Biology subjects

Sherman, R. M.

Publications and source records attributed to Sherman, R. M..

4 recordsLinked to original sources

bioRxiv2021

Widespread germline genetic heterogeneity of human ribosomal RNA genes

Polymorphism drives survival under stress and provides adaptability. Genetic polymorphism of ribosomal RNA (rRNA) genes derives from internal repeat variation of this multicopy gene, and from interindividual variation. A considerable amount of rRNA sequence heterogeneity has been proposed but has been challenging to estimate given the scarcity of accurate reference sequences. We identified four rDNA copies on chromosome 21 (GRCh38) with 99% similarity to recently introduced reference sequence KY962518.1. Pairwise alignment of the rRNA coding sequences of these copies showed differences in sequence and length. We customized a GATK bioinformatics pipeline using the four rDNA loci, spanning a total 145 kb, for variant calling. We employed whole genome sequencing (WGS) data from the 1000 Genomes Project phase 3 and analyzed variants in 2,504 individuals from 26 populations. Using the pipeline, we identified a total of 3,790 variant positions. The variants positioned non-randomly on the rRNA gene. Invariant regions included the promoter, early 5 ETS, 5.8S, ITS1 and certain regions of the 28S rRNA, and large areas of the intragenic spacer. 18S rRNA coding region had very few variants, while a total of 470 variant positions were observed on 28S rRNA. The majority of the 28S rRNA variants located on highly flexible human-expanded rRNA helical folds ES7L and ES27L, suggesting that these represent positions of diversity and are potentially under continuous evolution. These findings provide a genetic view for rRNA heterogeneity and raise the need to functional assess how the 28S rRNA variants affect ribosome functions.

bioinformatics↗

bioRxiv2021

Local adaptation and archaic introgression shape global diversity at human structural variant loci

Large genomic insertions, deletions, and inversions are a potent source of functional and fitness-altering variation, but are challenging to resolve with short-read DNA sequencing alone. While recent long-read sequencing technologies have greatly expanded the catalog of structural variants (SVs), their costs have so far precluded their application at population scales. Given these limitations, the role of SVs in human adaptation remains poorly characterized. Here, we used a graph-based approach to genotype 107,866 long-read-discovered SVs in short-read sequencing data from diverse human populations. We then applied an admixture-aware method to scan these SVs for patterns of population-specific frequency differentiation--a signature of local adaptation. We identified 220 SVs exhibiting extreme frequency differentiation, including several SVs that were among the lead variants at their corresponding loci. The top two signatures traced to separate insertion and deletion polymorphisms at the immunoglobulin heavy chain locus, together tagging a 325 Kbp haplotype that swept to high frequency and was subsequently fragmented by recombination. Alleles defining this haplotype are nearly fixed (60-95%) in certain Southeast Asian populations, but are rare or absent from other global populations composing the 1000 Genomes Project. Further investigation revealed that the haplotype closely matches with sequences observed in two of three high-coverage Neanderthal genomes, providing strong evidence of a Neanderthal-introgressed origin. This extraordinary episode of positive selection, which we infer to have occurred between 1700 and 8400 years ago, corroborates the role of immune-related genes as prominent targets of adaptive archaic introgression. Our study demonstrates how combining recent advances in genome sequencing, genotyping algorithms, and population genetic methods can reveal signatures of key evolutionary events that remained hidden within poorly resolved regions of the genome.

evolutionary biology↗

bioRxiv2020

Assembly and Annotation of an Ashkenazi Human Reference Genome

Here we describe the assembly and annotation of the genome of an Ashkenazi individual and the creation of a new, population-specific human reference genome. This genome is more contiguous and more complete than GRCh38, the latest version of the human reference genome, and is annotated with highly similar gene content. The Ashkenazi reference genome, Ash1, contains 2,973,118,650 nucleotides as compared to 2,937,639,212 in GRCh38. Annotation identified 20,157 protein-coding genes, of which 19,563 are >99% identical to their counterparts on GRCh38. Most of the remaining genes have small differences. 40 of the protein-coding genes in GRCh38 are missing from Ash1; however, all of these genes are members of multi-gene families for which Ash1 contains other copies. 11 genes appear on different chromosomes from their homologs in GRCh38. Alignment of DNA sequences from an unrelated Ashkenazi individual to Ash1 identified ~1 million fewer homozygous SNPs than alignment of those same sequences to the more-distant GRCh38 genome, illustrating one of the benefits of population-specific reference genomes.

genomics↗

bioRxiv2019

Paragraph: A graph-based structural variant genotyper for short-read sequence data

Accurate detection and genotyping of structural variations (SVs) from short-read data is a long-standing area of development in genomics research and clinical sequencing pipelines. We introduce Paragraph, an accurate genotyper that models SVs using sequence graphs and SV annotations. We demonstrate the accuracy of Paragraph on whole-genome sequence data from three samples using long read SV calls as the truth set, and then apply Paragraph at scale to a cohort of 100 short-read sequenced samples of diverse ancestry. Our analysis shows that Paragraph has better accuracy than other existing genotypers and can be applied to population-scale studies.

genomics↗