Fold-back structures at the distal end influence DNA slippage at the proximal end during mononucleotide repeat expansions

AbstractReplicative strand slippage is a biological phenomenon, ubiquitous among different organisms. However, slippage events are also relevant to non-natural replication models utilizing synthetic polymerase substrates. Strand slippage may notably affect the outcome of the primer extension reaction with repetitive templates in the presence of non-natural nucleoside triphosphates. In the current paper, we studied the ability of Taq, Vent (exo-), and Deep Vent (exo-) polymerases to produce truncated, full size, or expanded modified strands utilizing non-natural 2′-deoxyuridine nucleotide analogues and different variants of the homopolymer template. Our data suggest that the slippage of the primer strand is dependent on the duplex fluttering, incorporation efficiency for a particular polymerase-dNTP pair, rate of non-templated base addition, and presence of competing nucleotides.

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Patients With Extreme Early Onset Juvenile Huntington Disease Can Have Delays in Diagnosis: A Case Report and Literature Review

Child Neurology Open ◽

10.1177/2329048x211036137 ◽

2021 ◽

Vol 8 ◽

pp. 2329048X2110361

Author(s):

Ashley A. Moeller ◽

Marcia V. Felker ◽

Jennifer A. Brault ◽

Laura C. Duncan ◽

Rizwan Hamid ◽

...

Keyword(s):

Symptom Onset ◽

Huntington Disease ◽

Early Onset ◽

Trinucleotide Repeat ◽

Cerebellar Atrophy ◽

Cag Repeats ◽

Ataxic Gait ◽

Repeat Expansions ◽

Delays In Diagnosis ◽

Juvenile Huntington Disease

Huntington disease (HD) is caused by a pathologic cytosine-adenine-guanine (CAG) trinucleotide repeat expansion in the HTT gene. Typical adult-onset disease occurs with a minimum of 40 repeats. With more than 60 CAG repeats, patients can have juvenile-onset disease (jHD), with symptom onset by the age of 20 years. We report a case of a boy with extreme early onset, paternally inherited jHD, with symptom onset between 18 and 24 months. He was found to have 250 to 350 CAG repeats, one of the largest repeat expansions published to date. At initial presentation, he had an ataxic gait, truncal titubation, and speech delay. Magnetic resonance imaging showed cerebellar atrophy. Over time, he continued to regress and became nonverbal, wheelchair-bound, gastrostomy-tube dependent, and increasingly rigid. His young age at presentation and the ethical concerns regarding HD testing in minors delayed his diagnosis.

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Generation of an induced pluripotent stem cell line (ZZUi020-A) from a patient with Parkinson’s disease harboring the intermediate-length GGC repeat expansions in the NOTCH2NLC gene

Stem Cell Research ◽

10.1016/j.scr.2021.102257 ◽

2021 ◽

Vol 52 ◽

pp. 102257

Author(s):

Yu Fan ◽

Fen Liu ◽

Li-yuan Fan ◽

Cheng-yuan Mao ◽

Han Liu ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Stem Cell ◽

Cell Line ◽

Pluripotent Stem Cell ◽

Induced Pluripotent Stem Cell ◽

Stem Cell Line ◽

Repeat Expansions ◽

Induced Pluripotent

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REscan: inferring repeat expansions and structural variation in paired-end short read sequencing data

Bioinformatics ◽

10.1093/bioinformatics/btaa753 ◽

2020 ◽

Author(s):

Russell Lewis McLaughlin

Keyword(s):

Structural Variation ◽

Sequence Data ◽

Neurological Diseases ◽

Repeat Expansion ◽

Sequencing Data ◽

Short Read ◽

Short Read Sequencing ◽

Repeat Expansions ◽

Paired End Sequencing

Abstract Motivation Repeat expansions are an important class of genetic variation in neurological diseases. However, the identification of novel repeat expansions using conventional sequencing methods is a challenge due to their typical lengths relative to short sequence reads and difficulty in producing accurate and unique alignments for repetitive sequence. However, this latter property can be harnessed in paired-end sequencing data to infer the possible locations of repeat expansions and other structural variation. Results This article presents REscan, a command-line utility that infers repeat expansion loci from paired-end short read sequencing data by reporting the proportion of reads orientated towards a locus that do not have an adequately mapped mate. A high REscan statistic relative to a population of data suggests a repeat expansion locus for experimental follow-up. This approach is validated using genome sequence data for 259 cases of amyotrophic lateral sclerosis, of which 24 are positive for a large repeat expansion in C9orf72, showing that REscan statistics readily discriminate repeat expansion carriers from non-carriers. Availabilityand implementation C source code at https://github.com/rlmcl/rescan (GNU General Public Licence v3).

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