Analysis of ancestry heterozygosity suggests that hybrid incompatibilities in threespine stickleback are environment dependent

Hybrid incompatibilities occur when interactions between opposite ancestry alleles at different loci reduce the fitness of hybrids. Most work on incompatibilities has focused on those that are “intrinsic,” meaning they affect viability and sterility in the laboratory. Theory predicts that ecological selection can also underlie hybrid incompatibilities, but tests of this hypothesis using sequence data are scarce. In this article, we compiled genetic data for F2 hybrid crosses between divergent populations of threespine stickleback fish (Gasterosteus aculeatus L.) that were born and raised in either the field (seminatural experimental ponds) or the laboratory (aquaria). Because selection against incompatibilities results in elevated ancestry heterozygosity, we tested the prediction that ancestry heterozygosity will be higher in pond-raised fish compared to those raised in aquaria. We found that ancestry heterozygosity was elevated by approximately 3% in crosses raised in ponds compared to those raised in aquaria. Additional analyses support a phenotypic basis for incompatibility and suggest that environment-specific single-locus heterozygote advantage is not the cause of selection on ancestry heterozygosity. Our study provides evidence that, in stickleback, a coarse—albeit indirect—signal of environment-dependent hybrid incompatibility is reliably detectable and suggests that extrinsic incompatibilities can evolve before intrinsic incompatibilities.

Supergene formation is associated with a major shift in genome-wide patterns of diversity in a butterfly

Selection shapes genetic diversity around target mutations, yet little is known about how selection on specific loci affects the genetic trajectories of populations, including their genome-wide patterns of diversity and demographic responses. Adaptive introgression provides a way to assess how adaptive evolution at one locus impacts whole-genome biology. Here we study the patterns of genetic variation and geographic structure in a neotropical butterfly, Heliconius numata, and its closely related allies in the so-called melpomene-silvaniform subclade. H. numata is known to have evolved a supergene via the introgression of an adaptive inversion about 2.2 million years ago, triggering a polymorphism maintained by balancing selection. This locus controls variation in wing patterns involved in mimicry associations with distinct groups of co-mimics, and butterflies show disassortative mate preferences and heterozygote advantage at this locus. We contrasted patterns of genetic diversity and structure 1) among extant polymorphic and monomorphic populations of H. numata, 2) between H. numata and its close relatives, and 3) between ancestral lineages in a phylogenetic framework. We show that H. numata populations which carry the introgressed inversions in a balanced polymorphism show markedly distinct patterns of diversity compared to all other taxa. They show the highest diversity and demographic estimates in the entire clade, as well as a remarkably low level of geographic structure and isolation by distance across the entire Amazon basin. By contrast, monomorphic populations of H. numata as well as its sister species and their ancestral lineages all show the lowest effective population sizes and genetic diversity in the clade, and higher levels of geographical structure across the continent. This suggests that the large effective population size of polymorphic populations could be a property associated with harbouring the supergene. Our results are consistent with the hypothesis that the adaptive introgression of the inversion triggered a shift from directional to balancing selection and a change in gene flow due to disassortative mating, causing a general increase in genetic diversity and the homogenisation of genomes at the continental scale.

Exome Sequencing Reveals a Putative Role for HLA-C*03:02 in Control of HIV-1 in African Pediatric Populations

Human leucocyte antigen (HLA) class I molecules present endogenously processed antigens to T-cells and have been linked to differences in HIV-1 disease progression. HLA allelotypes show considerable geographical and inter-individual variation, as does the rate of progression of HIV-1 disease, with long-term non-progression (LTNP) of disease having most evidence of an underlying genetic contribution. However, most genetic analyses of LTNP have occurred in adults of European ancestry, limiting the potential transferability of observed associations to diverse populations who carry the burden of disease. This is particularly true of HIV-1 infected children. Here, using exome sequencing (ES) to infer HLA allelotypes, we determine associations with HIV-1 LTNP in two diverse African pediatric populations. We performed a case-control association study of 394 LTNPs and 420 rapid progressors retrospectively identified from electronic medical records of pediatric HIV-1 populations in Uganda and Botswana. We utilized high-depth ES to perform high-resolution HLA allelotyping and assessed evidence of association between HLA class I alleles and LTNP. Sixteen HLA alleles and haplotypes had significantly different frequencies between Uganda and Botswana, with allelic differences being more prominent in HLA-A compared to HLA-B and C allelotypes. Three HLA allelotypes showed association with LTNP, including a novel association in HLA-C (HLA-B∗57:03, aOR 3.21, Pc = 0.0259; B∗58:01, aOR 1.89, Pc = 0.033; C∗03:02, aOR 4.74, Pc = 0.033). Together, these alleles convey an estimated population attributable risk (PAR) of non-progression of 16.5%. We also observed novel haplotype associations with HLA-B∗57:03-C∗07:01 (aOR 5.40, Pc = 0.025) and HLA-B∗58:01-C∗03:02 (aOR 4.88, Pc = 0.011) with a PAR of 9.8%, as well as a previously unreported independent additive effect and heterozygote advantage of HLA-C∗03:02 with B∗58:01 (aOR 4.15, Pc = 0.005) that appears to limit disease progression, despite weak LD (r2 = 0.18) between these alleles. These associations remained irrespective of gender or country. In one of the largest studies of HIV in Africa, we find evidence of a protective effect of canonical HLA-B alleles and a novel HLA-C association that appears to augment existing HIV-1 control alleles in pediatric populations. Our findings outline the value of using multi-ethnic populations in genetic studies and offer a novel HIV-1 association of relevance to ongoing vaccine studies.

Large scale genomic and transcriptomic profiles of rice hybrids revealed a novel universal mechanism underlying yield heterosis

The utilization of heterosis (or hybrid vigor) is a revolutionary technology in agricultural. However, its genetic mechanisms are still unclear in plants. Here we develop, sequence and record the phenotypes of 418 hybrids from crosses between two testers and a diverse mini core collection. Phenotypic analysis showed that heterosis is an extensive but not necessary phenomenon, which varied by combinations and environments. Evidence from both GWAS on the 418 hybrids and their parents and transcriptomics of the traditional rice hybrid Liangyoupei 9, indicated that dominance and overdominance are the main genetic contributions to heterosis. Furthermore, cumulation or complementation of repulsive genetic factors may account for 37.8% of the overdominant QTL and nearly half of the genes with overdominant expression pattern. We systematically compared non-additive and additive factors and observed a common phenomenon that non-additive factors are more sensitive to background than that of additive ones across species, phenotypes, QTLs and transcription levels, further evidence from both simulations and experiment demonstrated a novel universal molecular mechanism underlying heterosis, i.e. homo-insufficiency under insufficient background (HoIIB), which expounds that heterosis in most cases is not the heterozygote advantage but the homozygote disadvantage under the insufficient genetic background. The HoIIB model can explain most known hypotheses and phenomena about heterosis, thus provides a novel theory for future hybrid rice breeding.

Individual HLA-A, -B, -C, and -DRB1 Genotypes Are No Major Factors Which Determine COVID-19 Severity

HLA molecules are key restrictive elements to present intracellular antigens at the crossroads of an effective T-cell response against SARS-CoV-2. To determine the impact of the HLA genotype on the severity of SARS-CoV-2 courses, we investigated data from 6,919 infected individuals. HLA-A, -B, and -DRB1 allotypes grouped into HLA supertypes by functional or predicted structural similarities of the peptide-binding grooves did not predict COVID-19 severity. Further, we did not observe a heterozygote advantage or a benefit from HLA diplotypes with more divergent physicochemical peptide-binding properties. Finally, numbers of in silico predicted viral T-cell epitopes did not correlate with the severity of SARS-CoV-2 infections. These findings suggest that the HLA genotype is no major factor determining COVID-19 severity. Moreover, our data suggest that the spike glycoprotein alone may allow for abundant T-cell epitopes to mount robust T-cell responses not limited by the HLA genotype.

Borrelia Infection in Bank Voles Myodes glareolus Is Associated With Specific DQB Haplotypes Which Affect Allelic Divergence Within Individuals

The high polymorphism of Major Histocompatibility Complex (MHC) genes is generally considered to be a result of pathogen-mediated balancing selection. Such selection may operate in the form of heterozygote advantage, and/or through specific MHC allele–pathogen interactions. Specific MHC allele–pathogen interactions may promote polymorphism via negative frequency-dependent selection (NFDS), or selection that varies in time and/or space because of variability in the composition of the pathogen community (fluctuating selection; FS). In addition, divergent allele advantage (DAA) may act on top of these forms of balancing selection, explaining the high sequence divergence between MHC alleles. DAA has primarily been thought of as an extension of heterozygote advantage. However, DAA could also work in concert with NFDS though this is yet to be tested explicitly. To evaluate the importance of DAA in pathogen-mediated balancing selection, we surveyed allelic polymorphism of MHC class II DQB genes in wild bank voles (Myodes glareolus) and tested for associations between DQB haplotypes and infection by Borrelia afzelii, a tick-transmitted bacterium causing Lyme disease in humans. We found two significant associations between DQB haplotypes and infection status: one haplotype was associated with lower risk of infection (resistance), while another was associated with higher risk of infection (susceptibility). Interestingly, allelic divergence within individuals was higher for voles with the resistance haplotype compared to other voles. In contrast, allelic divergence was lower for voles with the susceptibility haplotype than other voles. The pattern of higher allelic divergence in individuals with the resistance haplotype is consistent with NFDS favouring divergent alleles in a natural population, hence selection where DAA works in concert with NFDS.

Genetic Variation and Population Differentiation in the Bovine Lymphocyte Antigen DRB3.2 Locus of South African Nguni Crossbred Cattle

The bovine lymphocyte antigen (BoLA-DRB3) gene is an important region that codes for glycoproteins responsible for the initiation of an immune response. BoLA-DRB3 alleles have been demonstrated to be associated with disease resistance/tolerance. Therefore, great genetic diversity is correlated with better adaptation, fitness, and robustness. The current study was conducted to assess the population genetic structure of the BoLA-DRB3 gene in Nguni crossbred cattle using polymerase chain reaction-sequence based typing (PCR-SBT). High genetic diversity was detected, with 30 alleles, 11 of which are novel to the study. Alleles DRB3*0201, DRB3*0701, DRB*0901, and DRB*1601 were present in all populations and accounted for nearly around 50% of all observed alleles. A mean genetic diversity (HE) of 0.93 was detected. The high overall genetic diversity is possibly associated with pathogen-assisted selection and heterozygote advantage. Such high diversity might explain the hardiness of the Nguni crossbred cattle to the Southern African region. Low population genetic structure was identified (FST = 0.01), suggesting possible gene flow between populations and retention of similar alleles. The study was undertaken to bridge the dearth of such studies in South African breeds and it is imperative for effective sustainability of indigenous breeds and the implementation of effective breeding strategies.

Racial Disparities Among Clinical Trials for Inherited Forms of Lipodystrophy

Background: There has been renewed interest in understanding how medical research serves minority communities disproportionally affected by disease. A recent study in a predominantly white population identified 12 subjects with partial lipodystrophy by genetics without clinical diagnosis of lipodystrophy (Gonzaga-Jauregui et al., 2020). Partial lipodystrophies are rare monogenic disorders leading to diabetes that can be challenging to diagnosis due to their similarity with common obesity-associated metabolic syndrome. We hypothesize minority populations may be underdiagnosed with lipodystrophy, and thus underrepresented in clinical trials. Methods: We compared racial demographics of lipodystrophic subjects participating in clinical trials to subjects with predicted loss-of-function (pLOF) mutations in 4 genes associated with lipodystrophy in the GnomAD dataset (>140K exome sequences): LMNA & PPARG (causing dominantly inherited partial lipodystrophy), and AGPAT2 & BSCL2 (causing recessively inherited generalized lipodystrophy, which is more phenotypically apparent, as an internal control for the study design). We also compared rates of synonymous mutations in these 4 genes among races to test if subjects of different ethnicities may be more genetically predisposed to developing inherited forms of lipodystrophy. Comparisons were done using chi-square analysis. Results: We identified 322 subjects with pLOF mutations in genes associated with lipodystrophy in the GnomAD dataset. The racial composition of GnomAD subjects with pLOF mutations in each gene was different than GnomAD subjects without pLOF mutations (p<0.001). 144 lipodystrophic subjects with known pathogenic variants in these genes participated in clinical trials. The racial composition of GnomAD and clinical trial subjects with LMNA mutations were significantly different (p=0.024) with the clinical trial cohort being more enriched for white patients (78 vs 21%) and less enriched for Latino patients (7 vs. 21%). There were no differences for other genes. The rates of synonymous mutations were different among patients of different ethnicities, p<0.001 for all genes. Discussion: Partial lipodystrophy due to LMNA mutations may be underdiagnosed in Latinos, leading to reduced participation in clinical trials. The lack of differences in other genes suggests there is no overall cohort bias. Different rates of synonymous mutations suggest there may be evolutionary drivers to racial differences in inherited forms of lipodystrophy, such as founder mutations or heterozygote advantage. Future work will determine prevalence of pLOF variants in lipodystrophy-associated genes in other genetic data sets enriched for minority subjects.

On the Fixation or Non-Fixation of Adaptive Inversions

Several recent publications have stated that epistatic fitness interactions cause the fixation of inversions that suppress recombination among the loci involved. Under this model, however, the suppression of recombination in an inversion heterozygote creates a form of heterozygote advantage, which prevents the inversion from becoming fixed by selection. This process has been explicitly modelled by previous workers.