Biology subjects

Melissa Gymrek

Publications and source records attributed to Melissa Gymrek.

6 recordsLinked to original sources

bioRxiv2016

Genome-wide profiling of heritable and de novo STR variations

Short tandem repeats (STRs) are highly variable elements that play a pivotal role in multiple genetic diseases, population genetics applications, and forensic casework. However, STRs have proven problematic to genotype from high-throughput sequencing data. Here, we describe HipSTR, a novel haplotype-based method for robustly genotyping, haplotyping, and phasing STRs from whole genome sequencing data and report a genome-wide analysis and validation of de novo STR mutations.

Genomics↗

bioRxiv2016

PCR-free library preparation greatly reduces stutter noise at short tandem repeats

Over the past several decades, the forensic and population genetic communities have increasingly leveraged short tandem repeats (STRs) for a variety of applications. The advent of next-generation sequencing technologies and STR-specific bioninformatic tools has enabled the profiling of hundreds of thousands of STRs across the genome. Nonetheless, these genotypes remain error-prone, hindering their utility in downstream analyses. One of the primary drivers of STR genotyping errors are \"stutter\" artifacts arising during the PCR amplification step of library preparation that add or delete copies of the repeat unit in observed sequencing reads. Recently, Illumina developed the TruSeq PCR-free library preparation protocol which eliminates the PCR step and theoretically should reduce stutter error. Here, I compare two high coverage whole genome sequencing datasets prepared with and without the PCR-free protocol. I find that this protocol reduces the percent of reads due to stutter by more than four-fold and results in higher confidence STR genotypes. Notably, stutter at homopolymers was decreased by more than 6fold, making these previously inaccessible loci amenable to STR calling. This technological improvement shows good promise for significantly increasing the feasibility of obtaining high quality STR genotypes from next-generation sequencing technologies.

Bioinformatics↗

bioRxiv2016

Population-Scale Sequencing Data Enables Precise Estimates of Y-STR Mutation Rates

Short Tandem Repeats (STRs) are mutation-prone loci that span nearly 1% of the human genome. Previous studies have estimated the mutation rates of highly polymorphic STRs using capillary electrophoresis and pedigree-based designs. While this work has provided insights into the mutational dynamics of highly mutable STRs, the mutation rates of most others remain unknown. Here, we harnessed whole-genome sequencing data to estimate the mutation rates of Y-chromosome STRs (Y-STRs) with 2-6 base pair repeat units that are accessible to Illumina sequencing. We genotyped 4,500 Y-STRs using data from the 1000 Genomes Project and the Simons Genome Diversity Project. Next, we developed MUTEA, an algorithm that infers STR mutation rates from population-scale data using a high-resolution SNP-based phylogeny. After extensive intrinsic and extrinsic validations, we harnessed MUTEA to derive mutation rate estimates for 702 polymorphic STRs by tracing each locus over 222,000 meioses, resulting in the largest collection of Y-STR mutation rates to date. Using our estimates, we identified determinants of STR mutation rates and built a model to predict rates for STRs across the genome. These predictions indicate that the load of de novo STR mutations is at least 75 mutations per generation, rivaling the load of all other known variant types. Finally, we identified Y-STRs with potential applications in forensics and genetic genealogy, assessed the ability to differentiate between the Y-chromosomes of father-son pairs, and imputed Y-STR genotypes.

Genomics↗

bioRxiv2015

Abundant contribution of short tandem repeats to gene expression variation in humans

Expression quantitative trait loci (eQTLs) are a key tool to dissect cellular processes mediating complex diseases. However, little is known about the role of repetitive elements as eQTLs. We report a genome-wide survey of the contribution of Short Tandem Repeats (STRs), one of the most polymorphic and abundant repeat classes, to gene expression in humans. Our survey identified 2,060 significant expression STRs (eSTRs). These eSTRs were replicable in orthogonal populations and expression assays. We used variance partitioning to disentangle the contribution of eSTRs from linked SNPs and indels and found that eSTRs contribute 10%-15% of the cis-heritability mediated by all common variants. Functional genomic analyses showed that eSTRs are enriched in conserved regions, co-localize with regulatory elements, and are predicted to modulate histone modifications. Our results show that eSTRs provide a novel set of regulatory variants and highlight the contribution of repeats to the genetic architecture of quantitative human traits.

Genomics↗

bioRxiv2014

The Landscape of Human STR Variation

Short Tandem Repeats are among the most polymorphic loci in the human genome. These loci play a role in the etiology of a range of genetic diseases and have been frequently utilized in forensics, population genetics, and genetic genealogy. Despite this plethora of applications, little is known about the variation of most STRs in the human population. Here, we report the largest-scale analysis of human STR variation to date. We collected information for nearly 700,000 STR loci across over 1,000 individuals in phase 1 of the 1000 Genomes Project. This process nearly saturated common STR variations. After employing a series of quality controls, we utilize this call set to analyze determinants of STR variation, assess the human reference genomes representation of STR alleles, find STR loci with common loss-of-function alleles, and obtain initial estimates of the linkage disequilibrium between STRs and common SNPs. Overall, these analyses further elucidate the scale of genetic variation beyond classical point mutations. The resource is publicly available at http://strcat.teamerlich.org/ both in raw format and via a graphical interface.

Genomics↗

bioRxiv2013

OTX2 Dosage Sensitivity is Implicated in Hemifacial Microsomia

Hemifacial microsomia (HFM) is the second most common facial anomaly after cleft lip and palate. The phenotype is highly variable and most cases are sporadic. Here, we investigated the disorder in a large pedigree with five affected individuals spanning eight meioses. We performed whole-exome sequencing and a genome-wide survey of segmental variations. Analysis of the exome sequencing results indicated the absence of a pathogenic coding point mutation. Inspection of segmental variations identified a 1.3Mb duplication of chromosome 14q22.3 in all affected individuals that was absent in more than 1000 chromosomes of ethnically matched controls. The duplication was absent in seven additional sporadic HFM cases, which is concordant with the known heterogeneity of the disorder. To find the critical gene in the duplicated region, we analyzed signatures of human craniofacial disease networks, mouse expression data, and predictions of dosage sensitivity. All of these approaches implicated OTX2 as the most likely causal gene. Moreover, OTX2 is a known oncogenic driver in medulloblastoma, a condition that was diagnosed in the proband during the course of our study. Our findings highlight dosage sensitivity of OTX2 in human craniofacial development and suggest a possible shared etiology between a subtype of hemifacial microsomia and medulloblastoma.

Genetics↗