scholarly journals Large scale in silico characterization of repeat expansion variation in human genomes

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
Sarah Fazal ◽  
Matt C. Danzi ◽  
Vivian P. Cintra ◽  
Dana M. Bis-Brewer ◽  
Egor Dolzhenko ◽  
...  

Abstract Significant progress has been made in elucidating single nucleotide polymorphism diversity in the human population. However, the majority of the variation space in the genome is structural and remains partially elusive. One form of structural variation is tandem repeats (TRs). Expansion of TRs are responsible for over 40 diseases, but we hypothesize these represent only a fraction of the pathogenic repeat expansions that exist. Here we characterize long or expanded TR variation in 1,115 human genomes as well as a replication cohort of 2,504 genomes, identified using ExpansionHunter Denovo. We found that individual genomes typically harbor several rare, large TRs, generally in non-coding regions of the genome. We noticed that these large TRs are enriched in their proximity to Alu elements. The vast majority of these large TRs seem to be expansions of smaller TRs that are already present in the reference genome. We are providing this TR profile as a resource for comparison to undiagnosed rare disease genomes in order to detect novel disease-causing repeat expansions.

Author(s):  
Neha Rajput ◽  
Gagandeep Kaur Gahlay

ZP2, an important component of the zona matrix, surrounds mammalian oocytes and facilitates fertilization. Recently, some studies have documented the association of mutations in genes encoding the zona matrix with the infertile status of human females. Single nucleotide polymorphisms are the most common type of genetic variations observed in a population and as per the dbSNP database, around 5,152 SNPs are reported to exist in the human ZP2 (hZP2) gene. Although a wide range of computational tools are publicly available, yet no computational studies have been done to date to identify and analyze structural and functional effects of deleterious SNPs on hZP2. In this study, we conducted a comprehensive in silico analysis of all the SNPs found in hZP2. Six different computational tools including SIFT and PolyPhen-2 predicted 18 common nsSNPs as deleterious of which 12 were predicted to most likely affect the structure/functional properties. These were either present in the N-term region crucial for sperm-zona interaction or in the zona domain. 31 additional SNPs in both coding and non-coding regions were also identified. Interestingly, some of these SNPs have been found to be present in infertile females in some recent studies.


2005 ◽  
Vol 125 (1) ◽  
pp. 83-93 ◽  
Author(s):  
Emmanuel Jacquot ◽  
Michel Tribodet ◽  
Flora Croizat ◽  
Valérie Balme-Sinibaldi ◽  
Camille Kerlan

2018 ◽  
Vol 84 (23) ◽  
Author(s):  
Carlos A. Loncoman ◽  
Carol A. Hartley ◽  
Mauricio J. C. Coppo ◽  
Glenn F. Browning ◽  
Gabriela Beltrán ◽  
...  

ABSTRACT Infectious laryngotracheitis (ILTV; Gallid alphaherpesvirus 1) causes mild to severe respiratory disease in poultry worldwide. Recombination in this virus under natural (field) conditions was first described in 2012 and more recently has been studied under laboratory conditions. Previous studies have revealed that natural recombination is widespread in ILTV and have also demonstrated that recombination between two attenuated ILTV vaccine strains generated highly virulent viruses that produced widespread disease within poultry flocks in Australia. In the United States, natural ILTV recombination has also been detected, but not as frequently as in Australia. To better understand recombination in ILTV strains originating from the United States, we developed a TaqMan single nucleotide polymorphism (SNP) genotyping assay to detect recombination between two virulent U.S. field strains of ILTV (63140 and 1874c5) under experimental in vivo conditions. We also tested the capacity of the Innovax-ILT vaccine (a recombinant vaccine using herpesvirus of turkeys as a vector) and the Trachivax vaccine (a conventionally attenuated chicken embryo origin vaccine) to reduce recombination. The Trachivax vaccine prevented ILTV replication, and therefore recombination, in the trachea after challenge. The Innovax-ILT vaccine allowed the challenge viruses to replicate and to recombine, but at a significantly lower rate than in an unvaccinated group of birds. Our results demonstrate that the TaqMan SNP genotyping assay is a useful tool to study recombination between these ILTV strains and also show that vaccination can limit the number and diversity of recombinant progeny viruses. IMPORTANCE Recombination allows alphaherpesviruses to evolve over time and become more virulent. Historically, characterization of viral vaccines in poultry have mainly focused on limiting clinical disease, rather than limiting virus replication, but such approaches can allow field viruses to persist and evolve in vaccinated populations. In this study, we vaccinated chickens with Gallid alphaherpesvirus 1 vaccines that are commercially available in the United States and then performed coinoculations with two field strains of virus to measure the ability of the vaccines to prevent field strains from replicating and recombining. We found that vaccination reduced viral replication, recombination, and diversity compared to those in unvaccinated chickens, although the extent to which this occurred differed between vaccines. We suggest that characterization of vaccines could include studies to examine the ability of vaccines to reduce viral recombination in order to limit the rise of new virulent field strains due to recombination, especially for those vaccines that are known not to prevent viral replication following challenge.


2019 ◽  
Author(s):  
Pauline C. Schut ◽  
Erwin Brosens ◽  
Frietson Galis ◽  
Clara M. A. Ten Broek ◽  
Inge M.M. Baijens ◽  
...  

AbstractObjectiveTo assess the vertebral pattern in a cohort of deceased fetuses and neonates, and to study the possible impact of DNA Copy Number Variations (CNVs) in coding regions and/or disturbing enhancers on the development of the vertebral pattern.MethodRadiographs of 445 fetuses and infants, deceased between 2009 and 2015, were assessed. Terminations of pregnancies, stillbirths and neonatal deaths were included. Patients were excluded if the vertebral pattern could not be determined. Copy number profiles of 265 patients were determined using single nucleotide polymorphism array.Results274/374 patients (73.3%) had an abnormal vertebral pattern. Cervical ribs were present in 188/374 (50.3%) and were significantly more common in stillbirths (69/128 (53.9%)) and terminations of pregnancies (101/188 (53.7%)), compared to live births (18/58, 31.0%, p = 0.006). None of the rare CNVs were recurrent or overlapped candidate genes for vertebral patterning.ConclusionThe presence of an abnormal vertebral pattern, particularly in the cervical region, could be a sign of disruption at critical, highly interactive and conserved stages of embryogenesis. The vertebral pattern might provide valuable information regarding fetal and neonatal outcome. CNV analyses did not identify a mutual genetic cause for the occurrence of vertebral patterning abnormalities, indicating genetic heterogeneity.


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