Abstract
Nephrotic syndrome (NS) gene discovery efforts are now occurring in small kindreds and cohorts of sporadic cases. Power to identify causal variants in these groups beyond a statistical significance threshold is challenging due to small sample size and/or lack of family information. There is a need to develop novel methods to identify NS-associated variants. One way to determine putative functional relevance of a gene is to measure its strength of negative selection, as variants in genes under strong negative selection are more likely to be deleterious. We created a gene-level, integrated metric of negative selection (GIMS) score for 20,079 genes by combining multiple comparative genomics and population genetics measures. To understand the utility of GIMS for NS gene discovery, we examined this score in a diverse set of NS-relevant gene sets. These included genes known to cause monogenic forms of NS in humans as well as genes expressed in the cells of the glomerulus and, particularly, the podocyte. We found strong negative selection in the following NS-relevant gene sets: (1) autosomal-dominant Mendelian focal segmental glomerulosclerosis (FSGS) genes (p= 0.03 compared to reference), (2) glomerular expressed genes (p = 4×10-23), and (3) predicted podocyte genes (p = 3×10-9). Eight genes causing autosomal dominant forms of FSGS had a stronger combined score of negative selection and podocyte enrichment as compared to all other genes (p=1 x 10-3). As a whole, recessive FSGS genes were not enriched for negative selection. Thus, we also created a transcript-level, integrated metric of negative selection (TIMS) to quantify negative selection on an isoform level. These revealed transcripts of known autosomal recessive disease-causing genes that were nonetheless under strong selection. We suggest that a filtering strategy that includes measuring negative selection on a gene or isoform level could aid in identifying NS-related genes. Our GIMS and TIMS scores are available at http://glom.sph.umich.edu/GIMS/.
Highlights
Minimal change disease [MCD] and focal segmental glomerulosclerosis [FSGS]) are rare forms of nephrotic syndrome (NS) with incidence rates of between 2-4/100,000/ year in children in North America and the United Kingdom[1] and 1.4/100,000/year in adults from around the world[2]
We calculated the fraction of common single nucleotide variants (SNV), defined as those with minor allele frequency (MAF) >0.5% for each gene, among the variants observed in the 1000 Genomes in the nucleotide positions in the CDS (ndCDS)
Our results demonstrate strong enrichment signatures of negative selection in the following gene sets: (1) genes causing dominant Mendelian form of FSGS, (2) glomerular-enriched genes, and (3) podocyteenriched genes
Summary
Minimal change disease [MCD] and focal segmental glomerulosclerosis [FSGS]) are rare forms of nephrotic syndrome (NS) with incidence rates of between 2-4/100,000/ year in children in North America and the United Kingdom[1] and 1.4/100,000/year in adults from around the world[2]. The prevalence of known Mendelian forms of steroid resistant nephrotic syndrome (SRNS) With the increased application of sequencing technologies, rare single nucleotide variants (SNV) in genes that cause Mendelian forms of FSGS are being discovered at increasing rates[4,5,6,7]. Variants are filtered by such means as mode of inheritance, population allele frequency, and predicted function of the variants.
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