Demographic history and conservation genomics of caribou (Rangifer tarandus) in Québec

The loss of genetic diversity is a challenge many species are facing, and genomics is a potential tool that can inform and prioritize decision making. Caribou populations have experienced significant recent declines throughout Québec, Canada, and some are considered threatened or endangered. We calculated the ancestral and contemporary patterns of genomic diversity of five caribou populations and applied a comparative framework to assess the interplay between demography and genomic diversity. We calculated a caribou specific mutation rate, μ, by extracting orthologous genes from related ungulates. Whole genome re-sequencing was completed on 67 caribou and genotype likelihoods were estimated. We calculated nucleotide diversity, θπ and estimated the coalescent or ancestral Ne, which ranged from 12,030 to 15,513. When compared to the census size, NC, the endangered Gaspésie Mountain caribou population had the highest Ne:NC ratio which is consistent with recent work suggesting high ancestral Ne:NC is of conservation concern. These ratios were highly correlated with genomic signatures (i.e. Tajima’s D) and explicit demographic model parameters. Values of contemporary Ne, estimated from linkage-disequilibrium, ranged from 11 to 162, with Gaspésie having among the highest contemporary Ne:NC ratio. Importantly, conservation genetics theory would predict this population to be of less concern based on this ratio. Of note, F varied only slightly between populations, and runs of homozygosity were not abundant in the genome. Our study highlights how genomic patterns are nuanced and misleading if viewed only through a contemporary lens; a holistic view should integrate ancestral Ne and Tajima’s D into conservation decisions.

Genetic diversity in the IZUMO1-JUNO protein-receptor pair involved in human reproduction

Fertilization in mammals begins with the union of egg and sperm, an event that starts a cascade of cellular processes. The molecular-level understanding of these processes can guide the development of new strategies for controlling and/or promoting fertilization, and inform researchers and medical professional on the best choice of interventions. The proteins encoded by the IZUMO1 and JUNO genes form a ligand-receptor protein pair involved in the recognition of sperm and egg. Due to their role in the fertilization process, these proteins are potential targets for the development of novel anti-contraceptive, as well as infertility treatments. Here we present a comprehensive analysis of these gene sequences, with the objective of identifying evolutionary patterns that may support their relevance as targets for preventing or improving fertility among humans. JUNO and IZUMO1 gene sequences were identified within the genomes of over 2,000 humans sequenced in the 1000 Genomes Project. The human sequences were subjected to analyses of nucleotide diversity, deviation from neutrality of genetic variation, population-based differentiation (FST), haplotype inference, and whole chromosome scanning for signals of positive or of balancing selection. Derived alleles were determined by comparison to archaic hominin and other primate genomes. The potential effect of common non-synonymous variants on protein-protein interaction was also assessed. IZUMO1 displays higher variability among human individuals than JUNO. Genetic differentiation between continental population pairs was within whole-genome estimates for all but the JUNO gene in the African population group with respect to the other 4 population groups (American, East Asian, South Asian, and European). Tajima’s D values demonstrated deviation from neutrality for both genes in comparison to a group of genes identified in the literature as under balancing or positive selection. Tajima’s D for IZUMO1 aligns with values calculated for genes presumed to be under balancing selection, whereas JUNO’s value aligned with genes presumed to be under positive selection. These inferences on selection are both supported by SNP density, nucleotide diversity and haplotype analysis. A JUNO haplotype carrying 3 derived alleles out of 5, one of which is a missense mutation implicated in polyspermy, was found to be significant in a population of African ancestry. Polyspermy has a disadvantageous impact on fertility and its presence in approximately 30% of the population of African ancestry may be associated to a potentially beneficial role of this haplotype. This role has not been established and may be related to a non-reproductive role of JUNO. The high degree of conservation of the JUNO sequence combined with a dominant haplotype across multiple population groups supports JUNO as a potential target for the development of contraceptive treatments. In addition to providing a detailed account of human genetic diversity across these 2 important and related genes, this study also provides a framework for large population-based studies investigating protein-protein interactions at the genome level.

Metagenomic targets of balancing selection in the human gut

Bacteria in the human gut contend with numerous fluctuating environmental variables, including bouts of extreme selective agents like antibiotics. Theory predicts that oscillations in the adaptive landscape can impose balancing selection on bacterial populations, leaving characteristic signatures in the sequence variation of functionally significant genomic loci. Despite their potential importance for gut bacterial adaptation, the metagenomic targets of balancing selection have not been identified. Here, I present population genetic evidence that balancing selection maintains allelic diversity in multidrug efflux pumps of multiple predominant bacterial species in the human gut metagenome. Metagenome wide scans of 566,958 core open reading frames (CORFs) from 287 bacterial species represented by 118,617 metagenome assembled genomes (MAGs) indicated that most CORFs have been conserved by purifying selection. However, dozens of CORFs displayed positive Tajima’s D values that deviated significantly from their species’ genomic backgrounds, indicating the action of balancing selection. The AcrB subunit of a multidrug efflux pump (MEP) in Bacteroides dorei displayed the highest Tajima’s D of any CORF, and AcrB and other MEPs from a diversity of bacterial species were significantly enriched among the CORFs with the highest Tajima’s D values. Crystal structures indicated that the regions under balancing selection bind tetracycline and macrolide antibiotics. Other proteins identified as targets of balancing selection included synthases, hydrolases, and ion transporters. Intriguingly, bacterial species experiencing balancing selection were the most abundant in the human gut based on metagenomic data, further suggesting fitness benefits of the allelic variation identified.

Genome-wide scans for signatures of selection in Mangalarga Marchador horses using high-throughput SNP genotyping

Background The detection of signatures of selection in genomic regions provides insights into the evolutionary process, enabling discoveries regarding complex phenotypic traits. In this research, we focused on identifying genomic regions affected by different selection pressures, mainly highlighting the recent positive selection, as well as understanding the candidate genes and functional pathways associated with the signatures of selection in the Mangalarga Marchador genome. Besides, we seek to direct the discussion about genes and traits of importance in this breed, especially traits related to the type and quality of gait, temperament, conformation, and locomotor system. Results Three different methods were used to search for signals of selection: Tajima’s D (TD), the integrated haplotype score (iHS), and runs of homozygosity (ROH). The samples were composed of males (n = 62) and females (n = 130) that were initially chosen considering well-defined phenotypes for gait: picada (n = 86) and batida (n = 106). All horses were genotyped using a 670 k Axiom® Equine Genotyping Array​ (Axiom MNEC670). In total, 27, 104 (chosen), and 38 candidate genes were observed within the signatures of selection identified in TD, iHS, and ROH analyses, respectively. The genes are acting in essential biological processes. The enrichment analysis highlighted the following functions: anterior/posterior pattern for the set of genes (GLI3, HOXC9, HOXC6, HOXC5, HOXC4, HOXC13, HOXC11, and HOXC10); limb morphogenesis, skeletal system, proximal/distal pattern formation, JUN kinase activity (CCL19 and MAP3K6); and muscle stretch response (MAPK14). Other candidate genes were associated with energy metabolism, bronchodilator response, NADH regeneration, reproduction, keratinization, and the immunological system. Conclusions Our findings revealed evidence of signatures of selection in the MM breed that encompass genes acting on athletic performance, limb development, and energy to muscle activity, with the particular involvement of the HOX family genes. The genome of MM is marked by recent positive selection. However, Tajima’s D and iHS results point also to the presence of balancing selection in specific regions of the genome.

Functional Haplotypes and Evolutionary Insight into the Granule-Bound Starch Synthase II (GBSSII) Gene in Korean Rice Accessions (KRICE_CORE)

Granule-bound starch synthase 2 (GBSSII), a paralogous isoform of GBSSI, carries out amylose biosynthesis in rice. Unlike GBSSI, it mainly functions in transient organs, such as leaves. Despite many reports on the starch gene family, little is known about the genetics and genomics of GBSSII. Haplotype analysis was conducted to unveil genetic variations (SNPs and InDels) of GBSSII (OS07G0412100) and it was also performed to gain evolutionary insight through genetic diversity, population genetic structure, and phylogenetic analyses using the KRICE_CORE set (475 rice accessions). Thirty nonsynonymous SNPs (nsSNPs) were detected across the diverse GBSSII coding regions, representing 38 haplotypes, including 13 cultivated, 21 wild, and 4 mixed (a combination of cultivated and wild) varieties. The cultivated haplotypes (C_1–C_13) contained more nsSNPs across the GBSSII genomic region than the wild varieties. Nucleotide diversity analysis highlighted the higher diversity values of the cultivated varieties (weedy = 0.0102, landrace = 0.0093, and bred = 0.0066) than the wild group (0.0045). The cultivated varieties exhibited no reduction in diversity during domestication. Diversity reduction in the japonica and the wild groups was evidenced by the negative Tajima’s D values under purifying selection, suggesting the domestication signatures of GBSSII; however, balancing selection was indicated by positive Tajima’s D values in indica. Principal component analysis and population genetics analyses estimated the ambiguous evolutionary relationships among the cultivated and wild rice groups, indicating highly diverse structural features of the rice accessions within the GBSSII genomic region. FST analysis differentiated most of the classified populations in a range of greater FST values. Our findings provide evolutionary insights into GBSSII and, consequently, a molecular breeding program can be implemented for select desired traits using these diverse nonsynonymous (functional) alleles.

In silico characterisation of putative Plasmodium falciparum vaccine candidates in African malaria populations

Genetic diversity of surface exposed and stage specific Plasmodium falciparum immunogenic proteins pose a major roadblock to developing an effective malaria vaccine with broad and long-lasting immunity. We conducted a prospective genetic analysis of candidate antigens (msp1, ama1, rh5, eba175, glurp, celtos, csp, lsa3, Pfsea, trap, conserved chrom3, hyp9, hyp10, phistb, surfin8.2, and surfin14.1) for malaria vaccine development on 2375 P. falciparum sequences from 16 African countries. We described signatures of balancing selection inferred from positive values of Tajima’s D for all antigens across all populations except for glurp. This could be as a result of immune selection on these antigens as positive Tajima’s D values mapped to regions with putative immune epitopes. A less diverse phistb antigen was characterised with a transmembrane domain, glycophosphatidyl anchors between the N and C- terminals, and surface epitopes that could be targets of immune recognition. This study demonstrates the value of population genetic and immunoinformatic analysis for identifying and characterising new putative vaccine candidates towards improving strain transcending immunity, and vaccine efficacy across all endemic populations.

Genetic Diversity in the IZUMO1-JUNO Protein-Receptor Pair Involved in Human Reproduction

Fertilization in mammals begins with the union of egg and sperm, an event that starts a cascade of cellular processes. The molecular-level understanding of these processes can guide the development of new strategies for controlling and/or promoting fertilization, and inform researchers and medical professional on the best choice of interventions. The proteins encoded by the IZUMO1 and JUNO genes form a ligand-receptor protein pair involved in the recognition of sperm and egg. Due to their role in the fertilization process, these proteins are potential targets for the development of novel anti-contraceptive, as well as infertility treatments. Here we present a comprehensive analysis of these gene sequences, with the objective of identifying evolutionary patterns that may support their relevance as targets for preventing or improving fertility among humans. JUNO and IZUMO1 gene sequences were identified within the genomes of over 2000 humans sequenced in the 1000 Genomes Project. The human sequences were subjected to analyses of nucleotide diversity, selection neutrality, population-based differentiation (FST), haplotype inference, and whole chromosome scanning for signals of positive or of balancing selection. Derived alleles were determined by comparison to archaic hominin and other primate genomes. The potential effect of common non-synonymous variants on protein-protein interaction was also assessed. IZUMO1 displays higher variability among human individuals than JUNO. Genetic differentiation between continental population pairs was within whole-genome estimates for all but the JUNO gene in the African population group with respect to the other 4 population groups (American, East Asian, South Asian, and European). Tajima's D values demonstrated deviation from neutrality for both genes in comparison to a group of genes identified in the literature as under balancing or positive selection. Tajima's D for IZUMO1 aligns with values calculated for genes presumed to be under balancing selection, whereas JUNO's value aligned with genes presumed to be under positive selection. These inferences on selection are both supported by SNP density, nucleotide diversity and haplotype analysis. A JUNO haplotype carrying 3 derived alleles out of 5, one of which is a missense mutation implicated in polyspermy, was found to be significant in a population of African ancestry. Polyspermy has a disadvantageous impact on fertility and its presence in approximately 30% of the population of African ancestry may be associated to a potentially beneficial role of this haplotype. This role has not been established and may be related to a non-reproductive role of JUNO. The high degree of conservation of the JUNO sequence combined with a dominant haplotype across multiple population groups supports JUNO as a potential target for the development of contraceptive treatments. In addition to providing a detailed account of human genetic diversity across these 2 important and related genes, this study also provides a framework for large population-based studies investigating protein-protein interactions at the genome level.

A New Likelihood-based Test for Natural Selection

We present a new statistic for testing for neutral evolution from allele frequency data summarised as a site frequency spectrum, which we call the relative likelihood neutrality test or ρ. Classical methods of testing for natural selection, such as Tajima's D and its relatives, require the null model to have constant population size over time and therefore can confound demographic change with natural selection. ρ can directly incorporate a null hypothesis reflecting general demographic histories. It has a natural Bayesian interpretation as an approximation to the log-probability of the null model, given the data. We use simulations to show that ρ has greater power than Tajima's D to detect departure from neutrality for a range of scenarios of positive and negative selection. We also show how ρ can be adapted to account for sequencing error. Application to the ACKR1 (FYO) gene in humans supported previous studies inferring positive selection in sub-Saharan populations which were based on inter-population comparisons. However, we did not find the signal of selection to be maximal in the region of the FY*O or Duffy-null allele in these populations. We also applied ρ to investigate in greater detail a region on the 2q11.1 band of the human genome that has previously been identified as showing evidence of selection. This was done for a range of populations: for the European populations we incorporated a demographic history with a bottleneck corresponding to the putative out of Africa event. We were able to localise signals of selection to some specific regions and genes. Overall, we suggest that ρ will be a useful tool for identifying genomic regions that may be subject to natural selection.

Phylogeography of the Central american red brocket deer, Mazama temama (Artiodactyla, Cervidae) in southeastern Mexico

Anthropogenic threats have increasingly isolated the populations of Mazama temama (Erxleben, 1777) and limited the gene flow in this species. Knowledge of the phylogeographic structure of this species is therefore essential for its conservation. Thus, in this study, we describe the phylogeographic structure of two M. temama populations of Veracruz and Oaxaca, Mexico. We sequenced the D-Loop region of the mitochondrial DNA of 16 individuals, in order to estimate the diversity and genetic differentiation (FST), Tajima’s D index, "Mismatch distribution" test; a phylogram and a haplotype network was constructed and we performed multidimensional scaling analysis to test the hypothesis of association between geographic distance and genetic diversity. The haplotypic and nucleotide diversity was high, indicating divergent populations (FST = 0.223), while the Tajima’s D index (-1,03300; P > 0.10) determined disequilibrium in the D-Loop region, derived from a population expansion that was evidenced in the "Mismatch distribution" test and confirmed with the haplotype network in the form of a star. Four lineages were identified in the phylogram (Veracruz n = 3, Oaxaca n = 1), evidencing geographic and reproductive isolation between the two populations. This was confirmed by the multidimensional scaling analysis, which evidenced recent evolutionary divergence between the populations analyzed, which are considered evolutionary units of conservation.