Biology subjects

Raheleh Rahbari

Publications and source records attributed to Raheleh Rahbari.

2 recordsLinked to original sources

bioRxiv2016

Detection of structural mosaicism from targeted and whole-genome sequencing data

Structural mosaic abnormalities are large post-zygotic mutations present in a subset of cells and have been implicated in developmental disorders and cancer. Such mutations have been conventionally assessed in clinical diagnostics using cytogenetic or microarray testing. Modern disease studies rely heavily on exome sequencing, yet an adequate method for the detection of structural mosaicism using targeted sequencing data is lacking. Here, we present a method, called MrMosaic, to detect structural mosaic abnormalities using deviations in allele fraction and read coverage from next generation sequencing data. Whole-exome sequencing (WES) and whole-genome sequencing (WGS) simulations were used to calculate detection performance across a range of mosaic event sizes, types, clonalities, and sequencing depths. The tool was applied to 4,911 patients with undiagnosed developmental disorders, and 11 events in 9 patients were detected. In 8 of 11 cases, mosaicism was observed in saliva but not blood, suggesting that assaying blood alone would miss a large fraction, possibly more than 50%, of mosaic diagnostic chromosomal rearrangements.

Genomics↗

bioRxiv2016

A direct multi-generational estimate of the human mutation rate from autozygous segments seen in thousands of parentally related individuals

Heterozygous mutations within homozygous sequences descended from a recent common ancestor offer a way to ascertain de novo mutations (DNMs) across multiple generations. Using exome sequences from 3,222 British-Pakistani individuals with high parental relatedness, we estimate a mutation rate of 1. 45 {+/-} 0.05 x 10-8 per base pair per generation in autosomal coding sequence, with a corresponding noncrossover gene conversion rate of 8.75 {+/-} 0.05 x 10-6 per base pair per generation. This is at the lower end of exome mutation rates previously estimated in parent-offspring trios, suggesting that post-zygotic mutations contribute little to the human germline mutation rate. We found frequent recurrence of mutations at polymorphic CpG sites, and an increase in C to T mutations in a 5 CCG 3 [->] 5 CTG 3 context in the Pakistani population compared to Europeans, suggesting that mutational processes have evolved rapidly between human populations.

Genomics↗