Biology subjects

McCoy, R. C.

Publications and source records attributed to McCoy, R. C..

22 records · Page 2Linked to original sources

bioRxiv2020

SVCollector: Optimized sample selection for cost-efficient long-read population sequencing

An increasingly important scenario in population genetics is when a large cohort has been genotyped using a low-resolution approach (e.g. microarrays, exome capture, short-read WGS), from which a few individuals are selected for resequencing using a more comprehensive approach, especially long-read sequencing. The subset of individuals selected should ensure that the captured genetic diversity is fully representative and includes variants across all subpopulations. For example, human variation has historically been focused on individuals with European ancestry, but this represents a small fraction of the overall diversity. To address this goal, SVCollector (https://github.com/fritzsedlazeck/SVCollector) identifies the optimal subset of individuals for resequencing. SVCollector analyzes a population-level VCF file from a low resolution genotyping study. It then computes a ranked list of samples that maximizes the total number of variants present from a subset of a given size. To solve this optimization problem, SVCollector implements a fast greedy heuristic and an exact algorithm using integer linear programming. We apply SVCollector on simulated data, 2504 human genomes from the 1000 Genomes Project, and 3024 genomes from the 3K Rice Genomes Project and show the rankings it computes are more representative than widely used naive strategies. Notably, we show that when selecting an optimal subset of 100 samples in these two cohorts, SV-Collector identifies individuals from every subpopulation while naive methods yield an unbalanced selection. Finally, we show the number of variants present in cohorts of different sizes selected using this approach follows a power-law distribution that is naturally related to the population genetic concept of the allele frequency spectrum, allowing us to estimate the diversity present with increasing numbers of samples.

bioinformatics↗

bioRxiv2020

Single-cell analysis of human embryos reveals diverse patterns of aneuploidy and mosaicism

Less than half of human zygotes survive to live birth, primarily due to aneuploidies of meiotic or mitotic origin. Mitotic errors lead to chromosomal mosaicism, defined by multiple cell lineages with distinct chromosome complements. The incidence and fitness consequences of chromosomal mosaicism in human embryos remain controversial, with most previous studies based on bulk DNA assays or comparisons of multiple biopsies of a few embryonic cells. Single-cell genomic data provide an opportunity to quantify mosaicism on an embryo-wide scale. To this end, we extended an approach to infer aneuploidies based on chromosome dosage-associated changes in gene expression by integrating signatures of allelic imbalance. We applied this method to published single-cell RNA sequencing data from 74 disaggregated human embryos, spanning the morula to blastocyst stages. Our analysis revealed widespread mosaic aneuploidies across preimplantation development, with 59 of 74 (80%) embryos harboring at least one aneuploid cell (1% FDR). By clustering copy number calls, we reconstructed histories of chromosome mis-segregation, distinguishing meiotic and early mitotic errors from those occurring after lineage differentiation. We observed no significant enrichment of aneuploid cells in the trophectoderm compared to the inner cell mass, though we do detect such an enrichment in published data from later post-implantation stages. Finally, we observed that aneuploid cells exhibit upregulation of immune response genes, as well as downregulation of genes involved in proliferation, metabolism, and protein processing, consistent with stress responses previously documented in other stages and systems. Together, our work provides a high-resolution view of aneuploidy in preimplantation embryos and supports the conclusion that low-level mosaicism is a common feature of early human development.

genomics↗

bioRxiv2017

Tripolar mitosis drives the association between maternal genotypes of PLK4 and aneuploidy in human preimplantation embryos

Aneuploidy is prevalent in human preimplantation embryos and is the leading cause of pregnancy loss. Many aneuploidies arise during oogenesis, increasing in frequency with maternal age. Superimposed on these meiotic aneuploidies are a range of errors occurring during early mitotic divisions of the embryo, contributing to widespread chromosomal mosaicism. Here we reanalyzed a published dataset comprising preimplantation genetic testing for aneuploidy in 24,653 blastomere biopsies from day-3 cleavage-stage embryos, as well as 17,051 trophectoderm biopsies from day-5 blastocysts. We focused on complex abnormalities that affected multiple chromosomes simultaneously, seeking to quantify their incidences and gain insight into their mechanisms of formation. In addition to well-described patterns such as triploidy and haploidy, we identified 4.7% of day-3 blastomeres possessing karyotypes suggestive of tripolar mitosis in normally-fertilized diploid zygotes or descendant diploid cells. We further supported this hypothesis using time-lapse data from an intersecting set of 77 cleavage-stage embryos. The diploid tripolar signature was rare among day-5 blastocyst biopsies (0.5%), suggesting that complex aneuploidy generated by tripolar mitosis impairs cellular and/or early embryonic survival. Strikingly, we found that the tripolar mitosis mechanism is responsible for the previously described association with common maternal genetic variants spanning PLK4. Our findings are consistent with the role of PLK4 as the master regulator of centriole duplication with a known capacity to induce tripolar mitosis when mutated or mis-expressed. Taken together, we propose that tripolar mitosis is a key mechanism generating karyotype-wide aneuploidy in cleavage-stage embryos and implicate PLK4-mediated centrosome abnormality as a factor influencing its occurrence.

genetics↗

bioRxiv2017

Short tandem repeats with massive variation and functional consequences across strains of Arabidopsis thaliana

Short tandem repeat (STR) mutations may be responsible for more than half of the mutations in eukaryotic coding DNA, yet STR variation is rarely examined as a contributor to complex traits. We assess the scope of this contribution across a collection of 96 strains of Arabidopsis thaliana by massively parallel STR genotyping. We found that 95% of examined STRs are polymorphic, with a median of six alleles per STR in these strains. Modest STR expansions are found in most strains, some of which have evident functional effects. For instance, three of six intronic STR expansions are associated with intron retention. Coding STRs are depleted of variation relative to non-coding STRs, consistent with the action of purifying selection, and some STRs show hypervariable patterns consistent with diversifying selection. Finally, we detect dozens of novel STR-phenotype associations that could not be detected with SNPs alone, validating several with follow-up experiments. Our results demonstrate that STRs comprise a large, unascertained reservoir of functionally relevant genomic variation.

genomics↗