Biology subjects

Kasperaviciute, D.

Publications and source records attributed to Kasperaviciute, D..

3 recordsLinked to original sources

bioRxiv2024

Genome-wide profiling of highly similar paralogous genes using HiFi sequencing

Variant calling is hindered in segmental duplications by sequence homology. We developed Paraphase, a HiFi-based informatics method that resolves highly similar genes by phasing all haplotypes of a gene family. We applied Paraphase to 160 long (>10 kb) segmental duplication regions across the human genome with high (>99%) sequence similarity, encoding 316 genes. Analysis across five ancestral populations revealed highly variable copy numbers of these regions. We identified 23 families with exceptionally low within-family diversity, where extensive gene conversion and unequal-crossing over have resulted in highly similar gene copies. Furthermore, our analysis of 36 trios identified 7 de novo SNVs and 4 de novo gene conversion events, 2 of which are non-allelic. Finally, we summarized extensive genetic diversity in 9 medically relevant genes previously considered challenging to genotype. Paraphase provides a framework for resolving gene paralogs, enabling accurate testing in medically relevant genes and population-wide studies of previously inaccessible genes.

genomics↗

bioRxiv2022

Comprehensive SMN1 and SMN2 profiling for spinal muscular atrophy analysis using long-read PacBio HiFi sequencing

Spinal muscular atrophy, a leading cause of early infant death, is caused by biallelic mutations of the SMN1 gene. Sequence analysis of SMN1 is challenging due to high sequence similarity with its paralog SMN2. Both genes have variable copy numbers across populations. Furthermore, without pedigree information, it is impossible to identify silent carriers (2+0) with two copies of SMN1 on one chromosome and zero copies on the other. We developed Paraphase, an informatics method that identifies full-length SMN1 and SMN2 haplotypes, determines the gene copy numbers and calls phased variants using long-read PacBio HiFi data. The SMN1 and SMN2 copy number calls by Paraphase are highly concordant with orthogonal methods (99.2% for SMN1 and 100% for SMN2). We applied Paraphase to 438 samples across five ethnic populations to conduct a population-wide haplotype analysis of these highly homologous genes. We identified major SMN1 and SMN2 haplogroups and characterized their co-segregation through pedigree-based analyses. We identified two SMN1 haplotypes that form a common two-copy SMN1 allele in African populations. Testing positive for these two haplotypes in an individual with two copies of SMN1 gives a silent carrier risk of 88.5%, which is significantly higher than the currently used marker (1.7-3.0%). Extending beyond simple copy number testing, Paraphase can detect pathogenic variants and enable potential haplotype-based screening of silent carriers through statistical phasing of haplotypes into alleles. Future analysis of larger population data will allow identification of more diverse haplotypes and genetic markers for silent carriers.

genetics↗

bioRxiv2020

Whole genome sequencing for diagnosis of neurological repeat expansion disorders

BackgroundRepeat expansion (RE) disorders affect ~1 in 3000 individuals and are clinically heterogeneous diseases caused by expansions of short tandem DNA repeats. Genetic testing is often locus-specific, resulting in under diagnosis of atypical clinical presentations, especially in paediatric patients without a prior positive family history. Whole genome sequencing (WGS) is emerging as a first-line test for rare genetic disorders, but until recently REs were thought to be undetectable by this approach. MethodsWGS pipelines for RE disorder detection were deployed by the 100,000 Genomes Project and Illumina Clinical Services Laboratory. Performance was retrospectively assessed across the 13 most common neurological RE loci using 793 samples with prior orthogonal testing (182 with expanded alleles and 611 with alleles within normal size) and prospectively interrogated in 13,331 patients with suspected genetic neurological disorders. FindingsWGS RE detection showed minimum 97{middle dot}3% sensitivity and 99{middle dot}6% specificity across all 13 disease-associated loci. Applying the pipeline to patients from the 100,000 Genomes Project identified pathogenic repeat expansions which were confirmed in 69 patients, including seven paediatric patients with no reported family history of RE disorders, with a 0.09% false positive rate. InterpretationWe show here for the first time that WGS enables the detection of causative repeat expansions with high sensitivity and specificity, and that it can be used to resolve previously undiagnosed neurological disorders. This includes children with no prior suspicion of a RE disorder. These findings are leading to diagnostic implementation of this analytical pipeline in the NHS Genomic Medicine Centres in England. FundingMedical Research Council, Department of Health and Social Care, National Health Service England, National Institute for Health Research, Illumina Inc

genomics↗