Biology subjects

Yan, S. M.

Publications and source records attributed to Yan, S. M..

3 recordsLinked to original sources

bioRxiv2021

A complete reference genome improves analysis of human genetic variation

Compared to its predecessors, the Telomere-to-Telomere CHM13 genome adds nearly 200 Mbp of sequence, corrects thousands of structural errors, and unlocks the most complex regions of the human genome to clinical and functional study. Here we demonstrate how the new reference universally improves read mapping and variant calling for 3,202 and 17 globally diverse samples sequenced with short and long reads, respectively. We identify hundreds of thousands of novel variants per sample--a new frontier for evolutionary and biomedical discovery. Simultaneously, the new reference eliminates tens of thousands of spurious variants per sample, including up to 12-fold reduction of false positives in 269 medically relevant genes. The vast improvement in variant discovery coupled with population and functional genomic resources position T2T-CHM13 to replace GRCh38 as the prevailing reference for human genetics. One Sentence SummaryThe T2T-CHM13 reference genome universally improves the analysis of human genetic variation.

genomics↗

bioRxiv2021

Haplotype-aware inference of human chromosome abnormalities

Extra or missing chromosomes--a phenomenon termed aneuploidy--frequently arises during human meiosis and embryonic mitosis and is the leading cause of pregnancy loss, including in the context of in vitro fertilization (IVF). While meiotic aneuploidies affect all cells and are deleterious, mitotic errors generate mosaicism, which may be compatible with healthy live birth. Large-scale abnormalities such as triploidy and haploidy also contribute to adverse pregnancy outcomes, but remain hidden from standard sequencing-based approaches to preimplantation genetic testing (PGT-A). The ability to reliably distinguish meiotic and mitotic aneuploidies, as well as abnormalities in genome-wide ploidy may thus prove valuable for enhancing IVF outcomes. Here, we describe a statistical method for distinguishing these forms of aneuploidy based on analysis of low-coverage whole-genome sequencing data, which is the current standard in the field. Our approach overcomes the sparse nature of the data by leveraging allele frequencies and linkage disequilibrium (LD) measured in a population reference panel. The method, which we term LD-informed PGT-A (LD-PGTA), retains high accuracy down to coverage as low as 0.05x and at higher coverage can also distinguish between meiosis I and meiosis II errors based on signatures spanning the centromeres. LD-PGTA provides fundamental insight into the origins of human chromosome abnormalities, as well as a practical tool with the potential to improve genetic testing during IVF. Significance StatementWhole chromosome gains and losses--termed aneuploidies--are the leading cause of human pregnancy loss and congenital disorders. Recent work has demonstrated that in addition to harmful meiotic aneuploidies, mitotic aneuploidies (which lead to mosaic embryos harboring cells with different numbers of chromosomes) may also be common in preimplantation embryos but potentially compatible with healthy birth. Here we developed and tested a method for distinguishing these forms of aneuploidy using genetic testing data from 8154 IVF embryos. We re-classified embryos based on signatures of meiotic and mitotic error, while also revealing lethal forms of chromosome abnormality that were hidden to existing approaches. Our method complements standard protocols for preimplantation and prenatal genetic testing, while offering insight into the biology of early development.

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↗