scholarly journals The Role of Knockout Olfactory Receptor Genes in Odor Discrimination

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 631
Author(s):  
Maria Pina Concas ◽  
Massimiliano Cocca ◽  
Margherita Francescatto ◽  
Thomas Battistuzzi ◽  
Beatrice Spedicati ◽  
...  
Keyword(s):  
Olfactory Receptor ◽  
Recursive Partitioning ◽  
Odor Discrimination ◽  
Recursive Partitioning Analysis ◽  
Whole Genome Sequencing Data ◽  
P Value ◽  
Sequencing Data ◽  
Mouse Tissues ◽  
Or Genes

To date, little is known about the role of olfactory receptor (OR) genes on smell performance. Thanks to the availability of whole-genome sequencing data of 802 samples, we identified 41 knockout (KO) OR genes (i.e., carriers of Loss of Function variants) and evaluated their effect on odor discrimination in 218 Italian individuals through recursive partitioning analysis. Furthermore, we checked the expression of these genes in human and mouse tissues using publicly available data and the presence of organ-related diseases in human KO (HKO) individuals for OR expressed in non-olfactory tissues (Fisher test). The recursive partitioning analysis showed that age and the high number (burden) of OR-KO genes impact the worsening of odor discrimination (p-value < 0.05). Human expression data showed that 33/41 OR genes are expressed in the olfactory system (OS) and 27 in other tissues. Sixty putative mouse homologs of the 41 humans ORs have been identified, 58 of which are expressed in the OS and 37 in other tissues. No association between OR-KO individuals and pathologies has been detected. In conclusion, our work highlights the role of the burden of OR-KO genes in worse odor discrimination.

scholarly journals De novo indels within introns contribute to ASD incidence

2017 ◽  
Author(s):  
Adriana Munoz ◽  
Boris Yamrom ◽  
Yoon-ha Lee ◽  
Peter Andrews ◽  
Steven Marks ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Target Genes ◽  
De Novo ◽  
Whole Genome Sequencing Data ◽  
P Value ◽  
Whole Genome ◽  
Sequencing Data ◽  
Control Sets ◽  
The Difference

AbstractCopy number profiling and whole-exome sequencing has allowed us to make remarkable progress in our understanding of the genetics of autism over the past ten years, but there are major aspects of the genetics that are unresolved. Through whole-genome sequencing, additional types of genetic variants can be observed. These variants are abundant and to know which are functional is challenging. We have analyzed whole-genome sequencing data from 510 of the Simons Simplex Collections quad families and focused our attention on intronic variants. Within the introns of 546 high-quality autism target genes, we identified 63 de novo indels in the affected and only 37 in the unaffected siblings. The difference of 26 events is significantly larger than expected (p-val = 0.01) and using reasonable extrapolation shows that de novo intronic indels can contribute to at least 10% of simplex autism. The significance increases if we restrict to the half of the autism targets that are intolerant to damaging variants in the normal human population, which half we expect to be even more enriched for autism genes. For these 273 targets we observe 43 and 20 events in affected and unaffected siblings, respectively (p-value of 0.005). There was no significant signal in the number of de novo intronic indels in any of the control sets of genes analyzed. We see no signal from de novo substitutions in the introns of target genes.

scholarly journals An Increased Burden of Highly Active Retrotransposition Competent L1s Is Associated with Parkinson’s Disease Risk and Progression in the PPMI Cohort

2020 ◽  
Vol 21 (18) ◽  
pp. 6562 ◽  
Author(s):  
Abigail L. Pfaff ◽  
Vivien J. Bubb ◽  
John P. Quinn ◽  
Sulev Koks
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Risk ◽  
Whole Genome Sequencing Data ◽  
Sequencing Data ◽  
Highly Active ◽  
Germline Variation ◽  
Progression Markers ◽  
Long Interspersed Element

Long interspersed element-1 (LINE-1/L1s) contributes 17% of the human genome with more than 1 million elements present; however, fewer than 100 of these have evidence for being retrotransposition competent (RC). In addition to those RC-L1s present in the reference genome, there are a small number of known non-reference L1 insertions that are also retrotransposition competent. L1 activity, whether through the potentially detrimental effects of their mRNA or protein expression or somatic retrotransposition events, has been linked to several neurological conditions. The polymorphic nature of both reference and non-reference RC-L1s in terms of their presence or absence will result in individuals harboring a different combination of these elements and it is currently unknown if this type of germline variation contributes to the risk of neurological disease. Here, we utilized whole-genome sequencing data from 178 healthy controls and 372 Parkinson’s disease (PD) subjects from the Parkinson’s Progression Markers Initiative (PPMI) to investigate the role of RC-L1s in PD. In the PPMI cohort, we identified 22 reference and 50 non-reference polymorphic RC-L1 loci. Focusing on 16 highly active RC-L1 loci, an increased burden of these elements (≥9) was associated with PD (OR 1.25, 95% CI 1.03–1.51, p = 0.02). In addition, we identified significant associations of progression markers of PD and the burden of highly active RC-L1s. This study has identified a novel type of genetic element associated with PD risk and disease progression.

scholarly journals TOMM40 ‘523’ poly-T repeat length is a determinant of longitudinal cognitive decline in Parkinson’s disease

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Megan C. Bakeberg ◽  
Anastazja M. Gorecki ◽  
Abigail L. Pfaff ◽  
Madison E. Hoes ◽  
Sulev Kõks ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cognitive Decline ◽  
Cognitive Performance ◽  
Disease Onset ◽  
Whole Genome Sequencing Data ◽  
Sequencing Data ◽  
Progression Markers ◽  
The Relationship

AbstractThe translocase of outer mitochondrial membrane 40 (TOMM40) ‘523’ polymorphism has previously been associated with age of Alzheimer’s disease onset and cognitive functioning in non-pathological ageing, but has not been explored as a candidate risk marker for cognitive decline in Parkinson’s disease (PD). Therefore, this longitudinal study investigated the role of the ‘523’ variant in cognitive decline in a patient cohort from the Parkinson’s Progression Markers Initiative. As such, a group of 368 people with PD were assessed annually for cognitive performance using multiple neuropsychological protocols, and were genotyped for the TOMM40 ‘523’ variant using whole-genome sequencing data. Covariate-adjusted generalised linear mixed models were utilised to examine the relationship between TOMM40 ‘523’ allele lengths and cognitive scores, while taking into account the APOE ε genotype. Cognitive scores declined over the 5-year study period and were lower in males than in females. When accounting for APOE ε4, the TOMM40 ‘523’ variant was not robustly associated with overall cognitive performance. However, in APOE ε3/ε3 carriers, who accounted for ~60% of the whole cohort, carriage of shorter ‘523’ alleles was associated with more severe cognitive decline in both sexes, while carriage of the longer alleles in females were associated with better preservation of global cognition and a number of cognitive sub-domains, and with a delay in progression to dementia. The findings indicate that when taken in conjunction with the APOE genotype, TOMM40 ‘523’ allele length is a significant independent determinant and marker for the trajectory of cognitive decline and risk of dementia in PD.

scholarly journals Transcriptomic Stratification of Late-Onset Alzheimer’s Cases Reveals Novel Genetic Modifiers of Disease Pathology

2019 ◽  
Author(s):  
Nikhil Milind ◽  
Christoph Preuss ◽  
Annat Haber ◽  
Guru Ananda ◽  
Shubhabrata Mukherjee ◽  
...  
Keyword(s):  
Late Onset ◽  
Genetic Disorder ◽  
Whole Genome Sequencing Data ◽  
P Value ◽  
Genetic Modifiers ◽  
Sequencing Data ◽  
Disease Heterogeneity ◽  
Association Testing ◽  
Novel Approach ◽  
A Genome

ABSTRACTLate-Onset Alzheimer’s disease (LOAD) is a common, complex genetic disorder well-known for its heterogeneous pathology. The genetic heterogeneity underlying common complex diseases poses a major challenge for targeted therapies and the identification of novel disease-associated variants. Case-control approaches are often limited to examining a specific outcome in a group of heterogenous patients with different clinical characteristics. Here, we developed a novel approach to define relevant transcriptomic endophenotypes and stratify decedents based on molecular profiles in three independent human LOAD cohorts. By integrating post-mortem brain gene co-expression data from 2114 human samples with LOAD, we developed a novel quantitative, composite phenotype that can better account for the heterogeneity in genetic architecture underlying the disease. We used iterative weighted gene co-expression network analysis (WGCNA) analysis to reduce data dimensionality and to isolate gene sets that are highly co-expressed within disease subtypes and represent specific molecular pathways. We then performed single variant association testing using whole genome-sequencing data for the novel composite phenotype in order to identify genetic loci that contribute to disease heterogeneity. Distinct LOAD subtypes were identified for all three study cohorts (two in ROSMAP, three in Mayo Clinic, two in Mount Sinai Brain Bank). Single variant association analysis identified a genome-wide significant variant in TMEM106B (p-value < 5×10−8, rs1990620G) in the ROSMAP cohort that confers protection from the inflammatory LOAD subtype. Taken together, our novel approach can be used to stratify LOAD into distinct molecular subtypes based on affected disease pathways.

EPCO-31. GERMLINE AND SOMATIC MUTATIONS IN PEDIATRIC GERM CELL TUMORS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi8-vi9
Author(s):  
Dong Song ◽  
Yang Zhao ◽  
Quanhua Mu ◽  
Zhuangzhuang Liang ◽  
Jiajia Wang ◽  
...  
Keyword(s):  
Germ Cell ◽  
Somatic Mutations ◽  
De Novo ◽  
Germ Cell Tumors ◽  
Germline Mutations ◽  
Driver Mutations ◽  
Whole Genome Sequencing Data ◽  
P Value ◽  
Sequencing Data ◽  
Disease Etiology

Abstract Pediatric germ cell tumors (pGCTs), a group of germ-cell-originated neoplasms, currently lack sufficient study. Although somatic activation of KIT/AKT and RAS/MAPK pathways have been revealed, no driver mutations have been detected in most of GCT cases. To extensively explore germline and somatic mutations, we analyzed genomic and/or transcriptomic sequencing data of 236 pGCTs, including data from not only public datasets but also newly collected whole-genome-sequencing data of tumor samples together with case-unaffected-parents trios collected in Shanghai Xinhua Hospital. A new computational pipeline was developed and carried out to identify functional germline and somatic variants. Overall, &gt; 30,000 germline and &gt; 100,000 somatic mutations were detected and prioritized. Particularly, we found germline trisomy 21 in three cases, germline XXY in five cases, and one germline XO, demonstrating the enrichment of germline chromosomal abnormality in pGCTs (p-value &lt; 0.0001). We identified 196 loss-of-function-like inherited germline mutations involving CBL (4/212), PTEN (3/212), TEX11 (2/212), and ATM (1/212). In addition, we detected 2,160 de novo germline mutations (DNMs), and showed an average of 69.7 DNMs per proband, which is compatible to the previously reported incidence. Moreover, we discovered recurrent somatic mutations in known driver genes such as KIT (27/110), KRAS (10/110), NRAS (4/110), MTOR (5/110), PTEN (3/110), and CBL (2/110). Interestingly, somatic hotspot RRAS2 mutations were detected in seven of 110 cases. Subsequent clinical association analysis showed that patients who harbored RRAS2 mutations were younger than those harboring KRAS mutations (p-value &lt; 0.05). Somatic copy number changes were frequently observed, including chr12p+ (47/110), chr21q+ (47/110), chrX+ (34/110), chr13q- (27/110), and chr20q+ (26/110). Furthermore, we identified chromoplexy in nine out of 62 cases, and this alteration is significantly enriched in yolk sac tumors with the occurrence 7/11. Collectively, portraying the mutational landscape of pGCTs, we revealed its disease etiology and potential new drug targets.

scholarly journals A Pan-Cancer Transcriptome Analysis Reveals Pervasive Regulation through Tumor-Associated Alternative Promoters

2017 ◽  
Author(s):  
Deniz Demircioğlu ◽  
Martin Kindermans ◽  
Tannistha Nandi ◽  
Engin Cukuroglu ◽  
Claudia Calabrese ◽  
...  
Keyword(s):  
Whole Genome Sequencing Data ◽  
Alternative Promoters ◽  
Cancer Genes ◽  
Sequencing Data ◽  
Protein Coding ◽  
Cancer Transcriptome ◽  
Dynamic Landscape ◽  
Specific Regulation ◽  
Context Specific

ABSTRACTMost human protein-coding genes are regulated by multiple, distinct promoters, suggesting that the choice of promoter is as important as its level of transcriptional activity. While the role of promoters as driver elements in cancer has been recognized, the contribution of alternative promoters to regulation of the cancer transcriptome remains largely unexplored. Here we infer active promoters using RNA-Seq data from 1,188 cancer samples with matched whole genome sequencing data. We find that alternative promoters are a major contributor to context-specific regulation of isoform expression and that alternative promoters are frequently deregulated in cancer, affecting known cancer-genes and novel candidates. Our study suggests that a highly dynamic landscape of active promoters shapes the cancer transcriptome, opening many opportunities to further explore the interplay of regulatory mechanism and noncoding somatic mutations with transcriptional aberrations in cancer.

scholarly journals Analysis of gene expression and mutation data points on contribution of transcription to the mutagenesis by APOBEC enzymes

NAR Cancer ◽  
2021 ◽  
Vol 3 (3) ◽  
Author(s):  
Almira Chervova ◽  
Bulat Fatykhov ◽  
Alexander Koblov ◽  
Evgeny Shvarov ◽  
Julia Preobrazhenskaya ◽  
...  
Keyword(s):  
Gene Expression ◽  
Whole Genome Sequencing Data ◽  
Sequencing Data ◽  
Induced Mutations ◽  
Cellular Processes ◽  
Human Cancers ◽  
Sense Strand ◽  
Data Points ◽  
Transcription And Replication

Abstract Since the discovery of the role of the APOBEC enzymes in human cancers, the mechanisms of this type of mutagenesis remain little understood. Theoretically, targeting of single-stranded DNA by the APOBEC enzymes could occur during cellular processes leading to the unwinding of DNA double-stranded structure. Some evidence points to the importance of replication in the APOBEC mutagenesis, while the role of transcription is still underexplored. Here, we analyzed gene expression and whole genome sequencing data from five types of human cancers with substantial APOBEC activity to estimate the involvement of transcription in the APOBEC mutagenesis and compare its impact with that of replication. Using the TCN motif as the mutation signature of the APOBEC enzymes, we observed a correlation of active APOBEC mutagenesis with gene expression, confirmed the increase of APOBEC-induced mutations in early-replicating regions and estimated the relative impact of transcription and replication on the APOBEC mutagenesis. We also found that the known effect of higher density of APOBEC-induced mutations on the lagging strand was highest in middle-replicating regions and observed higher APOBEC mutation density on the sense strand, the latter bias positively correlated with the gene expression level.

scholarly journals Analysis of gene expression and mutation data points on contribution of transcription to the mutagenesis by APOBEC enzymes

2021 ◽  
Author(s):  
Almira Chervova ◽  
Bulat Fatykhov ◽  
Alexander Koblov ◽  
Evgeny Shvarov ◽  
Julia Preobrazhenskaya ◽  
...  
Keyword(s):  
Gene Expression ◽  
Whole Genome Sequencing Data ◽  
Sequencing Data ◽  
Induced Mutations ◽  
Cellular Processes ◽  
Human Cancers ◽  
Sense Strand ◽  
Data Points ◽  
Transcription And Replication

Since the discovery of the role of the APOBEC enzymes in human cancers, the mechanisms of this type of mutagenesis remain little understood. Theoretically, targeting of single-stranded DNA by the APOBEC enzymes could occur during cellular processes leading to the unwinding of DNA double-stranded structure. Some evidence points to the importance of replication in the APOBEC mutagenesis, while the role of transcription is still underexplored. Here, we analyzed gene expression and whole genome sequencing data from five types of human cancers with substantial APOBEC activity to estimate the involvement of transcription in the APOBEC mutagenesis and compare its impact with that of replication. Using the TCN motif as the mutation signature of the APOBEC enzymes, we observed a correlation of active APOBEC mutagenesis with gene expression, confirmed the increase of APOBEC-induced mutations in early-replicating regions, and estimated the relative impact of transcription and replication on the APOBEC mutagenesis, which turned out to be approximately equal in transcribed regions. We also found that the known effect of higher density of APOBEC-induced mutations on the lagging strand was highest in middle-replicating regions, and observed higher APOBEC mutation density on the sense strand, the latter bias positively correlated with the gene expression level.

scholarly journals A functional variant of SHARPIN confers increased risk of late-onset Alzheimer’s disease

2021 ◽  
Author(s):  
Yuya Asanomi ◽  
Daichi Shigemizu ◽  
Shintaro Akiyama ◽  
Akinori Miyashita ◽  
Risa Mitsumori ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cellular Localization ◽  
Late Onset ◽  
Whole Genome Sequencing Data ◽  
Sequencing Data ◽  
Functional Variants ◽  
Increased Risk ◽  
Functional Variant

AbstractLate-onset Alzheimer’s disease (LOAD) is the most common form of dementia, and its pathogenesis is multifactorial. We previously reported a rare functional variant of SHARPIN (rs572750141, NP_112236.3:p.Gly186Arg) that was significantly associated with LOAD. In addition, several recent studies have suggested the potential role of SHARPIN in AD pathogenesis. In this study, we sought to identify additional functional variants of SHARPIN in Japanese population. Six highly deleterious variants of SHARPIN, comprising four missense variants, one frameshift variant, and one stop-gain variant were detected from whole-genome sequencing data for 180 patients with LOAD and 184 with mild cognitive impairment. One of these candidate variants (rs77359862, NP_112236.3:p.Arg274Trp) was significantly associated with an increased risk of LOAD in 5043 LOAD cases and 11984 controls (P = 0.0016, odds ratio = 1.43). Furthermore, this variant SHARPIN showed aberrant cellular localization and reduced the activation of NF-κB, a central mediator of inflammatory and immune responses. Further investigation of the physiologic role of SHARPIN may reveal the mechanism of onset of LOAD.

scholarly journals Assessment of LIN28A variants in Parkinson’s disease

2020 ◽  
Author(s):  
Monica Diez-Fairen ◽  
Mary B. Makarious ◽  
Sara Bandres-Ciga ◽  
Cornelis Blauwendraat
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Large Scale ◽  
Disease Risk ◽  
Age At Onset ◽  
European Ancestry ◽  
Whole Genome Sequencing Data ◽  
Sequencing Data ◽  
Common Genetic Variants

AbstractParkinson’s disease (PD) is a complex neurodegenerative disease with a strong genetic component in which both rare and common genetic variants contribute to disease risk, onset and progression. Despite that several genes have been associated with familial forms of disease, validation of novel genes associated with PD remains extremely challenging. Recently, a heterozygous loss-of-function variant in LIN28A was associated with PD pathogenesis in the Asian population. Here, we comprehensively assess the role of LIN28A variants in PD susceptibility using individual-level genotyping data from 14,671 PD cases and 17,667 controls, as well as whole-genome sequencing data from 1,647 PD patients and 1,050 controls. Additionally, we further assessed the summary statistics from the most recent GWAS meta-analyses to date for PD risk and age at onset. After evaluating these data, we did not find evidence to support a role for LIN28A as a major causal gene for PD. However, additional large-scale familial and case-control studies in non-European ancestry populations are necessary to further evaluate the role of LIN28A in PD etiology.

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