotype distributions of the 14 most significantly associated SNPs were completely correlated with horn status in goats, based on the whole-genome sequencing (WGS) data from JT and two other Chinese horned breeds. However, variant annotation suggested that none of the detected SNPs within the associated regions were plausible causal mutations. Via additional read-depth analyses and visual inspections of WGS data, we found a 10.1-kb deletion (CHI1:g. 129424781_129434939del) and a 480-kb duplication (CHI1:150,334,286–150,818,098 bp) encompassing two genes KCNJ15 and ERG in the associated regions of polled and PIS-affected goats. Notably, the 10.1-kb deletion also served as the insertion site for the 480-kb duplication, as validated by PCR and Sanger sequencing. Our WGS genotyping showed that all horned goats were homozygous for the reference alleles without either the structural variants (SVs), whereas the PIS-affected goats were homozygous for both the SVs. We also demonstrated that horned, polled, and PIS-affected individuals among 333 goats from JT and three other Chinese horned breeds can be accurately classified via PCR amplification and agarose gel electrophoresis of two fragments in both SVs. Conclusion Our results revealed that two genomic regions on chromosome 1 are major loci affecting the polled phenotypes in goats. We provided a diagnostic PCR to accurately classify horned, polled, and PIS-affected goats, which will enable a reliable genetic test for the early-in-life prediction of horn status in goats.

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Genome-wide sexually antagonistic variants reveal longstanding constraints on sexual dimorphism in the fruitfly

10.1101/117176 ◽

2017 ◽

Cited By ~ 1

Author(s):

Filip Ruzicka ◽

Mark S. Hill ◽

Tanya M. Pennell ◽

Ilona Flis ◽

Fiona C. Ingleby ◽

...

Keyword(s):

Sexual Dimorphism ◽

Evolutionary Dynamics ◽

Genome Wide Association Study ◽

Balancing Selection ◽

Sexual Antagonism ◽

Protein Coding ◽

Genome Wide ◽

Genomic Location ◽

Classic Theory ◽

A Genome

The evolution of sexual dimorphism is constrained by a shared genome, leading to ‘sexual antagonism’ where different alleles at given loci are favoured by selection in males and females. Despite its wide taxonomic incidence, we know little about the identity, genomic location and evolutionary dynamics of antagonistic genetic variants. To address these deficits, we use sex-specific fitness data from 202 fully sequenced hemiclonal D. melanogaster fly lines to perform a genome-wide association study of sexual antagonism. We identify ~230 chromosomal clusters of candidate antagonistic SNPs. In contradiction to classic theory, we find no clear evidence that the X chromosome is a hotspot for sexually antagonistic variation. Characterising antagonistic SNPs functionally, we find a large excess of missense variants but little enrichment in terms of gene function. We also assess the evolutionary persistence of antagonistic variants by examining extant polymorphism in wild D. melanogaster populations. Remarkably, antagonistic variants are associated with multiple signatures of balancing selection across the D. melanogaster distribution range, indicating widespread and evolutionarily persistent (>10,000 years) genomic constraints. Based on our results, we propose that antagonistic variation accumulates due to constraints on the resolution of sexual conflict over protein coding sequences, thus contributing to the long-term maintenance of heritable fitness variation.

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Whole genome sequencing identified a 16 kilobase deletion on ECA13 associated with distichiasis in Friesian horses

BMC Genomics ◽

10.1186/s12864-020-07265-8 ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

E. A. Hisey ◽

H. Hermans ◽

Z. T. Lounsberry ◽

F. Avila ◽

R. A. Grahn ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Genome Sequencing ◽

Genome Wide Association Study ◽

Secondary Infection ◽

Whole Genome Sequencing Data ◽

Incomplete Penetrance ◽

Whole Genome ◽

Genome Wide ◽

A Genome

Abstract Background Distichiasis, an ocular disorder in which aberrant cilia (eyelashes) grow from the opening of the Meibomian glands of the eyelid, has been reported in Friesian horses. These misplaced cilia can cause discomfort, chronic keratitis, and corneal ulceration, potentially impacting vision due to corneal fibrosis, or, if secondary infection occurs, may lead to loss of the eye. Friesian horses represent the vast majority of reported cases of equine distichiasis, and as the breed is known to be affected with inherited monogenic disorders, this condition was hypothesized to be a simply inherited Mendelian trait. Results A genome wide association study (GWAS) was performed using the Axiom 670 k Equine Genotyping array (MNEc670k) utilizing 14 cases and 38 controls phenotyped for distichiasis. An additive single locus mixed linear model (EMMAX) approach identified a 1.83 Mb locus on ECA5 and a 1.34 Mb locus on ECA13 that reached genome-wide significance (pcorrected = 0.016 and 0.032, respectively). Only the locus on ECA13 withstood replication testing (p = 1.6 × 10− 5, cases: n = 5 and controls: n = 37). A 371 kb run of homozygosity (ROH) on ECA13 was found in 13 of the 14 cases, providing evidence for a recessive mode of inheritance. Haplotype analysis (hapQTL) narrowed the region of association on ECA13 to 163 kb. Whole-genome sequencing data from 3 cases and 2 controls identified a 16 kb deletion within the ECA13 associated haplotype (ECA13:g.178714_195130del). Functional annotation data supports a tissue-specific regulatory role of this locus. This deletion was associated with distichiasis, as 18 of the 19 cases were homozygous (p = 4.8 × 10− 13). Genotyping the deletion in 955 horses from 54 different breeds identified the deletion in only 11 non-Friesians, all of which were carriers, suggesting that this could be causal for this Friesian disorder. Conclusions This study identified a 16 kb deletion on ECA13 in an intergenic region that was associated with distichiasis in Friesian horses. Further functional analysis in relevant tissues from cases and controls will help to clarify the precise role of this deletion in normal and abnormal eyelash development and investigate the hypothesis of incomplete penetrance.

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Genome-wide profiling of heritable and de novo STR variations

10.1101/077727 ◽

2016 ◽

Cited By ~ 7

Author(s):

Thomas Willems ◽

Dina Zielinski ◽

Assaf Gordon ◽

Melissa Gymrek ◽

Yaniv Erlich

Keyword(s):

Tandem Repeats ◽

High Throughput Sequencing ◽

De Novo ◽

Genetic Diseases ◽

Whole Genome Sequencing Data ◽

Sequencing Data ◽

High Throughput Sequencing Data ◽

Genome Wide ◽

A Genome ◽

Short Tandem

AbstractShort tandem repeats (STRs) are highly variable elements that play a pivotal role in multiple genetic diseases, population genetics applications, and forensic casework. However, STRs have proven problematic to genotype from high-throughput sequencing data. Here, we describe HipSTR, a novel haplotype-based method for robustly genotyping, haplotyping, and phasing STRs from whole genome sequencing data and report a genome-wide analysis and validation of de novo STR mutations.

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Investigating the Evolutionary Importance of Denisovan Introgressions in Papua New Guineans and Australians

10.1101/022632 ◽

2015 ◽

Author(s):

Ya Hu ◽

Qiliang Ding ◽

Yi Wang ◽

Shuhua Xu ◽

Yungang He ◽

...

Keyword(s):

False Positive Rate ◽

Whole Genome Sequencing Data ◽

Phase Method ◽

Sequencing Data ◽

Male Gonad ◽

Two Phase ◽

Genome Wide ◽

A Genome ◽

Positive Rate ◽

Olfactory Pit

Previous research reported that Papua New Guineans (PNG) and Australians contain introgressions from Denisovans. Here we present a genome-wide analysis of Denisovan introgressions in PNG and Australians. We firstly developed a two-phase method to detect Denisovan introgressions from whole-genome sequencing data. This method has relatively high detection power (79.74%) and low false positive rate (2.44%) based on simulations. Using this method, we identified 1.34 Gb of Denisovan introgressions from sixteen PNG and four Australian genomes, in which we identified 38,877 Denisovan introgressive alleles (DIAs). We found that 78 Denisovan introgressions were under positive selection. Genes located in the 78 introgressions are related to evolutionarily important functions, such as spermatogenesis, fertilization, cold acclimation, circadian rhythm, development of brain, neural tube, face, and olfactory pit, immunity, etc. We also found that 121 DIAs are missense. Genes harboring the 121 missense DIAs are also related to evolutionarily important functions, such as female pregnancy, development of face, lung, heart, skin, nervous system, and male gonad, visual and smell perception, response to heat, pain, hypoxia, and UV, lipid transport, metabolism, blood coagulation, wound healing, aging, etc. Taken together, this study suggests that Denisovan introgressions in PNG and Australians are evolutionarily important, and may help PNG and Australians in local adaptation. In this study, we also proposed a method that could efficiently identify archaic hominin introgressions in modern non-African genomes.

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Genome-wide discovery of epistatic loci affecting antibiotic resistance using evolutionary couplings

10.1101/325993 ◽

2018 ◽

Author(s):

Benjamin Schubert ◽

Rohan Maddamsetti ◽

Jackson Nyman ◽

Maha R. Farhat ◽

Debora S. Marks

Keyword(s):

Antibiotic Resistance ◽

Statistical Power ◽

Genome Wide Association Study ◽

Association Studies ◽

Genome Wide Association ◽

Whole Genome Sequencing Data ◽

Genome Wide Association Studies ◽

Sequencing Data ◽

Vast Number ◽

Genome Wide

ABSTRACTThe analysis of whole genome sequencing data should, in theory, allow the discovery of interdependent loci that cause antibiotic resistance. In practice, however, identifying this epistasis remains a challenge as the vast number of possible interactions erodes statistical power. To solve this problem, we extend a method that has been successfully used to identify epistatic residues in proteins to infer genomic loci that are strongly coupled and associated with antibiotic resistance. Our method reduces the number of tests required for an epistatic genome-wide association study and increases the likelihood of identifying causal epistasis. We discovered 38 loci and 250 epistatic pairs that influence the dose needed to inhibit growth for five different antibiotics in 1,102 isolates of Neisseria gonorrhoeae that were confirmed in an independent dataset of 495 isolates. Many known resistance-affecting loci were recovered; however, the majority of loci occurred in unreported genes, including murE which was associated with cefixime. About half of the novel epistasis we report involved at least one locus previously associated with antibiotic resistance, including interactions between gyrA and parC associated with ciprofloxacin. Still, many combinations involved unreported loci and genes. Our work provides a systematic identification of epistasis pairs affecting antibiotic resistance in N. gonorrhoeae and a generalizable method for epistatic genome-wide association studies.

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Frameshift Variant in MFSD12 Explains the Mushroom Coat Color Dilution in Shetland Ponies

Genes ◽

10.3390/genes10100826 ◽

2019 ◽

Vol 10 (10) ◽

pp. 826

Author(s):

Jocelyn Tanaka ◽

Tosso Leeb ◽

James Rushton ◽

Thomas R. Famula ◽

Maura Mack ◽

...

Keyword(s):

Genome Wide Association Study ◽

Coat Color ◽

Mixed Linear Model ◽

Major Facilitator Superfamily ◽

Recessive Trait ◽

Sequencing Data ◽

Gene Encoding ◽

Genome Wide ◽

A Genome ◽

Major Facilitator

Mushroom is a unique coat color phenotype in Shetland Ponies characterized by the dilution of the chestnut coat color to a sepia tone and is hypothesized to be a recessive trait. A genome wide association study (GWAS), utilizing the Affymetrix 670K array (MNEc670k) and a single locus mixed linear model analysis (EMMAX), identified a locus on ECA7 for further investigation (Pcorrected = 2.08 × 10−10). This locus contained a 3 Mb run of homozygosity in the 12 mushroom ponies tested. Analysis of high throughput Illumina sequencing data from one mushroom Shetland pony compared to 87 genomes from horses of various breeds, uncovered a frameshift variant, p.Asp201fs, in the MFSD12 gene encoding the major facilitator superfamily domain containing 12 protein. This variant was perfectly concordant with phenotype in 96 Shetland Ponies (P = 1.15 × 10−22), was identified in the closely related Miniature Horse for which the mushroom phenotype is suspected to occur (fmu = 0.02), and was absent in 252 individuals from seven additional breeds not reported to have the mushroom phenotype. MFSD12 is highly expressed in melanocytes and variants in this gene in humans, mice, and dogs impact pigmentation. Given the role of MFSD12 in melanogenesis, we propose that p.Asp201fs is causal for the dilution observed in mushroom ponies.

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Genome-wide association study in the pseudocereal quinoa reveals selection pattern typical for crops with a short breeding history

10.1101/2020.12.03.410050 ◽

2020 ◽

Author(s):

Dilan S. R. Patiranage ◽

Elodie Rey ◽

Nazgol Emrani ◽

Gordon Wellman ◽

Karl Schmid ◽

...

Keyword(s):

Association Study ◽

Genome Wide Association Study ◽

Agronomic Traits ◽

Sequence Data ◽

Genome Wide Association ◽

Sequencing Data ◽

Genome Wide ◽

A Genome ◽

Modern Breeding ◽

Orphan Crop

AbstractQuinoa germplasm preserves useful and substantial genetic variation, yet it remains untapped due to a lack of implementation of modern breeding tools. We have integrated field and sequence data to characterize a large diversity panel of quinoa. Whole-genome sequencing of 310 accessions revealed 2.9 million polymorphic high confidence SNP loci. Highland and Lowland quinoa were clustered into two main groups, with FST divergence of 0.36 and fast LD decay of 6.5 and 49.8 Kb, respectively. A genome-wide association study uncovered 600 SNPs stably associated with 17 agronomic traits. Two candidate genes are associated with thousand seed weight, and a resistance gene analog is associated with downy mildew resistance. We also identified pleiotropically acting loci for four agronomic traits that are highly responding to photoperiod hence important for the adaptation to different environments. This work demonstrates the use of re-sequencing data of an orphan crop, which is partially domesticated to rapidly identify marker-trait association and provides the underpinning elements for genomics-enabled quinoa breeding.

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