Aberrant landscapes of maternal meiotic crossovers contribute to aneuploidies in human embryos

Fig. 1

Meiotic recombination is a fundamental source of human genetic diversity and is also critical for ensuring the accuracy of chromosome segregation. Understanding the landscape of meiotic recombination, its variation across individuals, and the processes by which it goes awry are long-standing goals in human genetics. Current approaches for inferring the landscape of recombination either rely on population genetic patterns of linkage disequilibrium (LD)—capturing a time-averaged view—or direct detection of crossovers in gametes or multi-generation pedigrees, limiting the scale and availability of relevant datasets. Here, we introduce an approach for inferring sex-specific landscapes of recombination from retrospective analysis of data from preimplantation genetic testing for aneuploidy (PGT-A), which is based on low-coverage (<0.05x) whole-genome sequencing of biopsies from in vitro fertilized (IVF) embryos. To overcome the sparsity of these data, our method exploits its inherent relatedness structure, knowledge of haplotypes from external population reference panels, as well as the frequent occurrence of chromosome loss in embryos, whereby the remaining chromosome is phased by default. LD-CHASE is a generalizable tool for mapping crossovers in low-coverage sequencing data from multiple siblings, toward a better understanding of the factors that modulate the meiotic crossover landscape and the role of recombination in the origins of aneuploidies.

Daniel Ariad, Svetlana Madjunkova, Mitko Madjunkov, Siwei Chen, Rina Abramov, Clifford Librach and Rajiv C McCoy. "Aberrant landscapes of maternal meiotic crossovers contribute to aneuploidies in human embryos." Genome Res. January 2023 | bioRxiv, 2023.06.07.543910.

Haplotype-aware inference of human chromosome abnormalities

Fig. 2: Mosaic human embryos with aneuploid cells (dark blue), stemming from post-fertilization errors.

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 for aneuploidies (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. We developed 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 data sparsity 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. In summary, our method complements current approaches for PGT-A, while also offering insight into the origins of chromosome abnormalities in human development.

Daniel Ariad, Stephanie M. Yan, Andrea R. Victor, Frank L. Barnes, Christo G. Zouves, Manuel Viotti and Rajiv C. McCoy. "Haplotype-aware inference of human chromosome abnormalities." PNAS November 16, 2021 118 (46) e2109307118 | bioRxiv:10.1101/2021.05.18.444721 | The study is summarized in this poster

How vortex bound states affect the Hall conductivity of a chiral p_x ± ip_y superconductor

Fig. 3: The tight-binding result of c<sub

This work extend our understanding of the anomalous charge response, c_xy of chiral superconductors. It is established that in order to correctly apply the Streda formula for calculating c_xy it is necessary to employ compact geometries that avoid edge effects. This, in turn, requires a careful analysis of the effect of finite-radius vortex nucleation that leads to an adjustment of the Streda formula. The modified Streda formula is then applied to calculate c_xy for a p_x ± ip_y superconductor placed on a square lattice at zero magnetic field and zero vorticity. We show that $c_{xy}$ is a sum of two contributions, one which is non-universal and the other equals $\kappa/8\pi$, where $\kappa$ is the Chern number of the superconductor. Moreover, we note that c_xy is proportional to the anomalous Hall conductivity, which in turn is proportional to the polar Kerr angle. Thus, these results should affect the calculation of the polar Kerr effect, hence they are significant for the determination of the order parameter of superconductors.

Daniel Ariad, Yshai Avishai and Eytan Grosfeld. "How vortex bound states affect the Hall conductivity of a chiral p±ip superconductor." Phy. Rev. B 98, 104511 (2018) | arXiv:1603.00840 | The study is summarized in this poster.

Signatures of the topological spin of Josephson vortices in topological superconductors

Fig. 4: An annular Josephson junction with a trapped soliton and a bulk vortex at the center.

Realization of non-abelian quasi-particles known as Majorana fermions is an ongoing challenge for physicists exploring topological states of matter. Towards achieving this goal, we recently suggested that Josephson vortices in topological Josephson junctions (TJJ) would constitute such Majorana fermions and retain the exchange statistics of bulk vortices. We corroborated this hypothesis by finding the universal exchange phase of Josephson vortices. In order to do so, we derived the Hamiltonian governing the dynamics of a soliton in an annular Josephson junction. Our next step was to develop a procedure to calculate the Berry connection of systems that posses particle-hole symmetry. The procedure was applied to confirm that the Abelian phase due to the an exchange between a vortex in the bulk of a p-wave superconductor and a Josephson vortex is π/8. In addition, we suggested an experiment to measure it by.

Daniel Ariad and Eytan Grosfeld. "Signatures of the topological spin of Josesphson vortices in topological superconductors." Phys. Rev. B 95, 161401(R) (2017) | arXiv:1301.0538 | The study is summarized in this poster.

On the effective theory of vortices in two-dimensional spinless chiral p-wave superfluids

Fig. 5: Two vortices are exchanged in a chiral p-wave superconductor placed on a square lattice.

As the search for quantum computers evolves, new methods to realize an universal topological quantum computation are a explored. Vortex defects in a 2D spinless chiral p-wave superfluid bind Majorana zero modes that endow them with non-Abelian exchange statistics. Motivated by its potential for topological quantum information processing, we developed a ${\mathbb{U}(1) \times \mathbb{Z}_2}$ effective gauge theory for vortices in a ${p_x+ip_y}$ superfluid in two dimensions. The combined gauge transformation binds ${\mathbb{U}(1)}$ and ${\mathbb{Z}_2}$ defects so that the total transformation remains single-valued and manifestly preserves the particle-hole symmetry of the action. The ${\mathbb{Z}_2}$ gauge field introduces a complete Chern-Simons term in addition to a partial one associated with the ${\mathbb{U}(1)}$ gauge field. The theory reproduces the known physics of vortex dynamics such as a Magnus force proportional to the superfluid density. It also predicts a universal Abelian phase, ${\exp(i\pi/8)}$, upon the exchange of two vortices, modified by non-universal corrections due to the partial Chern-Simon term that are screened in a charged superfluid.

Daniel Ariad, Eytan Grosfeld, and Babak Seradjeh. "On the effective theory of vortices in two-dimensional spinless chiral p-wave superfluid." Phys. Rev. B 92, 035136 (2015) | arXiv:1407.2553.

The role pickup ions play in the termination shock

Fig. 6: Diagram of the heliosphere as it travels through the interstellar medium. Image Credit: Roen Kelly

An energy conservation paradox emerged from the data collected by Voyger 2 (V2) while crossing the Termination Shock in September 2013. The solar wind (SW) blows outward from the Sun and forms a bubble of solar material in the interstellar medium (ISM). The termination shock occurs where the SW changes from being supersonic to being subsonic. It was found that the sum of the flow energy and the thermal energy is not conserved. We showed that the pickup ions (PUI), a group of atoms from the ISM that are Ionized by the Sun's radiation and then swept along with the SW, which have an energy spectrum that lies outside the V2's equipment range of the measurement gain the missing energy. It was done with the use of the Liuoville theorem to map the PUI momentum distribution between the two sides of the shock. We found that: (a) the PUI can gain the missing energy and momentum along the shock with a Shock Drift Mechanism (SDM) (b) The SDM must be preliminary to the Shock.

Ariad, D., and M. Gedalin. "The role pickup ions play in the termination shock." Journal of Geophysical Research: Space Physics 118.6 (2013): 2854-2862 | Preprint