scholarly journals Genetic variant in SPDL1 reveals novel mechanism linking pulmonary fibrosis risk and cancer protection

2021 ◽  
Author(s):  
Jukka T. Koskela ◽  
Paavo Happola ◽  
Aoxing Liu ◽  
Juulia Partanen ◽  
Giulio Genovese ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Telomere Length ◽  
Cellular Senescence ◽  
Population Sample ◽  
Missense Variant ◽  
Length Variation ◽  
Uk Biobank ◽  
Cellular Division ◽  
Chromosomal Alterations ◽  
Risk Of Cancer

Idiopathic Pulmonary Fibrosis (IPF) is a rare disease with poor prognosis. By contrast, cancer is common in any elderly population and a leading killer, but is now often curable. Of note, whereas IPF is driven by cellular senescence, cancer is characterized by uncontrolled cell division. Using data available from two large biobank-based studies (Finnish FinnGen study and UK biobank), we conducted a comprehensive analysis of the shared genetic background of IPF and cancer. In a population sample of 218,792 Finns with complete longitudinal health histories, we estimated the effect of individual genetic variants to the lifetime risk of IPF and cancer. We extend the analysis from IPF-GWAS to pan-cancer meta-analysis over FinnGen and UK Biobank and finally to the identification of genetic drivers of somatic chromosomal alterations. We detected six loci (SPDL1, MAD1L1, MAP2K1, RTEL1-STMN3, TERC-ACTRT3, OBFC1) associated with both IPF and cancer, all closely related to cellular division. However, each individual signal is found with opposite effects over the two diseases, termed as antagonistic pleiotropy. Several of these loci (TERC-ACTRT3, RTEL1-STMN3, OBFC1) are among the strongest inherited factors for constitutive telomere length variation and consistently indicate that shorter telomere length would increase the risk for IPF but protect from malignancy. However, a Finnish enriched SPDL1 missense variant and a common MAD1L1 intronic variant had no effect on telomere length but were shown to protect individuals from accumulation of somatic mutations. The decreased risk of cancer in SPDL1 and MAD1L1 variant carriers might result from a lower number of chromosomal alterations accumulated over time, conversely leading to fibrosis in the lung due to cellular senescence-induced inflammation. We hypothesize that the SPDL1 missense variant functions as gain-of-function mutation, leading to cellular senescence, a barrier to cancer and a driver of fibrosis in IPF. If translated to therapy, these findings might not only be able to offer relief to individuals with IPF, but also to protect from onset of cancer.

scholarly journals Polygenic basis and biomedical consequences of telomere length variation

2021 ◽  
Author(s):  
Veryan Codd ◽  
Qingning Wang ◽  
Elias Allara ◽  
Crispin Musicha ◽  
Stephen Kaptoge ◽  
...  
Keyword(s):  
Telomere Length ◽  
Genetic Architecture ◽  
Cellular Proliferation ◽  
Genetic Regulation ◽  
Biological Traits ◽  
Length Variation ◽  
Uk Biobank ◽  
Naturally Occurring ◽  
Bone Marrow Function ◽  
Genetically Determined

Telomeres, the end fragments of chromosomes, play key roles in cellular proliferation and senescence. Here we characterize the genetic architecture of naturally-occurring variation in leucocyte telomere length (LTL) and identify causal links between LTL and biomedical phenotypes in 472,174 well-characterized participants in UK Biobank. We identified 197 independent sentinel variants associated with LTL at 138 genomic loci (108 novel). Genetically-determined differences in LTL were associated with multiple biological traits, ranging from height to bone marrow function, as well as several diseases spanning neoplastic, vascular, and inflammatory pathologies. Finally, we estimated that at age 40 years, people with >1-SD shorter compared to ≥1-SD longer LTL than the population mean had 2.5 years lower life expectancy. Overall, we furnish novel insights into the genetic regulation of LTL, reveal LTL's wide-ranging influences on physiological traits, diseases, and longevity, and provide a powerful resource available to the global research community.

scholarly journals Natural variation in plant telomere length is associated with flowering time

2021 ◽  
Author(s):  
Jae Young Choi ◽  
Liliia R Abdulkina ◽  
Jun Yin ◽  
Inna B Chastukhina ◽  
John T Lovell ◽  
...  
Keyword(s):  
Life History ◽  
Telomere Length ◽  
Flowering Time ◽  
Dna Sequences ◽  
Genome Wide Association Study ◽  
Genomic Analysis ◽  
Life History Strategies ◽  
Length Variation ◽  
Chromosomal Structure ◽  
Chromosome Integrity

Abstract Telomeres are highly repetitive DNA sequences found at the ends of chromosomes that protect the chromosomes from deterioration during cell division. Here, using whole genome re-sequencing and terminal restriction fragment assays, we found substantial natural intraspecific variation in telomere length in Arabidopsis thaliana, rice (Oryza sativa), and maize (Zea mays). Genome-wide association study (GWAS) mapping in A. thaliana identified 13 regions with GWAS-significant associations underlying telomere length variation, including a region that harbors the telomerase reverse transcriptase (TERT) gene. Population genomic analysis provided evidence for a selective sweep at the TERT region associated with longer telomeres. We found that telomere length is negatively correlated with flowering time variation not only in A. thaliana, but also in maize and rice, indicating a link between life history traits and chromosome integrity. Our results point to several possible reasons for this correlation, including the possibility that longer telomeres may be more adaptive in plants that have faster developmental rates (and therefore flower earlier). Our work suggests that chromosomal structure itself might be an adaptive trait associated with plant life history strategies.

scholarly journals A pooled sequencing approach identifies a candidate meiotic driver in Drosophila

2017 ◽  
Author(s):  
Kevin H-C Wei ◽  
Hemakumar M. Reddy ◽  
Chandramouli Rathnam ◽  
Jimin Lee ◽  
Deanna Lin ◽  
...  
Keyword(s):  
Telomere Length ◽  
Natural Populations ◽  
Meiotic Drive ◽  
Length Variation ◽  
Sequence Evolution ◽  
Nucleotide Polymorphisms ◽  
Mendelian Segregation ◽  
Transmission Frequency ◽  
Multiple Observations ◽  
Telomere Sequence

AbstractMeiotic drive occurs when a selfish element increases its transmission frequency above the Mendelian ratio by hijacking the asymmetric divisions of female meiosis. Meiotic drive causes genomic conflict and potentially has a major impact on genome evolution, but only a few drive loci of large effect have been described. New methods to reliably detect meiotic drive are therefore needed, particularly for discovering moderate-strength drivers that are likely to be more prevalent in natural populations than strong drivers. Here we report an efficient method that uses sequencing of large pools of backcross (BC1) progeny to test for deviations from Mendelian segregation genome-wide of single-nucleotide polymorphisms (SNPs) that distinguish the parental strains. We show that meiotic drive can be detected by a characteristic pattern of decay in distortion of SNP frequencies, caused by recombination unlinking the driver from distal loci. We further show that control crosses allow allele-frequency distortion caused by meiotic drive to be distinguished from distortion resulting from developmental effects. We used this approach to test whether chromosomes with extreme telomere-length differences segregate at Mendelian ratios, as telomeric regions are a potential hotspot for meiotic drive due to their roles in meiotic segregation and multiple observations of high rates of telomere sequence evolution. Using four different pairings of long and short telomere strains, we find no evidence that extreme telomere-length variation causes meiotic drive in Drosophila. However, we identify one candidate meiotic driver in a centromere-linked region that shows an ~8% increase in transmission frequency, corresponding to a ~54:46 segregation ratio. Our results show that candidate meiotic drivers of moderate strength can be readily detected and localized in pools of F1 progeny.

Traumatic stress and cellular senescence: The role of war-captivity and homecoming stressors in later life telomere length

2018 ◽  
Vol 238 ◽  
pp. 129-135 ◽  
Author(s):  
Jacob Y. Stein ◽  
Yafit Levin ◽  
Orit Uziel ◽  
Heba Abumock ◽  
Zahava Solomon
Keyword(s):  
Telomere Length ◽  
Cellular Senescence ◽  
Traumatic Stress ◽  
Later Life

scholarly journals Non-coding RNAs as Regulators of Cellular Senescence in Idiopathic Pulmonary Fibrosis and Chronic Obstructive Pulmonary Disease

2020 ◽  
Vol 7 ◽  
Author(s):  
Norihito Omote ◽  
Maor Sauler
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Pulmonary Disease ◽  
Cell Fate ◽  
Cellular Senescence ◽  
Cellular Stress ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Non Coding Rnas

Cellular senescence is a cell fate implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). Cellular senescence occurs in response to cellular stressors such as oxidative stress, DNA damage, telomere shortening, and mitochondrial dysfunction. Whether these stresses induce cellular senescence or an alternative cell fate depends on the type and magnitude of cellular stress, but also on intrinsic factors regulating the cellular stress response. Non-coding RNAs, including both microRNAs and long non-coding RNAs, are key regulators of cellular stress responses and susceptibility to cellular senescence. In this review, we will discuss cellular mechanisms that contribute to senescence in IPF and COPD and highlight recent advances in our understanding of how these processes are influenced by non-coding RNAs. We will also discuss the potential therapeutic role for targeting non-coding RNAs to treat these chronic lung diseases.

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