Coalescent tree recording with selection for fast forward-in-time simulations

Forward simulations are increasingly important in evolutionary genetics to simulate selection with realistic demography, mating systems and ecology. To reach the performance needed for genome-wide simulations a number of new simulation techniques have been developed recently. Kelleher et al. (2018) introduced a technique consisting in recording the entire genetic history of the population and placing mutations on the coalescent tree. This method cannot model selection. I recently introduced a simulation technique that speed up fitness calculation by assuming that fitness effects among haplotypes are multiplicative (Matthey-Doret, 2021). More precisely, fitness measures are stored for subsets of the genome and, at time of reproduction, if no recombination happen within a given subset, then the fitness for this subset for the offspring haplotype is directly inferred from the parental haplotype. Here, I present a hybrid of the above two techniques. The algorithm records the genetic history of a species, directly places the mutations on the tree and infers fitness of subsets of the genome from parental haplotypes. At recombinant sites, the algorithm explores the tree to reconstruct the genetic data at the recombining segment. I benchmarked this new technique implemented in SimBit and report an important improvement of performance compared to previous techniques to simulate selection. This improvement is particularly drastic at low recombination rate. Such developments of new simulation techniques are pushing the horizon of the realism with which we can simulate species molecular evolution.

Genomic evidence of paternal genome elimination in globular springtails

Paternal genome elimination (PGE) - a type of reproduction in which males inherit but fail to pass on the genome of their father - evolved independently in six to eight arthropod clades. Thousands of species, including several important for agriculture, reproduce via this mode of reproduction. While some of the clades are well established PGE systems, the evidence in globular springtails (Symphypleona) remains elusive, even though they represent the oldest and most species rich clade putatively reproducing via PGE. We sequenced genomic DNA from whole bodies of Allacma fusca males with sufficiently high fractions (31 - 38%) of sperm to conclusively confirm that all the sperm carry one parental haplotype only. Although it is suggestive that the single haplotype present in sperm is maternally inherited, definitive genetic proof of the parent of origin is still needed. The genomic approach we developed allows for detection of genotypic differences between germline and soma in all species with sufficiently high fraction of germline in their bodies. This opens new opportunities for scans for reproductive modes in small animals.

Noninvasive prenatal testing of α-thalassemia and β-thalassemia through population-based parental haplotyping

Background Noninvasive prenatal testing (NIPT) of recessive monogenic diseases depends heavily on knowing the correct parental haplotypes. However, the currently used family-based haplotyping method requires pedigrees, and molecular haplotyping is highly challenging due to its high cost, long turnaround time, and complexity. Here, we proposed a new two-step approach, population-based haplotyping-NIPT (PBH-NIPT), using α-thalassemia and β-thalassemia as prototypes. Methods First, we deduced parental haplotypes with Beagle 4.0 with training on a large retrospective carrier screening dataset (4356 thalassemia carrier screening-positive cases). Second, we inferred fetal haplotypes using a parental haplotype-assisted hidden Markov model (HMM) and the Viterbi algorithm. Results With this approach, we enrolled 59 couples at risk of having a fetus with thalassemia and successfully inferred 94.1% (111/118) of fetal alleles. We confirmed these alleles by invasive prenatal diagnosis, with 99.1% (110/111) accuracy (95% CI, 95.1–100%). Conclusions These results demonstrate that PBH-NIPT is a sensitive, fast, and inexpensive strategy for NIPT of thalassemia.

HapIso: An Accurate Method for the Haplotype-Specific Isoforms Reconstruction from Long Single-Molecule Reads

Sequencing of RNA provides the possibility to study an individual’s transcriptome landscape and determine allelic expression ratios. Single-molecule protocols generate multi-kilobase reads longer than most transcripts allowing sequencing of complete haplotype isoforms. This allows partitioning the reads into two parental haplotypes. While the read length of the single-molecule protocols is long, the relatively high error rate limits the ability to accurately detect the genetic variants and assemble them into the haplotype-specific isoforms. In this paper, we present HapIso (Haplotype-specific Isoform Reconstruction), a method able to tolerate the relatively high error-rate of the single-molecule platform and partition the isoform reads into the parental alleles. Phasing the reads according to the allele of origin allows our method to efficiently distinguish between the read errors and the true biological mutations. HapIso uses a k-means clustering algorithm aiming to group the reads into two meaningful clusters maximizing the similarity of the reads within cluster and minimizing the similarity of the reads from different clusters. Each cluster corresponds to a parental haplotype. We use family pedigree information to evaluate our approach. Experimental validation suggests that HapIso is able to tolerate the relatively high error-rate and accurately partition the reads into the parental alleles of the isoform transcripts. Furthermore, our method is the first method able to reconstruct the haplotype-specific isoforms from long single-molecule reads.The open source Python implementation of HapIso is freely available for download at https://github.com/smangul1/HapIso/

Comparative mapping among subsection Australes (genus Pinus, family Pinaceae)

Comparative mapping in conifers has not yet been used to test for small-scale genomic disruptions such as inversions, duplications, and deletions occurring between closely related taxa. Using comparative mapping to probe this smaller scale of inquiry may provide clues about speciation in a phylogenetically problematic taxon, the diploxylon pine subsection Australes (genus Pinus , family Pinaceae). Genetic maps were constructed for two allopatric species of Australes, P. elliottii var. elliottii and P. caribaea var. hondurensis , using microsatellites and an F1 hybrid. A third map was generated directly from the meiotic products of an adult F1 hybrid, eliminating the need for an F2 generation. Numerous small-scale disruptions were detected in addition to synteny and collinearity, and these included (1) map shrinkage, (2) a paracentric inversion, (3) transmission ratio distortion, and (4) mild selection against a parental haplotype. Such cryptic signatures of genomic divergence between closely related interfertile species are useful in elucidating this problematic evolutionary history.

Recombination Events Generating a Novel Rp1 Race Specificity

Genes at the maize Rpl rust resistance complex often mispair in meiosis, which allows genes to recombine unequally, creating recombinant haplotypes. Four recombinant haplotypes were identified from progeny of an Rpl-D/Rpl-I heterozygote that conferred a nonparental resistance specificity designated Rpl-I*. Sequence comparisons of paralogs in the recombinant and parental haplotypes demonstrated that all four recombinants were derived from intergenic (between gene) recombination events. The sequence of paralogs in the HRpl-I parental haplotype indicated this haplotype includes 41 or more rpl genes, at least 31 of which are transcribed. The results indicate that most of the novel resistance specificities that have arisen spontaneously at Rp1 are the result of reassortment of existing Rpl genes.

Self-recognition specificity expressed by T cells from nude mice. Absence of detectable Ia-restricted T cells in nude mice that do exhibit self-K/D-restricted T cell responses.

The presence in athymic nude mice of precursor T cells with self-recognition specificity for either H-2 K/D or H-2 I region determinants was investigated. Chimeras were constructed of lethally irradiated parental mice receiving a mixture of F1 nude mouse (6-8 wk old) spleen and bone marrow cells. The donor inoculum was deliberately not subjected to any T cell depletion procedure, so that any potential major histocompatibility complex-committed precursor T cells were allowed to differentiate and expand in the normal parental recipients. 3 mo after reconstitution, the chimeras were immunized with several protein antigens in complete Freund's adjuvant in the footpads and their purified draining lymph node T cells tested 10 d later for ability to recognize antigen on antigen-presenting cells of either parental haplotype. Also, their spleen and lymph node cells were tested for ability to generate a cytotoxic T lymphocyte (CTL) response to trinitrophenyl (TNP)-modified stimulator cells of either parental haplotype. It was demonstrated that T cell proliferative responses of these F1(nude)----parent chimeras were restricted solely to recognizing parental host I region determinants as self and expressed the Ir gene phenotype of the host. In contrast, CTL responses could be generated (in the presence of interleukin 2) to TNP-modified stimulator cells of either parental haplotype. Thus these results indicate that nude mice which do have CTL with self-specificity for K/D region determinants lack proliferating T cells with self-specificity for I region determinants. These results provide evidence for the concepts that development of the I region-restricted T cell repertoire is strictly an intrathymically determined event and that young nude mice lack the unique thymic elements responsible for education of I region-restricted T cells.

Mechanism responsible for the induction of I-J restriction on TS3 suppressor cells.

The mechanisms responsible for the induction of I-J restrictions on third-order suppressor T cells (TS3) were analyzed. The I-J phenotype of the antigen-coupled cells used for priming restricted the specificity of the TS3 population. Thus, TS3 cells were only generated after priming with antigen-coupled I-J homologous cells. Identity at the I-JM (and I-E) subregions was sufficient for TS3 induction. Furthermore, priming of H-2 heterozygous mice with antigen-coupled parental cells generated TS3 that were restricted to the parental haplotype used for priming. The splenic cell population responsible for antigen presentation and induction of TS3 cells was fractionated. The cells involved in antigen presentation were found in the splenic adherent population and were absent in the fraction containing splenic nonadherent T and B cells. The subsequent activation and interaction of TS3 cells is also restricted by genes in the H-2 complex. The results are discussed in terms of a general mechanism responsible for the induction of restrictions in T helper and TS3 cells.