Klinik Ekzom Sekans Trio Örneklerinde De Novo Mutasyonların Sıklığı ve Karakteristik Özlelliklerinin Araştırılması
Öz
Gelişmiş genom dizileme teknolojileri, genom ile ilişkilendirilen koşulların mekanizmalarını derinlemesine anlama fırsatı sunmuştur. Son zamanlarda, üreme hücrelerinde ortaya çıkan ve ebeveynlerde bulunmayan genetik değişiklikler olan de novo mutasyonların özelliklerini anlama konusunda önemli bir ilgi olmuştur ve oluşumlarına dahil olan mekanizmaları anlamak. Bu mutasyonlar sonraki nesillere aktarılabilir ve genetik çeşitliliği ve hastalıklara duyarlılığı etkileme potansiyeline sahiptir, bu nedenle bu konu önemlidir. Bu alandaki sınırlı çalışmalar nedeniyle, bu mutasyonların oluşum mekanizmaları ve karakteristik özellikleri henüz tam olarak anlaşılamamıştır.
Arka Plan/Hedefler: Bu çalışmada, üçlü klinik ekzom dizileme analizi geçiren ailelerde de novo mutasyonların kapsamlı bir analizini yapmayı amaçladık. Çalışmanın amaçları, ebeveyn yaşları ile de novo mutasyonların sıklığı arasındaki ilişkiyi, de novo mutasyonların dağılımını, yaygınlığını, ilişkilerini ve moleküler özelliklerini araştırmaktı.
Yöntemler: Selçuk Üniversitesi Tıp Fakültesi Tıbbi Genetik Anabilim Dalı'nda 1 Ocak 2017 ile 31 Aralık 2023 tarihleri arasında üçlü Klinik Ekzom Dizileme (CED) analizi geçiren toplam 69 aile çalışmaya dahil edildi. Bireylerin periferik venöz kanından elde edilen DNA örnekleri Roche CED kiti ve DNBSEQ-G400™ dizileme cihazı kullanılarak dizilendi ve Seq Platformu kullanılarak toplam 3892 gen analiz edildi.
Sonuçlar: Analizlerden sonra, çoğunluğu anlamsız varyantlar olan 407 de novo varyant belirlendi (%55.28). Baz değişim profilini incelediğimizde, en yaygın değişikliklerin C -> G, G -> A, A -> G olduğu bulundu. En sık mutasyona uğrayan genlerin DSPP, HPS4, VCL ve BMP4 genleri olduğu belirlendi.
Tartışma: Korelasyon analizi, ebeveyn yaşları ile de novo mutasyon sayısı arasında anlamlı bir ilişki bulunmadığını ortaya çıkardı ve regresyon analizi, yaşın de novo mutasyon sayısını belirlemede anlamlı bir parametre olmadığını gösterdi.
Anahtar Kelimeler
Kaynakça
- Rocio Acuna-Hidalgo, Joris A. Veltman, and Alexander Hoischen. New insights into the generation and role of de novo mutations in health and disease. Genome Biology. 2016; 17: 241
- H Duzkale, J Shen, H McLaughlin, A Alfares, M A Kelly, T J Pugh, B H Funke, H L Rehm, M S Lebo. A systematic approach to assessing the clinical significance of genetic variants. Clin Genet. 2013 Nov;84(5):453-63.
- Goldmann JM, Wong WSW, Pinelli M, Farrah T, Bodian D, Stittrich AB, et al. Parentof-origin-specific signatures of de novo mutations. Nat Genet. 2016; 48: 935–9.
- Conrad DF, Keebler JEM, DePristo MA, Lindsay SJ, Zhang Y, Casals F, et al. Variation in genome-wide mutation rates within and between human families. Nat Genet. 2011; 43: 712–4
- Korona DA, LeCompte KG, Pursell ZF. The high fidelity and unique error signature of human DNA polymerase. Nucleic Acids Res. 2011; 39: 1763–73.
- Schmitt MW, Matsumoto Y, Loeb LA. High fidelity and lesion bypass capability of human DNA polymerase δ. Biochimie. 2009; 91:1163–72
- Stamatoyannopoulos JA, Adzhubei I, Thurman RE, Kryukov GV, Mirkin SM, Sunyaev SR. Human mutation rate associated with DNA replication timing. Nat Genet. 2009; 41:393–5.
- Chen CL, Rappailles A, Duquenne L, Huvet M, Guilbaud G, Farinelli L, et al. Impact of replication timing on non-CpG and CpG substitution rates in mammalian genomes. Genome Res. 2010; 20: 447–57.
- Koren A, Polak P, Nemesh J, Michaelson JJ, Sebat J, Sunyaev SR, et al. Differential relationship of DNA replication timing to different forms of human mutation and variation. Am J Hum Genet. 2012; 91: 1033–40.
- Chan K, Gordenin DA. Clusters of multiple mutations: incidence and molecular mechanisms. Annu Rev Genet. 2015; 49: 243–67.
- Gao Z, Wyman MJ, Sella G, Przeworski M. Interpreting the dependence of mutation rates on age and time. PLoS Biol. 2016;14:e1002355.
- Makova KD, Hardison RC. The effects of chromatin organization on variation in mutation rates in the genome. Nat Rev Genet. 2015; 16: 213–23.
- Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415–21
- Kong A, Frigge ML, Masson G, Besenbacher S, Sulem P, Magnusson G, et al. Rate of de novo mutations and the importance of father’s age to disease risk. Nature. 2012;488:471–5.
- Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Al Turki S, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2015; 48: 126–33
- Francioli LC, Polak PP, Koren A, Menelaou A, Chun S, Renkens I, et al. Genome-wide patterns and properties of de novo mutations in humans. Nat Genet. 2015; 47: 822–6
- Stella Marie Reamon-Buettner, Si-Hyen Cho and Juergen Borlak. Mutations in the 3'-untranslated region of GATA4 as molecular hotspots for congenital heart disease (CHD). BMC Medical Genetics 2007, 8: 38
- Samantha L. Schuster, Sonali Arora, Cynthia L. Wladyka, Pushpa Itagi, Lukas Corey, Dave Young, Bethany L. Stackhouse, Lori Kollath, Qian V. Wu, Eva Corey, Lawrence D. True, Gavin Ha, Patrick J. Paddison, Andrew C. Hsieh. Multi-level functional genomics reveals molecular and cellular oncogenicity of patient-based 3′ untranslated region mutations. Cell Rep. 2023 Aug 29;42(8):112840
- Samantha L Schuster, Andrew C Hsieh. The Untranslated Regions of mRNAs in Cancer. Trends Cancer. 2019;5(4):245-262.
- Tychele N Turner, Evan E Eichler. The Role of De Novo Noncoding Regulatory Mutations in Neurodevelopmental Disorders. Trends Neurosci. 2019;42(2):115-127
- Amy B Wilfert, Arvis Sulovari, Tychele N Turner, Bradley P Coe, Evan E Eichler. Recurrent de novo mutations in neurodevelopmental disorders: properties and clinical implications. Genome Med. 2017;9(1):101
- Cody J Steely, W Scott Watkins, Lisa Baird, Lynn B Jorde. The mutational dynamics of short tandem repeats in large, multigenerational families. Genome Biol. 2022 Dec 12;23(1):253
- Reactome Pathway Database. https://reactome.org/
- Ivanova, Maria, "Evolutionary conservation and times of action of heterochronic genes" (2023). Thesesand Dissertations. 3169. https://rdw.rowan.edu/etd/3169
Investigation of the Frequency and Characteristic Features of De Novo Mutations in Clinical Exome Sequence Trio Samples
Öz
Advanced genome sequencing technologies have provided us with the opportunity to deeply understand the mechanisms underlying conditions associated with the genome. There has been significant interest recently in understanding the characteristics of de novo mutations, which are genetic changes that arise in reproductive cells and are not present in parents, as well as the mechanisms involved in their occurrence. These mutations can be transmitted to subsequent generations and have the potential to influence genetic diversity and susceptibility to diseases, making this topic important. Due to limited studies in this area, the formation mechanisms and characteristic features of such mutations have not yet been fully understood.
Background/Aims: In this study, we aimed to conduct a comprehensive analysis of de novo mutations in families undergoing trio clinical exome sequencing analysis. The objectives of the study were to investigate the relationship between parental ages and the frequency of de novo mutations, the distribution, prevalence, relationships, and molecular characteristics of de novo mutations.
Methods: A total of 69 families who underwent Trio Clinical Exome Sequencing (CES) analysis at the Department of Medical Genetics, Faculty of Medicine, Selçuk University, between January 1, 2017, and December 31, 2023, were included in the study. DNA samples extracted from peripheral venous blood of individuals were sequenced using the Roche CES kit and DNBSEQ-G400™ sequencing device, and a total of 3892 genes were analyzed using the Seq Platform.
Results: After analysis, 407 de novo variants were identified, with the majority being variants of unknown significance (55.28%). When examining the base change profile, the most common changes were found to be C -> G, G -> A, A -> G. The most commonly mutated genes were found to be DSPP, HPS4, VCL, and BMP4 genes.
Conclusions: Correlation analysis revealed no significant relationship between parental age and the number of de novo mutations, and regression analysis showed that age was not a significant parameter in determining the number of de novo mutations
Anahtar Kelimeler
Kaynakça
- Rocio Acuna-Hidalgo, Joris A. Veltman, and Alexander Hoischen. New insights into the generation and role of de novo mutations in health and disease. Genome Biology. 2016; 17: 241
- H Duzkale, J Shen, H McLaughlin, A Alfares, M A Kelly, T J Pugh, B H Funke, H L Rehm, M S Lebo. A systematic approach to assessing the clinical significance of genetic variants. Clin Genet. 2013 Nov;84(5):453-63.
- Goldmann JM, Wong WSW, Pinelli M, Farrah T, Bodian D, Stittrich AB, et al. Parentof-origin-specific signatures of de novo mutations. Nat Genet. 2016; 48: 935–9.
- Conrad DF, Keebler JEM, DePristo MA, Lindsay SJ, Zhang Y, Casals F, et al. Variation in genome-wide mutation rates within and between human families. Nat Genet. 2011; 43: 712–4
- Korona DA, LeCompte KG, Pursell ZF. The high fidelity and unique error signature of human DNA polymerase. Nucleic Acids Res. 2011; 39: 1763–73.
- Schmitt MW, Matsumoto Y, Loeb LA. High fidelity and lesion bypass capability of human DNA polymerase δ. Biochimie. 2009; 91:1163–72
- Stamatoyannopoulos JA, Adzhubei I, Thurman RE, Kryukov GV, Mirkin SM, Sunyaev SR. Human mutation rate associated with DNA replication timing. Nat Genet. 2009; 41:393–5.
- Chen CL, Rappailles A, Duquenne L, Huvet M, Guilbaud G, Farinelli L, et al. Impact of replication timing on non-CpG and CpG substitution rates in mammalian genomes. Genome Res. 2010; 20: 447–57.
- Koren A, Polak P, Nemesh J, Michaelson JJ, Sebat J, Sunyaev SR, et al. Differential relationship of DNA replication timing to different forms of human mutation and variation. Am J Hum Genet. 2012; 91: 1033–40.
- Chan K, Gordenin DA. Clusters of multiple mutations: incidence and molecular mechanisms. Annu Rev Genet. 2015; 49: 243–67.
- Gao Z, Wyman MJ, Sella G, Przeworski M. Interpreting the dependence of mutation rates on age and time. PLoS Biol. 2016;14:e1002355.
- Makova KD, Hardison RC. The effects of chromatin organization on variation in mutation rates in the genome. Nat Rev Genet. 2015; 16: 213–23.
- Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415–21
- Kong A, Frigge ML, Masson G, Besenbacher S, Sulem P, Magnusson G, et al. Rate of de novo mutations and the importance of father’s age to disease risk. Nature. 2012;488:471–5.
- Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Al Turki S, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2015; 48: 126–33
- Francioli LC, Polak PP, Koren A, Menelaou A, Chun S, Renkens I, et al. Genome-wide patterns and properties of de novo mutations in humans. Nat Genet. 2015; 47: 822–6
- Stella Marie Reamon-Buettner, Si-Hyen Cho and Juergen Borlak. Mutations in the 3'-untranslated region of GATA4 as molecular hotspots for congenital heart disease (CHD). BMC Medical Genetics 2007, 8: 38
- Samantha L. Schuster, Sonali Arora, Cynthia L. Wladyka, Pushpa Itagi, Lukas Corey, Dave Young, Bethany L. Stackhouse, Lori Kollath, Qian V. Wu, Eva Corey, Lawrence D. True, Gavin Ha, Patrick J. Paddison, Andrew C. Hsieh. Multi-level functional genomics reveals molecular and cellular oncogenicity of patient-based 3′ untranslated region mutations. Cell Rep. 2023 Aug 29;42(8):112840
- Samantha L Schuster, Andrew C Hsieh. The Untranslated Regions of mRNAs in Cancer. Trends Cancer. 2019;5(4):245-262.
- Tychele N Turner, Evan E Eichler. The Role of De Novo Noncoding Regulatory Mutations in Neurodevelopmental Disorders. Trends Neurosci. 2019;42(2):115-127
- Amy B Wilfert, Arvis Sulovari, Tychele N Turner, Bradley P Coe, Evan E Eichler. Recurrent de novo mutations in neurodevelopmental disorders: properties and clinical implications. Genome Med. 2017;9(1):101
- Cody J Steely, W Scott Watkins, Lisa Baird, Lynn B Jorde. The mutational dynamics of short tandem repeats in large, multigenerational families. Genome Biol. 2022 Dec 12;23(1):253
- Reactome Pathway Database. https://reactome.org/
- Ivanova, Maria, "Evolutionary conservation and times of action of heterochronic genes" (2023). Thesesand Dissertations. 3169. https://rdw.rowan.edu/etd/3169
Ayrıntılar
| Birincil Dil | İngilizce |
|---|---|
| Konular | Tıbbi Genetik (Kanser Genetiği hariç) |
| Bölüm | Original Article |
| Yazarlar | |
| Erken Görünüm Tarihi | 27 Nisan 2024 |
| Yayımlanma Tarihi | 30 Nisan 2024 |
| Gönderilme Tarihi | 18 Nisan 2024 |
| Kabul Tarihi | 26 Nisan 2024 |
| Yayımlandığı Sayı | Yıl 2024 Cilt: 34 Sayı: 2 |
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