Mitochondrial Genomes and Frameshift Mutations: Hidden Stop Codons, their Functional Consequences and Disease Associations

Abstract

Reprogramming of mRNA translation by localized alterations in the standard translational rules is termed as recoding. Frameshifting is one class of recoding and defined as protein translations that start not at the first, but either at the second (+1 frameshift) or the third (-1 frameshift) nucleotide of the codon. Apparently, most frameshifts would yield nonfunctional proteins. Therefore frameshifts lead to waste of energy, resources and activity of the biosynthetic machinery. In addition, some peptides synthesized after frameshifts are most likely cytotoxic. Coding sequences lack stop codons, but many stop codons generated due to frameshifted sequences, termed off-frame stops or hidden stop codons. These hidden stops terminate frame-shifted translation, potentially decreasing energy, and resource waste on nonfunctional proteins. Frameshift mutations for the sake of mitochondrial genomes were evaluated and results support this putative ancient adaptive event for the selection of codons that can be part of hidden stop codons. Mitochondrial genomic data analyses support this fact as most of the correlations between hidden stops and various functional and evolutionary parameters were positive. Association of frameshift mutations with many diseases is also being studied to represent the biological significance of this putative event. It is estimated that this kind of study will reveal momentous correlation between frameshift mutations and their biological consequences.

Substantial rearrangements, single nucleotide frameshift deletion and low diversity in mitogenome of Wolbachia-infected strepsipteran endoparasitoid in comparison to its tephritid hosts

“…It is noteworthy that our finding is, to our knowledge, the first example of -1 frameshift deletion found in an invertebrate mitogenome. So far single nucleotide deletions in mitochondrial PCGs have only been found in a few turtle species 58 , and, overall, -1 frameshift deletions appear to be rarer than +1 frameshift insertions 59 . Alternatively, the single nucleotide deletion in nad5 of D. daci could result in the expression of a truncated but still functional nad5 gene product because it still contained the proton-conducting transporter domain similar to nad5 genes in other species 60 , however, this scenario may be less likely because it would constitute a substantial truncation.…”

İdiyopatik Hipogonadotropik Hipogonadizme Neden Olan GNRH1 c.99delA Delesyonunun Klinik ve Genetik İncelemesi

“…Bir aminoasidi temsil eden kodonun ikinci nükleotidinde başlayan protein translasyonları "+1 çerçeve kayması", üçüncü nükleotidinde başlayanlar ise "-1 çerçeve kayması" olarak tanımlanmaktadır [11]. Primatların mitokondriyal genomlarında yapılan taksonomik çalışmalarda, +1 çerçeve kayması mutasyonlarının -1'e oranla daha fazla stop kodonu kombinasyonuna sahip olduğu bildirilmiştir [11,12]. Bu durumdan ortaya çıkan, +1 çerçeve kaymaları yoluyla doğal seleksiyonun optimize edildiği önermesi, +1 mutasyonlarının -1'e göre daha patojenik sonuçları olduğunu düşündürmektedir [12].…”

“…Primatların mitokondriyal genomlarında yapılan taksonomik çalışmalarda, +1 çerçeve kayması mutasyonlarının -1'e oranla daha fazla stop kodonu kombinasyonuna sahip olduğu bildirilmiştir [11,12]. Bu durumdan ortaya çıkan, +1 çerçeve kaymaları yoluyla doğal seleksiyonun optimize edildiği önermesi, +1 mutasyonlarının -1'e göre daha patojenik sonuçları olduğunu düşündürmektedir [12]. IHH kliniğindeki hastalarımızda tespit edilen c.99delA mutasyonu +1 sınıflandırmasına girmektedir.…”

FrameOUT and FrameOUTDB: A web based application and repository for the identification and analysis of frameshift mutations

“…Some peptides, synthesized after frame-shifts, are probably cytotoxic and serve as possible cause for innumerable diseases and disorders such as muscular dystrophies, lysosomal storage disorders, and cancer. Frame-shift mutations might be beneficial sometime such as a frameshift mutation was [7][8][9][10].…”