Biology subjects

Bortvin, A. N.

Publications and source records attributed to Bortvin, A. N..

3 recordsLinked to original sources

bioRxiv2025

A T2T-CHM13 recombination map and globally diverse haplotype reference panel improves phasing and imputation

The T2T-CHM13 complete human reference genome contains [~]200 Mb of previously unresolved sequence, improving read mapping and variant calling compared to GRCh38. However, the benefits of using complete reference genomes for phasing and imputation are unclear. Here, we present a reference T2T-CHM13 recombination map and phased haplotype panel derived from 3,202 samples from the 1000 Genomes Project (1kGP). Using published long-read based assemblies as a reference-neutral ground truth, we compared our T2T-CHM13 1kGP panel to the previously released GRCh38 1kGP panel. We found that alignment to T2T-CHM13 resulted in 38% fewer assembly-discordant SNP genotypes and 16% fewer phasing switch errors. The largest gains in panel accuracy were observed on chromosome X and in the regions flanking loci prone to disease-causing CNVs. Moreover, downsampled genomes from the Simons Genome Diversity Project attained higher imputation accuracy when using the T2T-CHM13 versus GRCh38 1kGP panel. Our study demonstrates that use of the T2T-CHM13 phased haplotype panel improves statistical phasing and imputation for samples from diverse human populations.

genomics↗

bioRxiv2021

Strict adherence to Mendel's First Law across a large sample of human sperm genomes

Mendels Law of Segregation states that the offspring of a diploid, heterozygous parent will inherit either allele with equal probability. While the vast majority of loci adhere to this rule, research in model and non-model organisms has uncovered numerous exceptions whereby "selfish" alleles are disproportionately transmitted to the next generation. Evidence of such "transmission distortion" (TD) in humans remains equivocal in part because scans of human pedigrees have been under-powered to detect small effects. Recently published single-cell sequencing data from individual human sperm (n = 41,189; 969-3,377 cells from each of 25 donors) offer an opportunity to revisit this question with unprecedented statistical power, but require new methods tailored to extremely low-coverage data ([~]0.01 x per cell). To this end, we developed a method, named rhapsodi, that leverages sparse gamete genotype data to phase the diploid genomes of the donor individuals, impute missing gamete genotypes, and discover meiotic recombination breakpoints, benchmarking its performance across a wide range of study designs. After applying rhapsodi to the sperm sequencing data, we then scanned the gametes for evidence of TD. Our results exhibited close concordance with binomial expectations under balanced transmission, in contrast to tenuous signals of TD that were previously reported in pedigree-based studies. Together, our work excludes the existence of even weak TD in this sample, while offering a powerful quantitative framework for testing this and related hypotheses in other cohorts and study systems.

genomics↗

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↗