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. 2019 Sep 3;10(1):3972.
doi: 10.1038/s41467-019-11771-z.

Meiotic sex in Chagas disease parasite Trypanosoma cruzi

Affiliations

Meiotic sex in Chagas disease parasite Trypanosoma cruzi

Philipp Schwabl et al. Nat Commun. .

Abstract

Genetic exchange enables parasites to rapidly transform disease phenotypes and exploit new host populations. Trypanosoma cruzi, the parasitic agent of Chagas disease and a public health concern throughout Latin America, has for decades been presumed to exchange genetic material rarely and without classic meiotic sex. We present compelling evidence from 45 genomes sequenced from southern Ecuador that T. cruzi in fact maintains truly sexual, panmictic groups that can occur alongside others that remain highly clonal after past hybridization events. These groups with divergent reproductive strategies appear genetically isolated despite possible co-occurrence in vectors and hosts. We propose biological explanations for the fine-scale disconnectivity we observe and discuss the epidemiological consequences of flexible reproductive modes. Our study reinvigorates the hunt for the site of genetic exchange in the T. cruzi life cycle, provides tools to define the genetic determinants of parasite virulence, and reforms longstanding theory on clonality in trypanosomatid parasites.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Phylogenomic relationships among T. cruzi I clones from southern Ecuador. a Data are represented as a split network by the Neighbor-Net algorithm. Pairwise genetic distances are defined as the proportion of non-shared genotypes across all biallelic SNP sites for which genotypes are called in >40 individuals (n = 68,449). Arrow (and flash) indicate a strong, unambiguous break in gene-flow between two reticulate assemblages, Cluster 1 (green) and Cluster 2 (blue). Though non-treelike phylogenetic models are better suited to the data, a maximum-likelihood tree is also provided for comparison in Supplementary Fig. 1. b A minimum-spanning network further illustrates the genetic disconnectivity between Clusters 1 and 2. Multi-furcating nodes are arranged such that cumulative edge distance is minimized among samples. Pairwise genetic distances are haplotype-based, defined as the proportion of non-shared alleles across all SNP sites for which genotypes are called for all individuals (n = 7,392). c Sampling regions in Loja Province, Ecuador, are abbreviated as BM Bella Maria, AR Ardanza, EH El Huayco, SR Santa Rita, and GE Gerinoma. Point sizes correspond to sample sizes and colors correspond to cluster membership (see phylogenetic networks). The upper map is adapted from https://d-maps.com/carte.php?num_car=3400&lang=en (d-maps.com). The close-up uses Landsat imagery courtesy of the U.S. Geological Survey
Fig. 2
Fig. 2
Haplotype co-ancestry among T. cruzi I clones from southern Ecuador. The heatmap of co-ancestry is based on a sorted haplotype co-ancestry matrix xij, which estimates the number of discrete segments of genome i that are most closely related to the corresponding segment of genome j. These nearest-neighbor relationships from fineSTRUCTURE analysis are sorted such that samples clustered along the diagonal are those that most share recent genealogical events, and pairwise comparisons outside of the diagonal indicate levels of genetic connectivity among these clusters. The matrix also includes ‘genomes’ of non-cloned T. cruzi cultures. Strong horizontal banding points to the accumulation of diversity from throughout the dataset in four of these original infections. Cell color represents the frequency of nearest-neighbor relationships for each sample pair, increasing from yellow (2) through red (68) and pink (134) to black (200). Four anomalous (outlier) samples are described further on in main text. Analysis uses 110,326 phased SNP sites
Fig. 3
Fig. 3
Linkage decay and different rates of recombination in T. cruzi I groups. a Decay of linkage disequilibrium on chromosome 1 for T. cruzi I clones from Bella Maria. Average pairwise linkage values (r2) among SNP sites present in at least 90% individuals (n = 5373) are plotted for map distance classes between 0 and 100 kb. b Local regression curves for the decay of linkage disequilibrium on chromosomes 1, 5, 21, and 26 for T. cruzi I clones from Bella Maria. c, d Lack of linkage decay on chromosome 1 for T. cruzi I clones from El Huayco (4093 SNPs) and Ardanza (3306 SNPs). Average pairwise linkage values (r2) are plotted against distance classes as for Bella Maria above
Fig. 4
Fig. 4
Genome-wide heterozygosity patterns and intra-chromosomal mosaics in T. cruzi I clones. In a, each column represents the genome of one clone, considering the dataset’s total 130,996 SNPs. Rows within each column represent consecutive 5 kb sequence bins. Alternate allele frequency means (AAFM) determine the color of each bin – blue (0) through green (0.5) to red (1). Clones from Bella Maria tend to carry patchy homozygosity while those of Cluster 2 appear highly heterozygous throughout the genome. Isolated tracts of high homozygosity (i.e., red patches) shared between pairs of Bella Maria clones imply sudden sequence similarity and fluctuating phylogenetic relationships inconsistent with divergence through drift. b provides a close-up on chromosome 1. c, d demonstrate the impact of this intra-chromosomal mosaicism on the topology of phylogenetic trees derived in a sliding window across chromosome 1. Multiple incongruent topologies are present in Bella Maria (c), consistent with widespread genetic exchange. Only a single topology dominates for samples of El Huayco d, consistent with limited genetic exchange in Cluster 2. An example of how AAFM heatmaps correspond to topology analyses is indicated in the heatmap close-up b and tree topologies in c: a shared red patch between TBM_2824_CL1 and MBC_1545_CL3 corresponds to neighbor-joining tree topology A in c. Later, near ca. 1100 kb, a shared patch of high AAFM between TBM_2824_CL1 and MCQ_1491_CL2 begins. This patch occurs where tree topology B best describes phylogenetic relationships in Bella Maria. Topology B is identical to topology A except for the replacement of MBC_1545_CL3 by MCQ_1491_CL2 as nearest neighbor to TBM_2824_CL1
Fig. 5
Fig. 5
Incongruent trees exemplify independent chromosomal ancestries among T. cruzi I clones. Within individual sample genomes from Cluster 1 and Cluster 2, different chromosomes present different phylogenetic ancestries. For example, when neighbor-joining trees are constructed separately for chromosomes 1, 5, and 19, Gerinoma clones (prefix TGM) cluster with those from Ardanza on chromosome 1. On chromosomes 5 and 19, they cluster with clones from Bella Maria. El Huayco clones THY 3973 CL3 and THY 4333 CL3 also join the Ardanza clade on chromosome 19. Within Cluster 1 (right panel), chromosome 1 presents a monophyletic clade composed of MBC_1545 + TBM_2824 (labeled B) and MBM_1466 + TBM_3297 clones (C). TBM_2795 + TBM_2823 + TBM_3329 clones (A) form an outgroup. These clades rearrange on chromosome 5, where A changes places with C. The A + B monophylum occurs again on chromosome 19, while the B + C group makes appearances on chromosomes 9 and 16, etc. Discrepant phylogenies such as those highlighted here occur in various chromosomal comparisons throughout the genome. Nodes are labeled in gray with support values from 100 bootstrap replicates. Green denotes the Cluster 1 clade. Blue denotes Cluster 2. Yellow highlights unstable phylogenetic positions among different chromosomes. Branch lengths are not proportional to genetic distance
Fig. 6
Fig. 6
Group-level aneuploidy among T. cruzi I clones. a We distinguished chromosomal and intra-chromosomal copy number variation by evaluating sequence read-depth kernel density distributions. For example, these distributions suggest multiple cases of whole-chromosome somy elevation (highlighted in pink) for El Huayco clone THY_4332_CL2 (bottom right). Several clones from El Huayco and Ardanza present similar patterns (see Supplementary Fig. 14 for more density plots), as summarized in the heatmap at left. Read-depth densities suggest few cases of whole-chromosome somy elevation for clones from Bella Maria (e.g., TBM_2823_CL4 and TBM_2824_CL2 at right). However, mapping coverage drops dramatically (yellow) on chromosome 13 in most clones of this group. b Chromosome-wide shifts in sequence read-depth (blue) and alternate allele frequency (black) support whole-chromosome aneuploidies inferred from read-depth kernel density distributions above. In El Huayco clone THY_4332_CL2 (left column), for example, read-depth is elevated over the entirety of trisomic chromosome 19 (sequence positions are plotted on the x-axis). Alternate allele frequencies at heterozygous sites also distribute around values of 0.33 and 0.67 on this chromosome (as compared to frequencies around 0.50 on disomic chromosome 18). Cases of intra-chromosomal copy number variation for sample THY_4332_CL2 are marked by local shifts in read-depth and alternate allele frequency on chromosome 7. Comprehensive read-depth reduction on chromosome 13 is exemplified for Bella Maria clone TBM_2823_CL4 (right column). Alternate allele frequency values of 0 (indicative of the reference allele) predominate on this chromosome. Patterns on chromosomes 7 and 18 also point to intra-chromosomal copy number variation and stable disomy, respectively, for the TBM_2823_CL4 clone

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