skip to main content


Title: Computational compensatory mutation discovery approach: Predicting a PARP1 variant rescue mutation
Award ID(s):
1943442
NSF-PAR ID:
10378773
Author(s) / Creator(s):
; ; ; ;
Date Published:
Journal Name:
Biophysical Journal
Volume:
121
Issue:
19
ISSN:
0006-3495
Page Range / eLocation ID:
3663 to 3673
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. Wong, A (Ed.)
    Abstract Archaea are a major part of Earth’s microbiota and extremely diverse. Yet, we know very little about the process of mutation that drives such diversification. To expand beyond previous work with the moderate halophilic archaeal species Haloferax volcanii, we performed a mutation-accumulation experiment followed by whole-genome sequencing in the extremely halophilic archaeon Halobacterium salinarum. Although Hfx. volcanii and Hbt. salinarum have different salt requirements, both species have highly polyploid genomes and similar GC content. We accumulated mutations for an average of 1250 generations in 67 mutation accumulation lines of Hbt. salinarum, and revealed 84 single-base substitutions and 10 insertion-deletion mutations. The estimated base-substitution mutation rate of 3.99 × 10−10 per site per generation or 1.0 × 10−3 per genome per generation in Hbt. salinarum is similar to that reported for Hfx. volcanii (1.2 × 10−3 per genome per generation), but the genome-wide insertion-deletion rate and spectrum of mutations are somewhat dissimilar in these archaeal species. The spectra of spontaneous mutations were AT biased in both archaea, but they differed in significant ways that may be related to differences in the fidelity of DNA replication/repair mechanisms or a simple result of the different salt concentrations. 
    more » « less
  2. Abstract Background

    Co‐occurrence of two genetic diseases is challenging for accurate diagnosis and genetic counseling. The recent availability of whole exome sequencing (WES) has dramatically improved the molecular diagnosis of rare genetic diseases in particular in consanguineous populations.

    Methods

    We report here on a consanguineous family from Southern Tunisia including three members affected with congenital ichthyosis. The index case had a hearing loss (HL) and ichthyosis and was primarily suspected as suffering from keratitis‐ichthyosis‐deafness (KID) syndrome.WESwas performed for the index case, and all members of the nuclear family were sequenced (Sanger method).

    Results

    TheWESapproach allowed the identification of two strong candidate variants in two different genes; a missense mutation c.1334T>G (p.Leu445Trp) in exon 11 ofSLC26A4gene, associated with isolatedHLand a novel missense mutation c.728G>T (p.Arg243Leu) in exon 8 ofCYP4F22gene likely responsible for ichthyosis. These two mutations were predicted to be pathogenic by three pathogenicity prediction softwares (Scale‐Invariant Feature Transform [SIFT], Polymorphism Phenotyping [PolyPhen], Mutation Taster) to underlie theHLand ichthyosis, respectively.

    Conclusions

    The present study raises awareness about the importance of familial history for accurate diagnosis of syndromic genetic diseases and differential diagnosis with co‐occurrence of two distinct clinical entities. In addition, in countries with limited resources,WESsequencing for a single individual provides a cost effective tool for molecular diagnosis confirmation and genetic counseling.

     
    more » « less